Canadian Family Physician by Wes Jackson

January • Janvier 2011

Inside this issue Epidemic vitamin D deficiency Commentary . . . 16 Carence épidémique de vitamine D Commentaire . . . e1 Healthy fish consumption Clinical Review . . . 26 CAM for the common cold Clinical Review . . . 31 Reducing antibiotic use for influenza Child Health Update . . . 42 Pharmacotherapy for smoking Tools for Practice . . . 47 Acute cough for adults Diagnosing ARIs Series . . . 48 Burden of acute otitis media Research . . . 60

Peer reviewed / Révisée par des pairs PubMed / PubMed Central / www.cfp.ca

The Faces of Family Medicine

Heather Armson MD CCFP FCFP

The relationship’s the thing, the forging of a bond, the making of a connection, the development of sharing, the interest in how things have been going and the curiosity about how they will go; medicine is often not about the solving of problems but the discussion of them, and it’s the relationship that makes the doctor, not the other way around, and Dr Armson, with previous degrees in psychology and education, understands that the patients of her practice need her, a relatable human being, in order to get well, or at least to have a forum for their disorders. Dr Armson is so passionate about relationships she trains remedial residents about the nature of relationship, about how one person approaches another person, about how one person can come to know things about another person beyond medical data and fact and into genuine appreciation, that every encounter is an opportunity for growth, that even the most difficult of encounters teaches physicians something about themselves. She has a patient who has countless comorbidities, a two-time transplant recipient with numerous infections and amputations, the kind of patient that doctors test out of uncertainty, and it’s her relationship with this patient, this chronically ill man, that has made a difference in his life: he has told her, and his family has told her, that just by knowing his context, just by knowing his living situation and his difficulties and his frustration with a system that inflicts upon him countless specialists, she has changed his life through the validation of suffering. This passion for relationships has developed into an academic pursuit: Dr Armson has trained physicians in Kenya about relationships, had to develop relationships with Muslim male physicians in a Muslim male world, had to develop a self-sustaining system in which these physicians would nurture one another’s curiosity and provide mutual assessment; these physicians have had to learn evidence-based practice and it wouldn’t, couldn’t, happen unless Dr Armson developed a relationship with them, the heart in the evidence-based machine. The program is still running, and the fact that it’s running, and being continually assessed itself, is a testament to the relationships she’s fostered, and the kind of family medicine she practises. Cover photo: Terence Law, Calgary, Alta Story: Shane Neilson MD CCFP, Erin, Ont Additional photos and the French translation of the story appear on page 118. D’autres photos et la traduction en français du récit se trouvent à la page 118.

THE COVER PROJECT Canadian Family Physician has

embarked on a project to assemble the portrait of family medicine in Canada. Each cover of the journal will feature a family physician chosen at random from our membership list, along with a short essay—a brief glimpse of the person and the practice. Over time, the randomness will become representative and the differences, taken together, will define what it is that all family physicians have in common. Inside half-cover (IHC)

January â&#x20AC;˘ Janvier 2011

Dr Heather Armson Family Physician Calgary, Alberta

Les visages de la mĂŠdecine familiale

The Faces of Family Medicine

NEW PrPRADAXâ&#x201E;˘ 150 mg BID

HELP

PREVENT STROKE WITH PRADAX AND SYSTEMIC EMBOLISM

PRADAX (dabigatran etexilate) is indicated for the prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate. PRADAX is contraindicated in patients with: severe renal impairment (CrCL <30 mL/min); hemorrhagic manifestations, bleeding diathesis, or patients with spontaneous or pharmacological impairment of hemostasis; lesions at risk of clinically significant bleeding, e.g. extensive cerebral infarction (hemorrhagic or ischemic) within the last 6 months, active peptic ulcer disease with recent bleeding; concomitant treatment with the strong P-glycoprotein (P-gp) inhibitors, i.e. oral ketoconazole, and with known hypersensitivity to dabigatran, dabigatran etexilate or to any ingredient in the formulation or component of the container. Bleeding is the most relevant side effect of PRADAX; bleeding of any type or severity occurred in long-term treatment in 16.5% of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism. As with all anticoagulants, PRADAX should be used with caution in circumstances associated with an increased risk of bleeding. Bleeding can occur at any site during therapy with PRADAX. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site. Patients at high risk of bleeding should not be prescribed PRADAX. Close clinical surveillance (looking for signs of bleeding or anemia) is recommended throughout the treatment period, especially if risk factors are combined. Should severe bleeding occur, treatment with PRADAX must be discontinued and the source of bleeding investigated promptly. Patients who develop acute renal failure must discontinue PRADAX. In

patients who are bleeding, an aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT >80 sec at trough, i.e. when the next dose is due, is associated with a higher risk of bleeding. Agents that may enhance the risk of hemorrhage should not be administered concomitantly with PRADAX, or, if necessary, should only be administered with caution. Treatments that should NOT be administered concomitantly with PRADAX due to increase in bleeding risk include: unfractionated heparin and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, bivalirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, sulfinpyrazone and vitamin K antagonists such as warfarin. The concomitant use of PRADAX with the following treatments has not been studied and may increase the risk of bleeding: rivaroxaban, prasugrel and the strong P-gp inhibitors itraconazole, tacrolimus, cyclosporine, ritonavir, tipranavir, nelfinavir and saquinavir. Unfractionated heparin may be administered at doses necessary to maintain a patent central venous or arterial catheter. In patients with atrial fibrillation treated for the prevention of stroke and systemic embolism, the co-administration of oral anti-platelet (including ASA and clopidogrel) and NSAID therapies increases the risk of bleeding by about two-fold (see ACTION and CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions). If necessary, co-administration of low-dose ASA, i.e. )100 mg daily with PRADAX may be considered for other indications than stroke prevention in atrial fibrillation. The concomitant use of PRADAX with the strong P-gp inducer, rifampicin, reduces dabigatran

PRADAX™

NOW INDICATED FOR THE PREVENTION OF STROKE AND SYSTEMIC EMBOLISM IN PATIENTS WITH ATRIAL FIBRILLATION, IN WHOM ANTICOAGULATION IS APPROPRIATE.1

For patients with atrial fibrillation, PRADAX demonstrated:

35% reduced risk of stroke or

systemic embolism vs. warfarin1-3*† Dabigatran 150 mg BID (1.1%/yr) vs. warfarin (1.7%/yr), p=0.0001.

59% reduced risk of intracranial bleeding‡ vs. warfarin1-3*§

Dabigatran 150 mg BID (0.3%/yr) vs. warfarin (0.8%/yr), p<0.0001.

No INR monitoring or dose titration1

plasma concentrations. Other P-gp inducers such as St. John’s Wort or carbamazepine are also expected to reduce dabigatran plasma concentrations and should be co-administered with caution. The most common adverse events observed in *1% of PRADAX 150 mg BID patients and 110 mg BID patients was anemia (1.6%, 1.2%), epistaxis (1.1%, 1.1%), gastrointestinal hemorrhage (4.6%, 3.3%), urogenital hemorrhage (1.4%, 1.1%), abdominal pain (2.2%, 2.3%), diarrhea (1.2%, 1.3%), dyspepsia (3.9%, 4.2%) and nausea (1.2%, 1.0%), respectively. Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort) or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis and gastrointestinal ulcer). Allergic reactions or drug hypersensitivity including urticaria, bronchospasm, rash and pruritus have been reported in patients who received dabigatran etexilate. Rare cases of anaphylactic reactions have also been reported. For complete prescribing information, please refer to the Product Monograph.

Gastrointestinal hemorrhage occurred at a higher frequency with PRADAX 150 mg BID and 110 mg BID (4.6%, 3.3%, respectively) compared to warfarin (2.6%). The underlying mechanism of the increased rate of GI bleeding has not been established. Patients at an increased risk of bleeding should be closely monitored clinically. A coagulation test, such as aPTT may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. *A randomized non-inferiority trial of 18,113 AF patients at risk of stroke. Patients received dabigatran 110 mg BID or 150 mg BID (blinded arm) and adjusted doses of warfarin (unblinded arm). †Stroke or systemic embolism: dabigatran 150 mg BID (n=6076, no. of events=134) vs. warfarin (n=6022, no. of events=202). ‡Intracranial bleeding includes adjudicated hemorrhagic stroke, subarachnoid, and/or subdural bleeding. §Intracranial bleeding: dabigatran 150 mg BID (no. of events=38) vs. warfarin (no. of events=90). References: 1. Pradax Product Monograph. Boehringer Ingelheim (Canada) Ltd., 11/08/10. 2. Connolly SJ et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361:1139–1151. 3. Connolly SJ et al. Newly Identified Events in the RE-LY Trial. N Engl J Med. 2010;363:1875-1876 supp appendix. Pradax™ is a trademark used under license by Boehringer Ingelheim (Canada) Ltd.

See prescribing summary on page108 See prescribing summary on page xxx

Help patients improve glycemic control with the efficacy of Onglyza

In addition to HbA1c, Onglyza significantly improved the key daily measures of FPG and PPG when added to metformin.1* HbA1c -0.8%, FPG -1.3 mmol/L, PPG -2.2 mmol/L (placebo adjusted)

Add Onglyza for patients with type 2 diabetes when their HbA1c is above 7.0% on metformin alone Onglyza is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a sulfonylurea, when metformin or the sulfonylurea used alone, with diet and exercise, does not provide adequate glycemic control.1 Onglyza is not recommended for the following: patients with moderate-to-severe renal impairment, including patients with end-stage renal disease requiring hemodialysis, patients with moderate-to-severe hepatic impairment, patients with congestive heart failure, or pregnant women. Onglyza should not be used by women who are nursing, pediatric patients (<18 years of age), patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.1 Onglyza is contraindicated in patients who have had a history of any serious hypersensitivity to this drug or any ingredient in the formulation or to another DPP-4 inhibitor.1 In a clinical study that combined Onglyza with metformin, the most commonly reported adverse events, regardless of causality and more common with Onglyza than placebo, were nasopharyngitis (11.0% vs. 10.6%) and bronchitis (9.4% vs. 6.1%).1 In a clinical study that combined Onglyza with a sulfonylurea (glyburide), the most commonly reported adverse events, regardless of causality and more common with Onglyza than placebo, were hypoglycemia (19.8% vs. 18.4%) and urinary tract infection (13.8% vs. 10.9%).1 Please consult prescribing information for warnings, precautions and adverse events. Reference: 1. AstraZeneca Canada Inc./Bristol-Myers Squibb Canada. Onglyza® Product Monograph, September 14, 2009. * Randomized, double-blind placebo-controlled study of 24-week duration. Evaluated efficacy and safety of Onglyza in combination with metformin in patients with inadequate glycemic control (HbA1c ≥7.0% and ≤10.0%) on metformin alone. Placebo mean baseline HbA1c: 8.1%. Patients were required to be on a stable dose of metformin (1500–2550 mg daily) for at least 8 weeks to be enrolled in trial. Results demonstrated at trial’s end were the following (placebo adjusted): -0.8% improvement in HbA1c, -1.3 mmol/L improvement in FPG and -2.2 mmol/L improvement in 2-hour PPG. Change in FPG and PPG from baseline was measured at 6 months. Onglyza baseline FPG was 9.9 mmol/L (n=187) and baseline PPG was 16.4 mmol/L (n=155). Placebo baseline FPG was 9.7 mmol/L (n=176) and baseline PPG was 16.4 mmol/L (n=135). P-values were p<0.0001 for HbA1c, FPG and 2-hour PPG when compared to placebo.

12/11

ONG073E

Onglyza is a registered trademark of Bristol-Myers Squibb Company used under license by Bristol-Myers Squibb Canada Co. The AstraZeneca logo is a trademark of the AstraZeneca group of companies.

See prescribing summary on page 87

Contents Sommaire

January • Janvier 2011 JANUARY JANVIER 2011;57:1-136

Canadian Family Physician

Inside this issue Epidemic vitamin D deficiency Commentary . . . 16 Carence épidémique de vitamine D Commentaire . . . e1

Le Médecin de famille canadien

Healthy fish consumption Clinical Review . . . 26 CAM for the common cold Clinical Review . . . 31 Reducing antibiotic use for influenza Child Health Update . . . 42

Vol 57:1-136 January • Janvier 2011

Pharmacotherapy for smoking Tools for Practice . . . 47 Acute cough for adults Diagnosing ARIs Series . . . 48 Burden of acute otitis media Research . . . 60

Peer reviewed / Révisée par des pairs PubMed / PubMed Central / www.cfp.ca

COMMENTARY ❖ COMMENTAIRE

The Faces of Family Medicine

IHC

The faces of family medicine: Heather Armson MD CCFP FCFP Shane Neilson, Terence Law

Editorial: Faces and voices of Canadian family medicine Nicholas Pimlott

Éditorial: Les visages et les voix de la médecine familiale canadienne Nicholas Pimlott

Mitigating epidemic vitamin D deficiency The agony of evidence

N.J. Bosomworth

EXCLUSIVEMENT SUR LE WEB: www.cfp.ca

Atténuer la carence épidémique en vitamine D La tourmente des données scientifiques

N.J. Bosomworth

Published monthly by the College of Family Physicians of Canada/ Publié mensuellement par le Collège des médecins de famille du Canada. 2630, avenue Skymark Avenue, Mississauga, ON L4W 5A4 Telephone/Téléphone 905 629-0900 Fax/Télécopieur 905 629-0893 www.cfp.ca Canada Post: Canadian Publications Mail Product Sales Agreement 40771558. Post Office Department, Winnipeg, and for payment of postage, paid at Winnipeg. Postes Canada: Envoi de publication. Enregistrement n° 40771558. Service des postes, Winnipeg, port payé à Winnipeg.

Letters ❖ Correspondance

Correction

PRACTICE ❖ PRATIQUE 26 M1

CREDIT

Clinical Review: Healthy fish consumption and reduced mercury exposure Counseling women in their reproductive years

Alan Abelsohn, Loren D. Vanderlinden, Fran Scott, Josephine A. Archbold, Tara L. Brown

Clinical Review: Complementary and alternative medicine for prevention and treatment of the common cold Richard Nahas, Agneta Balla

Motherisk Update: Effect of methotrexate treatment of ectopic pregnancy on subsequent pregnancy Rinat Hackmon, Sachi Sakaguchi, Gideon Koren

Child Health Update: Reducing inappropriate antibiotic use among children with influenza infection

Printed on recycled paper, including a minimum of 10% post-consumer waste, using vegetable oil–based inks/Imprimé sur papier recyclé, à partir d’au moins 10% de fibres après consommation, avec des encres à base d’huile végétale.

Emergency Files: Sticks and stones and broken bones

M1 CREDIT

Robert Primavesi

Printed in Canada/Imprimé au Canada.

ISSN 0008-350X

Bat-Chen Friedman, Derek Schwabe-Warf, Ran Goldman

Distal radius fractures in children

Tools for Practice: Pharmacotherapy for smoking G. Michael Allan, Noah Ivers, Charl Els

VOL 57: JANUARY • JANVIER 2011

| Canadian Family Physician

➣ •

Le Médecin de famille canadien

V to ic da to y. za ®

Tr y

Introducing once-daily Victoza®.

Victoza® (liraglutide) is indicated for once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control in combination with metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control, or with metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control. Victoza® should not be used in type 1 diabetes (formerly known as insulindependent diabetes mellitus or IDDM). Victoza® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), in patients who are hypersensitive to liraglutide or to any ingredient in the formulation and in pregnancy or breast-feeding women. Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumours at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumours, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumours. Patients should be counselled regarding the risk and symptoms of thyroid tumours. Because of limited clinical experience in patients who have cardiac conditions that might be worsened by an increase in heart rate, such as ischemic heart disease and tachyarrhythmia, caution should be observed in these patients. Because of limited clinical experience in patients with pre-existing conduction system abnormalities (e.g., marked first-degree AV block or second- or third-degree AV block) and heart rhythm disturbances (e.g., tachyarrhythmia), caution should be observed in these patients.

All trademarks owned by Novo Nordisk A/S and used by Novo Nordisk Canada Inc. Novo Nordisk Canada Inc., 300-2680 Skymark Avenue, Mississauga, Ontario L4W 5L6. Tel: (905) 629-4222 or 1-800-465-4334. www.novonordisk.ca © 10/2010 Novo Nordisk Canada Inc.

For treatment of patients who did not achieve adequate glycemic control on metformin, Victoza® + metformin provided:1, 2

Demonstrated mean reduction in A1C: up to -1.5%* (p<0.0001 vs. sitagliptin + MET)

G Victoza® 1.2 mg: -1.2%; Victoza® 1.8 mg: -1.5%; sitagliptin 100 mg: -0.9% (all in combination with MET)

Demonstrated mean change in weight: up to -2.8 kg† (p<0.0001 vs. glimepiride + MET)

G Victoza® 1.2 mg: -2.6 kg; Victoza® 1.8 mg: -2.8 kg; placebo: -1.5 kg; glimepiride: +1.0 kg (all in combination with MET)

Victoza® was generally well tolerated in clinical trials that included over 4600 patients.3

Victoza® is the first and only human GLP-1 analogue available in Canada.

Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Victoza® should not be administered intravenously or intramuscularly. Patients receiving Victoza® in combination with a sulfonylurea may have an increased risk of hypoglycemia. The risk of hypoglycemia can be lowered by reducing the dose of sulfonylurea. In clinical trials conducted in adult patients with type 2 diabetes, very rare cases of pancreatitis were reported more frequently in the Victoza®-treated group than in the comparator-treated group (2.2 vs. 0.6 cases per 1000 subject-years). In the Victoza®-treated group one fatal case of necrotizing pancreatitis was observed. The causality relationship to Victoza® is unclear. The most frequently reported adverse events with Victoza® (0.6 to 1.8 mg) treatment were nausea (10.7%-18.6%), diarrhea (8.3%-14.9%), headache (5.4%-12.4%), vomiting (5.4%-7.4%) and dyspepsia (2.1%-7.0%). Please see Product Monograph for complete recommendations. References: 1. Victoza® Product Monograph, Novo Nordisk Canada Inc., 2010. 2. Pratley R et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomized, parallel-group, open-label trial. Lancet. 2010;375:1447-1456. 3. Gallwitz B et al. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract. 2010;64(2):267-276. * Adapted from Pratley RE et al, 2010.2 A 26-week, active-comparator, parallel-group, open-label, multicentre trial randomized 665 patients with type 2 diabetes (1:1:1) to once-daily Victoza® (1.2 or 1.8 mg) or once-daily sitagliptin (100 mg) in combination with metformin (*1500 mg/day). The primary outcome measure was change in A1C. Change in A1C: Victoza® 1.2 mg + MET (-1.2%); Victoza® 1.8 mg + MET (-1.5%); sitagliptin + MET (-0.9%). † Adapted from Victoza® Product Monograph, 2010.1 A 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group, multicentre trial randomized 1091 patients with type 2 diabetes (2:2:2:1:2) to once-daily Victoza® (0.6, 1.2, or 1.8 mg), to placebo, or to glimepiride (4 mg once-daily) in combination with metformin (1 g bid). Metformin (MET) and glimepiride were gradually titrated up to a maximum dose level. The primary outcome measure was change in A1C. Change in weight: Victoza® 1.2 mg + MET (-2.6 kg); Victoza® 1.8 mg + MET (-2.8 kg); glimepiride + MET (+1.0 kg); placebo + MET (-1.5 kg).

VIC275E/October 2010

See prescribing summary on page 103 xxx

NEW Dual Delayed Release technology

The only PPI with a 2nd release that arrives later in the day *

Introducing DEXILANT—the only PPI with Dual Delayed Release (DDR) technology, which provides two distinct releases of drug*

Plasma concentration (ng/mL)

Mean plasma concentration (in healthy subjects over 5 days)1

• Achieves first peak plasma concentration 1–2 hours after dosing, followed by a second peak within 4–5 hours1

1200

• DEXILANT 60 mg provided an area under the concentration curve (AUC24) approximately 3 times greater than lansoprazole 30 mg on day 52

1000 800 600 400

DEXILANT 60 mg Lansoprazole 30 mg

200 0

12 Time (h)

DEXILANT is indicated in adults 18 years of age and older for healing of all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and the treatment of heartburn associated with symptomatic nonerosive gastroesophageal reflux disease (GERD) for 4 weeks. No dosage adjustment is necessary for patients >65 years of age.1 *Comparative clinical significance has not been established.

Time profile following oral administration of DEXILANT 60 mg or lansoprazole 30 mg once daily for 5 days in healthy subjects (n=40). Adapted from the DEXILANT Product Monograph.1,2

References: 1. DEXILANT (dexlansoprazole) Product Monograph, Takeda Canada, Inc. 2. Data on file [CSR Study T-P104-071], Takeda Pharmaceuticals North America, Inc. DEXILANT and Dual Delayed Release are trademarks of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Canada, Inc.

Important safety information Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking warfarin with PPIs may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Commonly reported treatment-related adverse events: diarrhea (3.7%), abdominal pain (2.6%), nausea (2.2%), headache (2.2%), flatulence (1.8%), and constipation (1.1%).1 ©2010 Takeda Canada, Inc. DEX_2010_0033 Printed in Canada.

See prescribing summary on page 91

Contents | Sommaire

January • Janvier 2011 JANUARY JANVIER 2011;57:1-136

Canadian Family Physician

Inside this issue Epidemic vitamin D deficiency Commentary . . . 16

Le Médecin de famille canadien

Carence épidémique de vitamine D Commentaire . . . e1 Healthy fish consumption Clinical Review . . . 26

Diagnosing ARIs Series: Acute cough in adults Graham Worrall

CAM for the common cold Clinical Review . . . 31 Reducing antibiotic use for influenza Child Health Update . . . 42

Pharmacotherapy for smoking Tools for Practice . . . 47 Acute cough for adults Diagnosing ARIs Series . . . 48 Burden of acute otitis media Research . . . 60

Praxis: Cognitive behavioural therapy series Part 2. Scalification

Greg Dubord

Peer reviewed / Révisée par des pairs PubMed / PubMed Central / www.cfp.ca

The Faces of Family Medicine

Dermacase: Well-demarcated, scaly, erythematous, droplike papules on the trunk and extremities Olivia Potok, Vimal Prajapati, Benjamin Barankin

Ophthaproblem: Runny nose and swelling in the left eye Ashley Brissette, Kelly Schweitzer, Brian Arthur

RESEARCH ❖ RECHERCHE e7

WEB EXCLUSIVE / EXCLUSIVEMENT SUR LE WEB: www.cfp.ca

Qualitative evaluation of strategies to increase colorectal cancer screening uptake Jill Tinmouth, Paul Ritvo, S. Elizabeth McGregor, Danielle Claus, George Pasut, Ronald E. Myers, Crissa Guglietti, Lawrence F. Paszat, Robert J. Hilsden, Linda Rabeneck

e16

WEB EXCLUSIVE / EXCLUSIVEMENT SUR LE WEB: www.cfp.ca

Continuity of care is good for elderly people with diabetes Retrospective cohort study of mortality and hospitalization

Graham Worrall, John Knight

e21 Canadian Family Physician is the only peer-reviewed family medicine journal published monthly in Canada that is indexed in PubMed Central, MEDLINE, EMBASE/Excerpta Medica, CINAHL, and Current Contents/Clinical Practice. All research, clinical review, program descriptions, and case reports are reviewed by at least 2 external readers, in addition to the editorial staff, to ensure that content is accurate and relevant. Peer review is the cornerstone of excellence in scientific publishing.

Julie Gladstone, Michelle Howard

e26

WEB EXCLUSIVE / EXCLUSIVEMENT SUR LE WEB: www.cfp.ca

Debiasing the hidden curriculum

Academic equality among medical specialties

Wayne Woloschuk, Bruce Wright, Kevin McLaughlin

Burden of acute otitis media on Canadian families

M1 CREDIT

Eve Dubé, Philippe De Wals, Vladimir Gilca, Nicole Boulianne, Manale Ouakki, France Lavoie, Richard Bradet

REFLECTIONS ❖ RÉFLEXIONS

Le Médecin de famille canadien est la seule revue de médecine familiale publiée mensuellement au Canada qui soit révisée par des pairs et fichée dans PubMed Central, MEDLINE, EMBASE/Excerpta Medica, CINAHL et listée dans Current Contents/Clinical Practice. Tous les articles de recherche, les études cliniques, les descriptions de programmes et les rapports de cas font l’objet d’une critique par au moins 2 lecteurs indépendants, sans compter l’équipe de la rédaction, pour assurer l’exactitude et la pertinence du contenu. L’évaluation par les pairs est la pierre angulaire de l’excellence des publications scientifiques.

WEB EXCLUSIVE / EXCLUSIVEMENT SUR LE WEB: www.cfp.ca

Effect of advanced access scheduling on chronic health care in a Canadian practice

Stories in Family Medicine ❖ Récits en médecine familiale Commentary: The importance of stories Ian A. Cameron

Commentaire: L'importance des histoires Ian A. Cameron

➣ VOL 57: JANUARY • JANVIER 2011

| Canadian Family Physician

•

Le Médecin de famille canadien

Once daily. Effective psoriasis therapy.

NOW ON PROVINCIAL FORMULARY IN AB, SK, ON AND QC*. (FOR QC USE CODE: DE128)

Help your patients treat their psoriasis. Available in 60 g and 120 g tubes. For the product monograph or for further information, please contact Medical Information at LEO Pharma Inc. 1-800-263-4218. Dovobet® (calcipotriol betamethasone dipropionate) ointment is indicated for the topical treatment of psoriasis vulgaris for up to 4 weeks. Application on large areas of damaged skin, in skin folds, or under occlusive dressings should be avoided due to increased systemic absorption of corticosteroids. Dovobet® (calcipotriol betamethasone dipropionate) should not be used on the face or on children. If long-term therapy is anticipated, it is recommended that treatment be interrupted periodically or that one area of the body be treated at a time. Prolonged use of corticosteroid-containing preparations may produce striae or atrophy of the skin or subcutaneous tissues. There may be a risk of rebound psoriasis when discontinuing corticosteroids after prolonged periods of use. Hypercalcemia can develop but is usually associated with excessive administration (maximum recommended weekly amount of 100 g). If serum calcium levels become elevated, Dovobet® should be discontinued and serum calcium levels measured once weekly until they return to normal. The most common adverse reaction associated with Dovobet® (calcipotriol/betamethasone dipropionate) was pruritus. Calcipotriol is associated with local reactions such as transient lesional and perilesional irritation. Topical corticosteroids can cause the same spectrum of adverse effects associated with systemic steroid administration, including adrenal suppression. Adverse effects associated with topical corticosteroids are generally local and include dryness, itching, burning, local irritation, striae, atrophy of the skin or subcutaneous tissues, telangiectasia, hypertrichosis, folliculitis, skin hypopigmentation, allergic contact dermatitis, maceration of the skin, miliaria, or secondary infection. If applied to the face, acne rosacea or perioral dermatitis can occur. In addition, there are reports of the development of pustular psoriasis from chronic plaque psoriasis following reduction or discontinuation of potent topical corticosteroid products. Due to the corticosteroid component, Dovobet® is contraindicated for the treatment of viral, fungal, or bacterial skin infections; tuberculosis of the skin; syphilitic skin infections; chicken pox; eruptions following vaccinations; and in viral diseases such as herpes simplex, varicella, and vaccinia. Calcipotriol when used in combination with ultraviolet radiation (UVR) may enhance the known skin carcinogenic effect of UVR. Not for ophthalmic use. * Exception medication. For the treatment of the psoriasis when calcipotriol is ineffective or poorly tolerated. ® Registered trademark of LEO Pharma A/S used under licence and distributed by LEO Pharma Inc., Thornhill, ON L3T 7W8 www.leo-pharma.com/canada

See prescribing summary on page 90 xxx

Contents | Sommaire

January • Janvier 2011 JANUARY JANVIER 2011;57:1-136

Canadian Family Physician

Inside this issue Epidemic vitamin D deficiency Commentary . . . 16

Le Médecin de famille canadien

Carence épidémique de vitamine D Commentaire . . . e1 Healthy fish consumption Clinical Review . . . 26

Throw me a line Pauline Pariser

CAM for the common cold Clinical Review . . . 31 Reducing antibiotic use for influenza Child Health Update . . . 42

e31

Pharmacotherapy for smoking Tools for Practice . . . 47 Acute cough for adults Diagnosing ARIs Series . . . 48 Burden of acute otitis media Research . . . 60

EXCLUSIVEMENT SUR LE WEB: www.cfp.ca

Une pêche miraculeuse Pauline Pariser

Peer reviewed / Révisée par des pairs PubMed / PubMed Central / www.cfp.ca

The Faces of Family Medicine

Cover Image Image de la couverture

Magbule Doko

e33

EXCLUSIVEMENT SUR LE WEB: www.cfp.ca

Qu’est-ce qui vous amène à consulter le médecin aujourd’hui? Magbule Doko

Photographer Terence Law Calgary, Alta

Why are you here to see the doctor today?

Le pouvoir de l’écoute Nicole Audet

e35

WEB EXCLUSIVE: www.cfp.ca

The power of listening Nicole Audet

Thank you, reviewers ❖ Merci aux évaluateurs

Classified Advertising ❖ Annonces classées

Index to Advertisers ❖ Index des annonceurs

COLLEGE ❖ COLLÈGE 118

The faces of family medicine ❖ Les visages de la médecine familiale Heather Armson MD CCFP FCFP Shane Neilson, Terence Law

120

Teaching Moment: Clinical uncertainty Helping our learners

Dale Guenter, Nancy Fowler, Linda Lee

123

Occasion d’enseignement: L'incertitude clinique Aider nos étudiants

Dale Guenter, Nancy Fowler, Linda Lee

126 EDITORIAL ADVISORY BOARD CONSEIL CONSULTATIF DE RÉDACTION

Marshall Godwin MD MSc FCFP St John’s, NL (Chair/Président) Brent Kvern MD CCFP FCFP Winnipeg, MB Victor Ng MSc MD London, ON

President’s Message: Epiphanies in family medicine Rob Boulay

127

Message du président: Épiphanies en médecine familiale Rob Boulay

128

Signes vitaux: Hommage à l’élite de la médecine familiale Cal Gutkin, Directeur général et chef de la direction

136

Vital Signs: Honouring the best of the best in family medicine Cal Gutkin, Executive Director and Chief Executive Officer

W. Wayne Weston MD CCFP FCFP London, ON Robert F. Woollard MD CCFP FCFP Vancouver, BC

VOL 57: JANUARY • JANVIER 2011

| Canadian Family Physician

•

Le Médecin de famille canadien

Start

with ARICEPT

Stay ®

for efficacy in mild, moderate and severe Alzheimer’s disease1

with ARICEPT for patients who benefit from treatment ARICEPT is indicated for the symptomatic treatment of patients with mild, moderate and severe dementia of the Alzheimer’s type. ARICEPT does not change the underlying course of the disease. In patients with mild-to-moderate AD, the most common adverse events with ARICEPT 10 mg/d after proper dose escalation include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia (occurring in at least 5% of patients and at twice the placebo rate). These events are usually mild and transient, resolving with continued ARICEPT treatment without the need for dose modification. In patients with severe AD, the most common adverse events were vomiting, diarrhea, nausea, and aggression (occurring in at least 5% of patients and at twice the placebo rate). Overall, the majority of adverse events were judged by the investigators to be mild or moderate in intensity. Reference: 1. ARICEPT/ARICEPT RDT Product Monograph, Pfizer Canada Inc., June 2007.

See prescribing summary on page 93

Vol 57: January • Janvier 1-136 SCIENTIFIC EDITOR RÉDACTEUR SCIENTIFIQUE

Nicholas Pimlott MD CCFP ASSOCIATE SCIENTIFIC EDITOR RÉDACTEUR SCIENTIFIQUE ADJOINT

Roger Ladouceur MD MSc FCMF EDITORIAL FELLOW BOURSIÈRE EN RÉDACTION MÉDICALE

Jessica Fulton MD CCFP MANAGING EDITOR RÉDACTRICE EN CHEF

Kathryn Harrington MANUSCRIPT EDITORS RÉVISEURS DE MANUSCRITS

Mirjana Macokatic Tasleen Adatia CONTRIBUTING EDITORS COLLABORATRICES DE RÉDACTION

Primrose E. Ketchum MA Allyn E. Walsh MD CCFP FCFP Michelle Howard MSc PhD Ian Cameron MD CCFP STATISTICAL REVIEWER ANALYSTE STATISQUE

Rahim Moineddin MSc PhD MANUSCRIPT AND CIRCULATION COORDINATOR COORDONNATRICE DES MANUSCRITS ET DE LA DISTRIBUTION

Mairi Abbott GRAPHICS MANAGER RESPONSABLE ARTISTIQUE

Deborah Doucette GRAPHIC DESIGNER CONCEPTRICE GRAPHIQUE

Katherine Aldous PRODUCTION COORDINATOR COORDONNATRICE DE LA PRODUCTION

Yvonne Fernandes TRANSLATION TRADUCTION

Marie Plante Michel Jobin Elizabeth Fairley ADVERTISING AND CLASSIFIEDS COORDINATOR COORDONNATRICE DE LA PUBLICITÉ ET ANNONCES CLASSÉES

Beth Carter ADVERTISING SALES VENTES DE PUBLICITÉ

Peter Craig (TORONTO) Pat Tramley (MONTRÉAL) DIRECTOR OF LIBRARY SERVICES DIRECTRICE DES SERVICES BIBLIOTHÉCAIRES

Lynn Dunikowski MLS ASSOCIATE PUBLISHER AND PRODUCTION MANAGER ÉDITEUR ASSOCIÉ ET RESPONSABLE À LA PRODUCTION

Peter Thomlison PUBLISHER ÉDITEUR

David Dehaas EXECUTIVE DIRECTOR AND CHIEF EXECUTIVE OFFICER DIRECTEUR GÉNÉRAL ET CHEF DE LA DIRECTION

Calvin Gutkin MD CCFP(EM) FCFP

UP FRONT Reducing the pain of childhood immunization Vaccinations are administered multiple times throughout infancy, childhood, and adolescence in almost all Canadian children, and the pain and fear associated with injections are a source of distress for the children, their parents, and the administrators. Moreover, untreated pain can have long-term consequences: 25% of adults have a fear of needles as a result of childhood experiences, leading to vaccination nonadherence, health care avoidance, hyperalgesia, and related anxiety. Minimizing pain during childhood vaccination can diminish these effects, prevent distress, and promote further trust in health care providers. To that end, members of the Ontario College of Family Physicians' Healthy Child Development Working Group partnered with The Hospital for Sick Children’s HELPinKIDs team to develop clinical practice guidelines based on systematic reviews of the literature to assist clinicians in managing procedure-related pain and distress among children receiving vaccinations. The guidelines, published in the CMAJ,1 comprise simple, cost-effective, evidence-based strategies and promote a simple “3-P” approach, in which pharmacologic, physical, and psychological factors are combined to substantially increase relief of pain experienced during injections. A detailed summary of the evidence and tools to support training and implementation are included with the guidelines. A website for parents and health care providers, which hosts an educational video, can be accessed at www.sickkids.ca/Learning/SpotlightOnLearning/ profiles-in-learning/help-eliminate-pain-in-kids/index.html. —Tasleen Adatia Reference 1. Taddio A, Appleton M, Bortolussi R, Chambers C, Dubey V, Halperin S, et al. Reducing the pain of childhood vaccination: an evidence-based clinical practice guideline. CMAJ 2010;182(18):E843-55. Epub 2010 Nov 22.

New best practice recommendations for stroke care The 2010 Best Practice Recommendations for Stroke Care were released in December by the Canadian Stroke Network and the Heart and Stroke Foundation of Canada. These new guidelines emphasize the importance of assisting the transition of stroke patients from emergency department to rehabilitation therapy and back into the community, in the hopes that ensuring seamless access to services and providing ample support through the transition phase will prevent patients from falling through the cracks. Updated recommendations also include the following: • Blood pressure should be maintained at levels lower than 140/90 mm Hg. • Patients with atrial fibrillation should be closely monitored and be considered for new drug therapies. • Patients who have transient ischemic attacks should be referred immediately to stroke specialists at prevention clinics or to the emergency department. • There should be greater use of telecommunications between stroke specialists and communities without good access to on-site stroke care. • Improved hospital discharge and community services programs are necessary to facilitate a faster return to the home after stroke. Stroke is the third leading cause of death in Canada, but most strokes are preventable and treatable. Increasing awareness is necessary to improving stroke care; therefore, for the first time, recommendations have been compiled in an easy-to-search, smartphone-accessible website. The website boasts resources for health care professionals and patients, including a patient’s guide to optimal stroke care, and can be accessed at www.strokebestpractices.ca. —T.A. VOL 57: JANUARY • JANVIER 2011

| Canadian Family Physician

•

Le Médecin de famille canadien

Editorial

Faces and voices of Canadian family medicine Nicholas Pimlott

MD CCFP, SCIENTIFIC EDITOR

Landscapes can be deceptive. Sometimes a landscape seems to be less a setting for the life of its inhabitants than a curtain behind which their struggles, achievements and accidents take place. For those who, with the inhabitants, are behind the curtain, landmarks are no longer geographic but also biographical and personal.1

o begins John Berger’s remarkable book A Fortunate Man: The Story of a Country Doctor, first published in 1967. I discovered this book, like most of the important books I have read in my life, by accident. I was a family practice resident waiting for an appointment in the office of the Department of Family and Community Medicine at the University of Toronto back in 1992. Now that I am a practising family doctor, I am usually running behind schedule, but back then if I wasn’t 10 minutes early I considered myself late. To pass the time I browsed the shelves of the nearby library and was intrigued by the title of this slender volume. I took it from the shelf and started to read it, then and there. I have long forgotten the reason for the appointment, but I signed the book out, took it home, and hungrily read it from cover to cover that night. I stumbled upon A Fortunate Man at a critical time early in my career as a family doctor, filled as I was with uncertainty about my choice. The power of Berger’s biography of Dr John Sassall, a country doctor in northern England, combined with my experiences working with Dr Bob Henderson in the picturesque town of Campbellford, Ont, changed my destiny. I have never really looked back. Berger’s book has found an important place in my library, and I have since joyfully shared the book with friends, colleagues, and the family medicine residents I have taught over the years. There are many wonderful things about this book, but none more so than Jean Mohr’s powerful and moving black-and-white photographs of Sassall and the landscape in which he goes about his work and his life. We don’t even learn Sassall’s name until page 44 of the book or see his face until well after that, but by then we are completely drawn in to his life and his story and those of the people he serves.

This issue of Canadian Family Physician (CFP) features some considerable changes in the cover and the format of the journal. Inspired by John Berger’s book and Jean Mohr’s beautiful and intimate photographs, each month we have chosen to feature a photograph of a randomly selected Canadian family physician going about his or her life and work on our cover. Inside the journal there is much more—more photographs and a story about the featured physician written by Dr Shane Neilson, a family doctor himself, but a writer and a poet of considerable talent. Over the course of time, we hope that these images and these stories will create a rich and accurate portrait of the work we do and the people we are. Once again the January issue of CFP also features the winning stories for the 2010 AMS–Mimi Divinsky Awards for History and Narrative in Family Medicine by Dr Pauline Pariser (page 71),2 Mrs Magbule Doko (page 73),3 and Dr Nicole Audet (page e35).4 We are privileged to also publish a pellucid, to borrow his own word, commentary on these stories by Dr Ian Cameron, a family physician and writer from Nova Scotia (page 66).5 There is much change afoot in family medicine across Canada, but the challenges and rewards of looking after Canadians remain constants. We at CFP are pleased to give faces and voices to Canada’s family physicians on the covers and in the pages of this journal. We hope that you will be inspired by the faces you will see and the voice you will hear.

Competing interests None declared References 1. Berger J. A fortunate man: the story of a country doctor. New York, NY: Vintage; 1997. 2. Pariser P. Throw me a line. Can Fam Physician 2011;57:1:71-2 (Eng), e31-2 (Fr). 3. Doko M. Why are you here to see the doctor today? Can Fam Physician 2011;57:73 (Eng), e33-4 (Fr). 4. Audet N. Le pouvoir de l’ecoute. Can Fam Physician 2011;57:74-5 (Fr), e35-6 (Eng). 5. Cameron I. The importance of stories. Can Fam Physician 2011;57:66-7 (Eng), 68-70 (Fr).

Cet article se trouve aussi en français à la page 13.

Canadian Family Physician • Le Médecin de famille canadien

| VOL 57: JANUARY • JANVIER 2011

Éditorial

Les visages et les voix de la médecine familiale canadienne Nicholas Pimlott Les paysages peuvent être trompeurs. Parfois, un paysage semble être moins la scène de la vie de ses habitants qu’un rideau derrière lequel se produisent leurs luttes, leurs accomplissements et leurs accidents. Pour ceux qui, avec les habitants, sont derrière le rideau, les points de repère ne sont plus seulement géographiques, mais aussi biographiques et personnels1.

insi débute le remarquable récit de John Berger, A Fortunate Man: The Story of a Country Doctor, publié initialement en 1967. J’ai découvert ce roman, comme la plupart des livres importants que j’ai lus dans ma vie, par le plus grand des hasards. J’étais résident en médecine familiale et j’avais rendez-vous au bureau du Département de la médecine familiale et communautaire de l’Université de Toronto en 1992. Maintenant que je pratique la médecine familiale, je suis habituellement en retard dans mon horaire mais, à cette époque, si je n’étais pas 10 minutes avant l’heure, je me considérais en retard. Pour passer le temps, je jetais un coup d’œil sur les étagères de la bibliothèque d’à côté et je fus intrigué par ce livre tout mince. Je l’ai retiré de l’étagère et j’ai commencé à en lire des bribes, ici et là. J’ai oublié depuis longtemps la raison de mon rendez-vous, mais je me rappelle avoir emprunté le livre, l’avoir apporté chez moi et l’avoir lu d’un bout à l’autre le même soir. Je suis tombé sur A Fortunate Man à un moment critique, tôt dans ma carrière de médecin de famille, alors que j’étais très incertain à propos de mon choix. La puissance de la biographie rédigée, par Berger, de Dr John Sassall, un médecin de campagne dans le Nord de l’Angleterre, combinée à mon expérience de travail avec Dr Bob Henderson, dans la pittoresque ville de Campbellford, en Ontario, ont changé ma destinée. Je n’ai jamais vraiment regretté depuis. Le livre de Berger s’est trouvé une place importante dans ma bibliothèque et, depuis, je l’ai fait connaître avec joie à mes amis, à mes collègues et aux résidents en médecine familiale à qui j’ai enseigné au fil des ans. Ce livre est rempli de choses magnifiques, dont l’une, et non la moindre, est la série de photographies en noir et blanc éloquentes et émouvantes de Sassall et du paysage qui l’entoure dans son travail et sa vie. Nous n’apprenons le nom de Sassall qu’à la page 44 du livre et nous ne voyons son visage que bien après, mais nous sommes malgré tout complètement captivés dès le

This article is also in English on page 12.

MD CCFP, RÉDACTEUR SCIENTIFIQUE

départ par sa vie et son histoire, et celles des personnes qu’il soigne. Dans le présent numéro du Médecin de famille canadien (MFC), la couverture et la présentation ont changé considérablement. Inspirés par le livre de Berger et les magnifiques photographies intimistes de Jean Mohr, nous avons décidé de mettre en vedette chaque mois, sur la couverture, la photographie d’un médecin de famille canadien choisi au hasard, qui le présente dans sa vie et son travail. À l’intérieur de la revue, il y a plus encore – plus de photos et un récit à propos du médecin en question, rédigé par Dr Shane Neilson, lui-même médecin de famille, mais aussi écrivain et poète très talentueux. Avec le temps, nous espérons que ces images et ces histoires créeront un portrait riche et exact du travail que nous faisons et des personnes que nous sommes. Une fois de plus, le numéro de janvier du MFC présente les textes des auteures gagnantes du Prix AMS Inc. – Mimi Divinsky d’histoire et de narration en médecine familiale, notamment D res Pauline Pariser (page e31)2, Magbule Doko (page e33)3 et Nicole Audet (page 74).4 Nous avons aussi le privilège de publier un commentaire pellucide, comme le dit l’auteur, au sujet de ces récits, par Dr Ian Cameron, médecin de famille et écrivain de la Nouvelle-Écosse (page 68)5. La médecine familiale change dans toutes les régions du Canada, mais les défis et les satisfactions de prendre soin des Canadiens demeurent constants. L’équipe du MFC est heureuse de prêter un visage et une voix aux médecins de famille du Canada sur la couverture et dans les pages de la revue. Nous espérons que vous serez inspirés par les visages que vous verrez et les voix que vous entendrez.

Intérêts concurrents Aucun déclaré Références 1. Berger J. A fortunate man: the story of a country doctor. New York, NY: Vintage; 1997. 2. Pariser P. Throw me a line. Can Fam Physician 2011;57:1:71-2 (ang), e31-2 (fr). 3. Doko M. Why are you here to see the doctor today? Can Fam Physician 2011;57:1:73 (ang), e33-4 (fr). 4. Audet N. Le pouvoir de l’écoute. Can Fam Physician 2011;57:1:74-5 (fr), e35-6 (ang). 5. Cameron I. The importance of stories. Can Fam Physician 2011;57:1:66-7 (ang), 68-70 (fr).

VOL 57: JANUARY • JANVIER 2011

| Canadian Family Physician

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Le Médecin de famille canadien

AZC-027E

The AstraZeneca logo is a registered trademark of the AstraZeneca group of companies. ÂŠ AstraZeneca 2011

Just imagine what could be?

Commentary

Mitigating epidemic vitamin D deficiency The agony of evidence N.J. Bosomworth

MD CCFP FCFP

For unless they see the sky But they can’t and that is why They know not if it’s dark outside or light Bernie Taupin, Elton John, 1972

f we define a vitamin as a required substance that is not endogenously produced, vitamin D does not meet the criteria. It is produced in skin upon UVB exposure, acting on 7-dehydrocholesterol and undergoing hydroxylation in the liver and kidneys. It behaves, in fact, more like a steroid hormone, binding to vitamin D receptors throughout the body.1 As humankind becomes increasingly urban and specialized, life choices have consequences, including reduced exposure of skin to sunlight and so, reduced ability of skin to synthesize vitamin D.2 Predicted future environmental changes could have unpredictable consequences. If weather becomes excessively wet or hot, people might be driven indoors. Should the behavioural response to warmer temperatures be increased time in the sun, use of sunscreens or sunblocks might be mandated to protect skin from the strengthened UVB rays from atmospheric ozone depletion, minimizing exposure necessary to vitamin D production. With the passage of time, it could be that vitamin D will become a true vitamin after all. Optimal health might, therefore, require an exogenous source, as there are few natural food sources apart from fatty fish.

Life choices and risk factors The genesis of mankind was almost certainly in subSaharan Africa, and these people were probably deeply pigmented. As some of them migrated northward some 60 000 years ago, they experienced less direct UVB radiation from the sun, and there were periods of time when no radiation was available during winter months.2,3 As they moved north and adapted to these conditions, their skin became increasingly depigmented, providing a survival advantage over more deeply pigmented subgroups whose vitamin D deficiency produced problems with mobility and reproduction.4 The possible exceptions were the Inuit in the far north, who consumed a diet of fat and oily fish, one of the few food sources high in vitamin D. Adaptation occurred gradually over generations and is reflected in such features as skin colour, clothing, rituals, and diet. These days there can be rapid changes in location and environment that cause new stresses, advantages,

This article has been peer reviewed. Can Fam Physician 2011;57:16-20 16

Canadian Family Physician • Le Médecin de famille canadien

and deprivations without time for adaptation. A variety of these changes and life choices strongly affect vitamin D levels, and some, such as advancing age, reduced exercise, obesity, and lack of sun exposure, act in synergy. Table 1 identifies risk factors, which can act individually or in concert to produce low levels of vitamin D.4-19

Prevalence of vitamin D deficiency Hepatic hydroxylation of vitamin D3 produced in skin or taken orally produces 25-hydroxyvitamin D (25[OH]D), a major metabolite, which has a long half-life, allowing measurement of serum vitamin D levels. There is no complete consensus on optimum serum levels of 25(OH) D needed for prevention of disease. There is some support, however, for using the following benchmarks20: • Deficiency: less than 25 nmol/L; leads to short-latency disease seen in rickets in children and osteomalacia in adults. • Insufficiency: 25 to 75 nmol/L; leads to long-latency disease such as osteoporosis, fractures, and falls. • Optimal: 75 to 110 nmol/L or more.7,21 Even in the sunniest places, such as Saudi Arabia and Australia, 30% to 50% of adults and children have deficient or insufficient levels of vitamin D.5 At the latitude of Edmonton, Alta, 90% of children have deficient or insufficient levels.6 There were 104 confirmed cases of rickets in Canada between 2002 and 2004.22 The frail elderly have particularly low levels, with one study showing an average decrease of 6 nmol/L over a 2-year period.23 Average 25(OH)D levels are also tending to fall over time. A US nutrition survey done in an interval between 1988 and 2004 showed prevalence increases in levels of marked deficiency from 2% to 6%, while prevalence of adequate levels fell from 45% to 23%.24

The evidence conundrum The development of evidence demonstrating the health effects of vitamin D deficiency has been delayed and confused owing to a combination of multiple factors: • The marketplace drives much research. There are low profit margins in vitamin D manufacturing. Some statins, for example, are thought to increase levels of vitamin D.25 Both statin administration26 and vitamin D levels27 correlate inversely with the prevalence of multiple

La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro de janvier 2011 à la page e1.

| VOL 57: JANUARY • JANVIER 2011

Mitigating epidemic vitamin D deficiency | Commentary Table 1. Risk factors for vitamin D deficiency RISK FACTOR

MECHANISM

Lack of sun exposure5 Latitude of residence6 Sunscreen use7 Urbanization8

Reduced skin synthesis

Aging9 Increased chronic disease prevalence10

Increased medication use11 Limited dietary choices12 Reliance on food fortification13 Migration of populations5 Traditional clothing14 Obesity15

Reduced exercise opportunities16 Skin pigmentation4 Season5 Sex17,18

Metabolic demand19 Malabsorption5

•

No skin synthesis November to March at 52° north (eg, Edmonton, Alta) SPF of 15 blocks 99% of skin synthesis Increasing time indoors and increased automobile use 75% reduction in skin production by age 70; increased institutionalization as a greater percent of the population ages Reduced sun exposure due to increased time indoors; some chronic conditions contribute physiologically to reduced vitamin D production (eg, chronic renal disease); as the population ages, prevalence of chronic disease will rise Anticonvulsants, glucocorticoids, HIV medications, and some antirejection drugs reduce levels of vitamin D Fatty fish and fish oils are the only ample food source, and are becoming increasingly unavailable Food sources are inadequate; in Canada, cow and soy milks and margarines are fortified Rapid migration of people with pigmented skin toward polar areas can reduce skin synthesis as much as 99% All clothing impairs synthesis; Muslim women wearing traditional clothing have a 2.3 odds ratio of developing osteoporosis A 2006 survey found that two-thirds of the US population was overweight or obese; vitamin D is sequestered in body fat, and levels are inversely related to BMI Vehicle prioritization, poor urban planning, and poor air quality force many to exercise indoors Melanin is a very efficient blocker of UVB radiation Very little vitamin D synthesis can occur from sun exposure in northern latitudes in winter months Women are at increased risk of deficiency because of reduced peak bone mass, increased pregnancy demands, and traditional attire in some areas Rapid skeletal growth in utero and in early infancy increases demand for calcium and vitamin D; breast milk is a poor source Vitamin D is fat-soluble; therefore, those with fat malabsorption syndromes such as Crohn disease or celiac disease are at risk

BMI—body mass index, SPF—skin protection factor.

sclerosis. Several prospective dosing studies treating multiple sclerosis with statins have now been done, with both negative28 and positive29 results; however, to date, no dosing studies have been done with vitamin D.

•

• •

Dosage is clearly important. Early, larger randomized trials used dosages that were probably too low to show statistically significant benefits.30-32 Subsequent smaller trials using higher dosages have had positive results, but have had less influence on outcomes when meta-analyses were done. Subgroup analysis to control dose heterogeneity has demonstrated the benefits of higher dosing.33 Control subjects in larger studies were not prevented from taking vitamin D on their own, potentially masking differences between groups.34 Food supplementation led to the assumption that deficiency was prevented and that no further studies were needed.35 It took some time to recognize the effects of insufficiency leading to long-latency disease. Calcium was often administered concurrently, which could have independently influenced end points.36,37 Despite a multitude of epidemiologic studies showing the association between low vitamin D levels and common diseases (Table 2),27,38-45 few follow-up, randomized, prospective dosing studies have been done, despite suggestions such studies are needed.27,46,47 Evidence frequently has never gone beyond hypothesis generation.

Proven and potential benefits Consequences of vitamin D deficiency were comprehensively outlined in this journal in 2007,48 and have been further addressed in recent reviews and meta-analyses. The more established benefits are summarized in Table 3.49-57 Potential benefits from epidemiologic studies or those for which level I and II studies provide conflicting evidence appear in Table 2.27,38-45 While these conditions can only be said to be associated with low levels of 25(OH)D, there are compelling data to prompt larger-scale randomized trials.

Supplementation to achieve adequate levels Available higher-level evidence provides some guidance on vitamin D intakes for health maintenance: • 400 IU daily is sufficient to prevent rickets in children and osteomalacia in adults, but is insufficient to achieve adequate serum levels of 25(OH)D.1 • 700 to 1000 IU daily is the minimum required to reduce risk of falling in the elderly.53 • 400 to 800 IU daily is the minimum required to reduce risk of fracture in the elderly.51 • 500 to 1500 IU daily reduced cancer mortality and allcause mortality in various studies.49,50,58 • 2000 IU daily reduced the incidence of type 1 diabetes in young children.56 • 1000 IU daily is required to bring 50% of adults to 25(OH)D levels above 75 nmol/L (considered adequate).59 • 2000 IU daily is required to bring 85% to 90% of the adult population to 25(OH)D levels above 75 nmol/L.59 The Canadian Paediatric Society22 has expressed concerns about insufficient vitamin D intake in children,

VOL VOL 57: 57: JANUARY JANUARY •• JANVIER 2011

| Canadian Family Physician

•

Le Médecin de famille canadien

Commentary | Mitigating epidemic vitamin D deficiency Table 2. Epidemiologic association or conflicting studies suggesting potential benefits of vitamin D supplementation CONDITION

BEST EVIDENCE

LEVEL OF EVIDENCE

Chronic unexplained pain

Straube et al,38 2009

Meta-analysis

Munger et al,27 2006

Deterioration of cognition

Annweiler et al,39 2009

Some infectious diseases

Yamshchikov et al,40 2009 Pittas et al,41 2010 Wang et al,42 2010

CVD

Type 2 diabetes

Pittas et al,41 2010

Periodontal disease

Dietrich et al,43 2004

Breast cancer

Garland et al,44 2007

Prostate cancer

Yin et al,45 2009

COMMENTS

Insufficient epidemiologic or RCT evidence for link between pain and insufficiency or deficiency Prospective nested Solid association between high 25(OH)D and low risk of case-control MS; no available dosing studies Systematic review No clear association between cognitive function and 25(OH)D, but considerable heterogeneity; intervention studies inconsistent Systematic review Strongest evidence for tuberculosis, influenza, and viral upper respiratory tract illness; considerable heterogeneity Systematic reviews Possible association of 25(OH)D with hypertension and CVD (not diabetes41); prospective dosing trials suggest benefit at moderate to high doses—more studies needed Systematic review Insufficient evidence for association of 25(OH)D levels with incident diabetes; no good evidence on dosing studies benefiting glycemic control Cross sectional Low 25(OH)D levels might be associated with periodontal disease independent of effects on bone mineral density Pooled analysis of Estimated 50% reduction in breast cancer incidence with longitudinal use of 2000 IU vitamin D daily; no available dosing studies studies Meta-analysis of Serum 25(OH)D not found to be associated with incident longitudinal prostate cancer studies

25(OH)D—25-hydroxyvitamin D, CVD—cardiovascular disease, MS—multiple sclerosis, RCT—randomized controlled trial.

Table 3. Currently established benefits of vitamin D CONDITION

BEST EVIDENCE

LEVEL OF EVIDENCE

COMMENTS

All-cause mortality

Autier et al, 2007

Meta-analysis

300-833 IU/d; mortality a secondary end point in all but 1 study

Cancer mortality

Lappe et al,50 2007

RCT

1000 IU/d; 1179 postmenopausal women; included calcium supplement

Fracture

Bischoff-Ferrari et al,51 2009

Meta-analysis

400-800 IU/d; dose dependent; 20 RCTs; independent of calcium

Muscle strength

Moreira-Pfrimer et al,52 2009

RCT

3000-5000 IU/d for 6 mo; elderly population

Falls

Bischoff-Ferrari et al,53 2009

Meta-analysis

700-1000 IU needed; elderly population; 8 trials

Colon cancer

Zhou et al,54 2009

Evidentiary review

1000 IU/d recommended; 25 studies included

Hypertension

Witham et al, 2009

Meta-analysis

11 studies; weak evidence for reduction in BP

Type 1 diabetes

Hyppönen et al, 2001

Prospective case control

2000 IU/d; 10 821 children; relative risk reduction of 0.22 in first year of life

Psoriasis

Kreuter et al,57 2006

RCT

Topical calcipotriol equivalent to topical steroid; 80 patients for 4 wk

BP—blood pressure, RCT—randomized controlled trial.

particularly at northern latitudes, where rickets continues to be reported. They also suggest higher doses than currently recommended might be required in adolescents and adults to achieve and maintain adequate bone mass, particularly during pregnancy. Recent recommendations by the Food and Nutrition Board of the US Institute of Medicine appear in Table 4.60 These doses do not seem adequate in view of current evidence.61

Canadian Family Physician • Le Médecin de famille canadien

Clearly, any decision made that increases dosing must take potential toxicity into consideration. Fortunately there seems to be a wide margin of safety, with trials of supplementation from 4000 to 10 000 IU daily causing no rise in serum or urinary calcium and no adverse events.3,62,63 An increase in urinary tract stones was reported as 5.7 per 10 000 participants in the Women’s Health Initiative study, despite

| VOL 57: JANUARY • JANVIER 2011

Mitigating epidemic vitamin D deficiency | Commentary Table 4. Adequate intakes of vitamin D AGE, Y

RECOMMENDED ADEQUATE INTAKE

using a lower dose. Serum levels can then be tracked. Other strategies are obviously possible, including intramuscular administration.

Birth to 13

600 IU

14-18

600 IU

Options for health care providers

600 IU

There are 2 approaches to prevention of disease: individual- or population-based strategies. 70 Populationbased programs, such as adding vitamin D to foodstuffs or increasing daily dosage recommendations, are of minimal benefit to individuals, and are very sensitive to slim risk-benefit ratios.70 With this scenario, as with vaccination, success is often a nonevent. Populationbased programs do, however, speak to the etiology of the illness in the population, and are of great public health importance. Recent guidelines reflect a gradually increasing acceptance of enhanced supplementation. The US Institute of Medicine’s recently released recommendations for vitamin D intake60 suggested that most Americans and Canadians up to age 70 needed no more than 600 IU of vitamin D daily to maintain health, and those 71 years of age and older might need 800 IU. These doses are still very conservative. In their review of more than 1000 studies, they found that considerable evidence confirmed the role of vitamin D in bone health, and that while numerous studies point to other possibilities that warrant further investigation, those studies have yielded conflicting and mixed results and do not offer the evidence needed to confirm that vitamin D has other health effects. New 2010 Canadian guidelines for management of osteoporosis71 recommend higher intakes, with routine supplementation at 400 to 1000 IU daily for those at low risk and up to 2000 IU daily for high-risk individuals. Until further research is done and more appropriate population strategies are made available, the office practitioner can make use of the individual or casefinding approach, identifying patients most likely to be vitamin D deficient by history. These individuals might need repletion therapy, while the remainder should probably consider maintenance supplementation. Screening serum levels would seldom be necessary unless used for treatment follow-up or patient motivation. The intervention of supplementation at 1000 to 2000 IU daily has a wide margin of safety, and the potential for individual health improvement is likely to be substantial.21,59,66 This measure would be an interim expedient to protect our patients until a more adequate population-level strategy is crafted.

•

Pregnant or lactating

19-50 •

Pregnant or lactating

600 IU 600 IU

51-70

600 IU

≥ 71

800 IU

Data from the Office of Dietary Supplements, National Institutes of Health.60

the low-dose supplementation. This might reflect the relatively high calcium intakes of the study population.34,64 We might, however, expect a slightly increased incidence of stones in a vitamin D–replete population. Maintaining vitamin D deficiency seems a poor strategy for preventing renal colic. Given the favourable risk-to-benefit ratio, it seems reasonable, and quite conservative, to recommend a supplemental intake of 1000 to 2000 IU daily to patients older than 1 year of age (Table 5). Higher-risk patients, such as the obese, those with chronic disease, or the elderly could take 2000 IU daily.65,66

Table 5. Suggested update to adequate intakes for vitamin D based on best evidence AGE

SUGGESTED ADEQUATE INTAKE

0-12 mo

400-800 IU

•

Below 55th parallel

400 IU

•

Above 55th parallel

800 IU

1-13 y

1000-2000 IU

14-18 y

1000-2000 IU

•

Pregnant or lactating

19-50 y •

Pregnant or lactating

2000 IU 1000-2000 IU 2000 IU

51-70 y

1000-2000 IU

≥ 71 y

1000-2000 IU

Patients with deficiency or insufficiency will require larger doses to raise 25(OH)D levels to normal. Increased doses are necessary for repletion, although it does not matter whether these doses are given daily, weekly, or monthly.67,68 The best-studied regimen is to give 600 000 IU of vitamin D2 (which is 60% less available than vitamin D3 at high doses)5,67,69 over a period of 8 weeks. Vitamin D2 is available in 50 000-IU capsules. Administration could then be 3 capsules of 50 000 IU every 2 weeks 4 times before reducing intake to maintenance levels. As D3 is now available in 50 000-IU capsules as well, a similar strategy could be employed

Dr Bosomworth is Clinical Instructor in the Department of Family Practice at the University of British Columbia in Vancouver. Competing interests None declared Correspondence Dr N.J. Bosomworth, 3413 Forsyth Dr, Penticton, BC V2A 8Z2; e-mail john.bosomworth@interiorhealth.ca The opinions expressed in commentaries are those of the authors. Publication does not imply endorsement by the College of Family Physicians of Canada.

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Le Médecin de famille canadien

Commentary | Mitigating epidemic vitamin D deficiency References 1. Zitterman A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 2003;89(5):552-72. 2. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69(5):842-56. 3. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77(1):204-10. Erratum in: Am J Clin Nutr 2003;78(5):1047. 4. Jablonski NG, Chaplin G. The evolution of human skin coloration. J Hum Evol 2000;39(1):57-106. 5. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357(3):266-81. 6. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988;67(2):373-8. 7. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005;135(2):317-22. 8. Wicherts IS, van Schoor NM, Boeke JP, Visser M, Deeg DJ, Smit J, et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab 2007;92(6):2058-65. Epub 2007 Mar 6. 9. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81(3):353-73. 10. Holick MF. The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action. Mol Aspects Med 2008;29(6):361-8. Epub 2008 Sep 2. 11. Seymour HM, Glendenning P. Fit for a fracture. Med J Aust 2005;183(4):213-4. 12. Brunner EJ, Jones PJ, Friel S, Bartley M. Fish, human health and marine ecosystem health: policies in collision. Int J Epidemiol 2009;38(1):93-100. Epub 2008 Aug 2. 13. Calvo MS, Whiting SJ. Are current dietary strategies in North America able to meet vitamin D needs in the absence of sun exposure? Toronto, ON: Canadian Cancer Society; 2006. Available from: www.cancer.ca/canada-wide/prevention/ vitamin%20d/~/media/CCS/Canada%20wide/Files%20List/English%20 files%20heading/pdf%20not%20in%20publications%20section/Mona%20 Calvo%20-%20pdf_899467559.ashx. Accessed 2008 Mar 13. 14. Allali F, El Aichaouli S, Saoud B, Maaroufi H, Abouqal R, Hajjaj-Hassouni N. The impact of clothing style on bone mineral density among post menopausal women in Morocco: a case-control study. BMC Public Health 2006;6:135-41. 15. Levi J, Segal LM, Julianno C. F as in fat: how obesity policies are failing in America, 2006. Washington, DC: Trust for America’s Health; 2006. Available from: http:// healthyamericans.org/reports/obesity2006/Obesity2006Report.pdf. Accessed 2008 Mar 16. 16. Duncan MJ, Mummery WK, Steele RM, Caperchione C, Schofield G. Geographic location, physical activity and perceptions of the environment in Queensland adults. Health Place 2009;15(1):204-9. Epub 2008 Apr 30. 17. Lehtonen-Veromaa MK, Möttönen TT, Nuotio IO, Irjala KM, Leino AE, Viikari JS. Vitamin D and attainment of peak bone mass among peripubertal Finnish girls: a 3-y prospective study. Am J Clin Nutr 2002;76(6):1446-53. 18. El-Hajj Fuleihan G, Nabulsi M, Tamim H, Maalouf J, Salamoun M, Khalife H, et al. Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial. J Clin Endocrinol Metab 2006;91(2):405-12. 19. Ward LM, Gaboury I, Ladhani M, Zlotkin S. Canadian Paediatric Surveillance Program. Vitamin D deficiency rickets among children living in Canada: a new look at an old disease. Presented at the Canadian Diabetes Association and Canadian Society of Endocrinology and Metabolism Professional Conference; 2003 Oct 15-19; Ottawa, ON. Available from: www.cps.ca/English/Surveillance/CPSP/ Abstract/abstractRickets.htm. Accessed 2008 Mar 17. 20. Whiting SJ, Calvo MS. Dietary recommendations for vitamin D: a critical need for functional end points to establish an estimated average requirement. J Nutr 2005;135(2):304-9. 21. Bischoff-Ferrari HA. The 25-hydroxyvitamin D threshold for better health. J Steroid Biochem Mol Biol 2007;103(3-5):614-9. Epub 2007 Jan 16. 22. First Nations, Inuit and Métis Health Committee, Canadian Paediatric Society. Vitamin D supplementation: recommendations for Canadian mothers and infants. Paediatr Child Health 2007;12(7):583-9. 23. Nakamura K, Nishiwaki T, Ueno K, Yamamoto M. Age-related decrease in serum 25-hydroxyvitamin D concentrations in the frail elderly: a longitudinal study. J Bone Miner Metab 2007;25(4):232-6. Epub 2007 Jun 25. 24. Ginde AA, Liu MC, Campargo CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med 2009;169(6):626-32. 25. Pérez-Castrillón JL, Vega G, Abad L, Sanz A, Chaves J, Hernandez G, et al. Effects of atorvastatin on vitamin D levels in patients with acute ischemic heart disease. Am J Cardiol 2007;99(7):903-5. Epub 2007 Feb 8. 26. Yavuz B, Ertugrul DT, Cil H, Ata N, Akin KO, Yalcin AA, et al. Increased levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins? Cardiovasc Drugs Ther 2009;23(4):295-9. 27. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296(23):2832-8. 28. Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 2008;71(18):1390-5. Epub 2008 Jun 4. 29. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004;363(9421):1607-8. 30. LaCroix AZ, Kotchen A, Anderson G, Brzyski R, Cauley JA, Cummings SR, et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci 2009;64(5):559-67. Epub 2009 Feb 16. 31. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354(7):669-83. Erratum in: N Engl J Med 2006;354(10):1102. 32. De Boer IH, Tinker LF, Connelly S, Curb JD, Howard BV, Kestenbaum B, et al. Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care 2008;31(4):701-7. Epub 2008 Jan 30. 33. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, DawsonHughes B. Fracture prevention with Vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005;293(18):2257-64. 34. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int 2010;21(7):1121-32. Epub 2009 Dec 3.

Canadian Family Physician • Le Médecin de famille canadien

35. Calvo MS, Whiting SJ, Barton CN. Vitamin D intake: a global perspective of current status. J Nutr 2005;135(2):310-6. 36. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007;370(9588):657-66. 37. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 2006;166(8):869-75. 38. Straube S, Moore RA, Derry S, McQuay HJ. Vitamin D and chronic pain. Pain 2009;141(1-2):10-3. Epub 2008 Dec 11. 39. Annweiler C, Allali G, Allain P, Bridenbaugh S, Schott AM, Kressig RW, et al. Vitamin D and cognitive performance in adults: a systematic review. Eur J Neurol 2009;16(10):1083-9. Epub 2009 Jul 29. 40. Yamshchikov AV, Desai MS, Blumberg HM, Ziegler TR, Tangpricha V. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract 2009;15(5):438-49. 41. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, et al. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med 2010;152(5):307-14. 42. Wang L, Manson JE, Song Y, Sesso H. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010;152(5):315-23. 43. Dietrich T, Joshipura KJ, Dawson-Hughes B, Bischoff-Ferrari HA. Association between serum concentrations of 25-hydroxy D3 and periodontal disease in the US population. Am J Clin Nutr 2004;80(1):108-13. 44. Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol 2007;103(3-5):708-11. 45. Yin L, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis of longitudinal studies: serum vitamin D and prostate cancer risk. Cancer Epidemiol 2009;33(6):435-45. 46. Grant WB, Boucher BJ. Current impediments to the ultraviolet-B-vitamin D-cancer hypothesis. Anticancer Res 2009;29(9):3597-604. 47. Gissel T, Rejnmark L, Mosekilde L, Vertergaard P. Intake of vitamin D and breast cancer—a meta-analysis. J Steroid Biochem Mol Biol 2008;111(3-5):195-9. Epub 2008 Jun 11. 48. Schwalfenberg G. Not enough vitamin D. Health consequences for Canadians. Can Fam Physician 2007;53:841-54. 49. Autier P, Gandini S. Vitamin D supplementation and total mortality. Arch Intern Med 2007;167(16):1730-7. 50. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85(6):1586-91. Erratum in: Am J Clin Nutr 2008;87(3):794. 51. Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med 2009;169(6):551-61. 52. Moreira-Pfrimer LD, Pedrosa MA, Teixeira L, Lazaretti-Castro M. Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized doubleblind controlled trial. Ann Nutr Metab 2009;54(4):291-300. Epub 2009 Aug 31. 53. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. BMJ 2009;339:b3692. DOI: 10.1136/ bmj.b3692. 54. Zhou G, Stoitzfus J, Swan BA. Optimizing vitamin D status to minimize colorectal cancer risk: an evidentiary review. Clin J Oncol Nurs 2009;13(4):E3-17. 55. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens 2009;27(10):1948-54. 56. Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth cohort study. Lancet 2001;358(9292):1500-3. 57. Kreuter A, Sommer A, Hyun J, Bräutigam M, Brockmeyer NH, Altmeyer P, et al. 1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone in the treatment of intertriginous psoriasis. Arch Dermatol 2006;142(9):1138-43. 58. Goodwin PJ. Vitamin D in cancer patients: above all, do no harm. J Clin Oncol 2009;27(13):2117-9. Epub 2009 Apr 6. 59. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006;84(1):18-28. Errata in: Am J Clin Nutr 2006;84(5):1253 and Am J Clin Nutr 2007;86(3):809. 60. Ross CA, Taylor CL, Yaktine AL, Del Valle HB, editors. Dietary reference intakes for calcium and vitamin D. Washington, DC: Institute of Medicine; 2010. Available from: www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-andVitamin-D.aspx. Accessed 2010 Dec 4 61. Vieth R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, et al. The urgent need to recommend an intake of Vitamin D that is effective. Am J Clin Nutr 2007;85(3):649-50. Erratum in: Am J Clin Nutr 2007;86(3):809. 62. Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr 2006;136(4):1117-22. 63. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007;85(1):6-18. 64. Cranney A, Horsley T, O’Donnell S, Weiler H, Puil L, Ooi D, et al. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep) 2007;158:1-235. 65. Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: a global perspective. Ann Epidemiol 2009;19(7):468-83. 66. Cherniack EP, Levis S, Troen BR. Hypovitaminosis D: a widespread epidemic. Geriatrics 2008;63(4):24-30. 67. Pepper KJ, Judd SE, Nanes MS, Tangpricha V. Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. Endocr Pract 2009;15(2):95-103. 68. Ish-Shalom S, Segal E, Salganik T, Raz B, Bromberg IL, Vieth R. Comparison of daily, weekly, and monthly vitamin D3 in ethanol dosing protocols for two months in elderly hip fracture patients. J Clin Endocrinol Metab 2008;93(9):3430-5. Epub 2008 Jun 10. 69. Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr 2006;84(4):694-7. 70. Rose G. Sick individuals and sick populations. Int J Epidemiol 2001;30(3):427-32. 71. Papaioannou A, Morin S, Cheung A, Atkinson S, Brown JP, Feldman S, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 2010;182(17):1864-73.

| VOL 57: JANUARY • JANVIER 2011

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Commentaire

Atténuer la carence épidémique en vitamine D La tourmente des données scientifiques N.J. Bosomworth

MD CCFP FCFP

À moins de voir le ciel, Mais ils ne le peuvent pas, et c’est pourquoi Ils ne savent pas s’il fait sombre ou clair dehors Bernie Taupin, Elton John, 1972 (traduction libre)

i nous définissons une vitamine comme une substance nécessaire qui n’est pas produite de manière endogène, la vitamine D ne répond pas à ce critère. Elle est produite au niveau de la peau exposée aux rayons UVB, agissant sur le 7-déhydrocholestérol et subissant une hydroxylation dans le foie et les reins. De fait, elle se comporte davantage comme des hormones stéroïdes, se liant aux récepteurs de vitamine D dans l’ensemble du corps1. L’urbanisation et la spécialisation croissantes des populations on des conséquences sur les choix de vie des populations, notamment une exposition réduite de la peau au soleil, d’où la capacité moindre de la peau de synthétiser la vitamine D2. Les changements environnementaux prévus pourraient avoir des conséquences imprévisibles. Si la température devenait excessivement humide ou chaude, les gens pourraient choisir de rester à l’intérieur. Si leur réaction aux températures plus chaudes les amenait à passer plus de temps au soleil, il leur faudrait utiliser des filtres ou des écrans solaires pour protéger leur peau des rayons UVB plus intenses à cause de la diminution de l’ozone atmosphérique, qui réduit l’exposition nécessaire à la production de vitamine D. Avec le temps, il se pourrait que la vitamine D devienne après tout une vraie vitamine. Par conséquent, pour une santé optimale, il faudrait une source exogène, puisqu’il existe très peu de sources alimentaires naturelles à part les poissons gras.

Choix de vie et facteurs de risque La genèse de l’humanité s’est presque assurément produite en Afrique subsaharienne et les gens avaient alors probablement une forte pigmentation. Avec la migration vers le Nord, il y a quelque 60 000 ans, ils étaient moins exposés directement aux rayons UVB du soleil et il fut des époques où il n’y avait aucun rayon de soleil durant les mois d’hiver2,3. Plus ils allaient vers le Nord et s’adaptaient à ces conditions, plus leur peau perdait progressivement sa pigmentation, leur donnant un avantage pour leur survie par rapport aux sous-groupes à la pigmentation plus forte, chez qui la carence en vitamine D

Cet article a fait l’objet d’une révision par des pairs. Can Fam Physician 2011;57:e1-6

posait des problèmes de mobilité et de reproduction4. Les exceptions possibles à ce phénomène étaient les Inuits, dans le Grand Nord, qui avaient un régime alimentaire composé de gras et de poissons huileux, l’une des rares sources alimentaires à forte teneur en vitamine D. L’adaptation s’est produite graduellement de génération en génération et elle se manifeste dans des caractéristiques comme la couleur de la peau, l’habillement, les rituels et l’alimentation. De nos jours, on change rapidement de lieux et d’environnements, ce qui cause du stress, des bienfaits et des carences, sans qu’il y ait de temps pour s’adapter. Ces changements et les choix de vie influencent fortement les niveaux de vitamine D, comme le vieillissement, le manque d’activité physique, l’obésité, le manque d’exposition au soleil, et ils agissent en synergie. Le Tableau 1 présente les facteurs de risque qui, à eux seuls ou combinés, se traduisent par de faibles taux de vitamine D4-19.

Prévalence de la carence en vitamine D L’hydroxylation hépatique de la vitamine D3 générée dans la peau ou prise par voie orale produit la 25-hydroxyvitamine D (25[OH]D), un important métabolite qui a une longue demi-vie, permettant la mesure des niveaux sériques de vitamine D. Il n’existe pas de consensus sur les niveaux sériques optimaux de 25(OH) D nécessaires à la prévention des maladies. Il existe cependant un certain accord sur l’utilisation des points de repère suivants20: • Carence: moins de 25 nmol/L; cause des maladies à courte latence comme le rachitisme chez l’enfant et l’ostéomalacie chez l’adulte. • Insuffisance: 25 à 75 nmol/L; cause des problèmes à longue latence comme l’ostéoporose, les fractures et les chutes. • Niveau optimal: 75 à 110 nmol/L ou plus7,21. Même dans les endroits les plus ensoleillés, comme en Arabie saoudite et en Australie, de 30 % à 50 % des adultes et des enfants ont une carence ou des niveaux insuffisants de vitamine D5. À la latitude d’Edmonton, en Alberta, 90 % des enfants ont une carence ou des niveaux trop bas6. Entre 2002 et 2004, on a compté 104 cas confirmés de rachitisme au Canada22. Chez les aînés frêles, les taux sont particulièrement bas selon une étude qui démontre une baisse moyenne de 6 nmol/L sur une période de 2 ans23. Les niveaux moyens de 25(OH)D ont aussi tendance à fléchir avec le temps. Selon une étude sur la nutrition This article is also in English on page 16.

VOL VOL 57: 57: JANUARY JANUARY •• JANVIER 2011

| Canadian Family Physician

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Le Médecin de famille canadien

Commentaire | Atténuer la carence épidémique en vitamine D Tableau 1. Facteurs de risque d’une carence en vitamine D FACTEUR DE RISQUE

aux États-Unis, durant une période allant de 1988 à 2004, on a constaté une hausse de la prévalence de carence notoire, passant de 2 % à 6 %, alors que la prévalence de taux suffisants baissait de 45 % à 23 %24.

MÉCANISME

Manque Moins grande synthèse au niveau de la peau. d’exposition au soleil5 Latitude de la Aucune synthèse au niveau de la peau de novembre à mars dans le Nord à une latitude de résidence6 52° (p. ex. Edmonton, Alberta). Un FPS de 15 bloque 99 % de la synthèse au Utilisation niveau de la peau. d’écran solaire7 Urbanisation8 Plus de temps passé à l’intérieur et plus grande utilisation de l’automobile. Vieilissement9 Réduction de 75 % de la régénération de la peau à 70 ans; plus grande institutionnalisation en raison d’un plus grand pourcentage de la population qui vieillit. Plus grande Exposition au soleil réduite en raison de plus prévalence des longues périodes à l’intérieur; certains problèmes chroniques contribuent physiologiquement à une maladies chroniques10 réduction de la production de vitamine D (p. ex. néphropathie chronique); avec le vieillissement de la population, la prévalence des maladies chroniques augmentera. Les anticonvulsifs, les glucocorticostéroïdes, les Utilisation médicaments contre le VIH et certains agents accrue de médicaments11 anti-rejets réduisent les taux de vitamine D. Les poissons gras et les huiles de poisson sont les Choix alimentaires seules sources alimentaires à forte teneur et ils deviennent de moins en moins disponibles. limités12 Dépendance à Les sources alimentaires sont insuffisantes; au l’endroit de la Canada, le lait de vache et de soja et la fortification margarine sont fortifiés. des aliments13 Migration des La migration rapide des personnes ayant une populations5 peau pigmentée vers les régions polaires peuvent réduire de jusqu’à 99 % la synthèse au niveau de la peau. Habillement Les vêtements nuisent à la synthèse; les traditionnel14 musulmanes qui portent des vêtements traditionnels présentent un rapport de cotes de 2,3 sur le plan du risque d’ostéoporose. Selon une étude en 2006, deux tiers des Obésité15 Américains avaient un excès de poids ou étaient obèses; la vitamine D est emprisonnée dans le gras corporel et ses taux sont inversement proportionnels à l’IMC. La préférence pour les déplacements motorisés, la Moins de mauvaise planification urbaine et la qualité possibilités médiocre de l’air contraignent à pratiquer les d’activité activités physiques à l’intérieur. physique16 Pigmentation La mélanine bloque efficacement les rayons UVB. de la peau4 Saisons5 Très peu de synthèse de la vitamine D peut se produire par exposition au soleil durant les mois d’hiver dans les pays nordiques. Les femmes sont à risque accru de carence en Sexe17,18 raison du pic de masse osseuse plus faible, des demandes accrues durant la grossesse et de l’habillement traditionnel dans certaines régions. La croissance squelettique rapide dans l’utérus et Demandes métaboliques19 durant la petite enfance augmente la demande de calcium et de vitamine D; le lait maternel en contient peu. 5 Malabsorption La vitamine D est liposoluble; ainsi, ceux qui souffrent de syndromes de malabsorption comme la maladie de Crohn ou la maladie cœliaque sont à risque.

L’énigme des données scientifiques La production de données probantes démontrant les effets sur la santé de la carence en vitamine D a été retardée et compliquée en raison d’une combinaison de multiples facteurs: • Le marché est un catalyseur de la recherche. Les marges de profits à réaliser dans la fabrication de la vitamine D sont faibles. Par exemple, on croit que certaines statines augmentent les taux de vitamine D25. L’administration de statines26 et les niveaux de vitamine D27 ont une corrélation inversement proportionnelle à la prévalence de la sclérose en plaques. Plusieurs études prospectives sur le dosage des statines dans le traitement de la sclérose en plaques ont été réalisées, constatant des résultats négatifs28 et positifs29; par ailleurs, jusqu’à présent, aucune étude sur le dosage de la vitamine D n’a été faite. • Le dosage est clairement important. Dans les premières études randomisées, on utilisait des dosages qui étaient probablement trop faibles pour montrer des bienfaits statistiquement significatifs30-32. De plus petites études subséquentes à l’aide de dosages plus élevés ont montré des résultats positifs, mais ont eu moins d’influence sur les résultats quand elles ont fait partie de méta-analyses. L’analyse des sous-groupes en vue de contrôler l’hétérogénéité des doses a fait valoir les avantages de doses plus élevées33. • Dans les études sur des sujets plus nombreux, on n’empêchait pas les sujets de prendre de la vitamine D de leur propre chef, ce qui a peut-être masqué les différences entre les groupes34. • Les suppléments alimentaires ont laissé croire que l’on prévenait la carence et qu’aucune autre étude plus approfondie n’était nécessaire 35. Il a fallu du temps pour reconnaître les effets d’une insuffisance, menant à des maladies à longue latence. • Du calcium était souvent administré en même temps, ce qui pourrait avoir indépendamment influencé les événements cibles 36,37. • En dépit d’une multitude d’études épidémiologiques démontrant l’association entre de faibles taux de vitamine D et des maladies courantes (Tableau 2)27,38-45, il y a eu très peu d’études de suivi randomisées prospectives sur le dosage malgré les suggestions les recommandant27,46,47. Bien souvent, les données probantes ne sont pas allées au-delà de la formulation d’hypothèses.

Bienfaits éprouvés et potentiels des suppléments Les conséquences de la carence en vitamine D ont été expliquées de manière exhaustive dans cette revue en

IMC—indice de masse corporelle, FPS—facteur de protection solaire

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Atténuer la carence épidémique en vitamine D | Commentaire Tableau 2. Associations épidémiologiques ou études contradictoires concernant les bienfaits potentiels des suppléments de vitamine D PROBLÈME

MEILLEURES DONNÉES PROBANTES

Douleur chronique inexpliquée

Straube et collab., 2009

Sclérose en plaques

NIVEAU DE PREUVE

COMMENTAIRE

Méta-analyse

Données épidémiologiques ou tirées d’ERC insuffisantes pour faire un lien entre la douleur et l’insuffisance ou la carence.

Munger et collab.,27 2006

Étude cas-témoin prospective nichée

Association solide entre le 25(OH)D élevé et un faible risque de sclérose en plaques; aucune étude disponible sur le dosage.

Détérioration de la fonction cognitive

Annweiler et collab.,39 2009

Synthèse critique

Aucune association évidente entre la fonction cognitive et la 25(OH)D, mais une hétérogénéité considérable; les études d’interventions ne sont pas uniformes.

Certaines maladies infectieuses

Yamshchikov et collab.,40 2009

Synthèse critique

Les données probantes sont les plus convaincantes pour la tuberculose, la grippe et les maladies des voies respiratoires supérieures d’origine virale; hétérogénéité considérable.

MCV

Pittas et collab.,41 2010 Wang et collab.,42 2010

Synthèses critiques Association possible entre la 25(OH)D, l’hypertension et les MCV (pas le diabète41); des études prospectives sur le dosage font valoir des bienfaits à des doses de modérées à élevées - plus d’études sont nécessaires.

Diabète de type 2

Pittas et collab.,41 2010

Synthèse critique

Il n’y a pas de données suffisantes pour associer les niveaux de 25(OH)D avec l’incidence de diabète; il n’y a pas de données convaincantes dans les études sur le dosage concernant les bienfaits pour le contrôle de la glycémie.

Maladies périodontiques

Dietrich et collab.,43 2004

Étude transversale

De faibles taux de 25(OH)D pourraient être associés à des maladies périodontiques indépendamment de leurs effets sur la densité minérale osseuse.

Cancer du sein

Garland et collab.,44 2007

Analyse combinée d’études longitudinales

Selon les estimations, l’utilisation de 2 000 IU de vitamine D par jour réduit de 50 % l’incidence du cancer du sein; aucune étude sur le dosage n’est disponible.

Cancer de la prostate

Yin et collab.,45 2009

Méta-analyse d’études longitudinales

Il n’est pas démontré que la 25(OH)D sérique soit associée à l’incidence du cancer de la prostate.

25(OH)D—25-hydroxyvitamine D, MCV—maladies cardiovasculaires, ERC—étude randomisée contrôlée

200748 et ont aussi fait l’objet de récentes synthèses et méta-analyses. Les bienfaits les plus reconnus sont résumés au Tableau 349-57. Les avantages potentiels signalés dans des études épidémiologiques ou ceux sur lesquels les données probantes sont contradictoires dans les études de niveau I et II sont indiqués au Tableau 227,38-45. Bien qu’on ne puisse que prétendre que ces problèmes sont associés à de faibles taux de 25(OH)D, il y a des données convaincantes pour inciter à faire des études randomisées à plus large échelle.

Suppléments nécessaires pour obtenir des niveaux suffisants de vitamine D Des données probantes de plus haut niveau donnent une certaine indication quant à l’apport nécessaire en vitamine D pour maintenir une bonne santé: • 400 UI par jour sont suffisants pour prévenir le rachitisme chez les enfants et l’ostéomalacie chez l’adulte, mais pas assez pour atteindre des niveaux sériques adéquats de 25(OH)D1.

• 700 à 1 000 UI par jour représentent le minimum nécessaire pour réduire le risque de chutes chez les aînés53. • 400 à 800 UI par jour sont le minimum requis pour réduire le risque de fractures chez les aînés51. • 500 à 1 500 UI par jour réduisent la mortalité due au cancer et toutes causes confondues selon diverses études49,50,58. • 2 000 UI par jour ont réduit l’incidence de diabète de type 1 chez les jeunes enfants56. • 1 000 UI par jour sont nécessaires pour que 50 % des adultes atteignent des niveaux 25(OH)D au-dessus de 75 nmol/L (considérés comme suffisants)59. • 2 000 UI par jour sont nécessaires pour que les taux de 25(OH)D se situent au-dessus de 75 nmol/L chez 85 % à 90 % de la population adulte59. La Société canadienne de pédiatrie22 a exprimé des inquiétudes au sujet d’une insuffisance de vitamine D chez les enfants, en particulier ceux qui vivent à des latitudes nordiques, où le rachitisme continue d’être signalé. La Société fait aussi valoir que de plus fortes doses que celles actuellement recommandées pourraient être

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Commentaire | Atténuer la carence épidémique en vitamine D Tableau 3. Bienfaits actuellement établis de la vitamine D PROBLÈME

MEILLEURES DONNÉES PROBANTES

NIVEAU DE PREUVE

COMMENTAIRES

Mortalité toutes causes confondues

Autier et collab.,49 2007

Méta-analyse

300-833 UI/j; la mortalité étant un événement cible secondaire dans toutes les études sauf 1

Mortalité due au cancer

Lappe et collab.,50 2007

ERC

1 000 UI/j; 1 179 femmes en postménopause; supplément de calcium inclus

Fractures

Bischoff-Ferrari et collab.,51 2009

Méta-analyse

400-800 UI/j; selon la dose; 20 ERC; indépendamment du calcium

Force musculaire

Moreira-Pfrimer et collab.,53 2009

ERC

3 000-5 000 UI/j pendant 6 mois; population d’aînés

Chutes

Bischoff-Ferrari et collab.,53 2009

Méta-analyse

700-1 000 UI nécessaires; population d’aînés; 8 études

Cancer du côlon

Zhou et collab.,54 2009

Étude des données probantes

1 000 UI/j recommandées; 25 études incluses

Hypertension

Witham et collab.,55 2009

Méta-analyse

11 études; données faibles pour étayer une réduction de la TA

Diabète de type 1

Hyppönen et collab.,56 2001

Étude cas-témoin prospective

2 000 UI/j; 10 821 enfants; réduction du risque relatif de 0,22 durant la première année de vie

Psoriasis

Kreuter et collab.,57 2006

ERC

Calcipotriol topique équivalent aux stéroïdes topiques; 80 patients pendant 4 semaines

TA—tension artérielle, ERC—étude randomisée contrôlée

nécessaires pour les adolescents et les adultes afin de maintenir une masse osseuse adéquate, en particulier durant la grossesse. De récentes recommandations faites par le Food and Nutrition Board de l’Institute of Medicine des États-Unis sont présentées dans le Tableau 460. Selon les données scientifiques actuelles, ces doses ne semblent pas suffisantes61. Évidemment, toute décision d’augmenter les doses doit prendre en considération la toxicité potentielle. Heureusement, la marge de manœuvre pour maintenir l’innocuité semble large: des études sur des suppléments allant de 4 000 à 10 000 UI par jour ne causaient pas d’augmentation du calcium sérique ou urinaire ni d’effets indésirables3,62,63. On a signalé une augmentation des calculs dans les voies urinaires dans 5,7 cas par 10 000 participantes dans l’étude du Women’s Health Initiative, en dépit de suppléments à faible dose. Cette conclusion pourrait refléter le fait que la population à l’étude prenait de fortes doses de calcium34,64. Cependant, nous pourrions nous attendre à une incidence légèrement plus forte de calculs dans une population dont le régime est riche en vitamine D. Maintenir une carence en vitamine D semble cependant une mauvaise stratégie pour prévenir la colique néphrétique. Étant donné le ratio risques-avantages favorable, il semble raisonnable et assez conservateur de recommander de prendre un supplément de 1 000 à 2 000 UI par jour aux patients de plus de 1 an (Tableau 5). Les patients à risque plus élevé, comme les obèses, les malades chroniques ou les plus âgés, pourraient prendre 2 000 UI par jour 65,66.

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Les patients qui présentent une carence ou une insuffisance auront besoin de plus fortes doses pour atteindre les niveaux normaux de 25(OH)D. Il faut des doses accrues pour atteindre la réplétion, mais il importe peu que ces doses soient administrées par jour, par semaine ou par mois67,68. Le régime le mieux étudié est de donner 600 000 UI de vitamine D2 (qui est 60 % moins disponible que la vitamine D3 à fortes doses)5,67,69 sur une période de 8 semaines. La vitamine D2 est disponible en capsule de 50 000 UI. L’administration pourrait donc se faire à raison de 3 capsules de 50 000 UI aux 2 semaines à 4 reprises avant de réduire à une dose suffisante pour maintenir les taux. Étant donné que la vitamine D3 est maintenant aussi disponible en capsules de 50 000 UI, une stratégie semblable pourrait être utilisée, à dose moins élevée. On pourra ensuite faire le suivi des taux sériques. D’autres stratégies sont évidemment possibles, notamment l’administration intramusculaire.

Options offertes aux professionnels de la santé Deux approches existent pour prévenir les maladies: les stratégies individuelles ou populationnelles70. Les programmes axés sur la population, comme l’ajout de vitamine D dans les aliments ou la hausse des doses quotidiennes recommandées, apportent des bienfaits minimaux aux individus et sont très sensibles à des ratios risques-avantages étroits70. Avec un tel scénario, comme avec la vaccination, la réussite passe souvent sous silence. Par ailleurs, les programmes axés sur la •

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Atténuer la carence épidémique en vitamine D | Commentaire Tableau 4. Apport suffisant en vitamine D ÂGE, ans

DOSE SUFFISANTE RECOMMANDÉE

Naissance à 13

600 UI

14 à 18

600 UI

•

Grossesse ou allaitement

19 à 50 •

600 UI 600 UI

Grossesse ou allaitement

600 UI

51 à 70

600 UI

≥ 71

800 UI

Données de l’Office of Dietary Supplements, National Institutes of Health6

Tableau 5. Mise à jour proposée de l’apport suffisant en vitamine D fondée sur les meilleures données probantes ÂGE

DOSES SUFFISANTES SUGGÉRÉES

0-12 mois

400-800 UI

•

Au sud du 55 parallèle

400 UI

•

Au nord du 55e parallèle

800 UI

1 à 13 ans

1000-2000 UI

14 à 18 ans

1000-2000 UI

•

Grossesse ou allaitement

19 à 50 ans •

Grossesse ou allaitement

2000 UI 1000-2000 UI 2000 UI

51 à 70 ans

1000-2000 UI

≥ 71 ans

1000-2000 UI

population touchent l’étiologie de la maladie dans la population et revêtent une grande importance en santé publique. Les récentes lignes directrices reflètent une acceptation graduellement grandissante de meilleurs suppléments. Les récentes recommandations de l’Institute of Medicine des États-Unis au sujet de l’apport en vitamine D60 faisaient valoir que la plupart des Américains et des Canadiens, jusqu’à l’âge de 70 ans, n’avaient pas besoin de plus de 600 UI de vitamine D par jour pour se maintenir en santé, et que ceux de 71 ans et plus pourraient en avoir besoin de 800 UI. Ces doses sont encore très conservatrices. Dans la synthèse de plus de 1 000 études, des chercheurs ont trouvé que d’abondantes données scientifiques confirmaient le rôle de la vitamine D dans la santé des os et, si de nombreuses études soulignent d’autres possibilités qui auraient besoin d’être étudiées plus en profondeur, ces études ont donné des résultats contradictoires et mixtes et n’offrent pas les données probantes nécessaires pour confirmer que la vitamine D a d’autres effets sur la santé. Le nouveau guide de pratique clinique canadien pour la prise en charge de l’ostéoporose71 recommande de plus grandes doses, soit un supplément systématique de 400 à 1 000 UI par jour

pour les personnes à faible risque et jusqu’à 2 000 UI par jour pour celles à risque élevé. Jusqu’à ce qu’on fasse d’autres recherches et qu’une stratégie populationnelle plus appropriée soit mise en œuvre, les médecins en cabinet peuvent utiliser une approche individuelle ou selon le cas et identifier les patients les plus susceptibles, selon l’anamnèse, d’avoir une carence en vitamine D. Ces personnes pourraient avoir besoin d’une thérapie pour combler cette carence, tandis que les autres pourraient envisager des suppléments de maintien. Le dépistage par mesure des niveaux sériques serait rarement nécessaire à moins que ce soit pour un suivi thérapeutique ou la motivation du patient. Une intervention avec des suppléments de 1 000 à 2 000 UI par jour comporte une large marge de sécurité et le potentiel d’améliorer la santé de la personne est probablement considérable21,59,66. Cette mesure serait provisoire pour protéger nos patients jusqu’à la mise au point d’une stratégie plus adéquate à l’échelle de la population. Dr Bosomworth est professeur clinicien au Département de pratique familiale de l’University of British Columbia à Vancouver. Intérêts concurrents Aucun déclaré Correspondance Dr N.J. Bosomworth, 3413 Forsyth Dr, Penticton, BC V2A 8Z2; courriel john. bosomworth@interiorhealth.ca Les opinions exprimées dans les commentaires sont celles des auteurs. Leur publication ne signifie pas qu’elles sont sanctionnées par le Collège des médecins de famille du Canada. Références 1. Zitterman A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 2003;89(5):552-72. 2. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69(5):842-56. 3. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77(1):204-10. Erratum dans: Am J Clin Nutr 2003;78(5):1047. 4. Jablonski NG, Chaplin G. The evolution of human skin coloration. J Hum Evol 2000;39(1):57-106. 5. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357(3):266-81. 6. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988;67(2):373-8. 7. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005;135(2):317-22. 8. Wicherts IS, van Schoor NM, Boeke JP, Visser M, Deeg DJ, Smit J, et collab. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab 2007;92(6):2058-65. Cyberpub. 6 mars 2007. 9. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81(3):353-73. 10. Holick MF. The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action. Mol Aspects Med 2008;29(6):361-8. Cyberpub. 2 septembre 2008. 11. Seymour HM, Glendenning P. Fit for a fracture. Med J Aust 2005;183(4):213-4. 12. Brunner EJ, Jones PJ, Friel S, Bartley M. Fish, human health and marine ecosystem health: policies in collision. Int J Epidemiol 2009;38(1):93-100. Cyberpub. 2 août 2008. 13. Calvo MS, Whiting SJ. Are current dietary strategies in North America able to meet vitamin D needs in the absence of sun exposure? Toronto, ON: Société canadienne du cancer; 2006. Accessible à: www.cancer.ca/canada-wide/prevention/vitamin%20d/~/media/CCS/Canada%20wide/ Files%20List/English%20files%20heading/pdf%20not%20in%20publications%20section/Mona%20Calvo%20-%20pdf_899467559.ashx. Accédé le 13 mars 2008. 14. Allali F, El Aichaouli S, Saoud B, Maaroufi H, Abouqal R, Hajjaj-Hassouni N. The impact of clothing style on bone mineral density among post menopausal women in Morocco: a case-control study. BMC Public Health 2006;6:135-41. 15. Levi J, Segal LM, Julianno C. F as in fat: how obesity policies are failing in America, 2006. Washington, DC: Trust for America’s Health; 2006.

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Commentaire | Atténuer la carence épidémique en vitamine D 42. Wang L, Manson JE, Song Y, Sesso H. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010;152(5):315-23. 43. Dietrich T, Joshipura KJ, Dawson-Hughes B, Bischoff-Ferrari HA. Association between serum concentrations of 25-hydroxy D3 and periodontal disease in the US population. Am J Clin Nutr 2004;80(1):108-13. 44. Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, et collab. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol 2007;103(3-5):708-11. 45. Yin L, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis of longitudinal studies: serum vitamin D and prostate cancer risk. Cancer Epidemiol 2009;33(6):435-45. Cyberpub. 25 novembre 2009. 46. Grant WB, Boucher BJ. Current impediments to the ultraviolet-B-vitamin D-cancer hypothesis. Anticancer Res 2009;29(9):3597-604. 47. Gissel T, Rejnmark L, Mosekilde L, Vertergaard P. Intake of vitamin D and breast cancer—a meta-analysis. J Steroid Biochem Mol Biol 2008;111(3-5):1959. Cyberpub. 11 juin 2008. 48. Schwalfenberg G. Not enough vitamin D. Health consequences for Canadians. Can Fam Physician 2007;53:841-54. 49. Autier P, Gandini S. Vitamin D supplementation and total mortality. Arch Intern Med 2007;167(16):1730-7. 50. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85(6):1586-91. Erratum dans: Am J Clin Nutr 2008;87(3):794. 51. Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, et collab. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med 2009;169(6):551-61. 52. Moreira-Pfrimer LD, Pedrosa MA, Teixeira L, Lazaretti-Castro M. Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial. Ann Nutr Metab 2009;54(4):291-300. Cyberpub. 31 août 2009. 53. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, et collab. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. BMJ 2009;339:b3692. DOI: 10.1136/bmj.b3692. 54. Zhou G, Stoitzfus J, Swan BA. Optimizing vitamin D status to minimize colorectal cancer risk: an evidentiary review. Clin J Oncol Nurs 2009;13(4):E3-17. 55. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens 2009;27(10):1948-54. 56. Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth cohort study. Lancet 2001;358(9292):1500-3. 57. Kreuter A, Sommer A, Hyun J, Bräutigam M, Brockmeyer NH, Altmeyer P, et collab. 1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone in the treatment of intertriginous psoriasis. Arch Dermatol 2006;142(9):1138-43. 58. Goodwin PJ. Vitamin D in cancer patients: above all, do no harm. J Clin Oncol 2009;27(13):2117-9. Cyberpub. 6 avril 2009. 59. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006;84(1):18-28. Errata dans: Am J Clin Nutr 2006;84(5):1253 et Am J Clin Nutr 2007;86(3):809. 60. Ross CA, Taylor CL, Yaktine AL, Del Valle HB, rédacteurs. Dietary reference intakes for calcium and vitamin D. Washington, DC: Institute of Medicine; 2010. Accessible à: www.iom.edu/Reports/2010/Dietary-Reference-Intakesfor-Calcium-and-Vitamin-D.aspx. Accédé le 4 décembre 2010. 61. Vieth R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, et collab. The urgent need to recommend an intake of Vitamin D that is effective. Am J Clin Nutr 2007;85(3):649-50. Erratum dans: Am J Clin Nutr 2007;86(3):809. 62. Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr 2006;136(4):1117-22. 63. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007;85(1):6-18. 64. Cranney A, Horsley T, O’Donnell S, Weiler H, Puil L, Ooi D, et collab. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Rapport intégral) 2007;158:1-235. 65. Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: a global perspective. Ann Epidemiol 2009;19(7):468-83. 66. Cherniack EP, Levis S, Troen BR. Hypovitaminosis D: a widespread epidemic. Geriatrics 2008;63(4):24-30. 67. Pepper KJ, Judd SE, Nanes MS, Tangpricha V. Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. Endocr Pract 2009;15(2):95-103. 68. Ish-Shalom S, Segal E, Salganik T, Raz B, Bromberg IL, Vieth R. Comparison of daily, weekly, and monthly vitamin D3 in ethanol dosing protocols for two months in elderly hip fracture patients. J Clin Endocrinol Metab 2008;93(9):3430-5. Cyberpub. 10 juin 2008. 69. Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr 2006;84(4):694-7. 70. Rose G. Sick individuals and sick populations. Int J Epidemiol 2001;30(3):427-32. 71. Papaioannou A, Morin S, Cheung A, Atkinson S, Brown JP, Feldman S, et collab. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 2010;182(17):1864-73.

Accessible à: http://healthyamericans.org/reports/obesity2006/ Obesity2006Report.pdf. Accédé le 16 mars 2008. 16. Duncan MJ, Mummery WK, Steele RM, Caperchione C, Schofield G. Geographic location, physical activity and perceptions of the environment in Queensland adults. Health Place 2009;15(1):204-9. Cyberpub, 20 avril 2008. 17. Lehtonen-Veromaa MK, Möttönen TT, Nuotio IO, Irjala KM, Leino AE, Viikari JS. Vitamin D and attainment of peak bone mass among peripubertal Finnish girls: a 3-y prospective study. Am J Clin Nutr 2002;76(6):1446-53. 18. El-Hajj Fuleihan G, Nabulsi M, Tamim H, Maalouf J, Salamoun M, Khalife H, et collab. Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial. J Clin Endocrinol Metab 2006;91(2):405-12. Cyberpub. 8 novembre 2005. 19. Ward LM, Gaboury I, Ladhani M, Zlotkin S. Canadian Paediatric Surveillance Program. Vitamin D deficiency rickets among children living in Canada: a new look at an old disease. Présenté à la Conférence professionnelle de l’Association canadienne du diabète et de l’Association canadienne d’endocrinologie et métabolisme; 15 au 19 octobre 2003; Ottawa, ON. Accessible à: www.cps.ca/English/Surveillance/CPSP/Abstract/abstractRickets.htm. Accédé le 17 mars 2008. 20. Whiting SJ, Calvo MS. Dietary recommendations for vitamin D: a critical need for functional end points to establish an estimated average requirement. J Nutr 2005;135(2):304-9. 21. Bischoff-Ferrari HA. The 25-hydroxyvitamin D threshold for better health. J Steroid Biochem Mol Biol 2007;103(3-5):614-9. Cyberpub. 16 janvier 2007. 22. Comité sur la santé des Premières nations, des Inuits et des Métis, Société canadienne de pédiatrie. Vitamin D supplementation: recommendations for Canadian mothers and infants. Paediatr Child Health 2007;12(7):583-9. 23. Nakamura K, Nishiwaki T, Ueno K, Yamamoto M. Age-related decrease in serum 25-hydroxyvitamin D concentrations in the frail elderly: a longitudinal study. J Bone Miner Metab 2007;25(4):232-6. Epub 2007 Jun 25. 24. Ginde AA, Liu MC, Campargo CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med 2009;169(6):626-32. 25. Pérez-Castrillón JL, Vega G, Abad L, Sanz A, Chaves J, Hernandez G, et collab. Effects of atorvastatin on vitamin D levels in patients with acute ischemic heart disease. Am J Cardiol 2007;99(7):903-5. Cyberpub 8 février 2007. 26. Yavuz B, Ertugrul DT, Cil H, Ata N, Akin KO, Yalcin AA, et collab. Increased levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins? Cardiovasc Drugs Ther 2009;23(4):295-9. 27. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296(23):2832-8. 28. Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 2008;71(18):1390-5. Cyberpub. 4 juin 2008. 29. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, et collab. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004;363(9421):1607-8. 30. LaCroix AZ, Kotchen A, Anderson G, Brzyski R, Cauley JA, Cummings SR, et collab. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci 2009;64(5):559-67. Cyberpub. 16 février 2009. 31. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et collab. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354(7):669-83. Erratum dans: N Engl J Med 2006;354(10):1102. 32. De Boer IH, Tinker LF, Connelly S, Curb JD, Howard BV, Kestenbaum B, et collab. Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care 2008;31(4):701-7. Cyberpub. 30 janvier 2008. 33. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with Vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005;293(18):2257-64. 34. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int 2010;21(7):1121-32. Cyberpub 3 décembre 2009. 35. Calvo MS, Whiting SJ, Barton CN. Vitamin D intake: a global perspective of current status. J Nutr 2005;135(2):310-6. 36. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007;370(9588):657-66. 37. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 2006;166(8):869-75. 38. Straube S, Moore RA, Derry S, McQuay HJ. Vitamin D and chronic pain. Pain 2009;141(1-2):10-3. Cyberpub. 11 décembre 2008. 39. Annweiler C, Allali G, Allain P, Bridenbaugh S, Schott AM, Kressig RW, et collab. Vitamin D and cognitive performance in adults: a systematic review. Eur J Neurol 2009;16(10):1083-9. Cyberpub. 29 juillet 2009. 40. Yamshchikov AV, Desai MS, Blumberg HM, Ziegler TR, Tangpricha V. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract 2009;15(5):438-49. 41. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, et collab. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med 2010;152(5):307-14.

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Letters | Correspondance Nonseptic olecranon bursitis management

read with some concern Lockman’s article on the treatment of nonseptic bursitis.1 Although Smith and colleagues2 confirmed his results, noting the superiority of intrabursal methylprednisolone acetate over oral naproxen or placebo at 6 months, with faster resolution and less reaccumulation of fluid with the steroid injection, this is not a benign procedure, despite Dr Lockman’s remarkably low rate of complications. I have practised throughout my career as an emergency physician and undoubtedly have a very biased view, insofar as I tend to see the treatment failures and complications in the emergency department, and never see the legions of happy patients who have been successfully treated by their family doctors. However, while I have not kept such impeccable records as Dr Lockman, I would estimate that between two-thirds and threequarters of all the patients with septic olecranon bursitis I have seen in the emergency department over the years (and they probably number in the hundreds) gave a history of their family doctor having “drained” their olecranon bursitis within the previous 2 days. Indeed, no other joint injection or aspiration appears to me to involve such considerable risk of introducing infection into what was a sterile environment. My own experience is borne out by Söderquist and Hedström,3 who noted an infection rate of up to 10% following bursal injection of corticosteroids. Given this, I would suggest that, at an absolute minimum (if the clinician is still bent on performing the procedure), full sterile skin preparation, surgical draping, and aseptic technique is necessary, with potent antiseptics such as povidone, followed by alcohol, in the same manner one would prepare for a lumbar puncture. Swiping the skin with an alcohol swab is wholly inadequate. I am also somewhat concerned by the description of the procedure, in which the bursa is first drained, followed by injection of steroid and lidocaine “into the elbow joint from a lateral approach.”1 The olecranon bursa is extra-articular; it does not communicate with the elbow joint. It is unclear from the description as to whether the injection is being made into the bursa (in which case the best approach is probably parallel to the forearm bones), or rather is truly being made into the elbow joint itself, in which case the lateral approach is entirely appropriate, but the mechanism of the anticipated benefit is less clear. The usual case of barfly elbow (or student’s elbow), presumably occasioned by the repeated minor trauma of resting the elbows on a hard surface, is entirely benign and will eventually resolve on its own if the patient stops the precipitating activity. Given the lack of adverse consequences associated with “benign neglect,” and the

clear risk of substantial harm consequent upon breaching the sterile environment, my own bias is towards primum non nocere. —David M. Maxwell MD CCFP(EM) LM Middle LaHave, NS References 1. Lockman L. Treating nonseptic olecranon bursitis. A 3-step technique. Can Fam Physician 2010;56:1157. 2. Smith DL, McAfee JH, Lucas LM, Kumar KL, Romney DM. Treatment of nonseptic olecranon bursitis. A controlled, blinded prospective trial. Arch Intern Med 1989;149:2527-30. 3. Söderquist B, Hedström SA. Predisposing factors, bacteriology and antibiotic therapy in 35 cases of septic bursitis. Scand J Infect Dis 1986;18(4):305-11.

Developmental disability application

found the research of Stewart and colleagues on integrating physician services in the home1 to be interesting and encouraging. There is always more than 1 way (and sometimes a better way) of doing things. We are looking for a better way of caring for our adults with developmental disabilities, especially the ones who have difficulty transitioning to adult care because of the complexity of their health issues. I was very encouraged by the program that the authors were able to develop. The outstanding features were the interest shown by the family doctors in the community, the support offered by the specialist, and the funding obtained for the nurse practitioner and medical coordinator. These are all challenges we are currently facing. I would be interested if the authors or others with similar successes have any practical advice on how such challenges can be tackled. —Karen A. Clarke MD CCFP FCFP Halifax, NS

Reference 1. Stewart M, Sangster JF, Ryan BL, Hoch JS, Cohen I, McWilliam CL, et al. Integrating Physician Services in the Home. Evaluation of an innovative program. Can Fam Physician 2010;56:1166-74.

The top 5 articles read online at cfp.ca 1. Clinical Review: Approach to assessing fitness to drive in patients with cardiac and cognitive conditions (November 2010) 2. Tools for Practice: Treating hypertension in the very elderly (November 2010) 3. Emergency Files: Anaphylaxis. A review and update (October 2010) 4. Clinical Review: Office management of urinary incontinence among older patients (November 2010) 5. Child Health Update: Use of dexamethasone and prednisone in acute asthma exacerbations in pediatric patients (July 2009)

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Letters | Correspondance

Support for home care

s a palliative care physician who cares for dying patients at home, I was struck by a few points in the project to integrate physician services in the home.1 One is the pivotal role of the nurse practitioner. Home care is extremely complex, and I think that without a dedicated manager such as a nurse practitioner, it is too much to ask of a busy family physician. Second, I was interested in the comments on cost; we often assume that home care is cheaper than hospital care (reduced use of acute care beds and emergency department visits), but Stewart and colleagues point out that this is not necessarily the case. I think it would be interesting to put some numbers to this, as that is likely to be the most telling argument for obtaining funding for these kinds of projects. Another point is that caregiver burden was not decreased in the group participating in the program, which is something I have noticed anecdotally. There seems to be considerable stress on caregivers of patients receiving in-home care that no amount of home visits can take away. I wonder if this is because caregivers feel that the ultimate responsibility for their loved ones’ well-being lies with them if they are at home, but not if they are in hospital. —Julia A. Wildish MD CCFP Quispamsis, NB

Correction

he incorrect correspondence information was provided in the Case Report, “Inadvertent use of a levonorgestrel-releasing intrauterine device as postcoital contraception,” which appeared in the December 2010 issue.1 The correct information is as follows: Correspondence Dr Adam Newman, Street Health Centre, 235 Wellington St, Kingston, ON K7K 0B5; telephone 613 549-1440; e-mail adamn@nkchc.kchc.ca

Canadian Family Physician apologizes for any inconvenience this might have caused. Reference 1. Newman A. Inadvertent use of a levonorgestrelreleasing intrauterine device as postcoital contraception. Can Fam Physician 2010;56:1301-2.

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PRISTIQ is indicated for the symptomatic relief of major depressive disorder. The short-term efficacy of PRISTIQ (desvenlafaxine succinate extended-release tablets) has been demonstrated in placebo-controlled trials of up to 8 weeks. The most commonly observed adverse events associated with the use of PRISTIQ (at an incidence 5% and at least twice the rate of placebo) were nausea (22%), dizziness (13%), hyperhidrosis (10%), constipation (9%), and decreased appetite (5%). PRISTIQ is not indicated for use in children under the age of 18. PRISTIQ is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs, including linezolid, an antibiotic) or in patients who have taken MAOIs within the preceding 14 days due to risk of serious, sometimes fatal, drug interactions with selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) treatment or with other serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Based on the half-life of desvenlafaxine succinate, at least 7 days should be allowed after stopping desvenlafaxine succinate and before starting an MAOI. PRISTIQ is contraindicated in patients demonstrating hypersensitivity to desvenlafaxine succinate extendedrelease, venlafaxine hydrochloride or to any excipients in the desvenlafaxine formulation. Concomitant use of PRISTIQ with products containing venlafaxine is not recommended. Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicide ideation and behaviour over that of placebo. The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among the drugs in the class. There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type events that include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression and depersonalization. In some cases, the events occurred within several weeks of starting treatment. Rigorous clinical monitoring for suicide ideation or other indicators of potential for suicide behaviour is advised in patients of all ages, especially when initiating therapy or during any change in dose or dosage regimen. This includes monitoring for agitation-type emotional and behavioural changes. Patients currently taking PRISTIQ should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose, rather than an abrupt cessation is recommended. Reference: 1. Wyeth Canada. PRISTIQ Product Monograph, August 2009. Product Monograph available upon request. PRISTIQ® ® Wyeth, owner, now a part of Pfizer Inc.

Count on

for powerful symptom relief

Canadian Family Physician • Le Médecin de famille canadien

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The colour of relief in major depressive disorder1

Count on

for powerful symptom relief See prescribing summary on page 100

EVEN WHEN ECZEMA PATIENTS ARE FLARE-FREE

ECZEMA FLARES CAN BE

NEW INDICATION PROTOPIC: The First and Only TCI Indicated for Maintenance Therapy to Prevent Flares and Prolong Flare-Free Intervals in Patients with Moderate to Severe Atopic Dermatitis Who are: Experiencing a high frequency of flares (i.e., occurring â&#x2030;Ľ5 times per year) and Who have had an initial response (i.e., lesions cleared, almost cleared or mildly affected) with up to 6 weeks of treatment with twice daily Protopic TCI=Topical Calcineurin Inhibitor.

TWICE-WEEKLY PROTOPIC. DEMONSTRATED TO HELP PREVENT ECZEMA FLARES.1

WAITING BELOW THE SURFACE

142*

Twice-Weekly 0.1% Protopic Maintenance Therapy (n=80) Twice-Weekly Vehicle Maintenance Therapy (n=73)

15*

DAYS TO FIRST FLARE

(p‹0.001)

DAYS TO FIRST FLARE

*Median time to first disease exacerbation (DE) requiring substantial intervention in adult patients.

New twice-weekly maintenance treatment to prevent eczema flares

Protopic® (tacrolimus ointment), both 0.03% and 0.1% for adults and only 0.03% for children aged 2 to 15 years, is indicated as a second-line therapy for short and long-term intermittent treatment of moderate to severe atopic dermatitis in non-immunocompromised patients, in whom the use of conventional therapies are deemed inadvisable because of potential risks, or who are not adequately responsive to or intolerant of conventional therapies. If signs and symptoms of atopic dermatitis do not improve within 6 weeks of twicedaily treatment, Protopic treatment should be discontinued and patients should be re-examined by their healthcare provider and their diagnosis be confirmed. There should be 2 to 3 days between twice-weekly maintenance applications of Protopic. After 12 months, a review of the patient`s condition should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data for maintenance treatment beyond 12 months. Long-term safety of topical calcineurin inhibitors has not been established. Although a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including Protopic ointment 0.1% and 0.03%. Therefore, continuous long-term use of topical calcineurin inhibitors including Protopic ointment 0.1% and 0.03% should be avoided, and application limited to areas of involvement with atopic dermatitis. Protopic ointment is not indicated in children less than 2 years of age. Only 0.03% Protopic ointment is indicated for use in children 2-15 years of age. The use of Protopic may cause local symptoms of short duration, such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of Protopic application and typically resolve as the lesions of atopic dermatitis heal. The nature and incidence of adverse events for maintenance therapy were consistent with the established safety profile of Protopic. The most common adverse events reported in Protopic maintenance clinical trials were application-site pruritus (17.5%, 15.4%), nasopharyngitis (13.8%, 38.5%) and headache (11.3%, 5.1%) in adult and pediatric patients who received 0.1% Protopic and 0.03% Protopic, respectively. There may also be an increased risk of varicella zoster virus infection, herpes simplex virus infection, or eczema herpeticum. In clinical studies, cases of lymphadenopathy were usually related to infections and resolved with antibiotic therapy. Patients who develop lymphadenopathy should be monitored to ensure that it resolves. Patients should be advised to minimize or avoid natural or artificial sunlight exposure. Protopic has not been studied for its efficacy and safety in the treatment of clinically infected atopic dermatitis. Please see Product Monograph for more information.

Seeprescribing prescribingsummary summaryand andstudy study See parameterson onpage pagexxx xxx parameters 115

Clinical Review | Environment and Health Series

Healthy fish consumption and reduced mercury exposure Counseling women in their reproductive years Alan Abelsohn MB CHB CCFP FCFP Loren D. Vanderlinden Josephine A. Archbold MSC Tara L. Brown MHSC RD

PHD

Fran Scott

MD CCFP FRCPC MSC

Abstract Objective To provide family physicians with a practical, evidence-based approach to counseling women about healthy fish eating. Sources of information MEDLINE was searched for articles published between 1999 and 2008. Most studies described in this article provide level II or III evidence. Main message Fish is an important component of a healthy diet for women in their reproductive years owing to the beneficial effects of omega-3 fatty acids on the neurologic development of the fetus. However, some fish species contain considerable methylmercury, which crosses the placenta and has harmful effects on neurobehavioural development. As many jurisdictions have issued fish consumption advisories, which can be confusing, women would benefit from individualized assistance from a trusted source, their family physicians, to clarify the risks and benefits of eating fish. Conclusion We recommend that family physicians counsel women in their reproductive years about healthy choices regarding fish in their diet, and provide appropriate resources.

Résumé Objectif Proposer au médecin de famille une méthode fondée sur des preuves pour conseiller les femmes au sujet d’une consommation saine de poisson. Sources de l’information On a cherché dans MEDLINE les articles publiés entre 1999 et 2008. La plupart des études décrites dans cet article possédaient des preuves de niveaux II et III. Principal message Le poisson est une composante importante d’une alimentation saine pour les femmes en âge de procréer, en raison des effets bénéfiques des acides gras oméga-3 sur le développement neurologique du fœtus. Toutefois, certains poissons contiennent des quantités considérable de mercure, lequel traverse la barrière placentaire et a des effets nocifs sur le développement neurocomportemental. Comme plusieurs organismes ont émis des avertissements au sujet de la consommation de poisson, créant ainsi une certaine confusion, il serait avantageux que les femmes bénéficient d’une assistance individualisée de la part d’une source fiable comme leurs médecins de famille afin de mieux comprendre les risques et avantages de la consommation de poisson. Conclusion Nous sommes d’avis que le médecin de famille doit conseiller les femmes en âge de procréer sur les choix sains concernant leur consommation de poisson en plus de leur fournir les ressources appropriées.

This article has been peer reviewed. Cet article a fait l’objet d’une révision par des pairs. Can Fam Physician 2011;57:26-30 26

Canadian Family Physician t Le Médecin de famille canadien

KEY POINTS Women should be encouraged to eat at least 2 servings a week of high–omega-3, low-mercury fish. Family physicians can play an important role in counseling women in their reproductive years about healthy consumption of fish, and they can provide appropriate resources. A patient handout is provided, which offers accessible advice on what fish can be eaten how often and high-mercury species to avoid or eat rarely. Because of the benefits of fish consumption, family physicians need to support individual awareness and behaviour shifts so benefits and risks are balanced. POINTS DE REPÈRE On devrait encourager les femmes à manger au moins 2 portions par semaine de poisson riche en oméga-3 et pauvre en mercure. Le médecin de famille peut jouer un rôle important pour conseiller les femmes en âge de procréer au sujet d’une consommation saine de poisson et pour leur fournir des ressources appropriées. Il existe un document à distribuer aux patients, qui offre des avis à la portée de tous sur les poissons qu’on peut consommer et à quelle fréquence, et sur les espèces à haute teneur en mercure qu’il faut éviter ou manger rarement.. Parce qu’il y a avantage à consommer du poisson, le médecin de famille doit être un agent de prise de conscience individuelle et de changements de comportement afin de trouver un équilibre entre les avantages et les risques.

This article is eligible for Mainpro-M1 credits. To earn credits, go to www.cfp.ca and click on the Mainpro link.

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Healthy fish consumption and reduced mercury exposure | Clinical Review Case description At her annual physical examination, a 28-year-old university student says that she is to be married next year, when she wants to go off the pill and try to conceive. She lives at home with her parents, immigrants to Canada from Hong Kong. She eats a tuna submarine sandwich for lunch at least 3 days a week at school and has sushi once a week. She also eats fish with her family approximately 3 times a week. She has read an article suggesting that she might be eating too much fish. How would you counsel her about fish eating and pregnancy?

Fish is a healthy dietary choice for women in their reproductive years, with health benefits for their future children, but there is concern that mercury in some fish species could harm a developing fetus. Preconception and prenatal visits offer effective opportunities for family physicians to improve maternal and child health.1 It is a challenge to offer clear, practical advice on the benefits and risks of fish consumption, as the evidence is complex and at times uncertain. To ensure that this advice is useful and not detrimental, it must be individualized, especially in ethnically diverse urban Canada. Two streams of evidence inform this debate. The first concerns the fetal health and developmental benefits of omega-3 fatty acids from maternal fish consumption. The second concerns the neurotoxicity to the fetal brain of mercury found in some commonly eaten fish species.

Sources of information MEDLINE was searched using terms relevant to each section of the article. Search terms included fish consumption, methylmercury, prenatal exposure, neurotoxicology, child development, developmental outcomes, and omega-3 fatty acids. Articles published between January 1999 and October 2008 were reviewed. Most studies provided level II (cohort or case-controlled epidemiologic studies) or III (expert opinion and consensus statements) evidence. Government websites were searched for relevant material on fish advisories and toxicologic profiles. We recommend a resource developed by Toronto Public Health, in consultation with other public health units in southern Ontario, based on a 2006 technical report that extensively reviewed the relevant evidence.2

Main message Health benefits of eating fish. The health benefits of eating fish are related to the presence in fish of 2 longchain omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Besides being obtained directly from fish, both DHA and EPA can be derived from a plant-based omega-3 fatty acid, α-linolenic acid (ALA); ALA is an essential fatty acid that cannot be synthesized by the body, so dietary sources are required. Fish in the mother’s diet is thought to provide the optimal source of

DHA and EPA, as the fetus and infant appear to have limited ability to synthesize DHA from dietary ALA.3 Health benefits for pregnancy. Docosahexaenoic acid is incorporated into the brain and retinal tissues during fetal development and into the developing human brain for the first 2 years of life. Randomized controlled trials of DHA-enriched infant formula demonstrate a modest positive effect on intelligence quotient, which is more pronounced in premature infants (level I evidence). 4 The relationship between maternal fish consumption during pregnancy and the child’s long-term cognitive development has recently been studied in cohorts in the United States and United Kingdom.5,6 In general, beneficial effects on child cognitive development were found when mothers ate fish for more than 2 meals per week. Prenatal dietary requirement for DHA. There has been much debate in the literature concerning the prenatal dietary requirement for DHA.7,8 A recent consensus statement confirms the importance of DHA in the maternal diet, and recommends that pregnant and lactating women consume at least 200 mg of DHA daily.9 Citing a lack of intervention studies and conflicting results from observational studies, Motherisk concluded in 2007 that until evidence accumulated, clinicians should not encourage women to take omega-3 fatty acid supplements during pregnancy.10 In recently released prenatal nutrition guidelines, Health Canada states that fish oil supplements should not be considered equivalent to eating fish, and recommends that a food-based approach should be emphasized for women who do not eat fish.11 Mercury in fish and its health effects. Fish consumption is the main source of exposure to methylmercury, which is bound to protein in the muscle of the fish.12,13 It is almost completely absorbed from the gastrointestinal tract, accumulates in the mother’s body, and is transferred across the placenta and the fetal blood-brain barrier.14 Levels in cord blood are approximately 1.7 times higher than in maternal blood,15,16 and levels in the fetal brain are higher than in the mother.17 Levels in breast milk, on the other hand, are substantially lower than in maternal blood. At high doses, methylmercury is neurotoxic to adults. Evidence of the effects on the developing fetal brain of lower doses of methylmercury (from fish in the maternal diet or from maternal body stores) comes from both animal and human studies.17 Animal models of in utero exposure indicate dose-related deficits in sensory, motor, and cognitive neurodevelopment in exposed offspring. Evidence in humans derives mainly from 3 longitudinal cohort studies of fish-eating populations, studies that reached conflicting results (Table 1).17-23 These divergent findings have been variously explained in terms of

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Clinical Review | Healthy fish consumption and reduced mercury exposure Table 1. Main studies exploring health effects of low-dose prenatal mercury exposure STUDY LOCATION

DETAILS

ASSOCIATIONS WITH PRENATAL MERCURY EXPOSURE

Faroe Islands18,19

More than 900 mother-child pairs; diet included PCB exposure (whale meat), but analyses controlled for PCBs

Memory, language, and attention deficits at age 7; fine motor, attention, visual-spatial, and verbal skill deficits at age 14

New Zealand20

237 mother-infant pairs; varying fish consumption patterns during pregnancy (low to high)

Reduced performance in scholastic and psychological tests during early school years

Seychelles Islands21,22

779 mother-infant pairs; approximately 12 fish meals a week on average during pregnancy

Pilot study showed lower Denver Developmental Screening Test scores; main study showed no delays in developmental milestones or deficits in neurodevelopmental tests

PCB—polychlorinated biphenyl.

differences in dietary composition as it relates to fish species, patterns of neurotoxicant intake, dietary intakes of “protective” omega-3 fatty acids and selenium, and possible genetic differences among the different populations studied.17,24 The Harvard Center for Risk Analysis23 estimated that prenatal mercury exposure that raises maternal hair mercury measured at birth by 1 µg/g reduces intelligence quotient by 0.7 points in the exposed child. This finding, although not clinically observable in individual patients, would have considerable societal effects at the population level.25 “Safer” levels of mercury: intake and tissue levels. There are no consistent guidelines for an “acceptable” or “tolerable” level of mercury for the developing brain.12 Health Canada has recently developed a provisional interim blood guidance value of 8 µg/L based on the existing provisional tolerable daily intake of 0.2 µg/kg daily for children, pregnant women, and women of childbearing age.26 Brodkin et al14 recommend that at blood mercury levels of 10 µg/L (50 nmol/L), the source of exposure to mercury should be assessed and reduced. The US Environmental Protection Agency (US EPA)27 set the reference dose (RfD) at 0.1 µg/kg daily, equivalent to a maternal blood mercury level of 5.8 µg/L (29 nmol/L).17 Mergler and colleagues point out, however, that in the risk assessment upon which the US EPA’s RfD is based, the US National Research Council used cord blood mercury measures and did not account for the bioconcentration of methylmercury across the placenta when determining a maternal reference blood mercury level.16 Mahaffey and colleagues suggest, therefore, that maternal blood mercury levels exceeding the range of values from 3.5 µg/L (15 nmol/L) to 5.8 µg/L (29 nmol/L) should be the reference point for preventing fetal neurotoxicity.28 A recent Motherisk systematic review of the literature identified 0.3 µg/g of hair mercury to be the lowest observable adverse effect level for adverse effects on child neurodevelopment resulting from fetal exposure.29 Motherisk advises that hair

Canadian Family Physician t Le Médecin de famille canadien

analysis of high fish-consuming populations might be warranted before pregnancy, as dietary modifications can decrease body burden of mercury.30 Mercury in fish. Mercury in the environment can come from natural sources, but anthropogenic emissions have increased environmental mercury by a factor of 2 to 4.31 Atmospheric mercury is converted by bacteria in lakes into organic methylmercury, which is taken up by microorganisms, such as plankton, in water. It is then biomagnified, being found at highest concentrations in longer-living and larger predatory fish species at the top of the aquatic food chain,31 including tuna, shark, swordfish, marlin, orange roughy, and escolar.32 Mercury levels also vary with the age and size of fish, the water body from which they originate, and even the season of capture. Species such as salmon, herring, sardines, Arctic char, Atlantic mackerel, and rainbow trout are lower in mercury and high in omega-3 fatty acids.33 Health Canada has set a regulatory limit, banning the sale of fish containing more than 0.5 ppm of total mercury, except for the predatory high-mercury fish listed above, for which a new limit of 1 ppm has recently been set.32 In a survey of fish from retail outlets in Vancouver, BC, Toronto, Ont, and Halifax, NS, mercury was found in all samples; the highest concentrations were found in swordfish, followed by shark, fresh tuna, and marlin.34

Table 2. Tuna as a source of mercury FOOD SOURCE

SPECIES

MERCURY CONTENT

Fresh or frozen tuna, including sushi tuna and tuna steaks

Larger species

Higher

Canned white tuna

Albacore species

Intermediate

Canned light tuna

Smaller species such as skipjack, yellowfin, and tongol

Lower

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Healthy fish consumption and reduced mercury exposure | Clinical Review Tuna deserves special mention, as it is so widely available and it is an economical protein source (Table 2). Exposure from eating fish: groups at higher risk. Average levels of mercury in the diet of a representative sample of Canadian adults and children were found to be low and below Health Canada guideline levels.35 The dietary intake estimates, however, were based on data from a 1977 Nutrition Canada survey, and consumption practices have likely changed over the past 3 decades. Other Canadian studies have documented higher methylmercury exposure in subgroups with higher fish consumption, such as anglers fishing in the Great Lakes in Ontario (with levels higher in Asian Canadians than in Canadians of European descent),36 Chinese-Canadian schoolchildren in Vancouver,37 and residents of the Canadian Arctic, where 3% of Inuit maternal blood and 56% of umbilical cord blood samples contained methylmercury levels above the 5.8 µg/L (29 nmol/L) reference level.38 Preliminary data from the 2007 to 2008 Canadian Health Measures Survey39 indicate that Canadian blood mercury levels might be slightly higher or about the same as those of the American general population. Data are not currently available for the upper percentiles, which would provide an estimate of blood mercury for those who consume large amounts of fish. Recent data from the US National Health and Nutrition Examination Survey40 indicated that blood mercury levels and fish consumption were higher in women living within 40 to 80 km of the Great Lakes, Asian women, and higherincome women, with more than 3 million American women (4.7%) estimated to have blood mercury levels exceeding 5.8 µg/L (29 nmol/L).28 The average mercury levels of adult women in New York City, NY, were more than 3 times those found in a national study. New Yorkers of Asian descent had higher blood mercury than did other racial or ethnic groups.41 Fish consumption advisories and advice. Fish consumption advice and advisories have been issued in many jurisdictions.32,42-44 The fish consumption advice issued by Toronto Public Health 33 (summarized in a patient handout available from CFPlus*) deserves highlighting for 2 reasons. First, the risk calculations are based on the US EPA RfD,27 a more conservative measure than Health Canada’s provisional tolerable daily intake.26 We consider this caution appropriate in a country with diverse population groups, many of which consume large amounts of fish for cultural reasons. Second, it identifies what fish species are the best choices and how often and in what quantity they can

CFPlus GO

*A patient handout is available at www.cfp.ca. Go to the full text of the article online, then click on CFPlus in the menu at the top right of the page.

be eaten, rather than simply advising vulnerable groups to limit high-mercury fish. This is important, in light of research demonstrating that pregnant women might respond to fish advisories warning about the intake of high-mercury fish by reducing or eliminating fish intake.45 The Toronto Public Health resource33 lists more than 80 species of fish commonly found in stores or fish markets in Canada and recommends eating a variety of fish. It also lists species caught or raised in environmentally unsustainable ways and provides a list of fish species that can be safely eaten every day, which is helpful for providing guidance to those subpopulations that consume large amounts of fish. Environment Canada provides a listing of provincial and territorial advisories46 for anglers who catch and eat their own freshwater sport fish. These fish could contain higher levels of mercury and other contaminants such as polychlorinated biphenyls. Resources. The fish consumption resources detailed in the handout* give accessible advice on what fish can be eaten how often, the number of servings per week for each age group, and the species of fish to avoid or eat rarely. A summary in the form of a wallet card is also available from Toronto Public Health.33 Referral to a registered dietitian is recommended if there are more detailed dietary issues. Families who catch and eat their own fish should be directed to sport fishing advisories.46

Case resolution Women who eat fewer than 2 servings of fish a week, as recommended by Canada’s Food Guide,47 should be encouraged to eat at least 2 servings a week of high–omega-3, low-mercury fish. The woman in our case ate approximately 7 servings of fish a week. She was encouraged to continue to eat fish but counseled on shifting to a variety of high–omega-3, low-mercury fish (see patient handout*), bearing in mind the family’s cultural dietary practices. Should her blood mercury level be tested? A blood mercury test is unnecessary in the clinical management of this case. The half-life of methylmercury in the blood averages approximately 70 days,14 so even if her level is elevated, with dietary changes for approximately 3 months her blood level and risk would be expected to drop accordingly. There are no guidelines as to when to test or what is an “acceptable” blood mercury level. However, we suggest that 5.8 µg/L (29 nmol/L) be considered the level to guide discussions for counseling women in their reproductive years who consume large amounts of fish.

Conclusion Although the ultimate “upstream” societal solution should be to reduce mercury discharges into the environment, family physicians can play an important

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Clinical Review | Healthy fish consumption and reduced mercury exposure role in counseling women in their reproductive years about healthy choices for fish consumption, and they can provide appropriate resources. Because of the benefits associated with fish consumption, we need to support individual awareness and a behaviour shift such that benefits and risks are better balanced. Dr Abelsohn is Assistant Professor in the Department of Family and Community Medicine and the Dalla Lana School of Public Health at the University of Toronto in Ontario. Dr Vanderlinden is Supervisor of Environmental Health Assessment and Policy for the Healthy Public Policy Directorate of Toronto Public Health and Assistant Professor in the Dalla Lana School of Public Health. Dr Scott is Associate Professor at the Dalla Lana School of Public Health. Ms Archbold is Research Consultant for the Healthy Public Policy Directorate of Toronto Public Health. Ms Brown is Nutrition Promotion Consultant for the Healthy Living, Chronic Disease Prevention Directorate of Toronto Public Health. Acknowledgment We thank the Toronto Public Health Fish Working Group for their important contributions. Contributors All authors contributed to the literature review and preparing the manuscript for submission. Competing interests Dr Abelsohn is funded by Canadian Institutes of Health Research grant number IOP-44972. Correspondence Dr Alan Abelsohn, 205-1466 Bathurst St, Toronto, ON M5R 3S3; telephone 416 483-8111; fax 416 483-8182; e-mail alan.abelsohn@utoronto.ca References 1. Atrash HK, Johnson K, Adams M, Cordero JF, Howse J. Preconception care for improving perinatal outcomes: the time to act. Matern Child Health J 2006;10(5 Suppl):S3-11. Epub 2006 Jun 14. 2. Vanderlinden L, Law M, Archbold J, Cook B, Fordham J. Fish consumption: benefits and risks for women in childbearing years and young children—summary report. Toronto, ON: Toronto Public Health; 2006. Available from: www.toronto.ca/ health/hphe/pdf/boh_fish_mercury.pdf. Accessed 2009 Oct 30. 3. Innis SM. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J Pediatr 2003;143(4 Suppl):S1-8. 4. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics 2003;111(1):e39-44. 5. Oken E, Radesky JS, Wright RO, Bellinger DC, Amarasiriwardena CJ, Kleinman KP, et al. Maternal fish intake during pregnancy, blood mercury levels, and child cognition at age 3 years in a US cohort. Am J Epidemiol 2008;167(10):1171-81. Epub 2008 Mar 18. 6. Hibbeln JR, Davis JM, Steer C, Emmett P, Rogers I, Williams C, et al. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study. Lancet 2007;369(9561):578-85. 7. Food and Nutrition Board; Institute of Medicine of the National Academies [website]. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. Washington, DC: National Academies Press; 2002. Available from: www.nap.edu/catalog.php?record_id=10490#toc. Accessed 2005 Apr 13. 8. Von Schacky C, Harris WS, Mozaffarian D, Kris-Etherton PM. Response to Hooper et al Cochrane Review. International Society for the Study of Fatty Acids and Lipids; 2006. Available from: www.issfal.org.uk/index.php/lipid-matters-mainmenu-8/hooper-rebuttal-mainmenu-38. Accessed 2009 Oct 30. 9. Koletzko B, Lien E, Agostoni C, Böhles H, Campoy C, Cetin I, et al. The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations. J Perinat Med 2008;36(1):5-14. 10. Dubnov-Raz G, Finkelstein Y, Koren G. ω-3 fatty acid supplementation during pregnancy. For mother, baby, or neither? Can Fam Physician 2007;53:817-8. 11. Health Canada. Prenatal nutrition guidelines for health professions. Fish and omega-3 fatty acids. Ottawa, ON: Health Canada; 2009. Available from: www. hc-sc.gc.ca/fn-an/alt_formats/hpfb-dgpsa/pdf/pubs/omega3-eng.pdf. Accessed 2009 Nov 1. 12. Mahaffey KR. Fish and shellfish as dietary sources of methylmercury and the omega-3 fatty acids, eicosahexaenoic acid and docosahexaenoic acid: risks and benefits. Environ Res 2004;95(3):414-28. 13. Ruxton CH, Reed SC, Simpson MJ, Millington KJ. The health benefits of omega-3 polyunsaturated fatty acids: a review of the evidence. J Hum Nutr Diet 2004;17(5):449-59. 14. Brodkin E, Copes R, Mattman A, Kennedy J, Kling R, Yassi A. Lead and mercury exposures: interpretation and action. CMAJ 2007;176(1):59-63. 15. Stern AH, Smith AE. An assessment of the cord blood:maternal blood methylmercury ratio: implications for risk assessment. Environ Health Perspect 2003;111(12):1465-70. 16. Mergler D, Anderson HA, Chan LH, Mahaffey KR, Murray M, Sakamoto M, et al. Methylmercury exposure and health effects in humans: a worldwide concern. Ambio 2007;36(1):3-11.

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17. National Research Council. Toxicological effects of methylmercury. Washington, DC: National Academy Press; 2000. 18. Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K, et al. Cognitive deficits in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 1997;19(6):417-28. 19. Debes F, Budtz-Jørgensen E, Weihe P, White RF, Grandjean P. Impact of prenatal methylmercury exposure on neurobehavioral function at age 14 years. Neurotoxicol Teratol 2006;28(3):363-75. Epub 2006 May 2. 20. Crump KS, Kjellström T, Shipp AM, Silvers A, Stewart A. Influence of prenatal mercury exposure upon scholastic and psychological test performance: benchmark analysis of a New Zealand cohort. Risk Anal 1998;18(6):701-13. 21. Myers GJ, Davidson PW, Cox C, Shamlaye CF, Palumbo D, Cernichiari E, et al. Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet 2003;361(9370):1686-92. 22. Huang LS, Cox C, Myers GJ, Davidson PW, Cernichiari E, Shamlaye CF, et al. Exploring nonlinear association between prenatal methylmercury exposure from fish consumption and child development: evaluation of the Seychelles child development study: nine-year data using semiparametric additive models. Environ Res 2005;97(1):100-8. 23. Cohen JT, Bellinger DC, Shaywitz BA. A quantitative analysis of prenatal methyl mercury exposure and cognitive development. Am J Prev Med 2005;29(4):353-65. 24. Rice DC, Schoeny R, Mahaffey K. Methods and rationale for derivation of a reference dose for methyl mercury by the US EPA. Risk Anal 2003;23(1):107-15. 25. Bellinger DC. Interpretation of small effect sizes in occupational and environmental neurotoxicology: individual versus population risk. Neurotoxicology 2007;28(2):245-51. Epub 2006 May 22. 26. Legrand M, Freeley M, Tikhonov C, Schoen D, Li-Muller A. Methylmercury blood guidance levels for Canada. Can J Public Health 2010;101(1):28-31. 27. United States Environmental Protection Agency [website]. Methylmercury (MeHg) (CASRN 22967-92-6). Washington, DC: United States Environmental Protection Agency; 2001. Available from: www.epa.gov/iris/subst/0073.htm. Accessed 2009 Oct 30. 28. Mahaffey KR, Clickner RP, Jeffries RA. Adult women’s blood mercury concentrations vary regionally in the United States: association with patterns of fish consumption (NHANES 1999-2004). Environ Health Perspect 2009;117(1):47-53. Epub 2008 Aug 25. 29. Schoeman K, Bend JR, Hill J, Nash K, Koren G. Defining a lowest observable adverse effect hair concentrations of mercury for neurodevelopmental effects of prenatal methylmercury exposure through maternal fish consumption: a systematic review. Ther Drug Monit 2009;31(6):670-82. 30. Koren G, Bend JR. Fish consumption in pregnancy and fetal risks of methylmercury toxicity. Can Fam Physician 2010;56:1001-2. 31. Environment Canada [website]. Mercury and the environment: basic facts. Ottawa, ON: Environment Canada; 2004. Available from: www.ec.gc.ca/ MERCURY/EN/bf.cfm. Accessed 2009 Oct 30. 32. Health Canada. Mercury in fish. Consumption advice: making informed choices about fish. Ottawa, ON: Health Canada; 2008. Available from: www.hc-sc. gc.ca/fn-an/securit/chem-chim/environ/mercur/cons-adv-etud-eng.php. Accessed 2009 Oct 30. 33. Toronto Public Health. A guide to eating fish for women, children and families. Toronto, ON: Toronto Public Health; 2008. Available from: www.toronto.ca/ health/hphe/fish_mercury.htm. Accessed 2009 Oct 30. 34. Forsyth DS, Casey V, Dabeka RW, McKenzie A. Methylmercury levels in predatory fish species marketed in Canada. Food Addit Contam 2004;21(9):849-56. 35. Dabeka RW, McKenzie AD, Bradley P. Survey of total mercury in total diet food composites and an estimation of the dietary intake of mercury by adults and children from two Canadian cities, 1998-2000. Food Addit Contam 2003;20(7):629-38. 36. Cole DC, Kearney J, Sanin LH, Leblanc A, Weber JP. Blood mercury levels among Ontario anglers and sport-fish eaters. Environ Res 2004;95(3):305-14. 37. Innis SM, Palaty J, Vaghri Z, Lockitch G. Increased levels of mercury associated with high fish intakes among children from Vancouver, Canada. J Pediatr 2006;148(6):759-63. 38. Butler Walker J, Houseman J, Seddon L, McMullen E, Tofflemire K, Mills C, et al. Maternal and umbilical cord blood levels of mercury, lead, cadmium, and essential trace elements in Arctic Canada. Environ Res 2006;100(3):295-318. Epub 2005 Aug 3. 39. Wong SL, Lye EJ. Lead, mercury and cadmium levels in Canadians. Component of Statistics Canada Catalogue no. 82-003-X. Health Reports. Ottawa, ON: Statistics Canada: 2008. Available from: www.statcan.ca/english/freepub/82-003XIE/2008004/article/10717-en.pdf. Accessed 2009 Oct 30. 40. Hightower JM, O’Hare A, Hernandez GT. Blood mercury reporting in NHANES: identifying Asian, Pacific Islander, Native American, and multiracial groups. Environ Health Perspect 2006;114(2):173-5. 41. McKelvey W, Gwynn RC, Jeffery N, Kass D, Thorpe LE, Garg RK, et al. A biomonitoring study of lead, cadmium, and mercury in the blood of New York City adults. Environ Health Perspect 2007;115(10):1435-41. 42. US Environmental Protection Agency. What you need to know about fish and shellfish. Washington, DC: US Environmental Protection Agency; 2004. Available from: www.epa.gov/waterscience/fish/advice/. Accessed 2009 Oct 30. 43. Health Professionals Taskforce, International Joint Commission. Great Lakes fish consumption advisories. The public health benefits and risks. Washington, DC: International Joint Commission; 2004. Available from: www.ijc.org/php/ publications/pdf/ID1540.pdf. Accessed 2009 Oct 30. 44. Food Standards Agency. Fish and shellfish. Pregnancy, children and babies. London, UK: Food Standards Agency. Available from: www.eatwell.gov.uk/healthydiet/ nutritionessentials/fishandshellfish/#cat232547. Accessed 2009 Oct 30. 45. Oken E, Kleinman KP, Berland WE, Simon SR, Rich-Edwards JW, Gillman MW. Decline in fish consumption among pregnant women after a national mercury advisory. Obstet Gynecol 2003;102(2):346-51. 46. Environment Canada. Mercury and the environment. Fish consumption. Ottawa, ON: Environment Canada; 2004. Available from: www.ec.gc.ca/MERCURY/EN/ fc.cfm. Accessed 2009 Oct 30. 47. Health Canada. Eating well with Canada’s food guide. Ottawa, ON: Health Canada; 2007. Available from: www.healthcanada.gc.ca/foodguide. Accessed 2009 Oct 30.

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Clinical Review

Complementary and alternative medicine for prevention and treatment of the common cold Richard Nahas

MD CCFP

Agneta Balla

Abstract Objective To review the evidence supporting complementary and alternative medicine approaches to treatment and prevention of the common cold in adults. Quality of Evidence MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched from January 1966 to September 2009 combining the key words common cold or influenza with echinacea, garlic, ginseng, probiotics, vitamin C, and zinc. Clinical trials and prospective studies were included. Main Message For prevention, vitamin C demonstrated benefit in a large metaanalysis, with possibly increased benefit in patients subjected to cold stress. There is inconsistent evidence for Asian ginseng (Panax ginseng) and North American ginseng (Panax quinquefolius). Allicin was highly effective in 1 small trial. For treatment, Echinacea purpurea is the most consistently useful variety; it was effective in 5 of 6 trials. Zinc lozenges were effective in 5 of 9 trials, likely owing to dose and formulation issues. Overall, the evidence suggests no benefit from probiotics for prevention or treatment of the common cold. Conclusion Vitamin C can be recommended to Canadian patients for prevention of the common cold. There is moderate evidence supporting the use of Echinacea purpurea and zinc lozenges for treatment. Ginseng and allicin warrant further research.

Résumé Objectif Examiner les données en faveur du recours aux médecines complémentaires et alternatives pour traiter et prévenir le rhume banal chez l’adulte. Qualité des preuves On a consulté MEDLINE, EMBASE et la Cochrane Database of Systematic Reviews entre janvier 1966 et septembre 2009, en combinant les rubriques common cold ou influenza avec les rubriques Echinacea, garlic, ginseng, probiotics, vitamin C et zinc. Des essais cliniques et des études prospectives ont été inclus. Principal message Pour ce qui est de la prévention, la vitamine C s’est avérée bénéfique dans une grande méta-analyse, avec une protection possiblement meilleure chez les sujets exposés au froid. Pour le ginseng asiatique (Panax ginseng) et le ginseng nord-américain (Panax quinquefolius), les données sont contradictoires. L’allicine était très efficace dans un petit essai. Pour le traitement, c’est l’Echinacea purpurea qui est le plus régulièrement utile, s’étant montré efficace dans 5 essais sur 6. Les losanges de zinc étaient efficaces dans 5 essais sur 9, possiblement à cause de différences de doses et de préparation. Dans l’ensemble, les données suggèrent que les probiotiques ne sont pas utiles pour prévenir ou traiter le rhume banal. Conclusion On peut recommander la vitamine C aux patients canadiens pour prévenir le rhume banal. Il existe certaines données en faveur de l’utilisation de l’Echinacea purpurea et des losanges de zinc pour le traitement. Le ginseng et l’allicine devront être étudiées davantage.

This article has been peer reviewed. Cet article a fait l’objet d’une révision par des pairs. Can Fam Physician 2011;57:31-6

KEY POINTS For prevention, the most consistent evidence supports use of at least 1 g of vitamin C daily, which decreased symptom duration by 8% in adults and 18% in children in several trials and which might be even more effective during Canadian winters. Use of ginseng and allicin could be considered; both show promise but larger trials are needed. Evidence from patients subjected to cold stress reinforces the importance of dressing warmly. For treatment, Echinacea purpurea taken at the first signs of a cold might reduce duration and severity of symptoms. Zinc lozenges might also be effective. Published studies are difficult to interpret in both cases because of differences in dose and formulation.

POINTS DE REPÈRE Pour ce qui est de la prévention, les preuves les plus solides obtenues dans plusieurs essais indiquent que la prise quotidienne d’au moins 1 g de vitamine C diminue la durée des symptômes de 8 % chez l’adulte et de 18 % chez l’enfant, et suggèrent que son efficacité pourrait être encore meilleure durant les hivers canadiens. Des résultats prometteurs permettent d’envisager l’usage du ginseng et de l’allicine, mais d’autres études seront nécessaires. Les données confirment l’importance d’être chaudement vêtu en cas d’exposition au froid. Pour ce qui est du traitement, la prise d’Echinacée purpurea aux premiers signes de rhume pourrait réduire la durée et la sévérité des symptômes. Les losanges de zinc pourraient aussi être efficaces. Dans ces deux derniers cas, les études publiées sont difficiles à interpréter en raison des différences de doses et de préparation.

This article is eligible for Mainpro-M1 credits. To earn credits, go to www.cfp.ca and click on the Mainpro link.

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| Canadian Family Physician

Le Médecin de famille canadien

Clinical Review | Complementary and alternative medicine for the common cold

he common cold is seen frequently by family physicians. It is almost always a viral illness; while rhinoviruses cause 30% to 50% of colds throughout the year and 80% of colds during peak season, up to 200 other viruses have been implicated.1 On average, it affects adults 2 to 4 times per year.2 Symptoms include nasal congestion and discharge, sneezing, cough, sore throat, and fever.3 While benign, they last for several days and cause 40% of all missed work days. Complications include sinusitis, otitis media and pneumonia, exacerbations of asthma and chronic obstructive pulmonary disease, and serious illness in immunocompromised patients. Influenza viruses cause 5% to 15% of acute respiratory infections, resulting in fever, headache, myalgia, and fatigue, and considerable overlap between influenza and the common cold can make accurate diagnosis difficult.3 Few effective treatments exist. Nonsteroidal antiinflammatory drugs reduce pain symptoms but not the overall duration or severity of a cold,4 and the antiviral drug oseltamivir only reduces symptom duration by 0.55 days in otherwise healthy adults.5 There is no role for antibiotics in the treatment of the common cold. While vaccination of healthy adults prevents influenza, it only reduces incidence of acute respiratory infections by 16%, and work absenteeism by 0.13 days.6 Many patients use complementary and alternative medicine (CAM) therapies to treat the common cold. Canadians spend more than $1 billion per year on CAM therapies, 7 but few physicians are familiar with their efficacy or safety. Here we review the evidence for frequently used CAM therapies to help physicians advise patients about the use of such therapies in treating and preventing the common cold.

on literature reviews and clinical experience. We identified clinical trials and other prospective studies, systematic reviews, and meta-analyses. Only trials evaluating single agents, mostly in healthy adults, were selected. Review articles and references were screened for additional trials. Each article was reviewed separately by both authors. The main limitation of the methodology used is the exclusion of other potentially useful interventions. This paper is not meant to be comprehensive, but rather to review the evidence for interventions that are commonly seen in clinical practice.

Main findings Relevant findings for each search term are briefly summarized in Table 18-37 and are detailed as follows: Echinacea. Echinacea roots and flowers were used medicinally by First Nations peoples and became popular in Europe for infectious problems. In laboratory studies, they activate macrophages, increase phagocytosis, enhance cytokine production38 and natural killer cell activity, and improve lymphocyte and monocyte cell counts10 and antibody response. 39 Many active ingredients have been identified, but recent attention has focused on alkylamides, which bind to cannabinoid receptors and upregulate the transcription of tumour necrosis factor.40 Clinical trial results have been difficult to interpret because they have used different species and plant parts. A recent Cochrane systematic review of echinacea for treatment and prevention of the common cold41 found more evidence for Echinacea purpurea than Echinacea angustifolia or Echinacea pallida, and more for aerial parts than roots. Given this, this review is limited to studies of E purpurea. Treatment: Of the 11 trials identified that studied echinacea,8-15,42-44 6 trials evaluated E purpurea in 764 healthy adults with cold symptoms.10-15 Symptom severity was reduced in 4 of 6 trials,10-12,14 measured using total daily symptom scores and Jackson scores. Of the

Quality of evidence MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched from January 1966 to August 2009. Key words used were common cold or influenza with echinacea, garlic, ginseng, probiotics, vitamin C, and zinc. The interventions were selected based

Table 1. Complementary and alternative medicine therapies for the common cold INTERVENTION

EVIDENCE FOR PREVENTION (LEVEL*)

EVIDENCE FOR TREATMENT (LEVEL*)

Echinacea purpurea

No evidence found in 2 RCTs (level IIa)8,9

Evidence found in 5 of 6 RCTs (level IIa)10-15

Zinc lozenges

No trials evaluate prevention

Evidence found in 5 of 9 RCTs (level IIa)16-24

Vitamin C

Evidence found in meta-analysis of 30 RCTs; more benefit in children and in adults under stress (level I)25

No evidence found in meta-analysis of 11 RCTs (level I)25

Ginseng

Inconsistent; evidence found in 2 of 4 RCTs (level IIb)26-29

No trials evaluate treatment

Garlic (allicin)

Evidence found in 1 RCT (level IIb)30

No trials evaluate treatment

Probiotics

No evidence found in 4 of 6 RCTs (level IIa)

31-36

RCTâ&#x20AC;&#x201D;randomized controlled trial. *Levels of evidence indicated are taken from the Oxford Centre for Evidence-Based Medicine.37

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No trials evaluate treatment

Complementary and alternative medicine for the common cold | Clinical Review 4 trials that measured duration of symptoms,12-15 3 found significant reductions of 1.5,12 3,14 and 4 days13 (P < .05 for all). Only 1 study found no reduction in symptom severity or duration.15 The 6 trials used 5 distinct preparations: 3 tinctures11,13-15 and 2 tablets derived from various extracts.10,12 Three trials studied healthy adults,11,14,15 while the other 3 studied adults with 2 or more colds in the previous year.10,12,13 Different clinical scoring systems were also used. There is moderate evidence that E purpurea might be effective for treatment of the common cold, but issues surrounding dose and formulation require clarification before it can be recommended for routine use. Prevention: Two trials evaluating E purpurea in cold prevention found no reduction in symptom duration or severity.8,9 Safety and use: A typical dose of echinacea is 2000 to 3000 mg of crude extract, 6 to 9 mL of pressed juice, or 0.75 to 1.5 mL of tincture per day. The most important concern is allergy; echinacea is a member of the Asteraceae family and can cause serious reactions in susceptible patients.45 Reported side effects include gastrointestinal upset, headache, and rash.39,46,47 No herbdrug interactions have been identified. Its safety in pregnancy or for long-term use is unknown. The theoretical risk of worsening autoimmune disease has not been reported but should be considered.39

infections, but found no reduction in the number of colds or in the duration or severity of symptoms.26 The study of 44 elderly patients reported fewer days of cold symptoms but only in the last 2 months of the 4-month trial; the number of colds was not reduced.27 The final study reported that healthy adults at risk who took COLD-fX experienced milder symptoms (Jackson score 77.5 vs 112.3, P = .002) for fewer days (10.8 vs 16.5 days, P < .001).28 Only 1 trial has studied P ginseng; 227 vaccinated healthy adults took 100 mg of an extract or placebo for 12 weeks. Those in the group taking ginseng suffered far fewer colds (15 vs 42, relative risk 0.35, P < .001).29 Safety and use: Reported side effects include headache, gastrointestinal upset, anxiety, and insomnia. Ginseng should be avoided during pregnancy and lactation because of potential teratogenicity and estrogenic effects.52 Case reports have described potential herb-drug interactions with phenelzine (induction of mania from depression), warfarin (increased international normalized ratio), and alcohol (increased blood clearance).53 There is conflicting and unclear evidence that P quinquefolius prevents colds. Although it is chemically similar to P ginseng, 1 clinical trial of P ginseng yielded better results, and its long history of traditional use is reassuring. Larger ginseng trials are warranted.

Ginseng. Panax means “heal-all” in Greek. Panax ginseng (Asian ginseng) has been used in Chinese medicine for millennia, and is believed to be an “adaptogen,” which enhances an individual’s ability to resist mental and physical stress.48 In animal and human studies, it has activated macrophages, natural killer cells, and lymphocytes, and increased cytokine and antibody production.49,50 Panax quinquefolius (North American ginseng) contains a similar chemical profile and is used to make COLD-fX, an extract standardized to polysaccharides and oligosaccharides. Treatment: There are no trials evaluating ginseng for treatment of the common cold. Prevention: Our search identified 3 trials comprising 564 patients that evaluated P quinquefolius for prevention of the common cold 26-28; all were funded by the manufacturer. These trials were also identified in a recent systematic review.51 Unfortunately, none involved healthy adults. One summarized 2 separate studies of 89 and 109 nursing home patients26; another involved 44 elderly patients (older than 65 years of age)27; and a third examined 323 unvaccinated adults with more than 2 colds in the previous year.31 All patients received 200 mg per day of COLD-fX or placebo for 2 to 4 months. Poor and misleading reporting of data makes it difficult to draw conclusions from these studies. The nursing home studies reported fewer laboratory-confirmed

Vitamin C. Albert Szent-Györgyi won the Nobel Prize for his discovery of vitamin C. Another Nobel laureate, Linus Pauling, popularized its use for disease prevention and longevity.54 Vitamin C has antioxidant properties, regenerates glutathione, and might stimulate neutrophil and monocyte activity.55 Treatment: A Cochrane systematic review identified 7 treatment trials evaluating 3294 cold episodes.25 One trial found that patients who took 8 g of vitamin C at the onset of symptoms had more “short colds” of less than a day than those who took 4 g (46% vs 39%, P = .046). All other trials found no benefit, even at similar doses.25 Prevention: The same review identified 30 prevention trials involving 11 350 subjects. Overall, there was a very slight decrease in the number of colds (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.92 to 1.0) but not in cold severity. Symptom duration decreased by 8.0% in trials that used more than 1 g daily in adults, and decreased by 18% (95% CI 7% to 30%) when this dose was used in children. Assuming that the average cold lasts for 7 to 10 days, this represents 1.5 to 2.0 days shorter duration, which is clinically relevant. More important, the reviewers identified a subgroup of 6 trials of 642 subjects exposed to severe stress in the form of subarctic cold or intense physical activity. In these trials, those taking vitamin C at doses of 200 to 2000 mg daily had half as many colds as those taking

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Clinical Review | Complementary and alternative medicine for the common cold placebo (OR 0.50, 95% CI 0.38 to 0.66). This seems very relevant to patients in many Canadian communities. Safety and use: Vitamin C is considered safe in doses up to several grams per day. The only occasional side effect is gastrointestinal upset, and doses in excess of 10 g can cause diarrhea. No drug interactions are known. Taking at least 1 g of vitamin C per day can be recommended for the prevention of colds based on good evidence of moderate reduction in symptom duration in adults and children. While it only reduces symptoms by 1 to 2 days, it is cheap, safe, and simple to use. It can also be recommended for use by athletes in intense training. Further research should explore the potential benefit in Canadians, who are subjected to cold winters.

involved atypical populations (military cadets33 and marathon runners32), but even when these are excluded, the results are unimpressive. There was no clear relationship between response and dose (measured in colony-forming units) or strain in studies that were large enough to be adequately powered. In a recent systematic review, there appeared to be more benefit in children,64 but this is beyond the scope of this review. Despite their lack of efficacy and potential for harm, antibiotics are still prescribed to patients with the common cold. These drugs alter intestinal flora, which can lead to potentially harmful side effects and complications. We recommend that patients use probiotics whenever antibiotics are prescribed.

Allicin. Allicin is an organosulfur compound found in garlic (Allium sativum), a food with known cardiovascular56,57 and anticancer benefits.58 Allicin is released when garlic is chopped or chewed, but is inactivated by cooking.59 It has demonstrated antiviral properties in vitro against rhinovirus and several other strains.60 Treatment: There are no trials evaluating allicin for treatment of the common cold. Prevention: One study of 146 healthy adults compared a high-dose allicin extract (180 mg daily) with placebo for 12 weeks during the winter months. The results were dramatic; the treatment group had 64% fewer colds (24 vs 65, P < .001), and symptom duration was reduced by 70% (1.52 vs 5.01 days, P < .001). Those in the treatment group were much less likely to develop more than 1 cold (2 vs 16 participants developed more than 1 cold).30 Safety and use: It should be emphasized that the allicin preparation used in this trial is unlike typical garlic preparations. It contained 180 mg of allicin; fresh garlic contains 5 to 9 mg per clove, and most extracts contain less than this. The only side-effect reported in the trial was malodorous belching. Little is known about the safety of high-dose allicin, but its use could be considered.

Zinc lozenges. Zinc is an essential mineral used in hundreds of biochemical pathways, and deficiency has long been associated with infection risk. Postulated mechanisms in the common cold include interfering with rhinovirus protein cleavage or capsid binding to intracellular adhesion moleculeâ&#x20AC;&#x201C;1 in nasal epithelium,65 and protecting plasma membranes from microbial toxins and complement.55 Treatment: Zinc was evaluated in 13 trials for treatment of the common cold in adults.16-24,66-69 A nasal spray was compared with placebo in 4 trials,16,67-69 and it reduced symptom duration and severity in only 2 of these.68,69 Irritation by the nasal sprays limits their use; they also appear to yield lower concentrations in the nasopharynx.70 Therefore, they are considered separately. Zinc lozenges reduced symptom duration and severity in 516,18-21 of 9 trials.16-24 The results are difficult to interpret for 2 reasons. The first is dose; 4 of 5 studies16,18-20 that used higher doses of elemental zinc (13 to 23 mg per lozenge every 2 hours) found a 1.3- to 6.9-day reduction in symptom duration and reduced symptom severity. Negative trials using lower doses have been criticized.71 The second issue is bioavailability. Negative trials have been criticized for using formulations that included citric or tartaric acids,70 sorbitol, or mannitol,72 all of which bind to and inactivate elemental zinc. More positive trials used acetate or gluconate, which do not bind to zinc as tightly as orotate or citrate. The importance of these differences is unclear. These factors might explain the variable results seen in a meta-analysis of 8 randomized controlled trials (OR 0.52, 95% CI 0.25 to 1.2) for symptoms after 7 days.71 It appears that zinc might be effective for treatment of colds, but issues surrounding dose and bioavailability require clarification. Future studies should use higher doses and ensure that formulations do not contain agents that could bind to or otherwise interfere with elemental zinc. Prevention: There are no trials evaluating zinc for prevention of the common cold.

Probiotics. The health benefits of fermented milk were first proposed in the early 20th century. These benefits are due to the presence of probiotic bacteria, which appear to be useful in several gastrointestinal and immune-mediated disorders.61 They interfere with toxin and cell binding sites, and improve mucosal barrier function, intestinal microflora, and gut-associated lymphoid tissue.62,63 Treatment: There are no trials evaluating probiotics for treatment of the common cold. Prevention: Probiotics were evaluated in 6 randomized controlled trials31-36 involving 1766 healthy adults. The number of colds was significantly reduced in only 1 of 6 trials,36 symptom severity in 1 of 6,31 and duration in 1 of 5 (P = .045). 31 Two of the negative trials

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Complementary and alternative medicine for the common cold | Clinical Review Safety and use: Lozenges containing at least 13 mg of elemental zinc can be used every 2 hours at the first sign of a cold. Reported side effects include bitter taste, nausea, and decreased smell and taste.73,74 Prolonged use of zinc (6 to 8 weeks) is not recommended, as it can lead to copper deficiency.

Conclusion For prevention, the most consistent evidence supports the use of at least 1 g of vitamin C per day, which decreased symptom duration by 8% in adults and 18% in children in several trials and which might be even more effective during Canadian winters. Use of ginseng and allicin can be considered; both show promise but larger trials are needed. Evidence from patients subjected to cold stress reinforces the importance of dressing warmly. For treatment, E purpurea might reduce duration and severity of symptoms when taken at the first signs of a cold. Zinc lozenges might also be effective. Published studies are difficult to interpret in both cases because of differences in dose and formulation. Once again, more trials are needed. These simple, safe recommendations might improve outcomes for patients with the common cold. Of equal importance, they offer an alternative when advising patients whose viral infections do not require antibiotics. Dr Nahas is Medical Director of the Seekers Centre for Integrative Medicine and a lecturer in the Department of Family Medicine at the University of Ottawa in Ontario. Dr Balla is a second-year family medicine resident at the University of Ottawa. Contributors Both authors contributed to the literature search and preparing the manuscript for submission. Competing interests None declared Correspondence Dr Richard Nahas, Medical Director, Seekers Centre for Integrative Medicine, 942 Merivale Rd, Ottawa, ON K1Z 5Z9; telephone 613 727-7246; e-mail richard@seekerscentre.com References 1. Mäkelä MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, Kimpimäki M, et al. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol 1998;36(2):539-42. 2. Monto AS. Epidemiology of viral respiratory infections. Am J Med 2002;112(Suppl 6A):4S-12S. 3. Heikkinen T, Järvinen A. The common cold. Lancet 2003;361(9351):51-9. 4. Kim SY, Chang YJ, Cho HM, Hwang YW, Moon YS. Non-steroidal antiinflammatory drugs for the common cold. Cochrane Database Syst Rev 2009;(3):CD006362. 5. Burch J, Corbett M, Stock C, Nicholson K, Elliot AJ, Duffy S, et al. Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis. Lancet Infect Dis 2009;9(9):537-45. Epub 2009 Aug 7. 6. Jefferson TO, Rivetti D, Di Pietrantonj C, Rivetti A, Demicheli V. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2007;(2):CD001269. 7. Esmail N. Complementary and alternative medicine in Canada: trends in use and public attitudes, 1997-2006. Vancouver, BC: Public Policy Sources, The Fraser Institute; 2007. 8. Grimm W, Müller HH. A randomized controlled trial of the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections. Am J Med 1999;106(2):138-43. 9. Melchart D, Walther E, Linde K, Brandmaier R, Lersch C. Echinacea root extracts for the prevention of upper respiratory tract infections: a doubleblind, placebo-controlled randomized trial. Arch Fam Med 1998;7(6):541-5.

10. Goel V, Lovlin R, Chang C, Slama JV, Barton R, Gahler R, et al. A proprietary extract from the echinacea plant (Echinacea purpurea) enhances systemic immune response during a common cold. Phytother Res 2005;19(8):689-94. 11. Brinkeborn RM, Shah DV, Degenring FH. Echinaforce and other echinacea fresh plant preparations in the treatment of the common cold. A randomized, placebo controlled, double-blind clinical trial. Phytomedicine 1999;6(1):1-6. 12. Goel V, Lovlin R, Barton R, Lyon MR, Bauer R, Lee TD, et al. Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther 2004;29(1):75-83. 13. Hoheisel O, Sandberg M, Bertram S, Bulitta M, Schafer M. Echinagard treatment shortens the course of the common cold: a double-blind placebo-controlled clinical trial. Eur J Clin Res 1997;9:261-8. 14. Schulten B, Bulitta M, Ballering-Brühl B, Köster U, Schäfer M. Efficacy of Echinacea purpurea in patients with a common cold. A placebo-controlled, randomised, double-blind clinical trial. Arzneimittelforschung 2001;51(7):563-8. 15. Yale SH, Liu K. Echinacea purpurea therapy for the treatment of the common cold: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 2004;164(11):1237-41. 16. Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother 1984;25(1):20-4. 17. Douglas RM, Miles HB, Moore BW, Ryan P, Pinnock CB. Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults. Antimicrob Agents Chemother 1987;31(8):1263-5. 18. Godfrey JC, Conant Sloane B, Smith DS, Turco JH, Mercer N, Godfrey NJ. Zinc gluconate and the common cold: a controlled clinical study. J Int Med Res 1992;20(3):234-46. 19. Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med 1996;125(2):81-8. 20. Petrus EJ, Lawson KA, Bucci LR, Blum K. Randomized, double-masked, placebo-controlled clinical study of the effectiveness of zinc acetate lozenges on the common cold symptoms in allergy-tested subjects. Curr Ther Res 1998;59(9):595-607. 21. Prasad AS, Fitzgerald JT, Bao B, Beck FW, Chandrasekar PH. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000;133(4):245-52. 22. Smith DS, Helzner EC, Nuttall CE Jr, Collins M, Rofman BA, Ginsberg D, et al. Failure of zinc gluconate in treatment of acute upper respiratory tract infections. Antimicrob Agents Chemother 1989;33(5):646-8. 23. Turner RB, Cetnarowski WE. Effect of treatment with zinc gluconate or zinc acetate on experimental and natural colds. Clin Infect Dis 2000;31(5):1202-8. Epub 2000 Nov 6. 24. Weismann K, Jakobsen JP, Weismann JE, Hammer UM, Nyholm SM, Hansen B, et al. Zinc gluconate lozenges for common cold. A double-blind clinical trial. Dan Med Bull 1990;37(3):279-81. 25. Douglas RM, Hemilä H, Chalker E, Treacy B. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2007;(3):CD000980. 26. McElhaney JE, Gravenstein S, Cole SK, Davidson E, O’neill D, Petitjean S, et al. A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr Soc 2004;52(1):13-9. Erratum in: J Am Geriatr Soc 2004;52(5):following 856. 27. McElhaney JE, Goel V, Toane B, Hooten J, Shan JJ. Efficacy of COLD-fX in the prevention of respiratory symptoms in community-dwelling adults: a randomized, double-blinded, placebo controlled trial. J Altern Complement Med 2006;12(2):153-7. 28. Predy GN, Goel V, Lovlin R, Donner A, Stitt L, Basu TK. Efficacy of an extract of North American ginseng containing poly-furanosyl-pyranosyl-saccharides for preventing upper respiratory tract infections: a randomized controlled trial. CMAJ 2005;173(9):1043-8. 29. Scaglione F, Cattaneo G, Alessandria M, Cogo R. Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Exp Clin Res 1996;22(2):65-72. Erratum in: Drugs Exp Clin Res 1996;22(6):338. 30. Josling P. Preventing the common cold with a garlic supplement: a doubleblind, placebo-controlled survey. Adv Ther 2001;18(4):189-93. 31. De Vrese M, Winkler P, Rautenberg P, Harder T, Noah C, Laue C, et al. Effect of Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, B. bifidum MF 20/5 on common cold episodes: a double blind, randomized, controlled trial. Clin Nutr 2005;24(4):481-91. Epub 2005 Apr 21. 32. Kekkonen RA, Vasankari TJ, Vuorimaa T, Haahtela T, Julkunen I, Korpela R. The effect of probiotics on respiratory infections and gastrointestinal symptoms during training in marathon runners. Int J Sport Nutr Exerc Metab 2007;17(4):352-63. 33. Tiollier E, Chennaoui M, Gomez-Merino D, Drogou C, Filaire E, Guezennec CY. Effect of a probiotics supplementation on respiratory infections and immune and hormonal parameters during intense military training. Mil Med 2007;172(9):1006-11.

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Clinical Review | Complementary and alternative medicine for the common cold 34. Tubelius P, Stan V, Zachrisson A. Increasing work-place healthiness with the probiotic Lactobacillus reuteri: a randomised, double-blind placebo-controlled study. Environ Health 2005;4:25. 35. Turchet P, Laurenzano M, Auboiron S, Antoine JM. Effect of fermented milk containing the probiotic Lactobacillus casei DN-114001 on winter infections in free-living elderly subjects: a randomised, controlled pilot study. J Nutr Health Aging 2003;7(2):75-7. 36. Winkler P, de Vrese M, Laue C, Schrezenmeir J. Effect of a dietary supplement containing probiotic bacteria plus vitamins and minerals on common cold infections and cellular immune parameters. Int J Clin Pharmacol Ther 2005;43(7):318-26. 37. Oxford Centre for Evidence-Based Medicine [website]. Levels of evidence. Oxford, UK: Oxford Centre for Evidence-Based Medicine; 2009. Available from: www.cebm.net/index.aspx?o=1025. Accessed 2010 Nov 30. 38. Sharma M, Arnason JT, Burt A, Hudson JB. Echinacea extracts modulate the pattern of chemokine and cytokine secretion in rhinovirus-infected and uninfected epithelial cells. Phytother Res 2006;20(2):147-52. 39. Barrett B. Medicinal properties of Echinacea: a critical review. Phytomedicine 2003;10(1):66-86. 40. Raduner S, Majewska A, Chen J, Xie X, Hamon J, Faller B, et al. Alkylamides from echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. J Biol Chem 2006;281(20):14192-206. Epub 2006 Mar 17. 41. Linde K, Barrett B, Wölkart K, Bauer R, Melchart D. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2006;(1):CD000530. 42. Dorn M, Knick E, Lewith G. Placebo-controlled, double-blind study of Echinaceae pallidae radix in upper respiratory tract infections. Complement Ther Med 1997;5(1):40-2. 43. Lindenmuth GF, Lindenmuth EB. The efficacy of echinacea compound herbal tea preparation on the severity and duration of upper respiratory and flu symptoms: a randomized, double-blind placebo-controlled study. J Altern Complement Med 2000;6(4):327-34. 44. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, D’Alessio D. Treatment of the common cold with unrefined echinacea. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002;137(12):939-46. 45. Mullins RJ, Heddle R. Adverse reactions associated with echinacea: the Australian experience. Ann Allergy Asthma Immunol 2002;88(1):42-51. 46. Huntley AL, Thompson Coon J, Ernst E. The safety of herbal medicinal products derived from Echinacea species: a systematic review. Drug Saf 2005;28(5):387-400. 47. Taylor JA, Weber W, Standish L, Quinn H, Goesling J, McGann M, et al. Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. JAMA 2003;290(21):2824-30. 48. Block KI, Mead MN. Immune system effects of echinacea, ginseng, and astragalus: a review. Integr Cancer Ther 2003;2(3):247-67. 49. Pannacci M, Lucini V, Colleoni F, Martucci C, Grosso S, Sacerdote P, et al. Panax ginseng C.A. Mayer G115 modulates pro-inflammatory cytokine production in mice throughout the increase of macrophage toll-like receptor 4 expression during physical stress. Brain Behav Immun 2006;20(6):546-51. 50. Scaglione F, Ferrara F, Dugnani S, Falchi M, Santoro G, Fraschini F. Immunomodulatory effects of two extracts of Panax ginseng C.A. Meyer. Drugs Exp Clin Res 1990;16(10):537-42. 51. Seida JK, Durec T, Kuhle S. North American (Panax quinquefolius) and Asian ginseng (Panax ginseng) preparations for prevention of the common cold in healthy adults: a systematic review. Evid Based Complement Alternat Med 2009 Jul 10. Epub ahead of print. 52. Seely D, Dugoua JJ, Perri D, Mills E, Koren G. Safety and efficacy of Panax ginseng during pregnancy and lactation. Can J Clin Pharmacol 2008;15(1):e87-94. Epub 2008 Jan 18.

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53. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf 2002;25(5):323-44. 54. Pauling L. The significance of the evidence about ascorbic acid and the common cold. Proc Natl Acad Sci U S A 1971;68(11):2678-81. 55. Wintergerst ES, Maggini S, Hornig DH. Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Ann Nutr Metab 2006;50(2):8594. Epub 2005 Dec 21. 56. Reinhart KM, Talati R, White CM, Coleman CI. The impact of garlic on lipid parameters: a systematic review and meta-analysis. Nutr Res Rev 2009;22(1):39-48. 57. Ried K, Frank OR, Stocks NP, Fakler P, Sullivan T. Effect of garlic on blood pressure: a systematic review and meta-analysis. BMC Cardiovasc Disord 2008;8:13. 58. Ngo SN, Williams DB, Cobiac L, Head RJ. Does garlic reduce risk of colorectal cancer? A systematic review. J Nutr 2007;137(10):2264-9. 59. Higdon J, Drake VJ, Lawson LD. Garlic and organosulfur compounds. Corvallis, OR: Linus Pauling Institute, Oregon State University; 2008. Available from: http://lpi.oregonstate.edu/infocenter/phytochemicals/ garlic. Accessed 2009 Oct 25. 60. Ankri S, Mirelman D. Antimicrobial properties of allicin from garlic. Microbes Infect 1999;1(2):125-9. 61. Lenoir-Wijnkoop I, Sanders ME, Cabana MD, Caglar E, Corthier G, Rayes N, et al. Probiotic and prebiotic influence beyond the intestinal tract. Nutr Rev 2007;65(11):469-89. 62. De Vrese M, Schrezenmeir J. Probiotics and non-intestinal infectious conditions. Br J Nutr 2002;88(Suppl 1):S59-66. 63. Yasui H, Shida K, Matsuzaki T, Yokokura T. Immunomodulatory function of lactic acid bacteria. Antonie Van Leeuwenhoek 1999;76(1-4):383-9. 64. Vouloumanou EK, Makris GC, Karageorgopoulos DE, Falagas ME. Probiotics for the prevention of respiratory tract infections: a systematic review. Int J Antimicrob Agents 2009;34(3):197.e1-10. Epub 2009 Jan 28. 65. Novick SG, Godfrey JC, Godfrey NJ, Wilder HR. How does zinc modify the common cold? Clinical observations and implications regarding mechanisms of action. Med Hypotheses 1996;46(3):295-302. 66. Eby GA, Halcomb WW. Ineffectiveness of zinc gluconate nasal spray and zinc orotate lozenges in common-cold treatment: a double-blind, placebocontrolled clinical trial. Altern Ther Health Med 2006;12(1):34-8. 67. Belongia EA, Berg R, Liu K. A randomized trial of zinc nasal spray for the treatment of upper respiratory illness in adults. Am J Med 2001;111(2):103-8. 68. Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J 2000;79(10):778-80, 782. 69. Mossad SB. Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults. QJM 2003;96(1):35-43. 70. Godfrey JC. Zinc for the common cold. Antimicrob Agents Chemother 1988;32(4):605-6. 71. Jackson JL, Lesho E, Peterson C. Zinc and the common cold: a meta-analysis revisited. J Nutr 2000;130(5S Suppl):1512S-5S. 72. Zarembo JE, Godfrey JC, Godfrey NJ. Zinc(II) in saliva: determination of concentrations produced by different formulations of zinc gluconate lozenges containing common excipients. J Pharm Sci 1992;81(2):128-30. 73. Cohen DA. The efficacy of zinc lozenges and zinc nasal sprays in the treatment of the common cold. Top Clin Nutr 2006;21(4):355-61. 74. Marshall S. Zinc gluconate and the common cold. Review of randomized controlled trials. Can Fam Physician 1998;44:1037-42.

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Motherisk Update

Effect of methotrexate treatment of ectopic pregnancy on subsequent pregnancy Rinat Hackmon

Sachi Sakaguchi

Gideon Koren

MD FRCPC FACMT

Abstract Question My last pregnancy was diagnosed as ectopic, and I was treated successfully with intramuscular methotrexate (MTX) 8 weeks ago. I am currently planning for another pregnancy; however, I have read that MTX causes birth defects and that it stays in my body for a very long time, ranging from 1 to 12 months after treatment. When is it safe to conceive? Answer We suggest that the outcomes of pregnancies conceived shortly after MTX therapy for extrauterine pregnancy are most likely to be favourable and similar to those pregnancies conceived 6 months after MTX treatment. However, as data are not sufficient to draw a definitive conclusion or to confirm the exact safe timing after MTX treatment, at least a 3-month waiting period is recommended for women who are planning pregnancy. Nevertheless, conception within 3 months of MTX treatment of extrauterine pregnancy should not be considered a definite indication of termination, and further targeted fetal anatomy assessment is recommended. Further retrospective and prospective studies are needed to define the safety period before 3 months and to solidify this recommendation.

Résumé Question J’ai eu un diagnostic de grossesse ectopique et on m’a traitée avec succès, il y a 8 semaines, par injection intramusculaire au méthotrexate (MTX). Je planifie actuellement une autre grossesse, mais j’ai lu que le MTX cause des malformations congénitales et que la substance persiste dans le corps pendant une très longue période après le traitement, pouvant aller de 1 à 12 mois. Réponse Nous sommes d’avis que l’issue d’une grossesse conçue peu après une thérapie au MTX pour une

grossesse ectopique sera probablement favorable et semblable à celle d’une grossesse conçue 6 mois après le traitement au MTX. Par ailleurs, puisque les données ne sont pas suffisantes pour tirer des conclusions définitives ou pour confirmer un délai d’attente exact après un traitement au MTX, nous recommandons aux femmes qui prévoient une grossesse d’attendre au moins 3 mois. Néanmoins, la conception dans les 3 mois suivant un traitement au MTX pour une grossesse extra-utérine ne devrait pas être considérée comme une indication définitive pour y mettre un terme et il est recommandé de procéder à une évaluation plus approfondie de l’anatomie fœtale. Il faut un plus grand nombre d’études rétrospectives et prospectives pour déterminer les risques d’une conception dans les 3 mois suivant la thérapie, et renforcer cette recommandation.

ethotrexate (MTX), an immunosuppressive drug, is a folic antagonist that binds to the enzyme dihydrofolate reductase. This inhibits synthesis of thymidylate, serine, and methionine, which disrupts synthesis of DNA, RNA, and protein and leads to cell death.1 Methotrexate is further metabolized to MTX polyglutamates, which are long-lived metabolites, inhibiting other folate-dependent enzymes. It is generally used to treat cancers, psoriasis, and rheumatic diseases, as well obstetric or gynecologic conditions, including extrauterine pregnancy (EUP), firsttrimester terminations, and gestational trophoblastic disease.2 A low-dose MTX treatment protocol introduced by Stovall et al3 20 years ago is to date the treatment of choice for EUP when possible.

Exposure Methotrexate is teratogenic or lethal to embryos of all animal species tested.4 In humans, MTX and aminopterin (another folate antagonist) have been associated with the following fetal malformations: central nervous system abnormalities, including spina bifida, hydrocephaly, anencephaly, and mental retardation; skeletal abnormalities, including synostosis of lambdoid sutures, partial or absent ossification of bones, micrognathia, cleft lip or palate, broad depressed nasal bone, hypertelorism, short limbs, syndactyly, absent digits, and clubfoot; and dextrocardia and intrauterine growth retardation.5,6 Feldkamp and Carey5 reviewed the literature about women exposed to MTX during pregnancy

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Motherisk Update and suggested that the minimal maternal dose necessary to induce defects was above 10 mg per week, and the postulated critical period was between 6 and 8 weeks after conception. This recommendation was supported by Donnenfeld et al,7 who reviewed information from 63 centres participating in the prospective evaluation of fetal abnormalities. However, owing to several different case reports of fetal malformations with lowdose MTX exposure after 8 weeks, this recommendation is considered controversial.6 Concerns about the effects of MTX on subsequent pregnancies’ outcomes arise mainly from the potent mechanism of action of the drug and its metabolites on pregnancy, as well as its detection in the kidney and liver weeks and even months after exposure. Although the half-life of MTX is 8 to 15 hours, its presence in the liver has been reported to last up to 116 days after exposure.8,9 Owing to concerns about MTX and its metabolites remaining in some organs and possibly affecting pregnancy or fetal development, manufacturers and several sources have arbitrarily recommended that women wait 3 to 6 months to become pregnant after stopping therapy.10 The specific question of “When is it safe to conceive after MTX treatment of EUP?” had not been studied until 2008.11 Thus, it is not surprising that there is no consensus regarding this period. Most physicians follow the manufacturers’ recommendations and advocate for a delayed period of 3 to 6 months. However this recommendation is based on animal models, sporadic human case reports, and various study designs. The goal of this update is to summarize the published data so far and to provide a scientific-oriented guideline.

Studies overview A literature search regarding safety of pregnancy after MTX exposure yields various study populations, protocols, and study designs. A French collaborative study in 2004 concluded there was no increase of teratogenicity among 28 women who were treated with low-dose MTX for chronic inflammatory disorders, once the drug had been discontinued as early as possible in pregnancy.12 In a 2009 systematic review, Martínez Lopez et al13 reported on 101 pregnancies exposed to low-dose MTX (5 to 25 mg/week) among rheumatic patients. The rates of miscarriages and of birth defects were found to be similar to those observed in healthy populations. In a large retrospective study, 387 women were treated with combined therapy, including MTX, for gestational trophoblastic tumour; the incidence of abnormal outcome (eg, miscarriages, stillbirth, repeat mole) was found to be significantly higher in women who conceived within 6 months of completing chemotherapy (4 out of 15) than in those who conceived after 12 months (10 out of 95) (P = .028). 14 In a similar study, Rustin et al15 reported a slightly increased

Canadian Family Physician t Le Médecin de famille canadien

but non-significant incidence of stillbirth and congenital malformations compared with the expected background group. Rustin and colleagues15 recommended postponing further conception for 1 year after cessation of chemotherapy, even though no significant difference was detected. A prospective study indicated that therapy with MTX increased the rate of early miscarriages and malformation when conceiving within 1 year of therapy; however, this study included only 9 women and the exposure to MTX was prolonged, ranging from 1 to 12 months.7 The studies cited above provide indirect and conflicting information on the safety of MTX during pregnancy, and none of them addresses this topic specifically enough to help us to answer the woman’s question.

Addressing the question In 2008, Svirsky et al11 addressed this topic in a retrospective study. They retrieved data on 314 women treated with MTX for EUP and evaluated the pregnancy outcomes among those who subsequently conceived. A total of 125 pregnancies were reported with complete information. Forty-five pregnancies occurred within 6 (mean [SD] 3.6 [1.7]) months of the last MTX treatment. The outcomes of those pregnancies were compared with those of 80 pregnancies that occurred more than or equal to 6 (mean [SD] 14.7 [23.6]) months after the last MTX treatment. The fetal malformations and adverse outcome rates, including miscarriages, for both groups were similar (odds ratio 1.003, 95% confidence interval 0.98 to 1.02). According to a logistic regression analysis, the interval between the last MTX treatment of EUP and the subsequent pregnancy had no effect on the outcome.11 Based on the result of this study and given that the actual fetal exposure to MTX released from maternal organs is considered to be minimal, we suggest that the outcomes of pregnancies conceived shortly after MTX therapy for EUP are most likely to be favourable and similar to those conceived after 6 months. As data are not sufficient to draw a definitive conclusion or to confirm the exact safe timing after the MTX treatment, a recommendation of at least a 3-month waiting period for women who are planning pregnancy seems to be prudent. Nevertheless, conception within 3 months of the MTX treatment of EUP should not be considered a definite indication of termination, and further targeted fetal anatomy assessment is recommended. Further retrospective and prospective studies are needed to define the safety period before 3 months and to solidify this recommendation. Competing interests None declared References 1. French AE, Koren G. Effect of methotrexate on male fertility. Can Fam Physician 2003;49:577-8. 2. Conaghan PG, Brooks P. Disease-modifying antirheumatic drugs, including methotrexate, gold, sulfasalazine, antimalarials, and D-penicillamine. Curr Opin Rheumatol 1996;8(3):176-82.

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Motherisk Update 3. Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol 1991;77(5):754-7. 4. Jordan RL, Wilson JG, Schumacher HJ. Embryotoxicity of the folate antagonist methotrexate in rats and rabbits. Teratology 1977;15(1):73-9. 5. Feldkamp M, Carey JC. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy. Teratology 1993;47(6):533-9. 6. Lloyd ME, Carr M, McElhatton P, Hall GM, Hughes RA. The effects of methotrexate on pregnancy, fertility and lactation. QJM 1999;92(10):551-63. 7. Donnenfeld AE, Pastuszak A, Noah JS, Schick B, Rose NC, Koren G. Methotrexate exposure prior to and during pregnancy. Teratology 1994;49(2):79-81. 8. Charache S, Condit PT, Humphreys SR. Studies on the folic acid vitamins. IV. The persistence of amethopterin in mammalian tissues. Cancer 1960;13:236-40. 9. Methotrexate. In: McEvoy GK, editor-in-chief. AHFS drug information. Bethesda, MD: American Society of Health-System Pharmacists; 1996. p. 751-9. 10. Health Canada [website]. Drug product databse online query. Methotrexate. Ottawa, ON: Health Canada; 2010. Available from: http://webprod.hc-sc. gc.ca/dpd-bdpp/info.do?lang=eng&code=44161. Accessed 2010 Dec 1. 11. Svirsky R, Rozovski U, Vaknin Z, Pansky M, Schneider D, Halperin R. The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol 2009;27(1):85-7. Epub 2008 Dec 3. 12. Lewden B, Vial T, Elefant E, Nelva A, Carlier P, Descotes J. Low dose methotrexate in the first trimester of pregnancy: results of a French collaborative study. J Rheumatol 2004;31(12):2360-5. 13. MartĂnez Lopez JA, Loza E, Carmona L. Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding). Clin Exp Rheumatol 2009;27(4):678-84. 14. Matsui H, Iitsuka Y, Suzuka K, Yamazawa K, Tanaka N, Seki K, et al. Risk of abnormal pregnancy completing chemotherapy for gestational trophoblastic tumor. Gynecol Oncol 2003;88(2):104-7. 15. Rustin GJ, Booth M, Dent J, Salt S, Rustin F, Bagshawe KD. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J (Clin Res Ed) 1984;288(6411):103-6.

Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Dr Hackmon and Dr Sakaguchi are members and Dr Koren is Director of the Motherisk Program. Dr Koren is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation. He holds the Ivey Chair in Molecular Toxicology in the Department of Medicine at the University of Western Ontario in London. Do you have questions about the effects of drugs, chemicals, radiation, or infections in women who are pregnant or breastfeeding? We invite you to submit them to the Motherisk Program by fax at 416 813-7562; they will be addressed in future Motherisk Updates. Published Motherisk Updates are available on the Canadian Family Physician website (www.cfp.ca) and also on the Motherisk website (www.motherisk.org).

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| Canadian Family Physician

Le MĂŠdecin de famille canadien

New to Canada!

New BuTrans 7-day patch: Introducing a new course for pain management.

BuTrans™ is the first and only pain treatment with 7-day dosing for moderate pain over an extended period of time:1,2 4 For pain management in patients requiring continuous opioid analgesia.1 4 Convenience of dosing every 7 days.1 4 A low starting dose (5 mcg/hr) with flexible dosing (5/10/20 mcg/hr).1 BuTrans (buprenorphine transdermal patch) is indicated for the management of persistent pain of moderate severity in adults requiring continuous opioid analgesia for an extended period of time. Please refer to prescribing information for BuTrans™. Warnings: As with other CNS depressants, patients who have received BuTrans should be monitored especially for signs of respiratory depression until a stable maintenance dose is reached. Due to the formation of a subcutaneous depot of buprenorphine, not only does continued exposure occur after patch removal but, in the case of removal prior to attainment of peak buprenorphine exposure, buprenorphine plasma levels may continue to increase after removal of BuTrans patches. BuTrans patches are intended for transdermal use on intact skin only; use on compromised skin can lead to increased exposure to buprenorphine. BuTrans™ has potential for abuse, dependence and diversion. BuTrans is contraindicated in patients who are hypersensitive to buprenorphine, opioids or to any ingredient in the formulation, and in patients suffering from delirium tremens. See Product Monograph for a list of contraindications. The safety and efficacy of BuTrans has not been studied in the pediatric population. Therefore, use of BuTrans is not recommended in patients under 18 years of age. The most common adverse effects in six randomized titration-to-effect clinical placebo-controlled clinical trials with BuTrans™ were anorexia, application site erythema, application site pruritus, asthenia, constipation, dizziness, dry mouth, headache, hyperhidrosis, insomnia, nausea, somnolence and vomiting. Product monograph available on request.

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The convenience of a 7-day opioid patch 96

Child Health Update

Reducing inappropriate antibiotic use among children with influenza infection Bat-Chen Friedman

Derek Schwabe-Warf

Ran Goldman

MD FRCPC

Abstract Question With the influenza season reaching a peak, I see numerous children in my clinic with fever and influenza-like illnesses. Parents are concerned and at times ask for antibiotic treatment in hopes that the treatment will shorten the duration of illness. What strategies can I use in order to minimize inappropriate prescription of antibiotics during the influenza season? Answer Use of antibiotics for treatment of viral infections such as influenza contributes to the emergence of resistant bacteria strains. Misuse and overuse of antibiotics can be reduced by preventing the infection and its complications through vaccination, point-of-care rapid influenza testing, and early antiviral treatment when appropriate, as well as constantly increasing the knowledge of both physicians and families regarding the appropriate use of antibiotics.

Résumé Question La saison de la grippe étant à son point culminant, je vois de nombreux enfants à ma clinique qui font de la fièvre et ont des syndromes grippaux. Les parents s’inquiètent et demandent parfois une antibiothérapie dans l’espoir que le traitement raccourcisse la durée de la maladie. Quelles stratégies puis-je utiliser pour minimiser une prescription inappropriée d’antibiotiques durant la saison de la grippe? Réponse L’utilisation d’antibiotiques pour le traitement d’infections virales comme la grippe contribue à l’émergence de souches de bactéries résistantes. L’utilisation abusive ou inappropriée d’antibiotiques peut être réduite par la prévention de l’infection et de ses complications grâce à la vaccination, aux tests rapides de dépistage de la grippe au point de service, par un traitement antiviral rapide, au besoin, et par une éducation accrue des médecins et des familles au sujet de l’usage approprié des antibiotiques.

ntibiotic resistance to pathogenic bacteria in the community setting has been identified as an emerging threat to public health. For example, 20% to 33% of Streptococcus pneumonia isolates are no longer susceptible to penicillin. 1,2 Methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage in children has increased dramatically in the past decade. In 2001, data from a large pediatric primary care practice in the United States demonstrated colonization rates of 0.8%. In 2005, a repeat survey in the same pediatric primary care practice found that MRSA nasal carriage exceeded 9%.3 During the same period of time, nasal carriage of MRSA was reported to be as high as 22% among children admitted to a pediatric hospital in Texas.4 As the rate of MRSA nasal carriage increases, there is a potential for increased co-infection with influenza virus, resulting in severe morbidity and potential mortality in children.5 An important factor in the development of antibiotic resistance is overuse of antibiotics.6 Of particular concern is overprescription of antibiotics for the treatment of viral upper respiratory infections and influenza-like

Canadian Family Physician t Le Médecin de famille canadien

illnesses.7 The results of a nationwide US survey published in 2004 showed 38% of more than 6.5 million visits (primary practice, outpatient, and emergency department) by children and adults with a sole diagnosis of influenza were associated with antibiotic prescriptions. 8 Studies limited to children demonstrated even higher rates of antibiotic treatment in children diagnosed with viral infections.9 Minimizing antibiotics on a national scale can reduce resistance rates. This goal might be achieved by better use of diagnostic tests and antiviral treatment and by enhancing physician and patient education.

Diagnostic strategies One of the prime factors leading to inappropriate prescription of antibiotics for children with influenza infection is the difficulty in making a reliable and rapid clinical diagnosis. Cough and fever are the most common symptoms, but influenza infection can have an atypical presentation, especially in children, and no single symptom can confirm or exclude influenza.10 The main challenge for physicians is distinguishing

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Child Health Update between the clinical features of influenza and bacterial infections. Laboratory tests such as complete blood count and C-reactive protein measurement might help recognize bacterial involvement but they are not readily available in most community settings. There are several diagnostic tests for influenza. Viral culture and reverse transcription polymerase chain reaction are the criterion standards for diagnosis, but both methods are time-consuming, expensive, and require specialized laboratory facilities. 11 Rapid tests based on immunoassays or neuraminidase activity can detect influenza A and B viruses within 30 minutes. They are of variable sensitivity (median 70% to 75%) and high specificity (median 90% to 95%).12 Significant false-negative rates were documented during times of high influenza prevalence.13 Nevertheless, by providing additional support for the initial clinical diagnosis, these assays promote the rational use of antiviral agents and discourage the inappropriate prescribing of antibiotics.14,15 Given time, cost, and accuracy constraints, rapid testing is the most common and practical way to test for influenza, and has the potential to reduce inappropriate antibiotic use and laboratory tests associated with influenza-like illness in up to 50% of cases.15

Vaccinations and antiviral therapy Preventive measures such as hand washing and vaccination are the most efficient and cost-effective ways to reduce the incidence of infection thus preventing the use of inappropriate antibiotics.16,17 Expanding vaccination guidelines to infants (aged 6 months or older) can improve antibiotic use for treatment of suspected secondary bacterial infections in young children. Use of live virus vaccines, which have 15% to 20% higher efficacy than inactivated vaccines, could further reduce the burden of influenza.16 Antiviral medications as post-exposure therapy or after confirming influenza have been shown to reduce the duration of infection and, when used as recommended, they can potentially reduce the demand for antibiotic treatment.18 Nevertheless, wide use of antiviral treatment is still controversial.

Physician and parent education Physicians might overprescribe antibiotics as a response to parents’ expectations. A survey of more than 600 practising pediatricians found that 96% had been asked by parents for antibiotics when they were unnecessary. One-third of doctors reported providing the medications, even though they were not indicated.19 Under pressure, especially during winter months, physicians might lack the time necessary to explain why antibiotics have no clinical effect on viral infections. Patient education programs can reduce the direct and indirect pressures on doctors to prescribe antibiotics.

When these programs have targeted those who receive antibiotics most frequently, they have proven successful in reducing patient uncertainty about the necessity of antibiotics.20 A study by Hemo et al demonstrated how a nationwide campaign based on television programming was an effective way to impart knowledge regarding antibiotic use. Antibiotic purchases following upper respiratory infection diagnosis during the postintervention period decreased compared with the parallel baseline period (odds ratio 0.75). A substantial reduction in antibiotic purchasing was also demonstrated for diagnosed otitis media (odds ratio 0.65).21 Physician education can also contribute to appropriate antibiotic use; however, changing physician behaviour is a complex task and educational strategies do not always accomplish the desired results.22

Conclusion Misuse of antibiotic treatment of influenza infections and the subsequent emergence of bacterial resistance can be reduced by limiting viral spread through hand hygiene and vaccination, using point-of-care rapid influenza tests, judicious use of antiviral medications, and expanding the knowledge of physicians and parents regarding appropriate use of antibiotics. Competing interests None declared Correspondence Dr Ran D. Goldman, BC Children’s Hospital, Department of Pediatrics, Room K4-226, Ambulatory Care Bldg, 4480 Oak St, Vancouver, BC V6H 3V4; telephone 604 875-2345, extension 7333; fax 604 875-2414; e-mail rgoldman@cw.bc.ca References 1. Whitney CG, Farley MM, Hadler J, Harrison LH, Lexau C, Reingold A, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumonia in the United States. N Engl J Med 2000;343(26):1917-24. 2. Finkelstein JA, Huang SS, Daniel J, Rifas-Shiman SL, Kleinman K, Goldmann D, et al. Antibiotic-resistant Streptococcus pneumoniae in the heptavalent pneumococcal conjugate vaccine era: predictors of carriage in a multi-community sample. Pediatrics 2003;112(4):862-9. 3. Creech CB 2nd, Kernodle DS, Alsentzer A, Wilson C, Edwards KM. Increasing rates of nasal carriage of methicillin-resistant Staphylococcus aureus in healthy children. Pediatr Infect Dis J 2005;24(7):617-21. 4. Alfaro C, Mascher-Denen M, Fergie J, Purcell K. Prevalence of methicillinresistant Staphylococcus aureus nasal carriage in patients admitted to Driscoll Children’s Hospital. Pediatr Infect Dis J 2006;25(5):459-61. 5. Finelli L, Fiore A, Dhara R, Brammer L, Shay DK, Kamimoto L, et al. Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection. Pediatrics 2008;122(4):805-11. 6. Cohen ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. Science 1992;257(5073):1050-5. 7. McCaig LF, Besser RE, Hughes JM. Trends in antimicrobial prescribing rates for children and adolescents. JAMA 2002;287(23):3096-102. 8. Ciesla G, Leader S, Stoddard J. Antibiotic prescribing rates in the US ambulatory care setting for patients diagnosed with influenza, 1997-2001. Respir Med 2004;98(11):1093-101. 9. Wilkes JJ, Leckerman K, Coffin SE, Keren R, Metigan TA, Hodinka LR, et al. Use of antibiotics in children hospitalized with community-acquired, laboratory-confirmed influenza. J Pediatr 2009;154(3):447-9. 10. Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP. Does this patient have influenza? JAMA 2005;293(8):987-97. 11. Harper SA, Bradley JS, Englund JA, File TM, Gravenstain S, Hayden FG, et al. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis and institutional outbreak management: clinical practice guidelines of the Infectious Disease Society of America. Clin Infect Dis 2009;48(8):1003-32. 12. World Health Organization [website]. WHO recommendations on the use of rapid testing for influenza diagnosis. Geneva, Switz: World Health Organization; 2005. Available from: www.who.int/csr/disease/avian_ influenza/guidelines/rapid_testing. Accessed 2010 Nov 15.

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Child Health Update 13. Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment of influenza. Pediatr Infect Dis J 2003;22(2):164-77. 14. Jennings LC, Skopnik H, Burckhardt I, Hribar I, Del Piero L, Deichmann KA. Effect of rapid influenza testing on the clinical management of paediatric influenza. Influenza Other Respi Viruses 2009;3(3):91-8. 15. Bonner AB, Monroe KW, Talley LI, Klasner AE, Kimberlin DW. Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial. Pediatrics 2003;112(2):363-7. 16. Manzoli L, Schioppa F, Boccia A, Villari P. The efficacy of influenza vaccine for healthy children: a meta-analysis evaluating potential sources of variation in efficacy estimates including study quality. Pediatr Infect Dis J 2007;26(2):97-106. 17. Grayson ML, Melvani S, Druce J, Barr IG, Ballard SA, Johnson PD, et al. Efficacy of soap and water and alcohol-based hand-rub preparations against live H1N1 influenza virus on the hands of human volunteers. Clin Infect Dis 2009;48(3):285-91. 18. Low D. Reducing antibiotic use in influenza: challenges and rewards. Clin Microbiol Infect 2008;14(4): 298-306. Epub 2007 Dec 18. 19. Bauchner H, Pelton SI, Klein JO. Parents, physicians, and antibiotic use. Pediatrics 1999;103(2):395-401. 20. De Marco G, Mangani S, Correra A, Di Caro S, Tarallo L, De Franciscis A, et al. Reduction of inappropriate hospital admissions of children with influenzalike illness through the implementation of specific guidelines: a case-controlled study. Pediatrics 2005;116(4):506-11.

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21. Hemo B, Shamir-Shtein NH, Silverman BG, Tsamir J, Heymann AD, Tsehori S, et al. Can a nationwide media campaign affect antibiotic use? Am J Manag Care 2009;15(8):529-34. 22. Davis DA, Thomson MA, Oxman AD, Haynes RB. Changing physician performance. A systematic review of the effect of continuing medical education strategies. JAMA 1995;274(9):700-5.

Child Health Update is produced by the Pediatric Research in Emergency Therapeutics (PRETx) program (www.pretx.org) at the BC Childrenâ&#x20AC;&#x2122;s Hospital in Vancouver, BC. Dr Friedman and Mr Schwabe-Warf are members and Dr Goldman is Director of the PRETx program. The mission of the PRETx program is to promote child health through evidence-based research in therapeutics in pediatric emergency medicine. Pediatric Research in Emergency Therapeutics

Do you have questions about the effects of drugs, chemicals, radiation, or infections in children? We invite you to submit them to the PRETx program by fax at 604 875-2414; they will be addressed in future Child Health Updates. Published Child Health Updates are available on the Canadian Family Physician website (www.cfp.ca).

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Emergency Files

Sticks and stones and broken bones Distal radius fractures in children Â Robert Primavesi MD CM FCFP(EM)

You are working in the emergency department at a small community hospital. William is a 6-year-old boy who presents with left wrist pain after a fall on the ice while playing hockey. On examination, his left wrist is swollen, but there is no deformity. He complains of pain when you press over the distal radius. There is no neurovascular compromise. You suspect a fracture and request an x-ray scan of his left wrist. On review of the radiographs there is a very obvious buckle fracture of the distal radius on the anteroposterior view (Figure 1). A buckle fracture is defined as a fracture in which the bony cortex is compressed on one side and the opposite cortex remains intact.

Buckle fractures Fractures of the wrist and forearm account for almost half of all pediatric fractures. Eighty percent of forearm fractures involve the distal radius and ulna. Most forearm fractures are buckle fractures, also known as torus fractures. The traditional treatment for a buckle fracture is to cast the injury for a short duration, usually about 3 weeks.1 Plint et al2 found that by using removable wrist immobilizers instead of casts there were significant differences in Activities Scales for Kids performance version scores, indicating better functioning in the splint group at 14 days postinjury (P = .041). Splinted children

Figure 1. The anteroposterior view of a buckle fracture of the distal radius

This article is eligible for Mainpro-M1 credits. To earn credits, go to www.cfp.ca and click on the Mainpro link.

had significantly less difficulty with bathing (P < .001) and with writing (P = .005), and they also returned to sports sooner (P = .031 at 20 days, P = .008 at 28 days). There were no significant differences in pain between groups as measured by the visual analog scale, and there were no refractures. Furthermore, Plint et al found that while splints were prescribed for 3 weeks, by day 7 only 15% of children reported wearing them all day and night. Thus, for many children with wrist buckle fractures, 3 weeks of constant immobilization is not necessary. Plint and colleagues conclude that children treated with removable splinting have better physical functioning and less difficulty with activities than those treated with casts, with no difference in their levels of pain. The use of removable splinting might reduce the need for follow-up visits and, as a result, health care costs. Plint et al recommend the use of removable splints in the treatment of this common injury.2

Metaphyseal fractures On closer inspection of the lateral view of the radiograph (Figure 2), the fracture line extends completely across the metaphysis of the distal radius, so that both cortices are involved. There is also a fracture that transverses the metaphysis of the distal ulna. There is no associated angulation or displacement.

Figure 2. The lateral view of a minimally displaced distal radius and ulna metaphyseal fracture

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Emergency Files The traditional treatment for distal radius and ulna fractures is an above-elbow cast for 4 to 6 weeks,3 owing to the possibility of periosteal disruption and instability that might result in further displacement and angulation. However, a wellmolded below-elbow cast might be equally effective. Sherbino4 performed a systematic review of the literature on the management of pediatric distal radius fractures, including removable splints versus circumferential casts for buckle fractures. Sherbino found the following: Removable splints versus circumferential casts for buckle fractures. Four trials, involving 417 children, compared a commercial splint, plaster splint, or soft bandage to a below-elbow circumferential cast. There were no short-term deformities associated with removable splints. Removable splints increased early functionality and comfort and were the self-reported preference of patients and their parents. Below-elbow versus aboveelbow casts for displaced fractures. Two studies, involving 229 children, did not demonstrate any difference in redisplacement between below- or above-elbow casts .â&#x20AC;Ś Belowelbow casts decreased the need for assistance with activities of daily living and reduced postâ&#x20AC;&#x201C; cast removal elbow stiffness. Above-elbow casts positioned in supination, pronation, or neutral for displaced fractures. One study of 109 children did not demonstrate any difference related to arm position on post-reduction angulation at 6 weeks.4

Interestingly, this systematic review of the literature on the

treatment of pediatric wrist fractures addresses buckle fractures and displaced fractures but not undisplaced or minimally angulated fractures. In 2010, Boutis et al5 provided the first study to challenge the current practice of routine casting and compare it with a commercially available wrist splint, with respect to recovery of physical function in children with acceptably angulated wrist fractures (< 15Â°). Management of these fractures varies widely, and up to now there has been virtually no scientific evidence supporting one treatment over another. These fractures carry an excellent long-term prognosis because of the unique capacity of skeletally immature bones to heal via remodeling. More important, the most common treatment of cast application for 4 to 6 weeks is associated with many inconveniences. Boutis et al5 show that wrist splints are a more convenient alternative and that splints offer comparable immobilization and symptom relief without compromise of fracture stability, with less reliance on subspecialty care.

Conclusion Given the evidence in the Canadian literature, the new standard of care for pediatric distal radius fractures, including buckle fractures and minimally angulated fractures (< 15Â°), is the application of a wrist immobilizer, which provides increased early functionality and comfort without the complications of a cast. While it is prudent to avoid high-risk activities that might lead to re-injury, a child can return to usual play. Dr Primavesi is an emergency physician at the McGill University Health Centre in Montreal, Que. Competing interests None declared References 1. Kliegman R, Behrman RE, Jenson HB, Stanton BF. Nelson textbook of pediatrics. 18th ed. Maryland Heights, MO: W.B. Saunders; 2007. 2. Plint AC, Perry JJ, Correll R, Gaboury I, Lawton L. A randomized, controlled trial of removable splinting versus casting for wrist buckle fractures in children. Pediatrics 2006;117(3):691-7.

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3. Morrissy RT, Weinstein SL, editors. Lovell and Winterâ&#x20AC;&#x2122;s pediatric orthopaedics. 6th ed. Vol. 2. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. p. 1472-3. 4. Sherbino J. How do I treat pediatric wrist fractures? Ann Emerg Med 2009;54(4):541-2. 5. Boutis K, Willan A, Babyn P, Goeree R, Howard A. Cast versus splint in children with minimally angulated fractures of the distal radius: a randomized controlled trial. CMAJ 2010;182(14):1507-12. Epub 2010 Sep 7.

BOTTOM LINE r 3BEJBM GSBDUVSFT BSF CZ GBS UIF NPTU common pediatric fractures (40% to 50%), and 80% of these involve the distal third of the radius. r 5SBEJUJPOBM USFBUNFOU PG CVDLMF GSBDUVSFT involved casting the injury for up to 3 XFFLT BOE GPS EJTUBM SBEJVT BOE VMOB fractures an above-elbow cast for up to 6 XFFLT IBT UZQJDBMMZ CFFO VTFE r 5IF NPTU VQ UP EBUF FWJEFODF TVHHFTUT that for pediatric distal radius fractures, XIJDI JODMVEF CVDLMF GSBDUVSFT BOE minimally angulated fractures (<15Â°), the new standard of care should be the use of a removable wrist immobilizer. POINTS SAILLANTS r -FT GSBDUVSFT EV SBEJVT TPOU EBOT une large mesure, les fractures les plus courantes chez lâ&#x20AC;&#x2122;enfant (de 40 % Ă 50 %) et, dans 80 % de ces cas, elles touchent le tiers distal du radius. r -F USBJUFNFOU USBEJUJPOOFM EFT GSBDUVSFT en motte de beurre comporte de plĂ˘trer la CMFTTVSF QFOEBOU KVTRV Ă&#x2020; TFNBJOFT EBOT les cas des fractures du radius distal et du cubitus, un plĂ˘tre jusquâ&#x20AC;&#x2122;au-dessus du coude est habituellement laissĂŠ en place pendant une pĂŠriode allant jusquâ&#x20AC;&#x2122;Ă 6 semaines. r -FT QMVT SĂ&#x160;DFOUFT EPOOĂ&#x160;FT QSPCBOUFT GPOU valoir que, pour les fractures pĂŠdiatriques du radius distal, incluant les fractures en motte de beurre et celles minimalement angulĂŠes (< 15Â°), la nouvelle norme de soins serait dâ&#x20AC;&#x2122;utiliser un dispositif amovible dâ&#x20AC;&#x2122;immobilisation du poignet. Emergency Files is a quarterly series in Canadian Family Physician coordinated by the members of the Emergency Medicine Committee of the College of Family Physicians of Canada. The series explores common situations experienced by family physicians doing emergency medicine as part of their primary care practice. Please send any ideas for future articles to Dr Robert Primavesi, Emergency Files Coordinator, at robert.primavesi@muhc.mcgill.ca.

Tools for Practice

Pharmacotherapy for smoking G. Michael Allan

MD CCFP

Noah Ivers

MD CCFP

Charl Els

MB Chb FCPsych

Clinical question

Bottom line

How effective are the treatments for smoking cessation and what are the potential concerns?

Nicotine replacement, bupropion, nortriptyline (off label), and varenicline are all effective in smoking cessation; AEs vary (and might relate to quitting smoking), but they are important and require monitoring.

Evidence Cochrane reviews: Nicotine replacement therapy (NRT): 132 RCTs.1 -Overall risk ratio (RR) and 95% confidence interval (CI) of abstinence: 1.58 (1.50 to 1.66); similar for gum, patch, inhaler, and lozenge.  -Adverse events (AEs): local irritation related to product type; no evidence of increased myocardial infarction. t Antidepressants: 49 bupropion and 9 nortriptyline RCTs.2  -The RR (95% CI) for cessation over placebo at 6 to 12 months: bupropion 1.69 (1.53 to 1.85); nortriptyline 2.03 (1.48 to 2.78).  -Bupropion AEs: primarily insomnia and dry mouth; 7% to 12% AE drop-out rate; rarely seizure (about 1/1000) and suicidal thoughts or behaviour (association unclear).  -Nortriptyline AEs: primarily dry mouth, drowsiness, light-headedness, and constipation (less at lower doses); 4% to 12% drop-out rate from AEs. t Varenicline: 9 RCTs.3  -The RR (95% CI) for cessation at 6 to 12 months over placebo was 2.33 (1.95 to 2.80).  -Varenicline AEs: primarily nausea, insomnia, and abnormal dreams; 10% AE drop-out rate4; neuropsychiatric AEs (eg, depression, agitation, suicidal thoughts or behaviour) are infrequent but require monitoring.5  -Reported benefit of varenicline might be influenced by industry funding and lack of a pragmatic design. Assuming 10% placebo cessation rates (mean across studies), approximate numbers needed to treat (at 6 to 12 months) are as follows: varenicline 8, nortriptyline 10, bupropion 10, and NRT 16. t

Context Smoking cessation is the most effective preventive maneuver for high-risk patients: an RCT6 of aggressive intervention for 209 patients after critical care admission achieved a 2-year quit rate of 39% (9% for placebo) and mortality of 3% (vs 12%); number needed to treat was 11. t Dosing: -Bupropion: 150 mg is equivalent to 300 mg.2,7 -Varenicline: 0.5 mg twice daily is as effective (or almost as effective)8,9 as 1 mg twice daily, but with fewer AEs. -Nortriptyline: start with 25 mg at bedtime and increase by 25 mg every 3 to 4 days, if the desire to smoke persists, to a maximum of 75 to 100 mg; encourage a quit date 10 days in (or so) and continue for 10 to 12 weeks. t

Implementation Primary care providers can increase smoking cessation simply by advising patients to quit.10 Although busy clinicians too often miss these opportunities,11 reminder checklists or EMR prompts can increase the frequency of such interventions.12 Smokers also benefit from help lines,13 such as the Canadian Cancer Society program, which offers telephone and online support (www.smokershelpline.ca). Dr Allan is Associate Professor in the Department of Family Medicine at the University of Alberta in Edmonton. Dr Ivers is a family physician at Women’s College Hospital in Toronto, Ont. Dr Els is an addiction psychiatrist and a medical review officer in Edmonton. Competing interests Dr Els received funding from the makers of medication for smoking cessation up to a year ago. Currently, his work is funded by Alberta Cancer Legacy Fund. The opinions expressed in Tools for Practice articles are those of the authors and do not necessarily mirror the perspective and policy of the Alberta College of Family Physicians. References 1. Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2008;(1):CD000146. 2. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2007;(1):CD000031. 3. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2008;(3):CD006103. 4. Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006;296(1):56-63. 5. Gunnell D, Irvine D, Wise L, Davies C, Martin RM. Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database. BMJ 2009;339:b3805. DOI: 10.1136/bmj.b3805. 6. Mohiuddin SM, Mooss AN, Hunter CB, Grollmes TL, Cloutier DA, Hilleman DE. Intensive smoking cessation intervention reduces mortality in high-risk smokers with cardiovascular disease. Chest 2007;131(2):446-52. 7. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, et al. A comparison of sustainedrelease bupropion and placebo for smoking cessation. N Engl J Med 1997;337(17):1195-202. 8. Nakamura M, Oshima A, Fujimoto Y, Maruyama N, Ishibashi T, Reeves KR. Efficacy and tolerability of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers. Clin Ther 2007;29(6):1040-56. 9. Oncken C, Gonzales D, Nides M, Rennard S, Watsky E, Billing CB, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med 2006;166(15):1571-7. 10. Stead LF, Bergson G, Lancaster T. Physician advice for smoking cessation. Cochrane Database Syst Rev 2008;(2):CD000165. 11. Thorndike AN, Regan S, Rigotti NA. The treatment of smoking by US physicians during ambulatory visits: 1994-2003. Am J Public Health 2007;97(10):1878-83. 12. Papadakis S, McDonald P, Mullen KA, Reid R, Skulsky K, Pipe A. Strategies to increase the delivery of smoking cessation treatments in primary care settings: a systematic review and meta-analysis. Prev Med 2010;51(3-4):199-213. 13. Stead LF, Perera R, Lancaster T. Telephone counselling for smoking cessation. Cochrane Database Syst Rev 2006;(3):CD002850.

Tools for Practice articles in Canadian Family Physician are adapted from articles published twice monthly on the Alberta College of Family Physicians (ACFP) website, summarizing medical evidence with a focus on topical issues and practice-modifying information. The ACFP summaries and the series in Canadian Family Physician are coordinated by Dr G. Michael Allan, and the summaries are co-authored by at least 1 practising family physician. Feedback is welcome and can be sent to toolsforpractice@cfpc.ca. Archived articles are available on the ACFP website: www.acfp.ca.

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Diagnosing ARIs Series

Acute cough in adults Graham Worrall

MB BS MSc FCFP

ecause acute cough has a different range of causes in adults than it does in children, adults should be assessed and treated differently. The American College of Chest Physicians’ evidence-based clinical practice guidelines1 recommend that patients with acute cough be divided into children (younger than 15 years of age) and adults (15 years of age or older). Also, people with underlying and chronic diseases or compromised immune systems should be considered and treated differently; primary care clinicians will have no difficulty recognizing such patients. Mr John Smith, a 37-year-old taxi driver, comes to see you on Thursday evening as a drop-in patient. He complains of a cough that has been bothering him for 9 days. He felt a bit shivery when it began, but that has passed. The cough is worse at night but it is also present during the day. He is coughing up slight amounts of yellow-green sputum, once with a slight streak of blood. He feels slightly under the weather because the cough is hindering his sleep. During the past 5 years, you have seen him 3 times. Once he had an ingrown toenail, once he had an acute back strain (helping a passenger unload at the airport), and once he had tonsillitis. He is not currently taking any medication and has no chronic diseases. His patient record mentions that he is a smoker.

Epidemiology and population at risk Acute cough is one of the most common presentations in general practice. This type of cough, also described as acute bronchitis, is the fifth most common new presentation to FPs in Australia2 and the United States.3 Figures from the United Kingdom suggest there are about 50 cases per 1000 people each year,4 and acute cough leads to 10 ambulatory visits per 1000 visits each year in the United States. 5 Evidence from such general practice reports and the US and UK morbidity surveys shows that the overwhelming majority of acute coughs are infectious in origin. Mr Smith’s story suggests an acute respiratory tract infection. He has no risk factors for serious respiratory disease, although you note he is a smoker and you do not know whether he has asthma. His job entails long hours in a confined space with many different people,

This article has been peer reviewed. Cet article a fait l’objet d’une révision par des pairs. Can Fam Physician 2010;57:48-51 48

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which would certainly increase his risk of picking up an infection. You question him further.

What else could it be? Figure 1 shows the distribution of cough causes in typical general practice.4 Mr Smith says he does not, as far as he knows, have asthma or any heart troubles. Although he has smoked for 20 years, he felt fine until 9 days ago; he has not noticed any weight loss, chest pain, or hemoptysis. Because recent Health Canada regulations have prohibited smoking in the taxi, he has actually reduced his daily cigarette consumption from 20 to about 10. He has not felt short of breath. The illness came on slowly, over a day or so. He has not traveled out of town for 2 years.

Alarm symptoms. The patient might report a sudden fever (eg, influenza, pneumonia, severe acute respiratory syndrome [SARS]) or might have been in contact with an infected person (eg, influenza, SARS). He or she will remember recent air travel or surgical procedures (eg, pulmonary embolism), or being exposed to an unusual respiratory irritant (eg, chemicals, gases, excessive tobacco smoke). The patient will usually remember wheezing. The doctor will know whether the patient is immunosuppressed or suffers from asthma or dementia. Alarm signs. The patient will seem unusually ill (eg, pneumonia, influenza) or short of breath (eg, congestive heart failure, SARS, acute asthma). There might be a high fever (eg, SARS, pneumonia, influenza). The respiratory rate might be increased. There might be signs of reduced air entry, consolidation, or restricted air entry. Mr Smith looks slightly tired but otherwise well. He coughs once into a tissue while in your office; a small amount of yellowish sputum appears on the tissue. His temperature is 37.0°C, his pulse is 82 beats/min, and his respiratory rate is 17 breaths/min. Ears, nose, and throat examination findings are normal; no cervical or axillary lymphadenopathy is present. There is good air entry into all zones of his lungs. You hear 1 or 2 faint crackles on inspiration; these disappear when he coughs. You have not heard of any outbreaks of influenza or other respiratory disease in your area. You are becoming almost certain that he has acute bronchitis.

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Diagnosing ARIs Series Figure 1. Distribution of causes of acute cough among adults in typical general practice

Common cold Acute bronchitis Asthma Chronic brochitis or COPD Environmental Influenza Rare serious disease

2% 2% 2%

10%

60%

20%

COPD—chronic obstructive pulmonary disease. Data from McCormick et al.4

How sure of the diagnosis are you? Acute bronchitis is usually a presumptive diagnosis, which is made based on history and examination, when the patient presents with an acute productive cough of less than 3 weeks’ duration. However, most GPs are worried that they might miss a case of acute community-acquired pneumonia (CAP), which still has relatively high mortality, especially among the elderly.6 The criterion standard for diagnosing CAP is the presence of consolidation on the chest radiograph, but GPs cannot be ordering chest x-ray scans for every patient with acute cough. As no one symptom or sign has a large effect of the likelihood of pneumonia being present in a person with an acute cough, investigators have combined various symptoms and signs to make clinical decision rules for CAP7-9; unfortunately, even if a patient without asthma has fever, tachycardia, and crackles—a combination of symptoms and signs very suggestive of pneumonia— the rules still do not have enough power to definitively “rule in” pneumonia. They do, however, certainly suggest a chest x-ray scan should be done. The American College of Chest Physicians1 recommends that absence of the following findings reduces

the likelihood of pneumonia sufficiently to eliminate the need for a chest x-ray scan: t heart rate greater than 100 beats/min; t respiratory rate greater than 24 breaths/min; t oral temperature greater than 38°C; and t chest examination showing focal consolidation, egophony, or fremitus. Similarly, when the history is suggestive of acute bronchitis and there are no alarm signs in the chest, there is no need for sputum analysis, viral culture, or serologic analysis. Table 1 shows positive and negative likelihood ratios for pneumonia of various respiratory symptoms and physical signs.10 Note that, apart from egophony, neither symptoms nor signs have high positive likelihood ratios for pneumonia; in a low-prevalence primary care situation, the positive likelihood ratio has to be very high to significantly increase the chances of pneumonia being present. Similarly, apart from a previous history of asthma and a currently runny nose, few symptoms or signs have much of a negative likelihood ratio. You decide that the absence of alarm symptoms and signs, together with the absence of any features that

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Diagnosing ARIs Series would increase the possibility of pneumonia, confirm your diagnosis of acute bronchitis.

Table 1. Likelihood ratios for pneumonia of various respiratory symptoms and physical signs SIGNS AND SYMPTOMS

POSITIVE LIKELIHOOD RATIO

NEGATIVE LIKELIHOOD RATIO

Respiratory symptoms r

Cough

1.8

0.3

Dyspnea

1.4

0.7

Sputum produced

1.3

0.6

Other symptoms r

Fever

2.1

0.7

Chills

1.7

0.8

Myalgia

1.3

0.6

Sore throat

0.8

1.6

Runny nose

0.8

2.4

Medical history r

Asthma

0.1

3.8

Immunosuppression

2.2

0.9

Dementia

3.4

0.9

Vital signs r

Tachypnea > 25 breaths/min

3.4

0.8

Temperature > 37.8°C

4.4

0.7

Chest signs r

Dull percussion

4.3

0.8

Decreased sounds

2.5

0.7

Crackles

2.7

0.8

Bronchial sounds

3.5

0.9

Egophony

8.6

1.0

Data from Metlay et al.10

Is it likely to get worse? Acute bronchitis is an infection of the tracheo-bronchial tree, which might transiently produce sputum and symptoms of airway obstruction. The cough commonly lasts 7 to 10 days, but can last up to 1 month in 25% of patients.11 When the clinical course of control-group patients in trials of antibiotic treatment of acute bronchitis was studied, it was found that 85% to 90% of patients improved spontaneously, just as quickly as if they had not taken antibiotics.12

Deciding on best treatment Reports have shown that up to 80% of non-smokers and 90% of smokers with acute bronchitis receive antibiotics. 13,14 There have been a number of reviews of the effects of antibiotics on the course of acute bronchitis. Half of them concluded that there was no benefit from taking antibiotics; the other half, including a

Canadian Family Physician t Le Médecin de famille canadien

Cochrane review, concluded that antibiotics can have some modest treatment effects compared with placebo.15 The use of antibiotics decreases the time feeling ill with cough and sputum production by about half a day, and reduces time lost from work by about a third of a day. These modest benefits, which might occur only in a subgroup of patients, must be weighed against the chance of antibiotic side effects. You explain to Mr Smith that there is no sign of serious illness; he has acute bronchitis due to a viral infection. The condition is like a “cold on the chest” and it will get better by itself; there is no need for antibiotic treatment. It should take about 2 weeks to get better. Mr Smith accepts your diagnostic explanation, but explains that the cough at night is preventing good sleep, and he does not wish to miss work because of the illness. Surely there is some medicine to relieve his illness?

Most adults who present to their FPs with cough are looking for relief of their symptoms.16 Unless the patient has a history of asthma, or the clinician can hear widespread wheezing, β-agonists are not recommended.17 There is no evidence that mucolytics help in acute bronchitis. Although cough suppressants and antihistamines have not specifically been well studied in patients with acute bronchitis, the former can be effective in chronic bronchitis and the latter provide some relief for patients with colds. It seems reasonable that a combined cough suppressant and antihistamine might provide short-term symptomatic relief in a patient with acute bronchitis. Your careful history has excluded any likely serious causes for Mr Smith’s acute cough; in particular, your careful clinical examination has ruled out asthma and CAP. You are certain that his recent-onset productive cough is due to acute bronchitis. He accepts your explanation that antibiotics will be of no use, and you have suggested a short-term cough suppressant and antihistamine to relieve his annoying symptoms so that he can continue working. You remind Mr Smith to try (once again) to give up smoking. You recommend that Mr Smith use an over-the-counter medication (dextromethorphan, with or without an antihistamine) at night for the next 7 to 10 days. You recommend that he return to see you if he gets worse, or does not improve, at the end of that time period. You make a mental note to consider a chest x-ray scan if his cough persists, he loses weight, or he remains unwell. Dr Worrall is an Honorary Research Professor in the Department of Family Medicine at Memorial University of Newfoundland in St John’s.

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Diagnosing ARIs Series Competing interests None declared Correspondence Dr Graham Worrall, Dr W.H. Newhook Memorial Clinic, Family Medicine, Box 449, Whitbourne, NF A0B 3K0; e-mail gworrall@mun.ca References 1. Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, et al. Diagnosis and management of cough executive summary: ACCP evidencebased clinical practice guidelines. Chest 2006;129(1 Suppl):1S-23S. 2. Meza RA, Bridges-Webb C, Sayer GP, Miles DA, Traynor V, Neary S. The management of acute bronchitis in general practice: results from the Australian Morbidity and Treatment Survey, 1990-1991. Aust Fam Physician 1994;23(8):1550-3. 3. Delozier JE, Gagnon RO. National ambulatory care survey: advance data. Publication no. 203. Hyattsville, MD: National Center for Health Statistics; 1991. 4. McCormick A, Fleming D, Charlton C. Morbidity statistics from general practice—fourth National Morbidity Survey, 1991-92. London, UK: HMSO, Office for National Statistics; 1995. 5. US Center for National Health Statistics. Data from the National Ambulatory Medical Care Survey 1999. Atlanta, GA: US Center for National Health Statistics; 2000. 6. Diehr P, Wood RW, Bushyhead J, Krueger L, Wolcott B, Tompkins RK. Prediction of pneumonia in outpatients with acute cough—a statistical approach. J Chronic Dis 1984;37(3):215-25. 7. Singal BM, Hedges JR, Radack KL. Decision rules and clinical prediction of pneumonia: evaluation of low-yield criteria. Ann Emerg Med 1989;18(1):13-20.

8. Fine MJ, Smith MA, Carson CA, Mutha SS, Sankey SS, Weissfeld LA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA 1996;275(2):134-41. 9. Heckerling PS, Tape TG, Wigton RS, Hissong KK, Leikin JB, Ornato JP, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med 1990;113(9):664-70. 10. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997;278(17):1440-5. 11. Hueston WJ, Mainous WG 3rd. Acute bronchitis. Am Fam Physician 1998;57(6):1270-6, 1781-2. 12. Alberta Clinical Guidelines Program. Guideline for the management and treatment of acute bronchitis. Edmonton, AB: Alberta Clinical Guidelines Program; 2000. Available from: www.albertadoctors.org. Accessed 2010 Nov 26. 13. Stocks NP, Fahey T. The treatment of acute bronchitis by general practitioners in the UK. Results of a cross-sectional postal survey. Aust Fam Physician 2002;31(7):676-9. 14. Linder JA, Sim I. Antibiotic treatment of acute bronchitis in smokers: a systematic review. J Gen Intern Med 2002;17(3):230-4. 15. Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database Syst Rev 2004;(4):CD000245. 16. Gonzales R, Barrett PH Jr, Crane LA, Steiner JF. Factors associated with antibiotic use in acute bronchitis. J Gen Intern Med 1998;13(8):541-8. 17. Smucny J, Becker LA, Glazier R. Beta2-agonists for acute bronchitis. Cochrane Database Syst Rev 2006;(4):CD001726.

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| Canadian Family Physician

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Constipation affects up to 95% of patients taking opioids.1

Introducing

速

DUAL THERAPEUTIC EFFECT

Controlled release oxycodone for the relief of moderate to severe pain, together with controlled release naloxone for relief of opioid-induced constipation...in one tablet.2*

A Novel Combination.

Demonstrated analgesic efficacy of OxyContin® demonstrated no statistically significant difference compared to OxyContin® for average pain scores (p=0.406).2,3† ®

Reduced constipation with naloxone demonstrated a statistically significant improvement in bowel function at 4 weeks compared to OxyContin®, as measured by Bowel Function Index ® (p<0.0001), with improvements already seen after 1 week. [ vs. ® vs. OxyContin® OxyContin®: -14.9; 95% CI: -17.9, -11.9 at 4 weeks, -13.8 (44.16 vs. 57.96) mean BFI at 1 week (p<0.0001)].2,3† ®

® * (oxycodone hydrochloride/naloxone hydrochloride) is a controlled release tablet having a dual therapeutic effect. ® is indicated for the relief of moderate to severe pain in adults who require continuous The oxycodone component in ® is indicated for the relief of around-the-clock opioid analgesia for several days or more. The naloxone component in opioid-induced constipation (OIC). ® . The most Adverse events often observed with other drugs with opioid-agonist activity, were also seen with frequently observed were nausea which tends to reduce with time, as well as constipation, diarrhea, fatigue, headache and ® is contraindicated in: patients hypersensitive to oxycodone or naloxone, other opioid analgesics, or to hyperhidrosis. any ingredient in the formulation; patients with gastrointestinal obstruction or diseases affecting bowel transit or suspected surgical abdomen; acute pain or perioperative pain; acute alcoholism or convulsive disorders; CNS depression; concomitant MOA inhibitors (or within 14 days of such therapy); pregnant or breast-feeding women; and moderate to severe hepatic impairment. ® is 80 mg oxycodone/40 mg naloxone, however, dosage limitations may be imposed by The maximum daily dose of adverse effects as well. If they occur, please refer to prescribing information.

Warning: Opioid analgesics should be prescribed and handled with a degree of caution appropriate to the use of a drug with ® , as it may increase the chance of abuse potential. Patients should be cautioned not to consume alcohol while taking ® should not be administered rectally due to the possible increased systemic experiencing dangerous side effects. ® 40/20 mg availability of naloxone by this route and the potential for the occurrence of severe withdrawal effects. tablets are for use in opioid tolerant patients only. There is potential for fatal respiratory depression in a single dose greater than 40 mg of oxycodone, or total daily doses greater than 80 mg of oxycodone, when administered to patients intolerant of the ® should not be used to treat patients with constipation not related to opioid respiratory depressant effects of opioids. ® tablets should be swallowed whole and should not be broken, chewed, dissolved or crushed since this can lead use. to the rapid release and absorption of a potentially fatal dose of oxycodone. Product monograph available on request. Multicentre, randomized, double-blind, double-dummy, active-controlled, parallel group study in patients with chronic back pain and osteoarthritis. BFI = 3-item questionnaire using (NAS) Numerical Analogue Scale (0-100) = low numbers for good bowel function. Pain Intensity Score (0-10) = average pain over last 24 hours over ® 10/5, 20/10, 40/20 mg q12h vs. OxyContin® 10, 20, 40 mg q12h, placebo q12h. IR oxycodone q4-6h p.r.n. for breakthrough pain. 80/40 mg 12 weeks. ( ® 4.13 vs. OxyContin® 3.94 at 12 weeks, (-0.19). maximum per day.)2,3 Average pain over last 24 hours was not statistically different and remained constant. ® vs. OxyContin® 0.10 difference, p=0.406; 95% CI: - 0.14, 0.34; pain intensity (NRS) Numerical Rating Scale 0-10).3 Bowel function improvement was ( ® ® . (Clinically meaningful difference in mean BFI scores >12 change.) (BFI mean at week 4: 40.9 vs. statistically significant in favour of OxyContin® 53.3).3 (12 weeks) (n=265).2,3 †

® TM

Controlled release oxycodone/naloxone HCl tablets

Partners in Pain Care

105

Praxis | Cognitive Behavioural Therapy Series

Part 2. Scalification Greg Dubord

nce a complaint (eg, depression, anxiety, loneliness) has been “goalified”1 (eg, happiness, calmness, community), the next step is “scalification.” Scalification is most easily defined with an example:

Pt: Doc, I’m so depressed [elaborates]. Dr: [Accurate empathic statement, then goalifying] It sounds like your goal is to make yourself happier. Have I got that right? Pt: [Responding rapidly] Yes, I guess you could say that. Dr: [Scalifying] OK, well let’s imagine a 0-to-10 scale of happiness, where 0 was your most depressed, and 10 was your happiest. Where are you along that scale today? Accountability is the primary purpose of scalifying (eg, patient-to-self, patient-to-doctor, and doctor-to-patient). The main application of scalification is for those psychological interventions with a medium level of formality— not likely to be a “one-off,” but not likely to be full-on “psychotherapy” either. One-offs don’t need scales, and formal psychotherapy lacks credibility without more formal psychometry (eg, Beck Depression Inventory, Beck Anxiety Inventory). Scalification continues with a “why-not-worse” question to reinforce the patient’s locus of control:

Dr: [Empathy, then …] You say 3. What are some of things you’re doing to keep it from being a 2?

The final component in scalifying is a “how-makebetter” question:

Dr: What are you willing to commit to [or experiment with] doing to try to make it a 4 between now and our next appointment? The “how-make-better” question might have to be repeated: it’s not uncommon for the patient to slip back into “complaint mode” at this time. Sometimes even regoalifying is required:

Dr: Sorry to interrupt, but when you say you’re so depressed, you’re also saying that happiness is your goal, right?

The doctor ends with a behavioural prescription—which is ideally recorded in the chart. An excellent opening question on follow-up is as follows:

Dr: Last time we agreed that you have a goal of happiness, and you said you were 3 on a 0-to-10 scale. You were doing A and B to keep it from getting worse, and said you’d try doing C and D to try to make it better. Where are you on our happiness scale today?

If there was good adherence and a good outcome, make sure you point out the correlation. If the link seems causal, say so. Many chronic patients have erroneously concluded that mood is randomly determined. To us causal connections are obvious, but to those with “learned helplessness” they are not. In the common scenario of poor adherence and a poor outcome, linger awhile. It’s vitally important that patients learn from natural consequences. Consider asking a question like “What do you make of that?” and pausing. Diving in too early with anesthetizing empathy can impair learning, and in the long run can be iatrogenic (this issue will be addressed in greater depth in a future article). In the unfortunate scenario of good adherence and poor outcome, begin with a good dose of empathy. Emphasize that efforts are essential even without a 100% guarantee of mood improvement. Discuss lag effects (if appropriate). Collaboratively explore whether another experiment with the same behavioural prescription is warranted, and tweak as required. Scalification is both a measurement tool and an intervention with an important role in psychological situations with medium formality. Dr Dubord teaches cognitive behavioural therapy (CBT) for the Department of Psychiatry at the University of Toronto. In this series of Praxis articles, he outlines the core principles and practices of medical CBT, his adaptation of orthodox CBT for primary care. Acknowledgment I thank the following CBT Blue 2010 participants for their helpful critique of this paper: Dr Chuck Adamson, Dr Ray Bouchard, and Dr Sandra Wismer. Correspondence Greg Dubord, e-mail greg.dubord@cbt.ca Reference 1. Dubord G. Part 1. Goalification. Can Fam Physician 2010;56:1312.

Next month: The Reward Chart

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Dermacase

Ophthaproblem

Can you identify this condition? Ashley Brissette Kelly Schweitzer Brian Arthur MD FRCSC

Can you identify this condition? Olivia Potok MD Vimal Prajapati Benjamin Barankin MD FRCPC

30-year-old man presents with a 5-day history of a bilateral, symmetric eruption consisting of multiple, well-demarcated, scaly, erythematous, droplike papules primarily distributed over his trunk and extremities. He denies having any systemic symptoms, but does note that he had a sore throat approximately 2 weeks ago.

The most likely diagnosis is 1. 2. 3. 4. 5.

4-year-old boy (accompanied by his mother) presents to your office with a 5-day history of runny nose and a 2-day history of swelling in the left eye. The swelling can be localized to the inner portion of the lower eyelid, at the medial angle of the eye. There is redness and some crusting at the eyelids, and the child is fussy when you try to examine the eye. You notice that the mother is continually wiping the eye on account of excessive tearing; when you apply digital pressure to the lacrimal sac, some purulent discharge is exuded from the punctum. The child has no past ocular complications or infections and is otherwise healthy.

The most likely diagnosis is 1. Acute ethmoid sinusitis 2. Facial cellulitis involving the medial angle of the eye 3. Dacryoadenitis 4. Dacryocystitis

Pityriasis rosea Secondary syphilis Nummular dermatitis Guttate psoriasis Pityriasis lichenoides

Answer on page 56 VOL 57: JANUARY t JANVIER 2011

Answer on page 58

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Dermacase Answer to Dermacase

continued from page 55

4. Guttate psoriasis Guttate psoriasis is a distinct eruptive dermatosis that classically occurs in children and young adults following a group A β-hemolytic streptococcal (GAS) infection. Guttate psoriasis might present as either the initial manifestation of psoriasis in individuals previously unaffected by psoriasis or as an acute exacerbation in individuals with pre-existing chronic plaque psoriasis. Affected patients are much more likely to have a family history of psoriasis, and might report experiencing a stressful life event in close association with the guttate eruption.1 Guttate psoriasis typically presents as an acute bilateral, symmetric eruption consisting of multiple, welldemarcated, salmon-pink to erythematous, round to oval papules ranging in size from 1 mm to 10 mm in diameter. A fine silvery scale is often present on more established lesions. The distribution is primarily on the trunk and proximal extremities. The palms, soles, and face are usually spared. The rash is often asymptomatic, although some patients might report mild pruritus. The word guttate is derived from the Latin word gutta, meaning “drop,” as the lesions can be likened to red drops splashed upon the skin. There is a well-established association between guttate psoriasis and antecedent or concurrent GAS infection.2,3 Typically, the GAS infection precedes onset of the guttate eruption by 1 to 3 weeks, and the patient might relate a history of recent upper respiratory tract infection, pharyngitis, or tonsillitis. There have also been several case reports of guttate eruptions following streptococcal perianal dermatitis in children.4 The exact pathophysiologic correlation between guttate psoriasis and streptococcal infection is not fully understood. It is postulated that the guttate eruption might result from an immune reaction to the streptococcal infection, usually in those with susceptible genotypes, particularly human leukocyte antigen–Cw*0602.5,6 Human leukocyte antigen genotypes might influence T-cell proliferation in response to streptococcal antigens (some of which have shown homology with human keratin) and thus might modulate the inflammatory response.7,8 Guttate psoriasis is usually a self-limiting process, especially in children, with full resolution occurring within 12 to 16 weeks without treatment. Limited information is available about the long-term prognosis of individuals with first-manifestation guttate psoriasis. However, data from 1 small study suggest that approximately 33% of patients with guttate psoriasis might eventually develop chronic plaque psoriasis.9

Diagnosis Guttate psoriasis is essentially a clinical diagnosis. Throat or perianal bacterial cultures to test for

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streptococcal infection might be performed, and elevated antistreptolysin O titre levels are common. The differential diagnosis includes pityriasis rosea, pityriasis lichenoides, small plaque parapsoriasis, nummular dermatitis, secondary syphilis, and viral or drug exanthem. Pityriasis rosea can be differentiated from guttate psoriasis on the basis of morphology and arrangement. Lesions of pityriasis rosea tend to be oval with collarette scaling (ie, circumferential scale just inside the peripheral margin) and their long axes are oriented along skincleavage lines on the trunk, thus creating the classic “Christmas tree” pattern. In addition, pityriasis rosea often begins with the “herald patch,” a solitary, large, oval to round, scaly, salmon-coloured or erythematous plaque that precedes the generalized eruption by several days. Pityriasis lichenoides differs from guttate psoriasis in that the eruptions are more often polymorphic (as lesions are present in various stages of evolution) and the papules are generally smaller than those observed in guttate psoriasis. Lesions of small plaque parapsoriasis are flatter and tend to appear as elongated fingerlike patches on the lateral aspects of the trunk, thus producing a characteristic digitate pattern. Nummular dermatitis preferentially involves the distal extremities, and plaques tend to be more coin-shaped and very pruritic; nummular dermatitis plaques are less numerous than those of guttate psoriasis. Secondary syphilis can closely resemble guttate psoriasis, and syphilis serology should be considered if the diagnosis is uncertain. Patients with secondary syphilis tend to have more systemic complaints; involvement of the palms, soles, and face is also common, a distribution pattern that is not usually seen with guttate psoriasis. Viral and drug exanthems should also be considered in the differential diagnosis, as guttate psoriasis can appear similar to these 2 entities, especially early in its course when there is minimal or no scaling. A careful history regarding recent illness or medication use can help to clarify the diagnosis.

Treatment Although guttate psoriasis is normally a self-limiting process, adjunct therapeutic agents might be beneficial in expediting resolution. Topical agents including emollients, corticosteroids, vitamin D3 analogues, or coal-tar preparations might be effective, but they are cumbersome to apply on account of the large area of involvement. In prolonged cases of guttate psoriasis, resolution might be further accelerated with the use of ultraviolet therapy, particularly narrowband UVB phototherapy, although psoralen-UVA photochemotherapy can also be used. However, firm evidence for the efficacy of these various therapies in the treatment of guttate psoriasis is currently lacking.10 If there is evidence of persistent or untreated streptococcal infection, a course of appropriate antibiotics is

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Dermacase indicated; however, there might be no associated improvement in the guttate psoriasis after therapy.11,12 Finally, there is some limited evidence that tonsillectomy might help to reduce frequently recurring or chronic guttate psoriasis associated with streptococcal tonsillitis, although controlled clinical trials have yet to be completed.13 Dr Potok is a first-year dermatology resident at the University of Alberta in Edmonton. Dr Prajapati is a third-year dermatology resident at the University of Alberta. Dr Barankin is a dermatologist practising in Toronto, Ont. Competing interests None declared References 1. Naldi L, Peli L, Parazzini F, Carrel CF; Psoriasis Study Group of the Italian Group for Epidemiological Research in Dermatology. Family history of psoriasis, stressful life events, and recent infectious disease are risk factors for a first episode of acute guttate psoriasis: results of a case-control study. J Am Acad Dermatol 2001;44(3):433-8. 2. Telfer NR, Chalmers RJ, Whale K, Colman G. The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol 1992;128(1):39-42. 3. Whyte HJ, Baughman RD. Acute guttate psoriasis and streptococcal infection. Arch Dermatol 1964;89(3):350-6. 4. Ulger Z, Gelenava T, Kosay Y, Darcan S. Acute guttate psoriasis associated with streptococcal perianal dermatitis. Clin Pediatr (Phila) 2007;46(1):70-2.

5. Mallon E, Bunce M, Savoie H, Rowe A, Newson R, Gotch F, et al. HLA-C and guttate psoriasis. Br J Dermatol 2000;143(6):1177-82. 6. Gudjonsson JE, Karason A, Antonsdottir A, Runarsdottir EH, Hauksson VB, Upmanyu R, et al. Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes. Br J Dermatol 2003;148(2):233-5. 7. Sigmundsdottir H, Sigurgeirsson B, Troye-Blomberg M, Good MF, Valdimarsson H, Jonsdottir I. Circulating T cells of patients with active psoriasis respond to streptococcal M-peptides sharing sequences with human epidermal keratins. Scand J Immunol 1997;45(6):688-97. 8. Baker BS, Brown DW, Fischetti VA, Ovigne JM, Porter W, Powles A, et al. Skin T cell proliferative response to M protein and other cell wall and membrane proteins of group A streptococci in chronic plaque psoriasis. Clin Exp Immunol 2001;124(3):516-21. 9. Martin BA, Chalmers RJ, Telfer N. R. How great is the risk of further psoriasis following a single episode of acute guttate psoriasis? Arch Dermatol 1996;132(6):717-8. 10. Chalmers RJ, O’Sullivan T, Owen CM, Griffiths CE. A systematic review of treatments for guttate psoriasis. Br J Dermatol 2001;145(6):891-4. 11. Dogan B, Karabudak O, Harmanyeri Y. Antistreptococcal treatment of guttate psoriasis: a controlled study. Int J Dermatol 2008;47(9):950-2. 12. Owen CM, Chalmers RJ, O’Sullivan T, Griffiths CE. A systematic review of antistreptococcal interventions for guttate and chronic plaque psoriasis. Br J Dermatol 2001;145(6):886-90. 13. McMillin BD, Maddern BR, Graham WR. A role for tonsillectomy in the treatment of psoriasis? Ear Nose Throat J 1999;78(3):155-8.

Help relieve the symptoms of GERD at night.* *TECTA® Product Monograph based on pantoprazole sodium data. TECTA® demonstrated comparable efficacy to pantoprazole sodium based on comparative pharmacodynamic effects.

NOW COVERED ON MOST PROVINCIAL FORMULARIES ‡ TECTA® (pantoprazole magnesium) is indicated for the treatment of conditions where a reduction of gastric acid secretion is required, such as duodenal ulcer, gastric ulcer, reflux esophagitis, symptomatic gastro-esophageal reflux disease (such as acid regurgitation and heartburn) and Helicobacter pylori associated duodenal ulcer; in combination with clarithromycin and either amoxicillin or metronidazole, for the treatment of patients with an active duodenal ulcer who are H. pylori positive. Contraindications: hypersensitivity to this drug or to any ingredient in the formulation or component of the container. Pantoprazole, like all PPIs, should not be concurrently administered with atazanavir.

‡ ON, BC, SK, Atlantic Canada.

® Registered trademark of Nycomed GmbH. Used under licence.

Ophthaproblem Answer to Ophthaproblem continued from page 55 4. Dacryocystitis Dacryocystitis is an inflammation and infection of the lacrimal sac, usually caused by nasolacrimal duct obstruction.1-3 It can be classified as acute, subacute, or chronic, and can be localized to the sac, extend to the pericystitis, or progress further to cause orbital cellulitis.3 Congenital lacrimal duct obstruction can carry a higher chance of secondary infection, leading to dacryocystocele formation. Most congenital dacryocystoceles will require surgical intervention.4 In dacryocystitis, patients often present with pain, tearing, redness, and swelling over the lacrimal sac (ie, the nasal aspect of the lower eyelid) as well as mucoid or purulent discharge when digital pressure is applied to the area.1-3 This most commonly occurs in infants and in adults older than 40 years of age.1 The etiology of dacryocystitis is well documented; the most common cause is nasolacrimal duct obstruction.1-3 The duct functions to drain tears from the eye to the nasal cavity. When it is blocked, material builds up within the sac, which can lead to inflammation and infection.2 The most common causative organisms are staphylococci, streptococci, and diptheroids.1,5 One study suggested a higher occurrence of methicillin-resistant Staphylococcus aureus in acute cases of dacryocystitis.5 Higher incidence of dacryocystitis has been reported in children born with craniofacial abnormalities and Down syndrome.6 It must be stressed that infantile dacryocystitis is a medical emergency. If the infection proceeds, it can cause serious complications such as orbital cellulitis, cutaneous fistula formation, septic shock, mass effects, optic neuropathy, and even blindness.1,7 Dacryoadenitis is a similar sounding condition; however, it involves inflammation and infection of the lacrimal gland, located at the outer upper eyelid. 1 In dacryoadenitis, there is pain, redness, swelling, tearing, and discharge over the lacrimal gland (ie, the lateral one-third of the upper eyelid). 1 Other common signs are ipsilateral preauricular lymphadenopathy, fever, and an elevated white blood cell count. Dacryoadenitis most commonly occurs in the pediatric population, as well as in young adults.1 Dacryoadenitis is most commonly due to inflammation, and occurs in conditions such as lymphoid proliferation, sarcoidosis, and orbital pseudotumour. Other causes are viral infections (eg, mumps, influenza, and herpes zoster) and, rarely, bacterial infections (eg, S aureus, Neisseria gonorrheae, or streptococci).1

Management It is important to know the cause of dacryocystitis in order for it to be properly treated. A thorough history followed by external and ocular examination should be

Canadian Family Physician t Le Médecin de famille canadien

conducted. It is essential to note any decrease in extraocular movement and any signs of proptosis, as these are suggestive of orbital cellulitis, a serious ocular complication. If discharge is released upon digital palpation of the punctum, it should be swabbed and sent for Gram stain and blood agar culture (as well as chocolate agar in the pediatric population).1 There is agreement in the literature that patients should immediately be started on systemic antibiotics, with further adjustments based on clinical response and culture or sensitivity results.1,2 The severity of the patient’s symptoms, as well as patient age, dictates the choice of treatment. The following describes the possible therapies for a bacterial or infectious (but currently unidentified) cause of dacryocystitis: In an afebrile child with a mild case, 20 to 40 mg/kg of oral amoxicillin-clavulanate taken daily in 3 divided doses will suffice. If the child is febrile and acutely ill, he or she should be hospitalized and treated with 50 to 100 mg/kg of intravenous cefuroxime taken daily in 3 divided doses.1 In the adult population, an afebrile patient with a mild case should be given 500 mg of oral cephalexin every 6 hours, and a febrile, acutely ill patient should be hospitalized and given 1 mg of intravenous cefazolin every 8 hours. All antibiotics should be continued for a full 10- to 14-day course.1 In addition to systemic therapy, patients can also use topical antibiotic eye drops, take over-the-counter analgesics to control pain, and apply warm compresses over the affected area. Patients should be clinically reassessed on a daily basis until their condition improves. Needle drainage of the abscess can be beneficial if the infection has come to a head.1 Once the initial infection has subsided, nasolacrimal duct probing is recommended to ensure that the condition does not recur. In this scenario, the patient is placed under general anesthesia or in restraints, and a probe is advanced into the nasolacrimal duct through the nose, which can be irrigated to test for patency. Care must be taken to advance the probe slowly to avoid complications, such as creating a “false passage.”7 In cases of dacryocystocele formation due to congenital nasolacrimal duct obstruction, the rule is first to treat the infection and afterward to consider surgical correction. If the condition is serious, or bilateral dacryocystoceles are obstructing ventilation, referral in the early neonatal period is necessary to prevent complications and infection. 4 Surgical options comprise recanalization of the nasolacrimal duct and external dacryocystorhinostomy, with success rates of 93% and 91%, respectively.8 Dacryoadenitis is also empirically treated with systemic antibiotics until the exact cause is identified. Inflammatory causes are treated with 80 to 100 mg of oral prednisone once daily, along with an antiulcer medication, such as 150 mg of oral ranitidine twice daily. Viral causes are treated for symptom relief, including

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Ophthaproblem cool compresses over the affected area and over-thecounter analgesics. Lastly, bacterial causes are treated with systemic antibiotics based on the age of the patient and severity of the symptoms, with the same medications and regimens as listed for dacryocystitis.1 Our patient was treated with oral amoxicillin clavulanate (20 to 40 mg/kg/d in 3 divided doses). His mother was advised to apply a warm compress to the affected area and to give the child some children’s acetaminophen, as required, for symptom relief. She was also advised to call if the boy’s symptoms were worsening or if she had any further concerns. The patient was seen in the office for the next 2 days, and because he was improving steadily, the antibiotics were continued for their full course.

Conclusion Dacryocystitis and dacryoadenitis are common infections and inflammations that can affect the pediatric as well as adult population. A thorough history and ocular physical examination are essential to diagnosing these conditions. Medical intervention is

often required. Empiric treatment should be started immediately, but can later be modified based on etiology and patient response. Ms Brissette is a fourth-year medical student at Queen’s University in Kingston, Ont. Dr Schweitzer is a fourth-year resident in the Department of Ophthalmology at Queen’s University. Dr Arthur is Associate Professor and a pediatric ophthalmologist in the Department of Ophthalmology at Queen’s University. Competing interests None declared References 1. Kunimoto DY, Kanitkar KD, Makar M, editors. The Wills eye manual: office and emergency room diagnosis and treatment of eye disease. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004. 2. Faden HS. Dacryocystitis in children. Clin Pediatr (Phila) 2006;45(6):567-9. 3. Yanoff M, Duker JS. Ophthalmology. 3rd ed. St Louis, MO: Mosby; 2009. p. 1482-7. 4. Wong RK, VanderVeen DK. Presentation and management of congenital dacryocystocele. Pediatrics 2008;122(5):e1108-12. Epub 2008 Oct 27. 5. Mills DM, Bodman MG, Meyer DR, Morton AD 3rd; ASOPRS Dacryocystitis Study Group. The microbiologic spectrum of dacryocystitis: a national study of acute versus chronic infection. Ophthal Plast Reconstr Surg 2007;23(4):302-6. 6. Berk AT, Saatci AO, Erçal MD, Tunç M, Ergin M. Ocular findings in 55 patients with Down’s syndrome. Ophthalmic Genet 1996;17(1):15-9. 7. Kapadia MK, Freitag SK, Woog JJ. Evaluation and management of congenital nasolacrimal duct obstruction. Otolaryngol Clin North Am 2006;39(5):959-77, vii. 8. Chen D, Ge J, Wang L, Gao Q, Ma P, Li N, et al. A simple and evolutional approach proven to recanalise the nasolacrimal duct obstruction. Br J Ophthalmol 2009;93(11):1438-43. Epub 2009 May 4.

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See prescribing summary on page 113

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Research

A qualitative evaluation of strategies to increase colorectal cancer screening uptake Jill Tinmouth MD PhD FRCPC Paul Ritvo PhD S. Elizabeth McGregor PhD Danielle Claus MPA George Pasut Ronald E. Myers PhD Crissa Guglietti MA Lawrence F. Paszat MD MS FRCPC Robert J. Hilsden MD PhD FRCPC Linda Rabeneck MD MSc FRCPC

MD MHSc CCFC

Abstract Objective To obtain data that could be used to optimize the content and design of the targeted, mailed invitations that Ontario’s provincewide colorectal cancer (CRC) screening program plans to use to increase screening uptake; to identify other strategies to increase CRC screening uptake; and to describe the effects of this qualitative work on a subsequent quantitative pilot study. Design Qualitative study using semistructured focus groups. Setting Four different Ontario communities. Participants Six focus groups comprising a total of 62 participants. Methods Six focus groups were conducted in 4 different Ontario communities. For 3 of the communities, participants were recruited from the general population by a private marketing firm, using random-digit dialing, and received a small honorarium for participating. In Sault Ste Marie, participants were convenience samples recruited from a large primary care practice and were not offered compensation. Responses were elicited regarding various strategies for promoting CRC screening. Findings represent all responses observed as well as recommendations to program planners based on focus groups observations. Main findings Key themes identified included the importance of receiving a CRC screening invitation from one’s family physician; a desire for personalized, brief communications; and a preference for succinct information in mailed materials. Strong support was indicated for direct mailing of the CRC screening kit (fecal occult blood test). Our findings substantially influenced the final design and content of the envelope and letter to be mailed in the subsequent quantitative pilot study. Conclusion We report strong support from our focus groups for a succinct, personalized invitation for CRC screening from one’s own family physician. We have also shown that qualitative evaluation can be used to provide decision makers with pertinent and timely knowledge. Our study is highly relevant to other public health programs, particularly other Canadian jurisdictions planning organized CRC screening programs.

EDITOR’S KEY POINTS r Colorectal cancer (CRC) screening can reduce mortality but requires broad uptake to be effective. Ontario’s provincewide CRC screening program plans to use large-scale targeted, mailed invitations to increase screening uptake. This study sought to solicit feedback on various strategies for promoting CRC screening, including the design content of mailed invitations. r Participants were generally in favour of concise, individualized communications from their family physicians, although many thought that having the provincial cancer agency logo appear on the envelope of mailed invitations raised privacy concerns, and some believed that using the family physician’s name was misleading. r Participants were also supportive of having fecal occult blood tests directly mailed to them, providing some sort of priming strategy was used to prepare them for the test’s arrival.

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Recherche | Exclusivement sur le web

Évaluation qualitative des stratégies pour augmenter l’utilisation du dépistage du cancer colorectal Jill Tinmouth MD PhD FRCPC Paul Ritvo PhD S. Elizabeth McGregor PhD Danielle Claus MPA George Pasut Ronald E. Myers PhD Crissa Guglietti MA Lawrence F. Paszat MD MS FRCPC Robert J. Hilsden MD PhD FRCPC Linda Rabeneck MD MSc FRCPC

MD MHSc CCFC

Résumé Objectif Obtenir des données pouvant servir à optimiser le contenu et la forme des lettres d’invitation que le programme ontarien de dépistage du cancer colorectal (CCR) s’apprête à lancer à travers le province pour augmenter l’utilisation du dépistage; identifier d’autres stratégies pour augmenter l’utilisation du dépistage; et décrire l’effet qu‘ont eu les données qualitatives obtenues sur une étude pilote quantitative ultérieure. Type d’étude Étude qualitative à l’aide de groupes de discussion semi-structurés. Contexte Quatre collectivités différentes de l’Ontario. Participants Six groupes de discussion, pour un total de 62 participants. Méthodes On a tenu 6 groupes de discussion dans 4 collectivités différentes. Dans 3 de celles-ci, les participants, qui avaient été recrutés dans la population générale par une firme de marketing privée par des appels téléphoniques au hasard, ne recevaient qu’une faible rémunération pour leur participation. À Sault Ste Marie, les participants avaient été recrutés par échantillonnage raisonné parmi la clientèle d’une grande clinique des soins de première ligne et ils ne recevaient aucune compensation. Les avis recherchés concernaient les diverses stratégies susceptibles de promouvoir le dépistage du CCR. Les opinions recueillies comprennent toutes les réponses obtenues ainsi que les recommandations des groupes de discussion à l’intention des responsables du programme. Principales observations Parmi les thèmes clés identifiés, mentionnons l’importance d’être invité à participer au programme de dépistage du CCR par son propre médecin de famille; une préférence pour un texte court et personnalisé; et le souhait que le matériel posté comporte une information succincte. On suggérait fortement que le kit de dépistage du CCR (recherche du sang occulte dans les selles) soit posté directement. Nos observations ont eu une influence considérable sur la forme et le contenu de l’enveloppe et des lettres qui seront envoyées dans une étude pilote subséquente. Conclusion Les opinions recueillies dans les groupes de discussion sont fortement favorables à une invitation pour un dépistage du CCR qui soit succincte et personnalisée, et qui provienne de son propre médecin de famille. Nous avons également démontré qu’une évaluation qualitative peut être une source de connaissances pertinentes et opportunes pour les responsables de programme. Cette étude est d’une grande pertinence pour d’autres programmes de santé publique, notamment pour d’autres compétences canadiennes qui planifient l’organisation de programmes de dépistage du CCR.

Cet article a fait l’objet d’une révision par des pairs. Can Fam Physician 2011;57:e7-15 e8

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POINTS DE REPÈRE DU RÉDACTEUR Le dépistage du cancer colorectal (CCR) peut réduire la mortalité mais il doit être largement utilisé pour être efficace. Le programme ontarien de dépistage du CCR a comme objectif d’utiliser une invitation postée à la grandeur de la province pour augmenter son utilisation. La présente étude voulait obtenir un feedback sur différentes stratégies pour promouvoir le dépistage du CCR, incluant le type de contenu des invitations postales.

Les participants étaient généralement favorables à des communications individualisées concises de leur médecin de famille, quoique plusieurs jugeaient que la présence du logo de l’agence provinciale du cancer sur l’enveloppe suscitait certaines inquiétudes par rapport à la confidentialité, alors que d’autres croyaient que l’utilisation du nom du médecin de famille portait à confusion.

Les participants souhaitaient aussi que les kits pour la recherche du sang occulte dans les selles leur soient postés directement, à condition qu’on utilise une quelconque stratégie de présentation pour les préparer a les recevoir.

Increasing colorectal cancer screening | Research

olorectal cancer (CRC) is the third most common cancer in the world and the fourth leading cause of cancer-related death.1 Screening is critical to prevent CRC-related mortality, as early detection is associated with improved prognosis. Colonoscopy, flexible sigmoidoscopy, barium enema, or fecal occult blood testing (FOBT) can be used to screen for CRC, although only FOBT has been shown to decrease CRC incidence and mortality2-4 in randomized controlled trials. Fecal occult blood testing is easy, safe, and economical (ie, inexpensive and requiring minimal human resources), 5 while colonoscopy or flexible sigmoidoscopy are more costly, risky, burdensome, resourceintensive, and not as well supported by the evidence. Among the 14 countries of the International Cancer Screening Network that have implemented organized national or regional CRC screening programs, 13 use FOBT or another stool-based test, while only Norway uses endoscopy (ie, flexible sigmoidoscopy).6,7 Recently, Ontario launched an organized provincewide CRC screening program, ColonCancerCheck. Through this program, FOBT is offered to those at average risk and colonoscopy is offered to those at increased risk based on family history. Family physicians play a critical role in the program and are responsible for patient outreach and education, initiating screening activities, and receiving and acting on results. Canadian CRC screening rates are low. In 2008, just 40% of eligible Canadians were up-to-date with CRC screening using FOBT or endoscopy, and only 23% were up-to-date using FOBT alone.8 Several strategies have been used to increase CRC screening uptake. According to a systematic review by the US Task Force on Community Preventive Services, client reminders (letters, postcards, or telephone calls to alert clients to obtain cancer screening) are effective. 9 ColonCancerCheck plans to issue mailed, targeted CRC screening invitations to eligible Ontarians, inviting them to contact their family physicians to arrange CRC screening. The most effective design and content of such targeted invitations, however, are unknown. The aims of our study were to inform the content and design of a mailed invitation to participate in a CRC screening program, to identify additional strategies that might increase CRC screening uptake by eligible persons, and to apply the results from this qualitative work to a subsequent quantitative pilot study of mailed, targeted CRC screening invitations.

METHODS We conducted semistructured focus groups (FGs) to explore the attitudes, beliefs, and emotional and behavioural responses of screening-eligible adults to possible

materials (envelopes, letters, informational materials, FOBT kits) and strategies being considered for a large-scale mailed, targeted CRC screening invitation pilot study, which is intended for eventual provincewide implementation. Approval was obtained from the Research Ethics Board at Sunnybrook Health Sciences Centre in Toronto, Ont, and the Group Health Centre in Sault Ste Marie, Ont.

Focus group participants Six 2-hour FG sessions were conducted in 4 communities in Ontario (large and small cities, representing different parts of the province) in June and July of 2009. Two single-sex FGs (1 each of women only and men only) were held in each of Toronto and Sault Ste Marie, and 1 with both men and women was held in each of Peterborough and Sudbury. In Toronto, Peterborough, and Sudbury, participants were recruited from the general population by a private marketing firm, using random-digit dialing and received a small honorarium ($75) for participating. In Sault Ste Marie, participants were convenience samples recruited from a large primary care practice and were not offered compensation. Informed consent was obtained by investigators before the actual sessions. Each FG consisted of screening-eligible adults aged 50 years and older. Among the subjects recruited through random-digit dialing, we sought to balance the groups by age (< 65 years, ≥ 65 years), employment status (working, retired, or at home), and previous screening experience (screened, never screened). We also endeavoured to ensure adequate urban-rural, educational, and ethnocultural representation.

Materials tested All FGs were moderated by a psychologist (P.R.) experienced in conducting cancer-prevention qualitative interview studies. During each session, the moderator presented 4 different versions of screening invitations. The first letter was a full page, and the 3 other letters were shorter half-page versions. The shorter letters were paired with a separate multicoloured, double-sided brochure, a separate full-page fact sheet, or a 5-bullet fact box located beneath the text of the letter. While all letters included both the ColonCancerCheck program logo and family physician’s name in an italicized font, none incorporated the physician’s actual signature. In addition, different envelopes with various return-address options were presented. Using interview-guided questions, opinions and preferences regarding content and design of the materials were carefully elicited. Emphasis was placed on features that would most attract individuals to open mailed envelopes and read materials, as well as help them to comprehend key messages. Also, the moderator explored the content that would be

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themes supporting this recommendation included that participants believed the physician’s name indicated that the contents were important, but the combination of the physician and provincial program names elicited strong negative responses, including anxiety and privacy concerns.

Data analysis

Obviously, if I see it’s from my doctor, I’d want to see [it] right away.” (FG 3, Peterborough)

The demographic characteristics of the FG members were tabulated. Where appropriate, the median or the number and proportion were reported. As the FG analyses were intended to inform a quantitative pilot study of materials and processes being considered for large-scale implementation, there were 2 analytic components: to responsibly guide the pilot study by responding to specific questions posed by program planners and to rigorously represent all findings. For the first component, which required rapid reporting to meet program planners’ timelines, we relied heavily on our detailed notes and preliminary analyses to make recommendations. The nature of this process generally required advising a single option based on the level of support in the FGs rather than representing all findings as is more traditional in qualitative research. For the second component, we used the verbatim transcripts of the interviews. The constant comparative method was used to identify key themes representing varying attitudes and preferences,10 with the coding of the content of each FG carried out on a line-by-line basis to identify all phrases, key words, and expressed concepts. NVivo 8 qualitative analysis software aided the process of coding the comparisons between expressed concepts identified by participants.

I like the idea of the doctor’s name on it because that makes it more personal, and, quite frankly, whether it’s good news or bad news, I want to hear it. (FG 5, Sudbury) There is so much junk mail that if your doctor’s name is there you will open it right away. (FG 2, Toronto) [Having the provincial logo on the envelope is an] invasion of privacy as far as I’m concerned. You’re telling too much. That’s my personal business. Nobody else should know. (FG 3, Peterborough) This causes a lot of people … even the postman [who] is gossiping at some time to your neighbours [to think] “There’s something wrong with that guy.” (FG 2, Toronto) If I saw the word ColonCancerCheck from my doctor, I wouldn’t open that up for about a week. I wouldn’t even call and I’d ditch the letter and make sure I ditch it in a good spot. I’d gradually work on trying to think about opening it, because I don’t want to read what’s on the inside .... That would scare the hell out of me. (FG 2, Toronto)

FINDINGS

Representing all FG responses: Some participants also believed that receiving letters from their family physicians, even without the program name, would cause anxiety because communications were generally conducted by telephone.

Focus groups The characteristics of the 62 FG attendees are described in Table 1. For each topic explored (envelope, letter, and directly mailed FOBT kits), our analyses revealed several key themes. We have organized these themes under 2 headings: those that were incorporated into our advice to the pilot study planners and those that are included so as to represent all data collected.

I’d say “What the heck is wrong now that he’s writing me?” (FG 5, Sudbury) If that was mailed to me from my doctor, I wouldn’t open that up for a week, maybe a month. (FG 5, Sudbury)

Envelope content and design. Program planners were interested in the responses of FG attendees to screening invitations with return-address options that included the name of the family physician, the provincial colorectal cancer screening program, or both. Advice to program planners: Based on FG responses, we recommended that only the family physician’s name appear on the outside of the envelope. The key

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Letter content and design. Additional questions pertained to the design and content of the letter (described above) to be sent during the planned quantitative study. Advice to program planners: A key theme was that a brief, direct letter was preferred. Based on this strong preference and on the participants’ specific reactions t

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Increasing colorectal cancer screening | Research Table 1. Characteristics of the focus group attendees, by group: N = 62. CHARACTERISTICS

FOCUS GROUP TORONTO, WOMEN (N = 12)

TORONTO, MEN (N = 12)

12 (100)

5 (42)

6 (50)

7 (100)

Median age, y

62.5

63.5

Marital status, n (%) r Married or common law r Divorced or separated r Single r Widowed

5 (42) 3 (25) 3 (25) 1 (8)

11 (92) 0 1 (8) 0

4 (33) 4 (33) 2 (17) 1 (8)

9 (75) 0 1 (8) 2 (17)

7 (100) 0 0 0

Work status, n (%) r Full-time r Part-time r Retired r Disability or unemployed r Homemaker

4 (33) 0 6 (50) 1 (8) 1 (8)

4 (33) 1 (8) 5 (42) 2 (17) 0

3 (25) 4 (33) 4 (33) 0 0

1 (8) 2 (17) 5 (42) 2 (17) 2 (17)

1 (14) 0 6 (86) 0 0

1 (14) 2 (29) 4 (57) 0 0

Income, n (%) r < $20 000 r $20 000 to $40 000 r $40 000 to $60 000 r > $60 000

2 (17) 4 (33) 2 (17) 4 (33)

1 (8) 4 (33) 3 (25) 4 (33)

0 5 (42) 3 (25) 3 (25)

1 (8) 3 (25) 3 (25) 5 (42)

0 0 6 (86) 1 (14)

0 0 5 (71) 2 (29)

Education, n (%) r High school or less r Some college or university r Completed college or university

2 (17) 3 (25) 7 (58)

4 (33) 5 (42) 2 (17)

7 (58) 1 (8) 4 (33)

5 (71) 0 2 (29)

7 (100) 0 0

Ethnicity, n (%) r European descent r West Indies r African Canadian r Dominican or Guyanese r Indian r Asian r South Asian

8 (67) 1 (8) 2 (17) 1 (8) 0 0 0

7 (58) 0 0 0 1 (8) 1 (8) 3 (25)

11 (92) 0 0 0 0 0 0

11 (92) 0 1 (8) 0 0 0 0

7 (100) 0 0 0 0 0 0

Prior colon cancer screening, n (%) r Yes r No

8 (67) 4 (33)

5 (42) 7 (58)

5 (42) 6 (50)

7 (58) 5 (42)

7 (100) 0

Type of prior screening, n (%) r FOBT alone r Colonoscopy alone r Sigmoidoscopy alone r More than 1 test r None

0 5 (42) 0 3 (25) 4 (33)

1 (8) 2 (17) 0 2 (17) 7 (58)

1 (8) 2 (17) 0 2 (17) 6 (50)

2 (17) 0 1 (8) 4 (33) 5 (42)

5 (71) 2 (29) 0 0 0

3 (43) 3 (43) 0 1 (14) 0

Men, n (%)

PETERBOROUGH* (N = 12)

SUDBURY (N = 12)

SAULT STE MARIE, WOMEN (N = 7)

SAULT STE MARIE, MEN (N = 7)

FOBT—fecal occult blood testing. *Data are missing for 1 participant in the Peterborough focus group.

to the example letters provided, we recommended the shorter letter with the 5-bullet fact box. I’ll go with [the brief letter] because it’s nice and short and ... to the point. It has complete information. (FG 2, Toronto) I like the little boxes with the brief points. If you want to know more ... you can definitely find out more.

When you get too many sheets, you tend to either ignore or drift over. When it’s all on 1 sheet, you’ve got it right there. It’s brief; it’s to the point ... it says what it needs to. (FG 6, Sault Ste Marie)

Representing all FG responses: Again, the FG questions about the 4 letter options elicited a spectrum of responses. All versions received some support from participants; however, an important theme was that some

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Research | Increasing colorectal cancer screening thought that all versions of the letters were misleading because their physicians did not actually personally write them.

there’s, I’m certain, lots of people [who] don’t have family physicians. I think it’s more available and everybody [could] be reached. (FG 1, Toronto)

Effect of qualitative findings on quantitative pilot study

This is not a letter from my doctor. If I open that up and find out it’s a mass mailing by ColonCancerCheck .... I think you’ve played on my concern .... and my relationship with my doctor. You’ve used that to get me to open that letter. (FG 6, Sudbury)

Before the study reported here was carried out, a longer, more detailed letter was planned for mailing in an envelope that carried the ColonCancerCheck logo along with the family physician’s name (Figure 1). After our results were communicated to program planners, a revised letter (brief, with a bulleted fact box) was mailed in an envelope that carried the physician’s name alone (Figure 2). Program planners had not originally intended to include FOBT kits in the mailing and did not do so as a result of our study. However, our findings stimulated considerable interest such that further studies of the use of directly mailed FOBT in more difficult to reach populations are planned.

I would first go, “Wait a minute; my doctor doesn’t write me? … Have I gotten on some list somewhere?” Something like that. (FG 1, Toronto) Too short of a letter with little information? I need more information. (FG 2, Toronto)

Mailing the FOBT kit directly to those eligible for screening. While some organized CRC screening programs mail FOBT kits directly, 11,12 ColonCancerCheck currently asks patients to visit their family physicians to obtain kits. Both researchers and program planners were interested in FG attendees’ reactions to direct mailing of FOBT kits. Advice to program planners: We recommended that kit mailing be considered as a second phase of activity, as an important theme was that a “priming communication,” such as a media campaign or a mailed notice about the campaign, should precede the direct mailing. Participants in more rural settings (ie, Sudbury, Peterborough) were most supportive of directly mailed FOBT, perhaps reflecting the inconvenience of traveling to the doctor and the relative paucity of doctors in these settings.

DISCUSSION The objective of this qualitative study was to report on recommendations made to program planners conducting a quantitative feasibility assessment of a large-scale mailed invitation for CRC screening that is intended for eventual provincewide implementation. Our recommendations included that screening-eligible individuals should receive mailed CRC screening invitations from their own family physicians and that information should be presented in a succinct, clear, easily read format. Additionally, we identified direct mailing of FOBT kits, after a “priming communication,” as a potentially powerful strategy to improve screening uptake. On each of these topics, we also reported on the full spectrum of FG responses. Previous studies have used FG methodology to evaluate use of reminder letters and mailed materials to increase uptake of various preventive health services before their implementation13 or following actual reminder mailings.14-17 Several of these studies examined the design and content of materials being used for cancer screening,13 including breast14 and cervical17 screening. Similar to our findings, these studies reported that FG participants preferred brief, personalized reminder letters with access to additional factual information, rather than more detailed letters. We found that having the family physician’s name on the letter was particularly important; this is a finding that has been reported in 1 other study.14 Our FG attendees preferred notification before receiving a direct mailing of FOBT kits. This finding is substantiated by a recent controlled trial, which found that a priming strategy elicited greater uptake of CRC screening compared with direct mailing of the kit alone.18

If you’re going to actually end up doing this anyway, then give them a little tip off .... When it comes, it’s like, “Oh, okay. This is what I was told about.” (FG 2, Toronto) You would have to send something back to the program saying “Yes, send me the kit.” Then you would feel better about getting the kit, and then you’d be ready to do your own thing .... I just would feel better that I’m part of the decision-making process. (FG 2, Toronto)

Representing all FG responses: Participants emphasized the immediacy, practicality, and the universality achieved, including for patients without regular physicians, by direct mailing with adequate priming. Best idea you’ve had all day. (FG 5, Sudbury) Just to reach people do you think it could be an advantage? A lot of people don’t know about it and

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Increasing colorectal cancer screening | Research Figure 1. Planned invitation for colorectal cancer screening before the study

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Increasing colorectal cancer screening | Research The qualitative project reported here was intended to guide a subsequent, quantitative pilot study of mailed, targeted CRC screening invitations; as such, it illustrates an often unacknowledged role of FG methodology in clinical research. While an increasing number of researchers identify qualitative methods as their primary research strategy, these methods are also often used to inform the design and structure of initiatives targeting large-scale populations. In the latter instance, FGs play a critical role, but results are often not reported in scientific publications. This study demonstrates that qualitative methodology can be applied in pragmatic and scientifically rigorous manners simultaneously. To support both goals, we reported on the themes that supported advice regarding further program planning as well as reporting all other key themes identified in our comparative analysis. While this approach deviates from the theoretical foundations of qualitative analyses, we were able to translate relevant and timely high-quality research knowledge to program planners in order to considerably affect the structure of a real-world program. Although we attempted to represent the diversity of responses to various CRC screening strategies and our participants represented a variety of perspectives (eg, region, income, previous screening experience), we recognize that our sample was predominantly white and spoke English sufficiently well to participate. Therefore, our findings might not be generalizable to certain groups.

Conclusion Consistent with other studies of preventive health interventions, we found strong support for a succinct, personalized invitation for CRC screening from the family physician. This paper illustrates the importance and feasibility of using qualitative research to provide meaningful, effective, and timely guidance for public health programs, and is particularly relevant to other Canadian jurisdictions planning organized CRC screening programs. Dr Tinmouth is a staff physician at Sunnybrook Health Sciences Centre in Toronto, Ont, Adjunct Scientist for the Institute for Clinical Evaluative Sciences, and Assistant Professor at the University of Toronto. Dr Ritvo is Associate Professor in the School of Kinesiology and Health Science and the Department of Psychology at York University and a Scientist for Cancer Prevention and Control at Cancer Care Ontario in Toronto. Dr McGregor is Research Scientist in Population Health Research at Alberta Health Services Cancer Care and Adjunct Associate Professor in the Department of Community Health Sciences and Preventive Oncology at the University of Calgary. Ms Claus is Director of Prevention and Screening Policy at Cancer Care Ontario. Dr Pasut is Vice-President of Prevention and Screening at Cancer Care Ontario. Dr Myers is Professor and Director of the Division of Population Science in the Department of Medical Oncology at Thomas Jefferson University in Philadelphia, Pa. Ms Guglietti is a doctoral candidate in the School of Kinesiology and Health Science at York University. Dr Paszat is a staff physician at Sunnybrook Health Sciences Centre, Senior Scientist at the Institute for Clinical Evaluative Sciences, and Associate Professor at the University of Toronto. Dr Hilsden is Associate Professor in the Department of Community Health Sciences and the Department of Medicine at the University of Calgary. Dr Rabeneck is Senior Scientist at Sunnybrook Health Sciences Centre and at the Institute for Clinical Evaluative Sciences, Professor at the University of Toronto, and Medical Director of the Ontario Colorectal Cancer Screening Program.

Acknowledgment This study was conducted with the support of the Ontario Institute for Cancer Research and Cancer Care Ontario through funding provided by the Government of Ontario. This work was also supported in part by a grant from the Canadian Institutes for Health Research (No. CST-85478). Contributors All authors contributed to the concept and design of the study; data gathering, analysis, and interpretation; and preparing the manuscript for submission. Dr Ritvo moderated the focus groups and shares first authorship with Dr Tinmouth. Competing interests None declared Correspondence Dr Jill Tinmouth, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Room HG40, Toronto, ON M4N 3M5; e-mail jill.tinmouth@sunnybrook.ca References 1. Center MM, Jemal A, Ward E. International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev 2009;18(6):1688-94. 2. Mandel JS, Church TR, Bond JH, Ederer F, Geisser MS, Mongin SJ, et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med 2000;343(22):1603-7. 3. Hardcastle JD, Chamberlain JO, Robinson MH, Moss SM, Amar SS, Balfour TW, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348(9040):1472-7. 4. Kronborg O, Fenger C, Olsen J, Jørgensen OD, Søndergaard O. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 1996;348(9040):1467-71. 5. Wilson JM, Jungner G. Principles and practice of screening for disease. Geneva, Switz: World Health Organization; 1968. 6. International Cancer Screening Network. Inventory of colorectal cancer screening activities in ICSN countries, May 2008. Bethesda, MD: International Cancer Screening Network; 2009. Available from: http://appliedresearch.cancer. gov/icsn/colorectal/screening.html. Accessed 2009 Oct 8. 7. Hoff G, Grotmol T, Skovlund E, Bretthauer M; Norwegian Colorectal Cancer Prevention Study. Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomised controlled trial. BMJ 2009;338:b1846. DOI: 10.1136/bmj.b1846. 8. Wilkins K, Shields M. Colorectal cancer testing in Canada—2008. Health Rep 2009;20(3):21-30. 9. Baron RC, Rimer BK, Breslow RA, Coates RJ, Kerner J, Melillo S, et al. Clientdirected interventions to increase community demand for breast, cervical, and colorectal cancer screening: a systematic review. Am J Prev Med 2008;35(1 Suppl):S34-55. 10. Flick U. An introduction to qualitative research. Thousand Oaks, CA: Sage Publications; 2006. 11. Malila N, Oivanen T, Malminiemi O, Hakama M, Malila N, Oivanen T, et al. Test, episode, and programme sensitivities of screening for colorectal cancer as a public health policy in Finland: experimental design. BMJ 2008;337:a2261. DOI: 10.1136/bmj.a2261. 12. UK Colorectal Cancer Screening Pilot Group. Results of the first round of a demonstration pilot of screening for colorectal cancer in the United Kingdom. BMJ 2004;329(7458):133. Epub 2004 Jul 5. 13. Ornstein SM, Musham C, Reid AO, Garr DR, Jenkins RG, Zemp LD. Improving a preventive services reminder system using feedback from focus groups. Arch Fam Med 1994;3(9):801-6. 14. Kaczorowski J, Karwalajtys T, Lohfeld L, Laryea S, Anderson K, Roder S, et al. Women’s views on reminder letters for screening mammography. Mixed methods study of women from 23 family health networks. Can Fam Physician 2009;55:622-3.e1-4. Available from: www.cfp.ca/cgi/reprint/55/6/622. Accessed 2010 Dec 7. 15. Ornstein SM, Musham C, Reid A, Jenkins RG, Zemp LD, Garr DR. Barriers to adherence to preventive services reminder letters: the patient’s perspective. J Fam Pract 1993;36(2):195-200. 16. Anderson KK, Sebaldt RJ, Lohfeld L, Karwalajtys T, Ismaila AS, Goeree R, et al. Patient views on reminder letters for influenza vaccinations in an older primary care patient population: a mixed methods study. Can J Public Health 2008;99(2):133-6. 17. Karwalajtys T, Kaczorowski J, Lohfeld L, Laryea S, Anderson K, Roder S, et al. Acceptability of reminder letters for Papanicolaou tests: a survey from 23 family health networks in Ontario. J Obstet Gynaecol Can 2007;29(10):829-34. 18. Cole SR, Smith A, Wilson C, Turnbull D, Esterman A, Young GP. An advance notification letter increases participation in colorectal cancer screening. J Med Screen 2007;14(2):73-5.

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Continuity of care is good for elderly people with diabetes Retrospective cohort study of mortality and hospitalization Graham Worrall

MB BS MSc FCFP

John Knight

MSc

Abstract Objective To examine the relationship between continuity of family physician care and all-cause mortality and acute hospitalizations in older people with diabetes. Design Retrospective cohort study of administrative health databases. Continuity of family physician care for elderly patients newly diagnosed with diabetes was estimated by 3 continuity indexes using physician claims data. The relationship of continuity of family physician care to mortality and acute hospitalizations was investigated. Setting The province of Newfoundland and Labrador. Participants A total of 305 family practice patients 65 years of age or older with diabetes. Main outcome measures Death rate and hospitalization rate during a 3-year period. Results Overall, continuity of family physician care was high. In the 3 years examined, the higher-continuity group had lower rates of hospitalization (53.5% vs 68.2%) and death (8.6% vs 18.5%) than the lower-continuity group. Conclusion The findings suggest an association between higher continuity of family physician care and reductions in likelihood of death and hospitalizations in older people with diabetes.

EDITORâ&#x20AC;&#x2122;S KEY POINTS r $POUJOVJUZ PG DBSF JT B EFGJOJOH QSJODJQMF PG GBNJMZ NFEJDJOF BOE JU IBT CFFO TIPXO UP JNQSPWF PVUDPNFT BOE EFDSFBTF DPTUT r 1FPQMF BHFE BOE PMEFS XJUI EJBCFUFT DPNQSJTF B IJHI SJTL HSPVQ UIF BVUIPST GPVOE B JO DIBODF PG EFBUI XJUIJO ZFBST PG UIF EJBHOPTJT CFJOH NBEF BOE B JO DIBODF PG IPTQJUBMJ[BUJPO r 0WFSBMM UIFSF XBT B IJHI MFWFM PG DPOUJOVJUZ PG DBSF JO UIF QPQVMBUJPO TUVEJFE #VU UIPTF XJUI IJHIFS DPOUJOVJUZ PG DBSF JOEFY TDPSFT XFSF TJHOJGJDBOUMZ MFTT MJLFMZ UP FYQFSJFODF IPTQJUBMJ[BUJPO P PS EFBUI P JO UIF ZFBS TUVEZ QFSJPE r 5IJT TUVEZ JT UIF GJSTU UP FYQMPSF UIF SFMBUJPOTIJQ CFUXFFO DPOUJOVJUZ PG DBSF BOE NPSUBMJUZ JO FMEFSMZ QFPQMF XJUI EJBCFUFT *U FYBNJOFE B SBOEPN TBNQMF PG QFPQMF GSPN BENJOJTUSBUJWF IFBMUI EBUBCBTFT XIJDI XFSF QPQVMBUJPO CBTFE BOE MPOHJUVEJOBM BOE JU XBT MPOHFS UIBO NPTU PUIFS TUVEJFT PG DPOUJOVJUZ PG DBSF )PXFWFS UIF EBUB VTFE BSF OPX B EFDBEF PME BOE UIF TUVEZ XBT POMZ BCMF UP FYBNJOF QBUJFOUT PG GFF GPS TFSWJDF QIZTJDJBOT

This article has been peer reviewed. Can Fam Physician 2011;57:e16-20 e16

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Recherche

Les diabĂŠtiques Ă˘gĂŠs bĂŠnĂŠficient dâ&#x20AC;&#x2122;un suivi continu Ă&#x2030;tude de cohorte rĂŠtrospective portant sur la mortalitĂŠ et lâ&#x20AC;&#x2122;hospitalisation Graham Worrall

MB BS MSc FCFP

John Knight

MSc

RĂŠsumĂŠ Objectif Examiner la relation entre la continuitĂŠ des soins dâ&#x20AC;&#x2122;un mĂŠdecin de famille et les taux de mortalitĂŠ toutes causes confondues et dâ&#x20AC;&#x2122;hospitalisation aiguĂŤ chez des diabĂŠtiques Ă˘gĂŠs. Type dâ&#x20AC;&#x2122;ĂŠtude Ă&#x2030;tude de cohorte rĂŠtrospective Ă partir de bases de donnĂŠes administratives sur la santĂŠ. La continuitĂŠ des soins dispensĂŠs par le mĂŠdecin de famille Ă des patients Ă˘gĂŠs ayant un diagnostic rĂŠcent de diabĂ¨te a ĂŠtĂŠ estimĂŠe Ă lâ&#x20AC;&#x2122;aide 3 indicateurs de continuitĂŠ, en utilisant des donnĂŠes sur la facturation des mĂŠdecins. On a examinĂŠ la relation entre la continuitĂŠ des soins du mĂŠdecin de famille et les taux de mortalitĂŠ et dâ&#x20AC;&#x2122;hospitalisation aiguĂŤ. Contexte La province de Terre-Neuve-et-Labrador. Participants Un total de 305 diabĂŠtiques de 65 ans et plus frĂŠquentant des cliniques de mĂŠdecine familiale. Principaux paramĂ¨tres Ă lâ&#x20AC;&#x2122;ĂŠtude Taux de dĂŠcĂ¨s et dâ&#x20AC;&#x2122;hospitalisation sur une pĂŠriode de 3 ans. RĂŠsultats Dans lâ&#x20AC;&#x2122;ensemble, il y avait un haut niveau de continuitĂŠ des soins par les mĂŠdecins de famille. Au cours de la pĂŠriode de 3 ans, ceux qui avaient un meilleur suivi avaient des taux dâ&#x20AC;&#x2122;hospitalisation (53,5 % vs 68,2 %) et de dĂŠcĂ¨s (8,6 % vs 18,5 %) plus faibles que ceux qui ĂŠtaient moins bien suivis. Conclusion Ces rĂŠsultats suggĂ¨rent une relation entre un meilleur suivi du mĂŠdecin de famille et une rĂŠduction de la mortalitĂŠ et des hospitalisations chez les diabĂŠtiques Ă˘gĂŠs.

POINTS DE REPĂ&#x2C6;RE DU RĂ&#x2030;DACTEUR r -B DPOUJOVJUĂ&#x160; EFT TPJOT FTU VO QSJODJQF GPOEBNFOUBM EF MB NĂ&#x160;EFDJOF GBNJMJBMF JM B Ă&#x160;UĂ&#x160; EĂ&#x160;NPOUSĂ&#x160; RV FMMF BNĂ&#x160;MJPSF MFT JTTVFT UPVU FO SĂ&#x160;EVJTBOU MFT DPĂ&#x161;UT r -FT EJBCĂ&#x160;UJRVFT EF BOT FU QMVT DPOTUJUVFOU VO HSPVQF Ă&#x2020; SJTRVF Ă&#x160;MFWĂ&#x160; MFT BVUFVST POU PCTFSWĂ&#x160; RV JMT POU VOF DIBODF TVS EF NPVSJS FU TVS E Ă&#x2039;USF IPTQJUBMJTĂ&#x160;T EBOT MFT BOT TVJWBOU MF EJBHOPTUJD r %BOT M FOTFNCMF JM Z BWBJU VO IBVU OJWFBV EF DPOUJOVJUĂ&#x160; EFT TPJOT EBOT MB QPQVMBUJPO Ă&#x2020; M Ă&#x160;UVEF 5PVUFGPJT DFVY RVJ BWBJFOU EFT TDPSFT QMVT Ă&#x160;MFWĂ&#x160;T QPVS MFT JOEJDBUFVST EF TVJWJ DPOUJOV Ă&#x160;UBJFOU TJHOJGJDBUJWFNFOU NPJOT TVTDFQUJCMFT E Ă&#x2039;USF IPTQJUBMJTĂ&#x160;T P PV EF NPVSJS P EVSBOU MFT BOOĂ&#x160;FT EF M Ă&#x160;UVEF r $FUUF Ă&#x160;UVEF FTU MB QSFNJĂ?SF Ă&#x2020; Ă&#x160;UVEJFS MB SFMBUJPO FOUSF DPOUJOVJUĂ&#x160; EFT TPJOT FU NPSUBMJUĂ&#x160; DIF[ MFT EJBCĂ&#x160;UJRVFT Ă&#x201E;HĂ&#x160;T % VOF EVSĂ&#x160;F TVQĂ&#x160;SJFVSF Ă&#x2020; MB QMVQBSU EFT Ă&#x160;UVEFT TFNCMBCMFT FMMF QPSUBJU TVS VO Ă&#x160;DIBOUJMMPO BMĂ&#x160;BUPJSF EF QBUJFOUT QSPWFOBOU EF CBTFT EF EPOOĂ&#x160;FT BENJOJTUSBUJWFT TUSBUJGJĂ&#x160;FT FU MPOHJUVEJOBMFT TVS MB TBOUĂ&#x160; 5PVUFGPJT MFT EPOOĂ&#x160;FT VUJMJTĂ&#x160;FT EBUFOU EĂ&#x160;KĂ&#x2020; E VOF EJ[BJOF E BOOĂ&#x160;FT FU M Ă&#x160;UVEF OF QPSUBJU RVF TVS EFT QBUJFOUT EF NĂ&#x160;EFDJOT SĂ&#x160;NVOĂ&#x160;SĂ&#x160;T Ă&#x2020; M BDUF

$FU BSUJDMF B GBJU M PCKFU E VOF SĂ&#x160;WJTJPO QBS EFT QBJST Can Fam Physician 2011;57:e16-20 VOL 57: JANUARY t JANVIER 2011

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Research | $POUJOVJUZ PG DBSF JT HPPE GPS FMEFSMZ QFPQMF XJUI EJBCFUFT

ontinuity of care is one of the defining principles of family medicine1,2; it is usually viewed as the relationship between a single practitioner and a patient that extends beyond single episodes of illness.3,4 Having a regular primary care provider is associated with better problem recognition, improved preventive care, improved patient satisfaction, reduced hospitalization and emergency department visits, and lower health care costs.5,6 A recent review, for example, found that health care costs were significantly lower when continuity was higher.7 Most of the work examining the relationship between continuity of care and patient outcomes has been done on pediatric8,9 or adult populations.10,11 Although elderly people have been found to value continuity of care more than younger people do12 and are more likely to have preventive procedures and checkups done,13,14 it is uncertain whether better continuity of care for older people is associated with better health outcomes. Also, there has been little investigation of the effects of continuity of care over time periods longer than 1 or 2 years.15,16 One of the most common health problems among the elderly is diabetes. In Canada, it is estimated that the number of individuals with diabetes will increase from 1.4 million in 2000 to 2.4 million in 2016, and that health care costs will increase by 80% in that time.17 The results of studies on the relationship between continuity and diabetes outcomes are conflicting, with some showing improvement18,19 and others showing no effect or a worsening of outcome.7,20 We conducted a study using secondary administrative databases to examine the relationship between 3 commonly used indices of continuity of care, death, and hospitalization in people 65 years of age or older with diabetes in Newfoundland and Labrador, the province with the highest prevalence of diabetes in Canada.21

METHODS A sample of 350 people with diabetes, 65 years of age or older, was randomly selected from the Newfoundland and Labrador portion of the National Diabetes Surveillance System (NDSS) database. To be considered a diabetes case in the NDSS, an individual must have had 1 of the following: 1 hospital discharge with mention of diabetes; 2 medical services records with mention of diabetes not more than 2 years apart; or 1 medical services record followed by a hospital discharge, both with mention of diabetes, not more than 2 years apart. Gestational diabetes is excluded from the definition. The case date (the date on which the person becomes a case in the database) is the date of hospital discharge or the date of the first physician visit. The sample was selected

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such that all members had a case date falling within a fiscal year (1998-1999). Database records for people with diabetes were linked using their provincial health insurance number to 3 administrative health databases, using SPSS 11.5 software. The 3 databases were the Medical Care Plan database, which is the provincial fee-for-service physician billing database; the Clinical Database Management System, which tracks acute hospitalizations; and the Mortality Surveillance System, which tracks all deaths occurring within the province. Information was obtained for each patient on all family physician contacts and all acute hospital discharges and deaths in a 3-year period after the diabetes case date. Family physician visits from the Medical Care Plan database were used to calculate the usual provider continuity (UPC) index, a commonly used, well-validated index of continuity; it is a simple ratio of the number of visits to the most frequently visited provider, to the total number of visits to all providers. The index score was calculated for each patient; it produces a score ranging from 0 (lowest possible continuity) to 1 (highest possible continuity).22,23 Patients were divided into low- and high-continuity groups; high continuity was defined as an index value of 0.75 or greater, and low continuity was defined as less than 0.75, following the convention of a previous Canadian study.15 The outcome measures were the rates of mortality and the proportion of people having acute hospitalizations during the 3-year period.

Statistics Descriptive statistics were used for the outcomes, as well as for the covariates of age, sex, and total number of physician visits. The Ď&#x2021;2 test, the t test, or the MannWhitney U test was used to examine differences in outcomes and covariates between low- and high-continuity groups. Backward, conditional, binary multiple logistic regression analyses were used to examine the relationship between continuity of care index scores and each of the outcomes variables separately. The following predictors were entered into all models: age, sex, number of family physician visits, and continuity score (high or low for UPC). All analyses were done using SPSS 11.5. The study protocol was approved by the Human Investigations Committee of Memorial University of Newfoundland.

RESULTS Although all 350 people in the sample met the NDSS case definition for diabetes, only 305 (87.1%) had 2 or more fee-for-service family physician visits, and thus comprised the sample for whom continuity indices could

| VOL 57: JANUARY t JANVIER 2011

$POUJOVJUZ PG DBSF JT HPPE GPS FMEFSMZ QFPQMF XJUI EJBCFUFT | Research be calculated. The mean (SD) age was 74.3 (6.7) years and 42.6% were men. In total 177 people (58.8%) had at least 1 acute hospitalization, and 39 (12.8%) died in the 3-year study period. During the 3 years, the 305 patients visited fee-forservice family physicians 9117 times, with a mean of 29.9 visits per patient during the 3-year study period and 10.0 visits per patient per year. There were 471 acute hospitalizations in the study period, giving a mean of 1.5 hospitalizations per patient over the study period. Table 1 shows the UPC score for 3 years; the score was skewed toward 1.0 with the top 50% of patients having perfect or near perfect continuity (0.9 or greater). Table 2 shows some characteristics of the high- and low-continuity groups. Most elderly people with diabetes in this study had high continuity of care. Patients in the high-continuity group were significantly younger than those in the low-continuity group (P = 0.13), although the difference was small. Patients in the high-continuity

group saw their family physicians more often, but the difference was small. Table 3 shows the proportions of the sample who died or had acute hospitalizations during the study period. The proportion of people dying was significantly lower in the high-continuity group (9.0% vs 18.1%, P = .025). The high-continuity group also had a significantly lower proportion of patients with at least 1 hospitalization (54.5% vs 67.5%, P = .027).

DISCUSSION

This was the first study to use administrative databases to examine the relationship between continuity of primary care provider and health care outcomes in Newfoundland and Labrador and, to our knowledge, the first in Canada to examine the relationship between continuity of primary care provider and mortality in people with diabetes. People aged 65 and older with Table 1. Usual provider continuity of care during a 3-year period: N = 305. diabetes comprise a high-risk INDEX QUARTILES group; we found a 1 in 7 chance MEASURE OF CONTINUITY MEAN SD MINIMUM MAXIMUM 25TH 50TH 75TH of death within 3 years of the diagnosis being made and a 1 in 2 *OEFY TDPSF 0.17 0.31 1.00 0.71 0.91 0.99 chance of hospitalization. Despite 1PTTJCMF VTVBM QSPWJEFS DPOUJOVJUZ JOEFY TDPSFT SBOHF GSPN MPXFTU QPTTJCMF DPOUJOVJUZ UP IJHIFTU known problems with adminisQPTTJCMF DPOUJOVJUZ trative data, we found that it was feasible to calculate the UPC index of continuity. The Table 2. Characteristics of high- and low-continuity UPC scores were high, as would be expected for a diagroups: N = 305. betic population with universal health care coverage. CHARACTERISTIC LOW-CONTINUITY HIGH-CONTINUITY P VALUE This has been found in previous studies of continuity GROUP (UPC INDEX GROUP (UPC INDEX LESS THAN 0.75) 0.75 OR GREATER) of care for people with diabetes18,19; like these previous / PG UPUBM

NA studies, we found that the distribution for the index was skewed toward 1.0, with 50% of patients having very .FO 42.2 45.5 .349 high levels of continuity (0.9 or greater). .FBO 4% BHF

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.142 found in other studies.7,10,17 We know of only 1 study that PG (1 WJTJUT examined the association between continuity of care /"Â&#x2021;OPU BQQMJDBCMF 61$Â&#x2021;VTVBM QSPWJEFS DPOUJOVJUZ and mortality17; it found that continuity of primary care *OEJDBUFT B TJHOJĂ DBOU CFUXFFO HSPVQT EJGGFSFODF P < .05). provider was associated with decreased mortality in mental health patients. Table 3. Proportion of sample deceased and proportion The observed reduction in hospitalization in the highhaving acute hospitalizations during the 3-year period, continuity group would most likely result in lower costs. by UPC continuity group: N = 305. Researchers have previously found that there is a genLOWHIGHeral reduction in health care costs as continuity of care CONTINUITY CONTINUITY 23,24 GROUP (UPC GROUP (UPC As the number of older people with diaimproves. P VALUE INDEX LESS INDEX 0.75 2 betes in Canada increases,17 cost factors will need to be (Ď&#x2021; ) OUTCOME THAN 0.75) OR GREATER) considered.

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Strengths and limitations The study is the first to examine the relationship between continuity of care and mortality in elderly people with diabetes. The study was carried out on a random sample

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Research | $POUJOVJUZ PG DBSF JT HPPE GPS FMEFSMZ QFPQMF XJUI EJBCFUFT of people from administrative health databases, which were population-based and longitudinal, and it was longer than most other studies of continuity of care. This study was limited by the fact that it retrospectively scanned existing databases. The data we used are now a decade old, and the situation might have changed. The study was also limited by the fact that the physician-visit database (Medical Care Plan), which provided data used to calculate the UPC index of family physician continuity, as well as specialist visit outcomes, tracked only fee-for-service physician visits. In Newfoundland and Labrador, approximately two-thirds of physicians are paid on a fee-for-service basis.25 The other third are salaried and are scattered outside urban centres; no information about their individual patient contact activities was available to us. Thus, the data most likely underestimate health care service utilization, especially in rural areas. In addition, although previous research has shown that health care service utilization and continuity of care are related to other important covariates such as socioeconomic status, 15 we were unable to incorporate these variables into our models owing to the limited number of variables captured in the NDSS and physician claims databases.

Conclusion Our findings suggest an association between higher continuity of family physician care and reductions in likelihood of death and hospitalizations in older people with diabetes. As the number of older people with diabetes in Canada increases, the benefits of continuity will become increasingly important. Dr Worrall is Honorary Research Professor in the Department of Family Medicine at Memorial University of Newfoundland in St John’s. Mr Knight is a doctoral candidate at Memorial University of Newfoundland and a statistical consultant at the Newfoundland and Labrador Centre for Health Information. Acknowledgment The study was supported by grant number 203981 from the Canadian Institutes of Health Research to Dr Worrall. Competing interests None declared Contributors Both authors contributed to concept and design of the study; data gathering, analysis, and interpretation; and preparing the manuscript for submission. Correspondence Dr Graham Worrall, Dr W.H. Newhook Memorial Clinic, Family Medicine, Box 449, Whitbourne, NL A0B 3K0; e-mail gworrall@mun.ca

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References 1. Kelly L. Four principles of family medicine. Do they serve us well? Can Fam Physician 1997;43:1902-4 (Eng), 1909-12 (Fr). 2. McWhinney IR. A textbook of family medicine. 2nd ed. Oxford, UK: Oxford University Press; 1997. 3. Hennen BK. Continuity of care in family practice. Part 1: dimensions of continuity. J Fam Pract 1975;2(5):371-2. 4. Rogers J, Curtis P. The concept and measurement of continuity in primary care. Am J Public Health 1980;70(2):122-7. 5. Starfield B. Primary care: balancing health needs, service and technology. New York, NY: Oxford University Press; 1998. 6. Saultz JW, Abedaiwi W. Interpersonal continuity of care and patient satisfaction: a critical review. Ann Fam Med 2004;2(5):445-51. 7. Saultz JW, Lochner J. Interpersonal continuity of care and care outcomes: a critical review. Ann Fam Med 2005;3(2):159-66. 8. Butler JA, Winter WD, Singer JD, Wenger M. Medical care use and expenditure among children and youth in the United States: analysis of a national probability sample. Pediatrics 1985;76(4):495-507. 9. Alpert JJ, Robertson LS, Hosa J, Haggerty RJ. Delivery of health care for children: report of an experiment. Pediatrics 1976;57(6):917-30. 10. Gill JM, Mainous AG 3rd. The role of provider continuity in preventing hospitalization. Arch Fam Med 1998;7(4):352-7. 11. Sweeney KG, Gray DP. Patients who do not receive continuity of care from their general practitioner—are they a vulnerable group? Br J Gen Pract 1995;45(392):133-5. 12. Kearley KE, Freeman GK, Heath A. An exploration of the value of the personal doctor-patient relationship in general practice. Br J Gen Pract 2001;51(470):712-8. 13. Steven ID, Dickens E, Thomas SA, Browning E, Eckerman E. Preventive care and continuity of attendance. Is there a risk? Aust Fam Physician 1998;27(Suppl 1):S44-6. 14. Ettner SL. The relationship between continuity of care and health behaviors of patients: does having a usual physician make a difference? Med Care 1999;37(6):547-55. 15. Menec VH, Sirski M, Attawar D. Does continuity of care matter in a universally insured population? Health Serv Res 2005;40(2):389-400. 16. Reid RJ, Barer ML, McKendry R, McGrail KM, Prosser B, Green B, et al. Patient-focused care over time: issues related to measurement, prevalence, and strategies for improvement among patients populations. Ottawa, ON; Canadian Health Services Research Foundation; 2003. Available from: www.chsrf.ca/ final_research/ogc/pdf/barer_final.pdf. Accessed 2006 Jan 20. 17. Ohinmaa O, Jacobs P, Simpson S, Johnson JA. The projection of prevalence and cost of diabetes in Canada: 2000 to 2016. Can J Diabetes 2004;28(2):1-8. 18. Parchman ML, Puch JA, Noël PH, Larme AC. Continuity of care, selfmanagement behaviors, and glucose control in patients with type 2 diabetes. Med Care 2002;40(2):137-44. 19. O’Connor PJ, Desai J, Rush WA, Cherney LM, Solberg LI, Bishop DB. Is having a regular provider of diabetes care related to intensity of care and glycemic control? J Fam Pract 1998;47(4):290-7. 20. Gill JM, Mainous AG 3rd, Diamond JJ, Lenhard MJ. Impact of provider continuity on quality of care for persons with diabetes mellitus. Ann Fam Med 2003;1(3):162-70. 21. Statistics Canada. Diabetes, by sex, household population aged 12 and over, Canada, provinces, territories, health regions and peer groups. Ottawa, ON: Statistics Canada; 2003. Available from: www.statcan.gc.ca/pub/82221-x/2005002/status-etat/4150492-eng.htm. Accessed 2005 Jan 16. 22. Steinwachs DM. Measuring provider continuity in ambulatory care: an assessment of alternative approaches. Med Care 1979;17(6):551-65. 23. Raddish M, Horn SD, Sharkey PD. Continuity of care: is it cost effective? Am J Manag Care 1999;5(6):727-34. 24. Weiss LJ, Blustein J. Faithful patient: the effect of long term physician patient relationships on the costs and use of health care by older Americans. Am J Public Health 1996;86(12):1742-7. 25. Government of Newfoundland and Labrador. Medical Care Plan annual report, 1999/00. St John’s, NL: Government of Newfoundland and Labrador; 2001.

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Research | Web exclusive

Effect of advanced access scheduling on chronic health care in a Canadian practice Julie Gladstone

Michelle Howard

MSc PhD

Abstract Objective To determine the effect of advanced access scheduling (AAS) on the care of patients with chronic disease within a Canadian family practice. Design Chart abstraction. Setting A single family physicianâ&#x20AC;&#x2122;s practice in Brantford, Ont. Participants Patient charts were reviewed for all patients with a history of hypertension, type 2 diabetes mellitus, or coronary artery disease during the years before and after implementation of AAS. Main outcome measures The following information was extracted for each study patient: total number of appointments, number of appointments specific to chronic disease management, number of appointments for nonchronic disease, blood pressure (BP), and laboratory markers, including hemoglobin A1c (HbA1c) and low-density lipoprotein levels. Results For the year before and the year after implementation of AAS, the mean number of visits per patient was 4.3. The mean number of appointments for chronic disease management decreased significantly from 2.6 to 2.2 (P = .024), and the mean number of visits for non-chronic disease increased significantly from 1.7 to 2.1 (P = .001). The number of times clinical parameters of BP, HbA1c, and low-density lipoprotein were measured decreased; however, there were no significant changes in actual BP or HbA1c levels. Conclusion Following a 1-year period using AAS, use of the family health practice by patients with chronic disease was unchanged overall; however, AAS allowed for an increase in visits for non-chronic health conditions without significantly affecting the clinical parameters of BP or HbA1C.

EDITORâ&#x20AC;&#x2122;S KEY POINTS r 8JUI BEWBODFE BDDFTT TDIFEVMJOH (AAS), patients are offered appointments the same day they call to see their QIZTJDJBOT 0OF PG UIF DIBMMFOHFT PG ""4 is care of chronic disease patients who SFRVJSF SFHVMBS GPMMPX VQ BQQPJOUNFOUT GPS PQUJNBM NFEJDBM NBOBHFNFOU r 5IF HPBM PG UIJT TUVEZ XBT UP determine the effect of AAS on patients with hypertension, type 2 diabetes NFMMJUVT PS DPSPOBSZ BSUFSZ EJTFBTF BT JU SFMBUFE UP UIF GSFRVFODZ BOE OBUVSF PG WJTJUT CZ DPNQBSJOH CMPPE QSFTTVSF IFNPHMPCJO "1c, and low-density lipoprotein levels before and after implementation of AAS. r 8IJMF UIF BWFSBHF OVNCFS PG DISPOJD EJTFBTF NBOBHFNFOU WJTJUT QFS ZFBS GPS patients with chronic diseases decreased after AAS implementation, overall NFBTVSFT PG UIFJS RVBMJUZ PG DBSF CMPPE QSFTTVSF IFNPHMPCJO "1c, and lowdensity lipoprotein) did not decline.

This article has been peer reviewed. Can Fam Physician 2011;57:e21-5 e21

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Exclusivement sur le web |

Recherche

Effets des rendez-vous accĂŠlĂŠrĂŠs sur les soins aux patients chroniques dans une clinique de mĂŠdecine familiale canadienne Julie Gladstone

Michelle Howard

MSc Ph

RĂŠsumĂŠ Objectif DĂŠterminer les effets des rendez-vous accĂŠlĂŠrĂŠs (RVA) sur les soins aux patients souffrant de maladies chroniques dans une clinique de mĂŠdecine familiale canadienne. Type dâ&#x20AC;&#x2122;ĂŠtude Revue de dossiers. Contexte Une clinique de mĂŠdecine familiale de Brantford, Ontario. Participants On a revu les dossiers de tous les patients ayant une histoire dâ&#x20AC;&#x2122;hypertension, de diabĂ¨te de type 2 ou de maladie coronarienne durant lâ&#x20AC;&#x2122;annĂŠe prĂŠcĂŠdant lâ&#x20AC;&#x2122;instauration des RVA et durant lâ&#x20AC;&#x2122;annĂŠe suivante. Principaux paramĂ¨tres Ă lâ&#x20AC;&#x2122;ĂŠtude Les donnĂŠes suivantes ont ĂŠtĂŠ extraites pour chaque patient de lâ&#x20AC;&#x2122;ĂŠtude du nombre total de rendez-vous, du nombre de rendez-vous pour la maladie chronique, du nombre de rendez-vous pour des maladies non chroniques, de la tension artĂŠrielle (TA) et des rĂŠsultats de laboratoire, y compris les niveaux dâ&#x20AC;&#x2122;hĂŠmoglobine A1c (HbA1c) et de lipoprotĂŠines de basse densitĂŠ. RĂŠsultats Pour lâ&#x20AC;&#x2122;annĂŠe prĂŠcĂŠdant comme pour celle suivant lâ&#x20AC;&#x2122;instauration des RVA, le nombre moyen de visites par patient ĂŠtait de 4,3. Le nombre moyen de visites pour la condition chronique montrait une diminution significative de 2,6 Ă 2,2 (P = ,024) tandis que le nombre de visites pour des problĂ¨mes non chroniques augmentait significativement de 1,7 Ă 2,1 (P = ,001). Le nombre de fois quâ&#x20AC;&#x2122;on a mesurĂŠ les paramĂ¨tres cliniques que sont la TA, lâ&#x20AC;&#x2122;HbA1c et les lipoprotĂŠines de basse densitĂŠ a diminuĂŠ; toutefois, il nâ&#x20AC;&#x2122;y a eu aucun changement significatif dans les valeurs de TA ou dâ&#x20AC;&#x2122;HbA1c. Conclusion AprĂ¨s une annĂŠe dâ&#x20AC;&#x2122;utilisation des RVA, lâ&#x20AC;&#x2122;utilisation de la clinique de mĂŠdecine familiale par les patients chroniques demeurait globalement inchangĂŠe; toutefois, les RVA ont permis un nombre accru de visites pour des conditions non chroniques, sans affecter significativement les paramĂ¨tres cliniques de TA ou dâ&#x20AC;&#x2122;HbA1c.

POINTS DE REPĂ&#x2C6;RE DU RĂ&#x2030;DACTEUR r "WFD MFT SFOEF[ WPVT BDDĂ&#x160;MĂ&#x160;SĂ&#x160;T 37" MFT QBUJFOUT TF WPJFOU PGGSJS VO SFOEF[ WPVT MF KPVS PĂ&#x153; JMT POU BQQFMĂ&#x160; QPVS SFODPOUSFS MFVS NĂ&#x160;EFDJO 6O EFT EĂ&#x160;GJT EF DF HFOSF EF SFOEF[ WPVT DPODFSOF MF TPJO EFT QBUJFOUT DISPOJRVFT RVJ EPJWFOU Ă&#x2039;USF TVJWJT SĂ&#x160;HVMJĂ?SFNFOU QPVS VO USBJUFNFOU optimal. r -F CVU EF DFUUF Ă&#x160;UVEF Ă&#x160;UBJU EF EĂ&#x160;UFSNJOFS MFT FGGFUT EFT 37" TVS MF USBJUFNFOU EFT QBUJFOUT TPVGGSBOU E IZQFSUFOTJPO EF EJBCĂ?UF EF UZQF PV EF NBMBEJF DPSPOBSJFOOF RVJ QPVSSBJU Ă&#x2039;USF JOGMVFODĂ&#x160; QBS MB GSĂ&#x160;RVFODF FU MB OBUVSF EFT WJTJUFT FO DPNQBSBOU MFT UFOTJPOT BSUĂ&#x160;SJFMMFT MFT OJWFBVY EF M IĂ&#x160;NPHMPCJOF "1c FU EFT MJQPQSPUĂ&#x160;JOFT EF CBTTF EFOTJU BWBOU FU BQSĂ?T M JOTUBVSBUJPO EFT 37" r "MPST RVF MF OPNCSF NPZFO EF WJTJUFT QBS BOOĂ&#x160;F EFT QBUJFOUT TPVGGSBOU EF NBMBEJFT DISPOJRVFT B EJNJOVĂ&#x160; BQSĂ?T M JOTUBVSBUJPO EFT 37" MB RVBMJUĂ&#x160; HMPCBMF EFT TPJOT UFOTJPO BSUĂ&#x160;SJFMMF IĂ&#x160;NPHMPCJOF "1c FU MJQPQSPUĂ&#x160;JOFT EF CBTTF EFOTJUĂ&#x160; O B QBT EJNJOVĂ&#x160;

$FU BSUJDMF B GBJU M PCKFU E VOF SĂ&#x160;WJTJPO QBS EFT QBJST Can Fam Physician 2011;57:e21-5 VOL 57: JANUARY t JANVIER 2011

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Research | &GGFDU PG BEWBODFE BDDFTT TDIFEVMJOH PO DISPOJD IFBMUI DBSF JO B $BOBEJBO QSBDUJDF

dvanced access scheduling (AAS) was designed by Murray and Berwick in an effort to improve continuity of care and overcome challenges of telephone triage encountered in traditional models of scheduling.1 With the AAS model, patients calling to see their physicians are offered appointments the same day they call. Some visits are scheduled in the future if patients decline offers for same-day visits or if they are seen on the day they call and need to return at some definite point in the future.1 Over the past few years, clinics that have adopted AAS have begun to publish accounts of their successes. O’Hare and Corlett, family physicians in Minneapolis, Minn, who implemented AAS in 1999, found patient demand for visits decreased, patient satisfaction increased, and use of urgent care services decreased.2 Similarly, in a Canadian family practice, Mitchell found that AAS resulted in fewer no-show appointments, increased patient satisfaction, and higher staff morale.3 Other authors have voiced similar opinions.4,5 Casual observation suggests there are challenges with the AAS model, especially care of those with chronic disease who require regular follow-up for optimal medical management. The Canadian Practice Guidelines (CPGs) suggest monitoring blood pressure (BP) in patients with hypertension (HTN) every 6 months, checking hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM) every 3 months, and evaluating lowdensity lipoprotein (LDL) levels yearly in order to minimize cardiovascular risk.6 It is possible that AAS places more responsibility on patients to return for follow-up and management of their diseases. This raises the question of whether, when left with the responsibility of telephoning to arrange follow-up, patients will continue to receive the same medical care as they would if appointments were prebooked at the most recent visit. Solberg et al addressed this question by studying office visit rates in 7000 patients with diabetes and 3800 patients with coronary artery disease (CAD) and found that AAS was associated with very little change in overall office visits or costs of care for chronic disease patients.7 Subramanian et al studied the effect of AAS on intermediate outcomes of diabetes care, including BP, HbA1c, and LDL levels, as well as albumin-to-creatinine ratios.8 They found that 1 year after the start of AAS there were small increases in BP rates and decreases in HbA1c levels.8 In a similar study by Sperl-Hillen et al, 7000 patients with T2DM were compared before and after implementation of AAS; improvements in HbA 1c and LDL control were documented.9 These studies suggest that although the responsibility for follow-up is placed on patients, there does not appear to be a change in the care provided or their overall health. The studies examining care of patients with chronic disease were conducted within large multidisciplinary health centres in the United States7-10; however, it is unclear how these

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Canadian Family Physician t Le Médecin de famille canadien

data would apply to a smaller, single-physician practice in Canada. In June 2007 a primary care physician working in Brantford, Ont, switched from standard booking to AAS. After implementing AAS, this physician preferred to have most appointments booked on the same day patients called, with exceptions being made for the elderly and those who lived out of town or had jobs that made same-day booking difficult. Casual observation of this practice suggested that indeed there was a group of patients who, left with the responsibility of arranging their own follow-up, appeared to return less frequently than recommended by the physician to align with CPGs. This observational data raises the question of whether this population of patients, coming in for fewer chronic disease management visits, might be receiving inadequate care, resulting in deterioration in their chronic diseases. The objective of this study was to determine the effect of AAS on patients with HTN, T2DM, or CAD as it related to the frequency and nature of visits, by comparing BP, HbA1c, and LDL levels before and after implementation of AAS.

METHODS This study reviewed all patients with HTN, T2DM, and CAD in a single family physician practice in the city of Brantford. This physician is reimbursed under a capitated funding model and has approximately 2990 patients. In June 2007 the physician changed from standard booking to AAS. A search was conducted in the “history and past health problems” (HPH) and “problems” (ie, current problems) sections of the electronic medical record for enrolled patients diagnosed with HTN, diabetes mellitus (DM), or CAD no later than January 1, 2007. All patient charts that included a diagnosis of HTN, DM, or CAD dating at least 1 year before the switch to AAS were selected. Patients were excluded if they no longer required medication for HTN, if they had type 1 DM (many in this population were youth patients and would not be responsible for booking their own return appointments), if they were deceased before the end of May 2009, or if they did not have at least 1 appointment during regular office hours in both years being studied. The first author (J.G.) reviewed the charts. For the purpose of the chart review, June 1, 2007, through May 31, 2008, was the pre-AAS year (ie, year 1) and June 1, 2008, through May 31, 2009, was the post-AAS year (ie, year 2). Diagnosis of HTN, T2DM, and CAD were confirmed through review of “HPH” and “problems” sections of the charts. For years 1 and 2, the number of visits during regular office hours with the primary care physician

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&GGFDU PG BEWBODFE BDDFTT TDIFEVMJOH PO DISPOJD IFBMUI DBSF JO B $BOBEJBO QSBDUJDF | Research was extracted. Additionally, the number of visits that were specifically for management of patientsâ&#x20AC;&#x2122; chronic diseases (as per a stamp inserted in the chart or if the assessment section of the SOAP note indicated HTN, T2DM, or CAD) was recorded. All other visits were considered nonâ&#x20AC;&#x201C;chronic disease visits. Clinical parameters including BP, HbA1c, and LDL levels were extracted from the â&#x20AC;&#x153;patient visitâ&#x20AC;? and â&#x20AC;&#x153;laboratory dataâ&#x20AC;? chart sections. Mean number of physician visits overall, those specifically for chronic and non-chronic disease, and number and value of laboratory and BP measurements were compared between year 1 and year 2. Control of BP among patients with HTN was calculated as the proportion of patients whose mean BP measurements of the past 3 readings within the time period were 140/90 mm Hg or lower among patients without diabetes or 130/80 mm Hg or lower for patients with diabetes. All other measures of chronic disease control were calculated using the means of all available readings. Paired t tests and McNemar Ď&#x2021;2 tests for paired comparisons were used to compare continuous and categorical variables, respectively. The criterion of statistical significance was set at Îą = .05 (2-tailed). The analysis was done using SPSS version 17.0. Hamilton Health Sciences and McMaster University Board of Ethics did not require ethics approval, as the project was a quality assurance chart audit.

RESULTS

Table 1. Visits and clinical parameters for year 1 and year 2 VISITS AND CLINICAL PARAMETERS

YEAR 1

YEAR 2

P VALUE

Mean (SD) visits r

No. of visits

4.3 (2.5)

4.3 (3.5)

.906

No. of visits for chronic disease

2.6 (1.8)

2.2 (1.9)

.024

No. of visits for non-chronic disease

1.7 (1.9)

2.1 (3.0)

.001

858

743

Clinical parameters r

Total no. of BP SFBEJOHT

Mean (SD) no. of #1 SFBEJOHT

3.3 (2.1)

2.9 (2.2)

.001

Mean (SD) systolic #1 NN )H

132.5 (13.1)

132.9 (13.3)

.626

Mean (SD) diastolic #1 NN )H

70.5 (8.0)

70.7 (8.1)

.737

Patients with elevated BP on last SFBEJOHT

41.8

41.4

>.99

Total no. of HbA1c NFBTVSFNFOUT

299

258

Mean (SD) no. of HbA1c NFBTVSFNFOUT

1.7 (1.3)

1.5 (1.2)

.012

Mean (SD) HbA1c

7.2 (1.1)

7.1 (1.1)

.168

376

301

1.5 (1.2)

1.2 (1.1)

<.001

2.7 (0.7)

2.6 (0.8)

.035

r 5PUBM OVNCFS PG

-%- NFBTVSFNFOUT Three hundred sixty-seven patients were identified using the search criteria. One hundred eight were excluded because they no longer required medication for HTN, they had diagnoses of pregnancy-induced DM or type 1 DM, or they did not have appointments in year 1 or year 2. Two hundred fifty-nine patients were included in the study. Fifty-one percent of the patients were male, with the average age being 69 years. Of the 259 patients, 216 (83.4%) had HTN, 156 (60.2%) had T2DM, and 77 (29.7%) had CAD. There was no statistically significant difference in mean number of appointments per patient between the study years (Table 1). There was, however, a statistically significant decrease in mean number of chronic health appointments (2.6 vs 2.2, P = .024) and an increase in mean number of nonâ&#x20AC;&#x201C;chronic disease appointments (1.7 vs 2.1, P = .001) from year 1 to year 2. There were statistically significant decreases in the numbers of times BP, HbA1c, and LDL were measured per patient from year 1 to year 2. Clinical parameters of BP and HbA 1c were not significantly different between the 2 years. There was a small but statistically significant reduction in LDL levels (2.7 vs 2.6 mmol/L, P = .035).

Mean (SD) no. of -%- NFBTVSFNFOUT

r .FBO 4% -%-

NNPM #1Â&#x2021;CMPPE QSFTTVSF )C"1cÂ&#x2021;IFNPHMPCJO "1c, -%-Â&#x2021;MPX EFOTJUZ MJQPQSPUFJO /"Â&#x2021;OPU BQQMJDBCMF (SFBUFS UIBO NN )H JO QBUJFOUT XJUI EJBCFUFT BOE NN )H JO QBUJFOUT XJUIPVU EJBCFUFT

DISCUSSION Similar to Solberg et al,7 we found that there was no difference in total number of office visits made by those with chronic disease following the implementation of AAS; however, we found a shift away from chronic disease management visits toward visits for non-chronic disease. Perhaps, before implementation of AAS, patients might have received advice regarding non-chronic health matters at regularly scheduled chronic disease visits, eliminating the need for nonâ&#x20AC;&#x201C;chronic health appointments. With respect to CPGs, this study population reached appropriate standards for measurement of BP and LDL levels in both years but fell short of the recommended frequency for measurements of HbA1c levels. There was

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Research | &GGFDU PG BEWBODFE BDDFTT TDIFEVMJOH PO DISPOJD IFBMUI DBSF JO B $BOBEJBO QSBDUJDF a decrease in frequency of measurement of all of these parameters in year 2. Despite this decreased frequency of measurement, and unlike Subramanian et al8 and Sperl-Hillen et al,9 we did not find any difference in clinical parameters of BP or HbA1c between years 1 and 2; however, there was a small, statistically significant decrease in LDL levels (P = .035). It can be hypothesized that, despite not always meeting CPGs standards for recommended follow-up, there were no significant changes in clinical parameters of BP or HbA1c levels owing to the relatively short study period. All selected patients with HTN were receiving treatment for their BP and all patients with T2DM were identified before the start of the study period. Hypothetically, with treatment initiated already in these patients, large fluctuations would not be seen over a 1-year period. It is unclear why, despite the decrease in number of LDL measurements in year 2, there was a small but statistically significant improvement in LDL values (P = .035). This study suggests that over a short period of time, AAS appears to be an acceptable method of scheduling for patients with HTN, T2DM, or CAD. Nearly all chronic disease monitoring parameters were within guidelinerecommended targets for frequency, on average, while also enabling more visits for non–chronic disease management or urgent care visits. This is an important finding, especially in these days of health care reform in which we recognize that patients are often being treated in inappropriate settings. The Health Council of Canada has found that too many Canadians have visited the emergency department for conditions that could have been treated by their primary care providers if they had been available.10 The primary difficulty affecting availability was long wait times for appointments with their primary care providers.10

Limitations Limitations to this study include that it was conducted in a single physician’s office and so results might not be generalizable to other settings. A recent study of 46 family physicians across Ontario found that in patients with diabetes, targets for monitoring and management processes were met in approximately 65% of patients, which appears to be lower than in our study.11 This might be due to this physician’s patient population, which can generally be described as compliant. As previously mentioned, the time frame of 1 year after AAS implementation might not be sufficient to see declines in disease parameters if they were to happen as a result of fewer chronic disease visits. The study exclusion of patients who did not have physician visits in both time

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Canadian Family Physician t Le Médecin de famille canadien

periods might have introduced bias, as results can be applied only to patients who routinely visit the office. Furthermore, the search strategy could have been limited if the charts’ “HPH” and “problem” sections were not appropriately updated and patients with a history of HTN, T2DM, or CAD were not included in the study as a result. There is no reason to suspect that these missed patients would have behaved differently than those whose charts were reviewed. Future studies that include a larger sample size, more chart reviewers, a longer time period, and a comparison group would strengthen the argument that AAS is an acceptable model of scheduling for patients with chronic disease.

Conclusion Following a 1-year period of AAS, use of the family

health practice by patients with chronic disease was unchanged overall; however, the AAS model allowed for an increase in non–chronic health visits without significantly affecting the clinical parameters of BP or HbA1c. Dr Gladstone recently completed family medicine residency at McMaster University in Hamilton, Ont. Dr Howard is Assistant Professor in Family Medicine at McMaster University. Contributors Dr Gladstone conducted the literature review, formulated the clinical question, and extracted information from charts, as well as wrote all drafts. Dr Howard performed statistical analyses and guided the writing of the results and discussion sections. Competing interests None declared Correspondence Dr Julie Gladstone; e-mail julie.gladstone@medportal.ca References 1. Murray M, Berwick DM. Advanced access: reducing waiting and delays in primary care. JAMA 2003;289(8):1035-40. 2. O’Hare CD, Corlett J. The outcomes of open-access scheduling. Fam Pract Manag 2004;11(2):35-8. 3. Mitchell V. Same-day booking. Success in a Canadian family practice. Can Fam Physician 2008;54:379-83. 4. Steinbauer JR, Korell K, Erdin J, Spann SJ. Implementing open-access scheduling in an academic practice. Fam Pract Manag 2006;13(3):59-64. 5. Murray M, Bodenheimer T, Rittenhouse D, Grumbach K. Improving timely access to primary care: case studies of the advanced access model. JAMA 2003;289(8):1042-6. 6. Greenberg DE, Muraca M. Canadian clinical practice guidelines. Toronto, ON: Elsevier Canada; 2008. 7. Solberg LI, Maciosek MV, Sperl-Hillen JM, Crain AL, Engebretson KI, Asplin BR, et al. Does improved access to care affect utilization and costs for patients with chronic conditions? Am J Manag Care 2004;10(10):717-22. 8. Subramanian U, Ackermann RT, Brizendine EJ, Saha C, Rosenman MB, Willis DR, et al. Effect of advanced access scheduling on process and intermediate outcomes of diabetes care and utilization. J Gen Intern Med 2009;24(3):327-33. Epub 2009 Jan 9. 9. Sperl-Hillen JM, Solberg LI, Hroscikoski MC, Crain AL, Engebretson K, O’Connor PJ. The effect of advanced access implementation on quality of diabetes care. Prev Chronic Dis 2008;5(1):A16. Epub 2007 Dec 15. 10. Health Council of Canada. Fixing the foundation: an update of primary health care and home care renewal in Canada. Toronto, ON: Health Council of Canada; 2008. Available from: www.healthcouncilcanada.ca/docs/ rpts/2008/phc/HCC_PHC_Main_web_E.pdf. Accessed 2010 Nov 25. 11. Holbrook A, Thabane L, Keshavjee K, Dolovich L, Bernstein B, Chan D, et al. Individualized electronic decision support and reminders to improve diabetes care in the community: COMPETE II randomized trial. CMAJ 2009;181(1-2):37-44.

| VOL 57: JANUARY t JANVIER 2011

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Research | Web exclusive

Debiasing the hidden curriculum Academic equality among medical specialties Wayne Woloschuk

PhD

Bruce Wright

Kevin McLaughlin

MB ChB PhD

Abstract Objective To compare the academic performance of students who entered family medicine residency programs with that of students who entered other disciplines and discern whether or not family physicians are as academically talented as their colleagues in other specialties. Design Retrospective quantitative study. Setting University of Calgary in Alberta. Participants Three graduating classes of students (2004 to 2006) from the University of Calgary medical school. Main outcome measures Student performance on various undergraduate certifying examinations in years 1, 2, and 3, along with third-year in-training evaluation reports and total score on the Medical Council of Canada Qualifying Examination Part I. Results Complete data were available for 99% of graduates (N = 295). In the analysis, residency program (family medicine [n = 96] versus nonâ&#x20AC;&#x201C;family medicine [n = 199]) served as the independent variable. Using a 1-way multivariate ANOVA (analysis of variance), no significant difference among any of the mean performance scores was observed (F5289 = 1.73, P > .05). Students who entered family medicine were also well represented within the top 10 rankings of the various performance measures. Conclusion The academic performance of students who pursued careers in family medicine did not differ from that of students who chose other specialties. Unfounded negativity toward family medicine has important societal implications, especially at a time when the gap between the number of family physicians and patients seeking primary care services appears to be widening.

Canadian Family Physician t Le MĂŠdecin de famille canadien

r 5IBU GBNJMZ NFEJDJOF JT QFSDFJWFE OFHBUJWFMZ BT B DBSFFS PQUJPO JO UIJT IJEEFO DVSSJDVMVN EJTTVBEFT TPNF TUVEFOUT GSPN DPOTJEFSJOH UIF EJTDJQMJOF BOE MFOET DSFEFODF UP UIF OPUJPO UIBU GBNJMZ QIZTJDJBOT BSF MFTT BDBEFNJDBMMZ DPNQFUFOU UIBO UIFJS QFFST JO PUIFS TQFDJBMUJFT r 5IJT TUVEZ DPNQBSFE UIF BDBEFNJD QFSGPSNBODFT PG NFEJDBM TUVEFOUT FOUFSJOH GBNJMZ NFEJDJOF SFTJEFOU QSPHSBNT XJUI UIPTF FOUFSJOH PUIFS TQFDJBMUZ QSPHSBNT BOE TIPXFE UIBU UIFSF XFSF OP EJGGFSFODFT CFUXFFO UIF HSPVQT SFWFBMJOH UIBU UIF OFHBUJWJUZ EJSFDUFE UPXBSE UIF BDBEFNJD QFSGPSNBODF PG UIPTF QVSTVJOH GBNJMZ NFEJDJOF JT OPU CBTFE JO GBDU r 5IF OFHBUJWF QFSDFQUJPOT PG GBNJMZ NFEJDJOF IBWF JNQPSUBOU TPDJFUBM DPOTFRVFODFT JO $BOBEB XIFSF UIFSF JT BO JODSFBTJOH HBQ CFUXFFO UIF OVNCFS PG JOEJWJEVBMT OFFEJOH GBNJMZ EPDUPST BOE UIF QSPQPSUJPO PG NFEJDBM TDIPPM HSBEVBUFT TFFLJOH GBNJMZ NFEJDJOF BT B DBSFFS TUSPOH NFBTVSFT TIPVME CF UBLFO XJUIJO NFEJDBM TDIPPMT MFBSOJOH BOE DVMUVSBM FOWJSPONFOUT UP SFNPWF UIF VOKVTUJGJFE TUJHNB QMBDFE VQPO GBNJMZ NFEJDJOF

This article has been peer reviewed. Can Fam Physician 2011;57:e26-30 e26

EDITORâ&#x20AC;&#x2122;S KEY POINTS r .FEJDBM TDIPPM FEVDBUJPO DPNQSJTFT OPU POMZ B GPSNBMMZ PGGFSFE DVSSJDVMVN CVU BMTP B iIJEEFO DVSSJDVMVNuÂ&#x2021;B TFU PG QFFS BOE FEVDBUPS JOGMVFODFT UIBU GVODUJPO XJUIJO UIF PSHBOJ[BUJPOBM BOE DVMUVSBM TUSVDUVSF PG UIF JOTUJUVUJPO

| VOL 57: JANUARY t JANVIER 2011

Exclusivement sur le web |

Recherche

DĂŠmythifier le curriculum cachĂŠ MĂŞmes compĂŠtences acadĂŠmiques pour les diverses spĂŠcialitĂŠs mĂŠdicales Wayne Woloschuk

PhD

Bruce Wright

Kevin McLaughlin

MB ChB PhD

RĂŠsumĂŠ Objectif Comparer le rendement acadĂŠmique des ĂŠtudiants en mĂŠdecine qui entraient dans le programme de rĂŠsidence en mĂŠdecine familiale Ă celles des ĂŠtudiants qui entraient dans les programmes dâ&#x20AC;&#x2122;autres spĂŠcialitĂŠs et dĂŠterminer si les mĂŠdecins de famille ĂŠtaient aussi talentueux sur le plan acadĂŠmique que leur confrĂ¨res des autres spĂŠcialitĂŠs. Type dâ&#x20AC;&#x2122;ĂŠtude Ă&#x2030;tude rĂŠtrospective quantitative. Contexte Lâ&#x20AC;&#x2122;universitĂŠ de Calgary, en Alberta. Participants Trois classes dâ&#x20AC;&#x2122;ĂŠtudiants finissants (2004 Ă 2006) de la facultĂŠ de mĂŠdecine de lâ&#x20AC;&#x2122;universitĂŠ de Calgary. Principaux paramĂ¨tres Ă lâ&#x20AC;&#x2122;ĂŠtude Rendement des ĂŠtudiants Ă divers examens de certification des annĂŠes 1, 2 et 3 du premier cycle, rapports dâ&#x20AC;&#x2122;ĂŠvaluation des stages de troisiĂ¨me annĂŠe et score total Ă la partie I de lâ&#x20AC;&#x2122;examen de certification du Conseil mĂŠdical du Canada. RĂŠsultats Des donnĂŠes complĂ¨tes ĂŠtaient disponibles pour 99 % des diplĂ´mĂŠs (n = 295). Dans lâ&#x20AC;&#x2122;analyse, les programmes de rĂŠsidence (mĂŠdecine familiale [n = 96] versus autres programmes [n = 199]) reprĂŠsentaient les variables indĂŠpendantes. Une ANOVA (analyse de variance) unidirectionnelle Ă variables multiples nâ&#x20AC;&#x2122;a trouvĂŠ aucune diffĂŠrence significative pour lâ&#x20AC;&#x2122;un ou lâ&#x20AC;&#x2122;autre des scores obtenus (F5289 = 1,73, P > ,05). En outre, les ĂŠtudiants qui entraient en mĂŠdecine familiale ĂŠtaient bien reprĂŠsentĂŠs parmi les 10 meilleurs rĂŠsultats de plusieurs des mesures de rendement. Conclusion Les ĂŠtudiants qui avaient optĂŠ pour une carriĂ¨re en mĂŠdecine familiale avaient un rendement acadĂŠmique semblable Ă celui des ĂŠtudiants qui avaient choisi dâ&#x20AC;&#x2122;autres spĂŠcialitĂŠs. Une attitude nĂŠgative injustifiĂŠe Ă ĂŠgard de la mĂŠdecine familiale a dâ&#x20AC;&#x2122;importantes rĂŠpercussions sociĂŠtales, particuliĂ¨rement Ă un moment oĂš lâ&#x20AC;&#x2122;ĂŠcart semble sâ&#x20AC;&#x2122;ĂŠlargir entre le nombre de mĂŠdecins de famille et le nombre de patients qui recherchent des services de premiĂ¨re ligne.

$FU BSUJDMF B GBJU M PCKFU E VOF SĂ&#x160;WJTJPO QBS EFT QBJST Can Fam Physician 2011;57:e26-30 VOL 57: JANUARY t JANVIER 2011

POINTS DE REPĂ&#x2C6;RE DU RĂ&#x2030;DACTEUR r -B GPSNBUJPO EBOT MFT GBDVMUĂ&#x160;T EF NĂ&#x160;EFDJOF DPNQSFOE OPO TFVMFNFOU VO DVSSJDVMVN GPSNFM NBJT BVTTJ VO jĂ¸DVSSJDVMVN DBDIĂ&#x160;Ă¸v D Ă&#x2020; E VO FOTFNCMF E JOGMVFODFT RVJ BHJTTFOU BV TFJO EF MB TUSVDUVSF PSHBOJTBUJPOOFMMF FU DVMUVSFMMF EF M JOTUJUVUJPO r -F GBJU RVF MB NĂ&#x160;EFDJOF GBNJMJBMF TPJU QFSĂ&#x2030;VF DPNNF VOF PQUJPO EF DBSSJĂ?SF NPJOT BUUSBZBOUF Ă&#x2020; DBVTF EF DF DVSSJDVMVN DBDIĂ&#x160; EJTTVBEF DFSUBJOT Ă&#x160;UVEJBOUT E FOWJTBHFS DFUUF EJTDJQMJOF FU SFOGPSDF M JEĂ&#x160;F RVF MFT NĂ&#x160;EFDJOT EF GBNJMMF TPOU NPJOT DPNQĂ&#x160;UFOUT TVS MF QMBO BDBEĂ&#x160;NJRVF RVF MFVST DPOGSĂ?SFT EFT BVUSFT TQĂ&#x160;DJBMJUĂ&#x160;T r $FUUF Ă&#x160;UVEF B DPNQBSĂ&#x160; MF SFOEFNFOU BDBEĂ&#x160;NJRVF EFT Ă&#x160;UVEJBOUT FO NĂ&#x160;EFDJOF RVJ FOUSBJFOU EBOT MF QSPHSBNNF EF SĂ&#x160;TJEFODF FO NĂ&#x160;EFDJOF GBNJMJBMF Ă&#x2020; DFMVJ EFT Ă&#x160;UVEJBOUT RVJ FOUSBJFOU EBOT MFT QSPHSBNNFT E BVUSFT TQĂ&#x160;DJBMJUĂ&#x160;T FU B NPOUSĂ&#x160; RV JM O Z BWBJU QBT EF EJGGĂ&#x160;SFODF FOUSF MFT HSPVQFT DF RVJ QSPVWF RVF MB QFSDFQUJPO OĂ&#x160;HBUJWF Ă&#x2020; M Ă&#x160;HBSE EV SFOEFNFOU EF DFVY RVJ PQUFOU QPVS MB NĂ&#x160;EFDJOF GBNJMJBMF O FTU QBT SĂ&#x160;FMMFNFOU GPOEĂ&#x160;F r -B QFSDFQUJPO OĂ&#x160;HBUJWF EF MB NĂ&#x160;EFDJOF GBNJMJBMF B EFT DPOTĂ&#x160;RVFODFT TPDJĂ&#x160;UBMFT JNQPSUBOUFT BV $BOBEB PĂ&#x153; PO PCTFSWF VO Ă&#x160;DBSU EF QMVT FO QMVT HSBOE FOUSF MF OPNCSF EF QFSTPOOFT RVJ POU CFTPJO E VO NĂ&#x160;EFDJO EF GBNJMMF FU MB QSPQPSUJPO EFT EJQMĂ&#x201D;NĂ&#x160;T EFT GBDVMUĂ&#x160;T EF NĂ&#x160;EFDJOF RVJ PQUFOU QPVS VOF DBSSJĂ?SF FO NĂ&#x160;EFDJOF GBNJMJBMF EFT NFTVSFT Ă&#x160;OFSHJRVFT EFWSBJFOU Ă&#x2039;USF QSJTFT BV TFJO EFT NJMJFVY DVMUVSFMT FU GPSNBUJGT EFT GBDVMUĂ&#x160;T EF NĂ&#x160;EFDJOF QPVS RVF EJTQBSBJTTF DFUUF BUUJUVEF JOKVTUJGJĂ&#x160;F FOWFST MB NĂ&#x160;EFDJOF GBNJMJBMF

| Canadian Family Physician

Le MĂŠdecin de famille canadien

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Research | %FCJBTJOH UIF IJEEFO DVSSJDVMVN

he insufficient supply of family physicians or general practitioners in Canada is a national concern. In recent years, fewer medical students have entered family medicine residency programs, and negative comments directed toward primary care have been identified as a factor that dissuade students from considering the discipline as a career option.1 Lack of respect for Canadian family physicians by colleagues from other disciplines has also been reported.2 Not all negativity, however, is delivered by physicians—both residents and students have also been participants in the “bashing.”3 Why is family medicine perceived so negatively? According to Hafferty,4 much of what is learned in medical school can be found within the hidden curriculum, which he defines as “a set of influences that function at the level of organizational structure and culture.”4 Negative comments degrading the discipline of family medicine are elements of the hidden curriculum that are not only powerful5,6 but also counterproductive to the efforts of medical schools and government bodies who are trying to bridge the primary care gap. By evading the scrutiny of the curriculum committee and accreditation body, this curricular agenda, which need not be evidence-based, provides an opportunity for the unfiltered biases of staff and students to be disseminated. Consequently, the hidden curriculum might exert a pernicious influence on the career choices of medical graduates and might even become self-fulfilling if students choose a career that they believe is congruent with their academic performance. Research suggests that negative comments toward the family medicine discipline become more frequent as students approach graduation7 and, for some students, can be instrumental in their career decisions.8 Negative comments frequently heard about family medicine imply that the content of the discipline is too vast to master competently and that family physicians are not as smart as physicians in other disciplines.9 A popular belief perpetuated by some faculty is that the top medical students should forego careers in family medicine to pursue subspecialty training.7,10 Nearly 20 years ago, Markert suggested that students selecting family medicine residency training had lower grade point averages (GPAs) and National Board of Medical Examiners certification scores compared with students selecting subspecialty training.8 Although these findings were largely countered by others,11,12 the perception that family medicine trainees are less academically talented than their peers seems to have lingered. Differences in both postgraduate training and the health care system in the United States suggest that previous research findings might not extrapolate to the Canadian context. There are no Canadian data to suggest that medical students who choose family medicine as a career differ academically from their peers, although students do report this perception.10 The purpose of our

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Canadian Family Physician t Le Médecin de famille canadien

study was to compare the academic performance of medical students who chose family medicine as a career with the academic performance of their classmates who trained in other disciplines.

METHODS We gathered data on the undergraduate academic performances of students from the University of Calgary in Alberta from 3 consecutive graduating medical classes (2004 to 2006) who entered the Canadian Resident Matching Service (CaRMS) match. Certifying examination results of the various system courses were used to calculate GPAs for students’ first and second years in the program. A clerkship GPA was also calculated based on the written examination scores of each of the 7 mandatory rotations, which include anesthesia, family medicine, internal medicine, obstetrics and gynecology, pediatrics, psychiatry, and surgery. A mean in-training evaluation report score was calculated based on clinical performance in each of the mandatory rotations. We also recorded each student’s performance on the Medical Council of Canada Qualifying Examination (MCCQE) Part I and career choice as reported by CaRMS. The Conjoint Health Research Ethics Board at the University of Calgary granted ethical approval for this study. We divided our graduates into 2 groups: those who entered a family medicine residency training program and those who entered any other residency training program. Career choice served as the independent variable, while the various performance measures served as dependent variables in the analysis. Using a 1-way multivariate ANOVA (analysis of variance), we compared the GPAs obtained in each year of the 3-year program, performance on clerkship in-training evaluation reports, and MCCQE Part I scores.

RESULTS Complete data were available for 295 (99.0%) of the 298 graduates who entered the CaRMS match. Ninety-six (32.5%) graduates entered training in family medicine and 199 (67.5%) entered training programs in other disciplines. The percentage of graduates from each class who entered family medicine training programs ranged from 29.9% (class of 2004) to 36.2% (class of 2006). Of the 295 participants, 164 (55.6%) were female. We found no significant difference in performance in undergraduate training measures or the MCCQE Part I scores between students who entered family medicine and those who entered other training programs (F5289 = 1.73, P > .05). These data are shown in Table 1. We also sorted (from highest to lowest) results of each of the 5 outcome

| VOL 57: JANUARY t JANVIER 2011

%FCJBTJOH UIF IJEEFO DVSSJDVMVN | Research Table 1. Mean performance scores of graduates (N = 295) who entered family medicine residency versus those who entered nonâ&#x20AC;&#x201C;family medicine residency programs: None of the differences between groups was statistically significant. GRADUATES TRAINING IN FAMILY MEDICINE (N = 96), MEAN (SD)

GRADUATES TRAINING IN NONâ&#x20AC;&#x201C;FAMILY MEDICINE PROGRAMS (N = 199), MEAN (SD)

GPA in year 1

80.7 (4.9)

80.9 (4.6)

GPA in year 2

80.5 (4.0)

80.3 (4.0)

(1" PG DMFSLTIJQ FYBNJOBUJPO TDPSFT

75.6 (4.0)

76.1 (3.5)

3.9 (0.3)

508.7 (70.0)

513.6 (65.6)

VARIABLE

(1" PG DMFSLTIJQ *5&3 TDPSFT .$$2& 1BSU * UPUBM TDPSFT

(1"Â&#x2021;HSBEF QPJOU BWFSBHF *5&3Â&#x2021;JO USBJOJOH FWBMVBUJPO SFQPSU .$$2&Â&#x2021;.FEJDBM $PVODJM PG $BOBEB 2VBMJGZJOH &YBNJOBUJPO .FBO TDPSF CBTFE PO B QPJOU TDBMF

measures to see how many students who entered family medicine residency programs ranked in the top 10 spots. We found that 4 students who entered family medicine were in the top 10 for the MCCQE Part I scores; with regard to the various undergraduate outcome measures, top 10 positions were occupied by 3 to 5 students who entered family medicine training programs.

DISCUSSION Over a 3-year period, medical school graduates from the University of Calgary pursuing family medicine training had academic performances comparable to those of their peers on measures taken between year 1 of undergraduate training and the licensing examination (ie, the MCCQE Part I), which is written at the time of graduation. Furthermore, these students were well represented among the top 10 performers on the various performance measures. Given that one-third of students in this study entered family medicine training programs, one would expect a similar proportion of students pursuing family medicine to rank in the top 10 positions of the various outcome measures. Results showed that these students occupied 30% to 50% of the top 10 positions when each outcome measure was ranked, thereby meeting or exceeding this expectation. It is certainly reassuring to find that the specialty with the broadest scope of clinical practice is not a home for the least successful academic performers. Our results are consistent with those of other studies that examined the academic performances of primary care and nonâ&#x20AC;&#x201C;primary care physicians and students who

entered any of 8 specialty groupings, including family practice.11,12 Our study of a 3-year cohort did not have a sufficient number of students to allow comparison of the academic performances of students among the different specialties. Grouping all of the nonâ&#x20AC;&#x201C;family medicine students together might have masked potential differences in performance across specialties and is worthy of further investigation. Examining the performances of students who entered family medicine and those training in other fields during residency is also recommended. Why all the unfounded negativity directed toward family medicine? We propose that this negativity is largely due to personal opinion that is voiced within the safety of the hidden curriculum. People are a primary source of hidden messages, 5 and faculty who speak poorly of other disciplines might be oblivious to the influence such behaviour can have on students.13 The extent to which these individuals, unintentionally or otherwise, stoke the fires of the hidden curriculum is unclear. Our study was not designed to address this important issue, but our results suggest that this topic warrants further study. Hojat et al12 found that, as students, primary care physicians displayed less interest in research than their nonâ&#x20AC;&#x201C;primary care peers. Investigating whether participation in scholarly activities such as research or teaching affects other specialistsâ&#x20AC;&#x2122; perception of family medicine might help to understand the negativity. The negative perceptions of family medicine as a career have important societal consequences. In Canada there has been a relentless increase in the number of individuals who are unable to secure a family doctor, while the proportion of medical school graduates selecting family medicine as a career remains low, resulting in a primary care gap. Despite some recent gains in the proportion of graduates selecting family medicine, medical schools need to do more to facilitate this upward trend. Clearly, this is a complex problem without a simple solution.

Limitations These data reflect the performances of students from a single medical school; it is not known whether these findings are representative of students from other medical schools across Canada. In the United States, students might take other routes into primary care practice such that these findings might not apply. Also, this study did not investigate opinions or attitudes, meaning the extent to which participants within the local educational environment denigrated family medicine is unknown. Furthermore, we did not have data to determine whether students who entered family medicine did so as their first choice of career or as an alternative. Consequently, we do not know if the academic performances of students in these 2 groups differ and whether this affected the findings.

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Research | %FCJBTJOH UIF IJEEFO DVSSJDVMVN Conclusion “Bad-mouthing” appears to be part of the medical education environment,1 and reducing the prevailing negativity might contribute to an increased number of students willing to consider careers in primary care.3 In order to debias the learning environment in which our students are immersed, medical schools need to be proactive14 by promoting a nonjudgmental setting for learning.3 Raising the consciousness of those who participate in the learning environment about this issue and promoting medicine as an interdisciplinary profession are sensible strategies that have been advanced.3 Most important, the profile of family medicine within the medical school environment should be enhanced in as many ways as possible.2 To best serve society, our ultimate goal should be to remove the unjustified stigma placed upon family medicine by the medical training environment. Dr Woloschuk is Director of Program Evaluation in the Faculty of Medicine at the University of Calgary in Alberta. Dr Wright is Associate Dean of Undergraduate Medical Education in the Faculty of Medicine at the University of Calgary. Dr McLaughlin is Assistant Dean of Undergraduate Medical Education in the Faculty of Medicine at the University of Calgary. Contributors Dr Woloschuk conceived the study, assisted with data collection and analysis, prepared the initial draft of the manuscript, and approved the final version. Dr Wright contributed to the study design and data collection, revised the manuscript for intellectual content, and approved the final version. Dr McLaughlin assisted with the data analysis and data interpretation, revised the manuscript for intellectual content, and approved the final version. Competing interests None declared

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Correspondence Dr Wayne Woloschuk, Department of Undergraduate Medical Education, Faculty of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, AB T2N 4N1; e-mail woloshu@ucalgary.ca References 1. Hunt DD, Scott C, Zhong S, Goldstein E. Frequency and effect of negative comments (“badmouthing”) on medical students’ career choices. Acad Med 1996;71(6):665-9. 2. Manca D, Varnhagen S, Brett-MacLean P, Allan GM, Szafran O. RESPECT from specialists. Concerns of family physicians. Can Fam Physician 2008;54:1434-5.e1-5. Available from: www.cfp.ca/cgi/reprint/54/10/1434. Accessed 2010 Dec 7. 3. Holmes D, Tumiel-Berhalter LM, Zayas LE, Watkins R. “Bashing” of medical specialties: students’ experiences and recommendations. Fam Med 2008;40(6):400-6. 4. Hafferty FW. Beyond curriculum reform: confronting medicine’s hidden curriculum. Acad Med 1998;73(4):403-7. 5. Anderson DJ. The hidden curriculum. AJR Am J Roentgenol 1992;159(1):21-2. 6. Mattsson B, Freeman GK, Coles CR, Schmedlin J. General practice in the undergraduate curriculum: 20 interviews with Southampton final-year students. Med Educ 1991;25(2):144-50. 7. Hearst N, Shore WB, Hudes ES, French L. Family practice bashing as perceived by students at a university medical center. Fam Med 1995;27(6):366-70. 8. Markert RJ. Why medical students change to and from primary care as a career choice. Fam Med 1991;23(5):347-50. 9. Campos-Outcalt D, Senf J, Kutob R. Comments heard by US medical students about family practice. Fam Med 2003;35(8):573-8. 10. Scott I, Wright B, Brenneis F, Brett-MacLean P, McCaffrey L. Why would I choose a career in family medicine? Reflections of medical students at 3 universities. Can Fam Physician 2007;53:1956-7.e1-8. Available from: www.cfp. ca/cgi/reprint/53/11/1956. Accessed 2010 Dec 7. 11. Xu G, Veloski JJ, Hojat M. Changing interest in family medicine and students’ academic performance. Acad Med 1993;68(10 Suppl):S52-4. 12. Hojat M, Gonnella JS, Erdmann JB, Veloski JJ, Xu G. Primary care and nonprimary care physicians: a longitudinal study of their similarities, differences, and correlates before, during, and after medical school. Acad Med 1995;70(1 Suppl):S17-28. 13. Kamien BA, Bassiri M, Kamien M. Doctors badmouthing each other. Does it affect medical students’ career choices? Aust Fam Physician 1999;28(6):576-9. 14. Peach HG. Badmouthing between disciplines. Aust Fam Physician 1999;28(6):581.

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L’évaluation par des pairs, ce n’est pas du tape-à-l’œil.

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Research

Burden of acute otitis media on Canadian families Eve Dubé PhD Philippe De Wals MD PhD Vladimir Gilca MD PhD Nicole Boulianne MSc Manale Ouakki MSc France Lavoie Richard Bradet

MSc

Abstract Objective To estimate the burden of acute otitis media (AOM) on Canadian families. Design Telephone survey using random-digit dialing. Setting All Canadian provinces between May and June 2008. Participants Caregivers of 1 or more children aged 6 months to 5 years. Main outcome measures Caregivers’ reports on the number of AOM episodes experienced by the child in the past 12 months, as well as disease characteristics, health services and medication use, time spent on medical consultations (including travel), and time taken off from work to care for the sick children. Results A total of 502 eligible caregivers were recruited, 161 (32%) of whom reported at least 1 AOM episode for their children and 42 (8%) of whom reported 3 or more episodes during the past 12 months. Most children (94%, 151 of 161) visited with health professionals during their most recent AOM episodes. The average time required for medical examination was 3.1 hours in an emergency department and 1.8 hours in an outpatient clinic. Overall, 93% of episodes resulted in antibiotics use. A EDITOR’S KEY POINTS substantial proportion of caregivers (38%) missed work during this time; the r Almost all cases of acute otitis media average time taken off work was 15.9 hours. Conclusion In Canada, episodes of AOM are still associated with substantial use of health services and indirect costs to the caregivers.

(AOM) described in this study were treated with antibiotics; extensive use of antibiotics causes resistance, which results in decreased treatment performance and meaningful economic burden. r $BSFHJWFS UJNF JT BO JNQPSUBOU GBDUPS associated with the burden of AOM; travel, waiting room, and medical examination time as well as time taken off work all contribute to the indirect costs associated with this condition. r #VSEFO PG "0. PO GBNJMJFT IBT received limited attention when the cost-effectiveness of AOM prevention and treatment programs has been assessed in the past. Results of this study indicate that this burden remains important in a country with wellestablished childhood immunization programs.

This article has been peer reviewed. Can Fam Physician 2011;57:60-5 60

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This article is eligible for Mainpro-M1 credits. To earn credits, go to www.cfp.ca and click on the Mainpro link.

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Recherche

Le fardeau qu’impose l’otite moyenne aiguë aux familles canadiennes Eve Dubé PhD Philippe De Wals MD PhD Vladimir Gilca MD PhD Nicole Boulianne MSc Manale Ouakki MSc France Lavoie Richard Bradet

MSc

Résumé Objectif Estimer le fardeau qu’impose l’otite moyenne aiguë (OMA) aux familles canadiennes. Type d’étude Enquête téléphonique à l’aide de numéros choisis au hasard. Contexte Toutes les provinces canadiennes, entre mai et juin 2008. Participants Soignants s’occupant d’au moins un enfant âgé entre 6 mois et 5 ans. Principaux paramètres à l’étude Déclarations des soignants concernant le nombre d’épisodes d’OMA subies par l’enfant au cours des 12 derniers mois, ainsi que les caractéristiques de la maladie, les médicaments et services de santé utilisés, le temps consacré aux consultations (incluant les déplacements) et le temps perdu au travail pour s’occuper des enfants malades. Résultats Un total de 502 soignants admissibles ont été recrutés, dont 161 (32 %) ont rapporté au moins un épisode d’OMA et 42 (8 %) au moins 3 épisodes parmi leurs enfants au cours des 12 derniers mois. La plupart des enfants (94 %, 151 sur 161) ont consulté leur professionnel de la santé durant l’épisode le plus récent. Le temps requis pour l’examen était en moyenne de 3,1 heure dans un service d’urgence et de 1,8 heure dans une clinique externe. Dans l’ensemble, 93 % des épisodes ont POINTS DE REPÈRE DU RÉDACTEUR abouti à une prescription d’antibiotiques. Une proportion appréciable de r Presque tous les cas d’otite moyenne soignants (38 %) ont dû s’absenter du travail à cette occasion; le temps perdu aiguë (OMA) rapportés dans cette étude au travail s’élevait en moyenne à 15,9 heures. Conclusion Au Canada, les épisodes d‘OMA demeurent responsables d’une importante utilisation des services de santé et de coûts indirects pour les soignants.

ont été traités par antibiotiques : une importante utilisation d’antibiotiques est une source de résistance, ce qui entraîne de moins bons résultats du traitement en plus d’un fardeau économique appréciable. r Le temps exigé des soignants est un facteur important qui s’ajoute au fardeau qu’imposent les OMA; les périodes consacrées au déplacement, à la salle d’attente et à l’examen médical en plus du temps de travail perdu contribuent tous aux coûts indirects de cette condition. r Lorsqu’on a évalué le rapport coûts/ bénéfices des programmes de prévention et de traitement de l’OMA dans le passé, on s’est peu préoccupé du fardeau imposé aux familles. Les résultats de cette étude indiquent que ce fardeau demeure important dans un pays qui dispose d’un programme de vaccination pour enfants bien établi.

Cet article a fait l’objet d’une révision par des pairs. Can Fam Physician 2011;57:60-5 VOL 57: JANUARY t JANVIER 2011

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cute otitis media (AOM) is one of the most common bacterial infections among children and a leading cause of health care visits and antibiotic prescriptions.1 In Quebec, 11% of physicians’ insurance claims for children younger than 10 years of age are associated with a diagnosis of otitis media2; the total annual cost to the health care system of otitis media and placement of ventilation tubes is more than $10 million.3 In the first 3 years of life, 60% to 70% of children will have experienced at least 1 episode of AOM,4 and recurrent episodes of AOM are common.5 The main characteristic symptom of AOM is effusion in the middle ear, accompanied by such signs of acute illness as earache, otorrhea (ie, runny, stuffed ear), ear tugging, fever, irritability, anorexia, vomiting, or diarrhea.6 A diagnosis of AOM is the most common reason for antibiotic prescribing in childhood, even though most cases of AOM resolve spontaneously.7 In fact, results of meta-analyses indicate that antibiotics are not very useful for most children with AOM.8-10 Antimicrobial resistance to bacterial otopathogens is an increasing public health concern worldwide. In the United States, strains of Streptococcus pneumoniae that are resistant to all Food and Drug Administration–approved antibiotics for the treatment of AOM in children have emerged in recent years.11 Primary prevention of AOM through immunization is an emerging issue,12 but few vaccines have the potential to prevent AOM.13-16 Another strategy to reduce the burden of AOM is to use antibiotics more selectively. With the so-called waitand-see approach, the use of antibiotics is deferred by 2 or 3 days, during which time only pain is treated; antibiotics are only prescribed if there is no improvement in the child’s clinical condition at the end of this period.7 In 2009, the Canadian Paediatric Society recommended the waitand-see approach as a valid option for otherwise healthy children older than 6 months of age who have mild clinical signs and symptoms of AOM.17 Precise knowledge of the frequency and consequences of AOM is needed to evaluate interventions that aim to reduce its societal costs, and an often-neglected aspect is the burden of disease on families. To our knowledge, the burden of AOM on Canadian families has never been estimated. Previous studies have assessed the societal costs of AOM in Canada before the addition of pneumococcal conjugate vaccine to the regular childhood vaccination schedule.18,19 These studies indicated that AOM had a relatively low family and health care system unit cost; however, owing to its frequency, the estimated overall burden was high. In 2001, the cost of an episode of AOM in Canada was estimated at $321, of which 82% was borne by families.18 Studies have also shown the negative effects of otitis media on parental stress, family functioning, and quality of life of the child and his or her family.20-25 In 2008, we surveyed a random sample of Canadian families; results pertaining to the quality of life of affected children and their parents and to parental

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knowledge, attitudes, and beliefs regarding AOM and its prevention have been reported elsewhere. 26,27 This report focuses on the frequency and severity of AOM, health services use, and absenteeism from work.

METHODS The Ethics Board of the Centre hospitalier universitaire de Québec approved the study protocol. From May to June 2008, stratified random sampling of households in all 10 Canadian provinces was performed using random-digit dialing. A sample size of 500 was needed to provide an overall precision of plus or minus 4% in the estimate of proportions (with a 95% confidence interval). Respondents in households with at least 1 child aged 6 months to 5 years were invited to participate, and the adult most involved in the care of the child was invited to complete a telephone interview in English or French. Questions about the occurrence of AOM were prefaced with a standard definition. The child having the most recent AOM episode in the past 12 months (ie, the index child) was selected for further analysis. The caregiver was asked to report on the number of AOM episodes experienced by the child in the previous 12 months; to describe the duration, symptoms, and health services and medication use of the last episode; and to quantify time spent on medical visits and time taken off from work to take care of the sick child. Information was also obtained on the caregiver’s age and sex, education, region of residence, number of persons in the household, and other relevant characteristics (eg, 1 or 2 caregivers per household, children in shared custody). The questionnaire used in this study was based on a questionnaire used to assess the burden of chickenpox on families in another study.28 Descriptive statistics were generated for all variables using SAS version 9.1. Comparisons of categorical responses were performed using χ2 or Fisher exact tests.

RESULTS Of the 28 374 telephone numbers randomly generated, 26 385 were reached: 12 269 were nonresidential or not in service; in 4796 households, the respondent refused to participate; and 8769 households were not eligible (ie, no child in the targeted age group). In the 551 eligible households, a caregiver was able to complete the survey in 502 cases (Figure 1). The number of respondents by province was proportional to the population weight of each province. Thirty-two percent of caregivers (161 of 502) reported at least 1 AOM episode during the past 12 months. Most caregivers were mothers (82%), 58% were aged 25 to 34 years old, and 65% had college or university degrees. In the 161 households, the mean number of AOM episodes

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Figure 1. Flow chart of participant selection 28 374 telephone numbers randomly generated 26 385 telephone numbers reached 12 269 telephone numbers nonresidential or not in service

8769 households ineligible (ie, no child aged 6 months to 5 years)

4796 households refused to participate or answer any questions

AOM—acute otitis media.

in the past 12 months was 2.2 (range 1 to 10), with 27% of caregivers reporting 3 or more episodes. The most recent episode of AOM in each household was included for analysis, for a total of 161 cases included for further study. The mean age of the index child was 37.4 months, 50% were girls, and 37% were living in shared custody. Reported characteristics of AOM episodes according to age are shown in Table 1. The mean duration of AOM episodes was 5.9 days (median 4 days) with no statistically significant differences among age groups. On average, caregivers reported 2.8 symptoms during the last occurrence of AOM (median 3 symptoms). Pain, otorrhea, and hearing loss were more frequently reported among children 3 years of age and older than among younger children. In 11% of cases, a medical help line was called. By far most episodes (94%) resulted in visits to physicians, more frequently in younger than in older children (100% vs 89%, P ≤ .05). Over-the-counter or prescribed medications were used in 100% of AOM episodes. A greater number of medications was used by older than by younger children; 28% of children 3 years of age and older used 3 or more medications during the last AOM episode compared with 14% of younger children (P ≤ .05). Antibiotics were used in 93% of episodes and there was no statistically significant difference according to age.

Analgesic or antipyretic drugs were used in 80% and natural products in 9% of episodes. Of the 151 patients who received medical care, the mean distance traveled for medical visits was 13.3 km (median 10 km), and most caregivers (n = 140) used their own vehicles; public transportation was used in a small number of cases (n = 6) and the remaining 5 patients (with their caregivers) 551 eligible households traveled on foot. agreed to participate When parents brought children to the emergency department, the mean total time needed for 502 questionnaires transportation, waiting, completed and medical examination was 3.1 hours; 21% of parents spent a total 161 households of 4 hours or more to a reported AOM maximum of 18 hours (Table 2). When the child was seen in an outpatient clinic, the average time required was 1.8 hours, with a maximum of 3 hours, excluding the time needed to get an appointment (Table 2). Work absenteeism to take care of the sick child was reported by 61 caregivers (38% of episodes), for an average of 15.9 hours (median 14 hours).

DISCUSSION Acute otitis media is a common occurrence in families with young children and a substantial cause of disturbance, health services use, and indirect costs. Results of this national survey showed that only 6% of children who presumably had AOM were not seen by physicians. Although the time spent on medical visits was high for the small number of children brought to the emergency department, overall results are reassuring as to the accessibility of primary health care in Canada. To our knowledge, this is the first study that estimated the burden of AOM on Canadian families. Even if estimated family costs of AOM seem relatively low, the burden of AOM on Canadian families is important; a substantial proportion of caregivers also missed an average of 2 days of work during their children’s last AOM episodes. This study has several limitations. The occurrence of AOM was lower than what would have been expected,

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Research | #VSEFO PG BDVUF PUJUJT NFEJB PO $BOBEJBO GBNJMJFT Table 1. Description of episodes, health services use, and medications for AOM, by age

TIME

AGE

CHARACTERISTICS

6 TO 36 MO,* N (%) (N = 43)

3 TO 4 Y,* N (%) (N = 93)

ALL AGES,† N (%) (N = 161)

Duration, d r

≤3

14 (33)

30 (32)

52 (32)

4 to 6

13 (30)

32 (34)

55 (34)

≥7

15 (35)

29 (31)

51 (32)

1 (2)

2 (2)

3 (2)

r Unknown

Symptoms reported r

Ear pain

32 (74)

82 (88)

139 (86)

Fever

34 (79)

76 (82)

130 (81)

Otorrhoea or ruptured tympanic membrane

4 (9)‡

28 (30)‡

38 (24)

Vertigo

5 (12)

13 (14)

23 (14)

Hearing loss

2 (5)

23 (25)

31 (19)

7 (16)

8 (9)

18 (11)

43 (100)‡

83 (89)‡

151 (94)

‡

Health services use r

Call to help line§

Visit to physician

Private clinic or community health centre

32 (74)

68 (73)

122 (76)

Emergency room

11 (26)

15 (16)

29 (18)

No. of medications taken r

12 (28)‡

10 (11)‡

26 (16)

25 (58)

‡

57 (61)

97 (60)

≥3

6 (14)‡

26 (28)‡

38 (24)

‡

Type of medications taken r

Antibiotics

41 (95)

84 (90)

149 (93)

Antipyretics or analgesics

31 (72)

79 (85)

129 (80)

Ear drops

5 (12)‡

26 (28)‡

37 (23)

Natural products

3 (7)

9 (10)

14 (9)

*Responses were compared between the 2 age groups using χ2 or Fisher exact tests. † Included in this group are 25 children aged 6 months to 5 years with their exact ages unknown (not included in previous 2 groups). ‡ Differences between the 2 age groups are statistically significant (P ≤ .05). § Some caregivers who used help lines also sought care from physicians.

Table 2. Time spent visiting a physician, including travel, waiting, and medical examination: N = 151.

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EMERGENCY ROOM (N = 29)

OUTPATIENT CLINIC (N = 118)*

HOURS, N (%)

<2 2<4 r 4<6 r ≥6 Maximum, h Mean, h Median, h r

10.0 (34) 13.0 (45) 4.0 (14) 2.0 (7) 18.0 3.1 2.0

74.0 (63) 34.0 (29) 5.0 (4) 5.0 (4) 3.0 1.8 1.5

*Four cases had missing responses for time spent vising a physician.

assuming an annual rate of 60 cases of AOM per 100 children younger than 6 years of age.19 However, the study was conducted in May to June 2008, right after the winter season when most AOM cases occur; therefore, there is no reason to believe that an important recall bias is present. It is worth noting that the 2007 to 2008 influenza season was of relatively low intensity, which might somewhat diminish the incidence of AOM. We used a telephone survey, which can typically result in a recruitment bias toward more educated people and against young or new residents of communities who do not have household telephone numbers. 29 However, it is known that in Canada most families with young children have been residents of the same community for several years and most of them have household telephone numbers. In 2008, 8% of Canadian households reported having cellular telephones only, and less than 1% did not have any telephone services.30 In addition, the survey sample was chosen by stratified random sampling of households in 5 Canadian regions, ensuring that the number of participants was proportional to each region’s population, diminishing the risk of selection bias.31 Results of randomized controlled trials have shown that antibiotic treatment is associated with a more favourable clinical course than placebo, but the overall benefit is rather small; this is a justification for the waitand-see approach.32 Most AOM episodes analyzed in this study resulted in at least 1 medical visit. Additionally, despite the new guidelines recommending a wait-andsee approach for the management of AOM, almost all medical visits resulted in antibiotic use. Reported use of antibiotics in our study is comparable with that observed in another study conducted more than a decade ago in Ontario.33 These similarities show that no important changes have taken place in AOM treatment strategies or in parents’ decisions to seek medical consultation for their children with AOM, despite the changes to official recommendations. Similar findings were identified in previous US studies in which only a minority of family physicians and pediatricians routinely recommended the wait-and-see approach for the management

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#VSEFO PG BDVUF PUJUJT NFEJB PO $BOBEJBO GBNJMJFT | Research of AOM, despite available scientific evidence of its safety and years of promotion.34-36 Authors of a recent study in Finland and the Netherlands suggested that changes in treatment practices for AOM require strong guidelines and education of physicians, but also a modification of parental expectations regarding the usefulness of antibiotics.37 Primary prevention using pneumococcal conjugate and influenza vaccines is a potentially more interesting and feasible avenue, and specific studies are required to demonstrate whether the immunization programs recently implemented in all Canadian provinces and territories effectively reduce AOM incidence, antibiotic use, and associated costs. Dr Dubé is an anthropologist with the Quebec National Institute of Public Health, a researcher with the Public Health Research Unit of the Centre hospitalier universitaire de Québec (CHUQ), and Associate Professor in the Department of Social and Preventive Medicine at Laval University in Quebec. Dr De Wals is medical consultant with the Quebec National Institute of Public Health, a researcher with the Public Health Research Unit of CHUQ, and Professor in the Department of Social and Preventive Medicine at Laval University. Dr Gilca is an epidemiologist with the Quebec National Institute of Public Health, a researcher with the Public Health Research Unit of CHUQ, and Associate Professor in the Department of Social and Preventive Medicine at Laval University. Ms Boulianne is Scientific Unit Head, Immunization, with the Quebec National Institute of Public Health, a researcher with the Public Health Research Unit of CHUQ, and Associate Professor in the Department of Social and Preventive Medicine at Laval University. Ms Ouakki is a statistician with both the Quebec National Institute of Public Health and the Public Health Research Unit of CHUQ. Ms Lavoie is a research professional with the Public Health Research Unit of CHUQ. Mr Bradet is a statistician with the Public Health Research Unit of CHUQ. Contributors All authors contributed to the concept and design of the study; data gathering, analysis, and interpretation; and preparing the manuscript for submission. Competing interests This study was supported by an unrestricted research grant from GlaxoSmithKline. No private company or its employees were involved in designing the study protocol and questionnaire or in collecting, analyzing, and interpreting data. Correspondence Dr Eve Dubé, Quebec National Institute of Public Health, 2400 d’Estimauville, Quebec, QC G1E 7G9; telephone 418 666-7000, extension 295; fax 418 6662776; e-mail eve.dube@ssss.gouv.qc.ca References 1. Klein JO. The burden of otitis media. Vaccine 2000;19(Suppl 1):S2-8. 2. Wals PD, Carbon M, Sévin E, Deceuninck G, Ouakki M. Reduced physician claims for otitis media after implementation of pneumococcal conjugate vaccine program in the province of Quebec, Canada. Pediatr Infect Dis J 2009;28(9):e271-5. 3. Poirier B, De Wals P, Petit G, Erickson LJ, Pépin J. Cost-effectiveness of a 3-dose pneumococcal conjugate vaccine program in the province of Quebec, Canada. Vaccine 2009;27(50):7105-9. Epub 2009 Sep 26. 4. Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis 1989;160(1):83-94. 5. Casselbrant ML, Mandel EM. Epidemiology. In: Rosenfeld RM, Bluestone CD, editors. Evidence-based otitis media. 1999. Hamilton, ON: Decker Publishing Inc; 1999. p. 117-36. 6. Jahn-Eimermacher A, du Prel JB, Schmitt HJ. Assessing vaccine efficacy for the prevention of acute otitis media by pneumococcal vaccination in children: a methodological overview of statistical practice in randomized controlled clinical trials. Vaccine 2007;25(33):6237-44. 7. Spiro DM, Arnold DH. The concept and practice of a wait-and-see approach to acute otitis media. Curr Opin Pediatr 2008;20(1):72-8. 8. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314(7093):1526-9. 9. Rosenfeld RM, Vertrees JE, Carr J, Cipolle RJ, Uden DL, Giebink GS, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials. J Pediatr 1994;124(3):355-67. 10. Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis media in children. Cochrane Database Syst Rev 2004;(1):CD000219.

11. Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA 2007;298(15):1772-8. 12. Straetemans M, Sanders EA, Veenhoven RH, Schilder AG, Damoiseaux RA, Zielhuis GA. Pneumococcal vaccines for preventing otitis media. Cochrane Database Syst Rev 2004;(1):CD001480. 13. Manzoli L, Schioppa F, Boccia A, Villari P. The efficacy of influenza vaccine for healthy children: a meta-analysis evaluating potential sources of variation in efficacy estimates including study quality. Pediatr Infect Dis J 2007;26(2):97106. 14. De Wals P, Erickson L, Poirier B, Pépin J, Pichichero ME. How to compare the efficacy of conjugate vaccines to prevent acute otitis media. Vaccine 2009;27(21):2877-83. Epub 2009 Mar 10. 15. Wyeth Canada. Prevnar 13 [product monograph]. Montreal, QC: Wyeth Canada; 2009. Available from: www.wyeth.ca/en/products/Product%20 Monographs%20PDFs/Prevnar_13_Product_Monograph_Dec_21_2009_ EN.pdf. Accessed 2010 Nov 17. 16. Prymula R, Peeters P, Chrobok V, Kriz P, Novakova E, Kaliskova E, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet 2006;367(9512):740-8. 17. Forgie S, Zhanel G, Robinson J. Management of acute otitis media. Paediatr Child Health 2009;14(7):457-64. 18. Petit G, De Wals P, Law B, Tam T, Erickson LJ, Guay M, et al. Epidemiological and economic burden of pneumococcal diseases in Canadian children. Can J Infect Dis 2003;14(4):215-20. 19. Morrow A, De Wals P, Petit G, Guay M, Erickson LJ. The burden of pneumococcal disease in the Canadian population before routine use of the seven-valent pneumococcal conjugate vaccine. Can J Infect Dis Med Microbiol 2007;18(2):121-7. 20. Asmussen L, Olson LM, Sullivan SA. “You have to live it to understand it”: family experiences with chronic otitis media in children. Ambul Child Health 1999;5:303-12. 21. Forgays DK, Hasazi JE, Wasserman RC. Recurrent otitis media and parenting stress in mothers of two-year-old children. J Dev Behav Pediatr 1992;13(5):321-5. 22. Rosenfeld RM, Goldsmith AJ, Tetlus L, Balzano A. Quality of life for children with otitis media. Arch Otolaryngol Head Neck Surg 1997;123(10):1049-54. 23. Brouwer CN, Rovers MM, Maillé AR, Veenhoven RH, Grobbee DE, Sanders EA, et al. The impact of recurrent acute otitis media on the quality of life of children and their caregivers. Clin Otolaryngol 2005;30(3):258-65. 24. Boruk M, Lee P, Faynzilbert Y, Rosenfeld RM. Caregiver well-being and child quality of life. Otolaryngol Head Neck Surg 2007;136(2):159-68. 25. Haggard MP, Smith SC. Impact of otitis media on child quality of life. In: Rosenfeld RM, Bluestone CD, editors. Evidence-based otitis media. Hamilton, ON: Decker Publishing Inc; 1999. p. 375-98. 26. Dubé E, De Wals P, Gilca V, Boulianne N, Ouakki M, Lavoie F, et al. New vaccines offering a larger spectrum of protection against acute otitis media: will parents be willing to have their children immunized? Int J Pediatr Otorhinolaryngol 2009;73(7):987-91. Epub 2009 May 6. 27. Dubé E, De Wals P, Gilca V, Boulianne N, Ouakki M, Lavoie F. Burden of acute otitis media: knowledge, attitudes, and beliefs of Canadian parents. Poster presented at the Canadian Paediatric Society 86th Annual Conference; 2009 Jun 23-27; Ottawa, ON. 28. De Wals P, Blackburn M, Guay M, Bravo G, Blanchette D, Douville-Fradet M. Burden of chickenpox on families. A study in Quebec. Can J Infect Dis 2001;12(1):27-32. 29. Dillman DA. Mail and telephone surveys. The total design method. Hoboken, NJ: John Wiley & Sons, Inc; 1978. 30. Statistics Canada. Residential telephone service survey. Ottawa, ON: Statistics Canada; 2008. Available from: www.statcan.gc.ca/daily-quotidien/090615/dq090615c-eng.htm. Accessed 2010 Nov 18. 31. Statistics Canada. Families and households highlight tables, 2006 census. Catalogue no. 97-551-XWE2006002. Ottawa, ON: Statistics Canada; 2007. Available from: www12.statcan.ca/census-recensement/2006/dp-pd/ hlt/97-553/index.cfm?Lang=E. Accessed 2010 Nov 18. 32. Vouloumanou EK, Karageorgopoulos DE, Kazantzi MS, Kapaskelis AM, Falagas ME. Antibiotics versus placebo or watchful waiting for acute otitis media: a meta-analysis of randomized controlled trials. J Antimicrob Chemother 2009;64(1):16-24. Epub 2009 May 19. 33. Pennie RA. Prospective study of antibiotic prescribing for children. Can Fam Physician 1998;44:1850-6. 34. Finkelstein JA, Stille CJ, Rifas-Shiman SL, Goldmann D. Watchful waiting for acute otitis media: are parents and physicians ready? Pediatrics 2005;115(6):1466-73. 35. Vernacchio L, Vezina RM, Mitchell AA. Knowledge and practices relating to the 2004 acute otitis media clinical practice guideline: a survey of practicing physicians. Pediatr Infect Dis J 2006;25(5):385-9. 36. Vernacchio L, Vezina RM, Mitchell AA. Management of acute otitis media by primary care physicians: trends since the release of the 2004 American Academy of Pediatrics/American Academy of Family Physicians clinical practice guideline. Pediatrics 2007;120(2):281-7. 37. Tähtinen PA, Boonacker CW, Rovers MM, Schilder AG, Huovinen P, Liuksila PR, et al. Parental experiences and attitudes regarding the management of acute otitis media—a comparative questionnaire between Finland and The Netherlands. Fam Pract 2009;26(6):488-92. Epub 2009 Sep 3.

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| Canadian Family Physician

Le Médecin de famille canadien

Stories in Family Medicine | Commentary

The importance of stories Ian A. Cameron

MD CCFP

art of my story is in British Columbia. When my wife, Bev, and I began our nursing and medical careers together, we went as far as you can go in British Columbia and 40 miles farther—the Queen Charlotte Islands. At the end of a year full of memory investments, we returned east to start our family. Time passed …. In the early ’90s Bev and I returned to BC to attend a family medicine meeting in Whistler. Tony Bennett left his heart in San Francisco; I lost some of my heart in Whistler. Time passed …. In the past year our youngest daughter and her husband have begun their careers in Kelowna. The cycle begins again. What I’ve just told you is narrative: the what and the then … and then. Now if I told you I lost some of my heart in Whistler trying desperately to win a tennis game from John Keddy, that’s plot: the why. In family medicine we deal with the what and the why—narrative and plot. Dr Arthur Frank gave this address last year in Calgary, Alta,1 honouring the family medicine story award winners.* A few years earlier Dr Frank wrote the introduction to In Our Hands, a collection of stories by medical students from across Canada, edited by Linda Clarke and Jeff Nisker.2 Dr Frank refers to the word liminal in his introduction. He defines liminal as being neither this nor that; for example, the area between the cultivated fields of a village and the forest. The medical students who wrote the stories in the collection were liminal: in a transition state, no longer lay persons, not yet doctors. He writes, “liminal transitions can be both dangerous and fascinating.”2 Our patients are often liminal (in transition states): health to illness, illness to health, illness to death, single to couple to family, couple to divorce, employment to retirement, innocence to adolescence. Daily we listen to individuals who have their own narratives and plot lines, and their stories too can be dangerous and fascinating. Can we be better physicians if we learn to see our patients in their contexts, in their stories? There was a patient in our practice. She was young and had come from the country to the city in search of her future. She had well-controlled asthma. One day a discharge summary arrived from the hospital. Our patient had had a severe asthma attack. She had been intubated but had made a good recovery. Over the next few months we saw her with increasing frequency. She *This article is based on a presentation by Dr Cameron at the awards ceremony for the winners of the 2010 AMS– Mimi Divinsky Awards for History and Narrative in Family Medicine at Family Medicine Forum in Vancouver, BC, on October 16, 2010.

Canadian Family Physician t Le Médecin de famille canadien

had changed. Her lung findings were normal but she looked tired, at times desperate. “Can you help me breathe?” she would ask. We consulted a respirologist. She fine-tuned her medication. It made no difference. At night our patient haunted the emergency department. Her diagnoses went from asthma to anxiety to panic attacks. We talked about a referral to psychiatry. “Can they help me breathe?” she asked. One day our resident concluded that we really hadn’t established our patient’s problem. It wasn’t acute asthma, she was sure. So she took a different approach and said to our patient, “Tonight I want you to write down what has happened to you and why you can’t breathe.” The next day our patient brought this written explanation: I was having a very bad asthma attack on the night I arrived at the emergency room. A nurse started an IV and someone injected something into it. Suddenly I couldn’t breathe. I couldn’t speak. I was paralyzed. I was in a room full of nurses and doctors and I couldn’t tell them my problem. Someone shoved something down my throat and then I was gone. I woke up in a dark room with a tube in my mouth on a machine. Since then I keep reliving that moment when I was paralyzed and couldn’t breathe.

Over the next few months our patient made a steady recovery. The next year she married. We delivered her first baby. The resident had found a way for our patient to reveal the “why” in her story. Jacques Ferron is considered in writing circles to be Canada’s pre-eminent physician-writer, and yet he is largely unknown to Canadian medical students and physicians. He was born in Louiseville, Que, in 1921, received his medical degree from Laval in 1945, and practised as a rural physician in Rivière-Madeleine, Gaspé, and later in Longueuil opposite Montreal on the south side of the St Lawrence River. During the October Crisis of 1970, he was chosen as a mediator between the government and the Laporte kidnappers. He founded the Rhinoceros Party. He was a playwright, essayist, novelist, and most of all a short story writer. His first collection of short stories won the Governor General’s Award. The stories are molded from his cultural heritage and his physician’s insight. Cet article se trouve aussi en français à la page 68.

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Commentary | Stories in Family Medicine Betty Bednarski has compiled and translated a new Ferron collection published by McClelland and Stewart, Tales from the Uncertain Country and Other Stories. 3 In the Afterword she outlines Ferron’s technique as he transforms the folktale, a combination of the magical and the commonplace, “from a spoken into a written art” and “broadens [its] relevance and appeal.”3 Likewise, in her award-winning story of therapeutic interconnectivity, “Throw Me a Line,” Dr Pauline Pariser takes the key question she asks her patient and his answer and broadens their relevance and appeal.4 You will find in Ferron’s tales contradictory elements of “pathos and humour,” “blunt down-to-earthness,” and “unrestrained fantasy.” These elements combine to “disconcert and delight.”3 Dr Nicole Audet, in her awardwinning story, “Le pouvoir de l’écoute,” needs to connect with her resident who is not patient-centred and who is at risk of failing her rotation. Dr Audet does this by learning her resident’s story. A key element she discovers is that her resident loved to go fishing with her father. Then, using metaphorical fantasy, Dr Audet teaches the resident that the patient’s concerns become fish that the resident must catch! The results are delightful and practical, and the resident passes her rotation and her exams. She later tells Dr Audet, “When I went into the five [exam] rooms, I caught every one of the patients’ fish.” Ferron’s tales often have a traditional pattern: an enigmatic beginning, a repetitious refrain, and a stereotype ending. Magbule Doko, in her award-winning story, “Why are you here to see the doctor today?” uses this traditional pattern in her effective “Knock, knock” repetitious refrain.6 Our award winners are using Ferron’s techniques and very effectively. “Cadieu” is the third story in the new Ferron collection.3 The protagonist, Cadieu moves from the country to the city and abandons his name. He becomes rootless, without a past and therefore without a future. Medicine trains us in deductive reasoning, taking information and reducing it to a diagnosis. In this story Ferron uses an inductive approach. Cadieu’s problem, an individual’s problem, can occur on a much larger scale. It can happen to a group of people, a society, a culture, the Province of Quebec. It could happen to family medicine. If we lose sight of our past and become rootless, will our future be endangered? Ferron helps us to see a problem with fresh eyes. He does it with a story. Other stories from the collection are instructive: “Little William” explores delivery positions (the lithotomy position and the Sims position—one is traditionally French, one English) and doctor-midwife roles and how they interact. In “The Grey Dog” we see collaborative care and distributed responsibility, change, decline in power, and how that is symbolically portrayed. The

empty nest is a theme in “The Parakeet,” and it contains the wonderful loving and grumpy refrain about a husband as seen by his wife: “The old woman looked at him and thought what a fool he was, what an old fool. What disconcerted her was that he had always been this way and that she loved him.”3 “La Mi-Carême” deals with the question, when a mother delivers at home, of how to explain the cries of pain to little children. La Mi-Carême is a legendary witchlike creature who flies into the room at the time of the delivery and beats the mother, resulting in the anguished cries. The midwife in turn takes her stick and beats La Mi-Carême, who in her hurry to get out of the room leaves behind a little baby. The narrator of the story, the oldest child, a boy (the nipper), concludes the story by saying, “My father bent over the tiny bundle. When he stood up he looked happy and younger than I’d ever seen him. The herring scales glistened on his arms. He rubbed his hands and stomped his feet in his big boots. And I thought to myself, I the nipper, that La Mi-Carême ought rightly to have beaten him.”3 The nipper had made the reality connection, and we the reader are given a little window on the moment when observation and knowledge fall into place and a child is transported out of the age of innocence. Are narrative, plot, words, the importance of listening, the importance of stories, and their value in the effective relationship between patients and doctors vital in the practice of medicine? I had a patient who in his mid-50s had a crisis of identity and purpose. I asked him to return in a week and tell me about his very first memories. He chronologically moved forward with his memories in 15-minute weekly sessions. By the sixth session he had reconnected with his story and rediscovered himself. Pellucid means admitting the maximum passage of light without distortion. It also means easy to understand. If we listen to our patients’ stories carefully and ask clarifying questions, the narrative and plot will become clear and we will understand: the Pellucid Moment. The relevance of the Pellucid Moment in our profession is that it can derive from a story and lead to a written story with a much broader relevance. It is that relevance that we are celebrating today: the importance of stories. Dr Cameron is a rural family physician in Sherbrooke, NS. Competing interests None declared References

1. Frank AW. Why doctors’ stories matter. Can Fam Physician 2010;56:51-4 (Eng), e39-42 (Fr). 2. Clarke LE, Nisker J, editors. In our hands. On becoming a doctor. East Lawrencetown, NS: Pottersfield Press; 2007. 3. Ferron J. Tales from the uncertain country and other stories. Bednarski B, translator. Toronto, ON: McClelland and Stewart; 2010. 4. Pariser P. Throw me a line. Can Fam Physician 2011;57:71-2 (Eng), e31-2 (Fr). 5. Audet N. Le pouvoir de l’écoute. Can Fam Physician 2011;57:74-5 (Fr), e35-6 (Eng). 6. Doko M. Why are you here to see the doctor today? Can Fam Physician 2011;57:73 (Eng), e33-4 (Fr).

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| Canadian Family Physician

Le Médecin de famille canadien

Récits en médecine familiale | Commentaire

L’importance des histoires Ian A. Cameron

MD CCFP

ne partie de mon histoire se déroule en Colombie-Britannique. Quand mon épouse et moi avons commencé en même temps nos carrières respectives en soins infirmiers et en médecine, nous sommes allés le plus loin qu’on puisse aller en Colombie-Britannique, puis 40 milles encore plus loin: aux îles de la Reine-Charlotte. À la fin d’une année pleine d’investissements en souvenirs, nous sommes revenus dans l’Est pour fonder notre famille. Le temps a passé… Au début des années 1990, Bev et moi sommes retournés en Colombie-Britannique pour assister à un colloque en médecine familiale à Whistler. Tony Bennett a laissé son cœur à San Francisco; j’ai perdu une partie du mien à Whistler. Le temps a passé… L’année dernière, la plus jeune de nos filles et son mari ont commencé leurs carrières à Kelowna. Le cycle recommence. Ce que je viens de vous écrire, c’est une narration: le quoi, le puis… et le puis après. Maintenant, si je vous disais que j’ai perdu une partie de mon cœur à Whistler en tentant désespérément de gagner un match de tennis contre John Keddy, c’est l’intrigue: le pourquoi. En médecine familiale, nous transigeons avec le quoi et le pourquoi - la narration et l’intrigue. D r Arthur Frank a prononcé cette allocution l’an dernier à Calgary, en Alberta1, quand il a rendu hommage aux lauréats des histoires en médecine familiale*. Quelques années plus tôt, Dr Frank avait rédigé l’avantpropos d’In Our Hands, un recueil de récits rédigés par des étudiants en médecine de tous les coins du Canada, révisés par Linda Clarke et Jeff Nisker2. Dr Frank utilise le mot liminal dans son introduction. Il définit liminal comme étant ni vraiment une chose ni vraiment l’autre, comme l’espace entre les champs cultivés d’un village et la forêt. Les étudiants en médecine qui ont rédigé les récits du recueil étaient liminaux: en état de transition, déjà plus des novices, mais pas encore des médecins. Il disait que les transitions liminales pouvaient être à la fois dangereuses et fascinantes2». Nos patients sont souvent liminaux (en état transitoire): de la santé à la maladie, de la maladie à la santé, de la maladie à la mort, du célibat à la vie de couple, puis à la famille, du couple au divorce, de l’emploi à la retraite, de l’innocence à l’adolescence. Tous les jours, nous écoutons des personnes qui ont leurs propres narrations et leurs propres intrigues. Leurs histoires aussi peuvent être dangereuses et fascinantes. *Cet article s’inspire d’une présentation de Dr Cameron à l’occasion de la remise des Prix AMS–Mimi Divinsky d’histoire et narration en médecine familiale au Forum en médecine familiale à Vancouver, en Colombie-Britannique, le 16 octobre 2010.

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Pouvons-nous être de meilleurs médecins si nous apprenons à voir nos patients dans leur propre contexte, dans leurs propres histoires? Nous avions une patiente à la clinique. C’était une jeune femme venue en ville de la campagne en quête de son avenir. Elle faisait de l’asthme, mais son problème était bien contrôlé. Un jour, nous avons reçu le résumé de son congé de l’hôpital. Elle avait eu un grave épisode d’asthme. On l’avait intubée, mais elle s’en était bien sortie. Au cours des mois qui suivirent, nous l’avons vue de plus en plus souvent. Elle avait changé. Selon les tests, sa fonction pulmonaire était normale, mais elle avait l’air fatigué, parfois désespéré. Elle demandait: «Pouvez-vous m’aider à respirer?» Nous avons consulté une pneumologue. Elle a rajusté ses médicaments. Rien n’a changé. La nuit, notre patiente hantait le service d’urgence. Son diagnostic est passé de l’asthme à l’anxiété, puis aux attaques de panique. Nous avons pensé à une demande de consultation en psychiatrie. «Pouvez-vous m’aider à respirer?» demandait-elle. Un jour, notre résidente a conclu que nous n’avions pas établi le vrai problème de notre patiente. Ce n’était pas de l’asthme aigu, elle en était sûre. Elle a pris une approche différente et a demandé à notre patiente: «Ce soir, je voudrais que vous écriviez ce qui vous est arrivé et pourquoi vous avez du mal à respirer». Le lendemain, notre patiente nous a apporté cette explication par écrit: J’ai eu une terrible attaque d’asthme le soir où je suis allée à l’urgence. Une infirmière m’a installé une intraveineuse et quelqu’un y a injecté un produit. Soudain, je n’arrivais plus à respirer. Je ne pouvais plus parler. J’étais paralysée. J’étais dans une salle remplie d’infirmières et de médecins et je ne pouvais pas leur expliquer mon problème. Quelqu’un m’a rentré quelque chose dans la gorge, puis j’ai perdu conscience. Je me suis réveillée dans une pièce sombre avec un tube dans la bouche branché à une machine. Depuis, je revis sans cesse le moment où j’étais paralysée et où je ne pouvais plus respirer.

Au cours des mois suivants, notre patiente s’est rétablie graduellement mais sûrement. L’année suivante, elle se mariait. Nous avons assisté à l’accouchement de son premier enfant. La résidente avait trouvé une façon de faire révéler par la patiente le «pourquoi» de son histoire. This article is also in English on page 66.

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Commentaire | Récits en médecine familiale Dans les cercles d’écrivains, Jacques Ferron est considéré comme étant un médecin-écrivain de grand renom et, pourtant, il est largement inconnu des étudiants en médecine et des médecins au Canada. Il est né en 1921 à Louiseville, au Québec, il a reçu son diplôme de médecine de l’Université Laval en 1945 et a exercé la médecine rurale à Rivière-Madeleine, en Gaspésie, et plus tard à Longueuil, de l’autre côté de Montréal, sur la rive sud du fleuve Saint-Laurent, Durant la Crise d’octobre 1970, il a été choisi comme médiateur entre le gouvernement et les kidnappeurs du ministre Laporte. Il a fondé le Parti Rhinocéros. Il écrivait des pièces de théâtre, des essais, des romans et surtout des nouvelles. Son premier recueil de nouvelles s’est mérité le Prix du gouverneur général. Les histoires sont inspirées de son patrimoine culturel et de son expérience en tant que médecin. Betty Bednarski a compilé et traduit un nouveau recueil de Ferrron, publié par McClelland and Stewart, intitulé Tales from the Uncertain Country and Other Stories3. Dans la postface, elle explique la technique de Ferron, sa façon de transformer le récit folklorique, une combinaison de magique et de lieu commun, d’un art raconté à un art écrit, pour élargir sa pertinence et son attrait3. Pareillement, dans son récit sur l’interconnectivité thérapeutique qui lui a mérité un prix, «Throw Me a Line», Dr Pauline Pariser prend la principale question qu’elle pose à son patient, ainsi que sa réponse, pour en élargir la pertinence et l’attrait4. Vous trouverez dans les contes de Ferron les éléments contradictoires du pathos et de l’humour, du terre-à-terre direct et de la fantaisie débridée. Ces éléments se combinent pour déconcerter et enchanter 3. D re Nicole Audet, dans son récit gagnant d’un prix, «Le pouvoir de l’écoute», doit établir un lien avec sa résidente qui n’est pas centrée sur le patient et risque l’échec dans son stage. D re Audet le fait en écoutant l’histoire de sa résidente. Elle découvre que sa résidente adorait aller à la pêche avec son père. Utilisant une fantaisie métaphorique, Dre Audet enseigne à sa résidente que les préoccupations du patient sont semblables à des poissons qu’elle doit attraper! Les résultats sont pratiques et productifs: la résidente réussit son stage et ses examens. Elle explique plus tard à D re Audet: «Quand je suis entrée dans les 5 salles d’examen, j’ai attrapé tous les poissons de chaque patient». Les contes de Ferron suivent souvent un modèle traditionnel: un début énigmatique, un refrain répétitif et une fin stéréotypée. Magbule Doko, dans son récit qui lui a mérité un prix, «Why are you here to see the doctor today?» utilise ce modèle traditionnel avec son refrain répétitif mais efficace du «toc, toc»6. Les lauréates de nos prix utilisent les techniques de Ferron très efficacement.

«Cadieu» est le troisième conte de la nouvelle collection de Ferron3. Le protagoniste Cadieu déménage de la campagne à la ville et abandonne son nom. Il perd ses racines, se retrouve sans passé, donc, sans avenir. La médecine nous enseigne le raisonnement par déduction, en rassemblant les renseignements pour les réduire en un seul diagnostic. Dans son récit, Ferron utilise une approche par induction. Le problème de Cadieu, le problème d’une personne, peut se produire à plus grande échelle. Il peut arriver à un groupe de personnes, à une société, à une culture, à la province de Québec. Il pourrait se produire en médecine familiale. Si nous perdons de vue notre passé et devenons sans racine, notre avenir sera-t-il en péril? Ferron nous aide à voir le problème sous un nouvel angle. Il le fait au moyen d’une histoire. D’autres récits de la collection sont instructifs: «Little William» explore les positions de l’accouchement (la position de lithotomie et la position Sims, l’une traditionnellement française, l’autre anglaise) et les rôles des médecins et des sages-femmes, ainsi que leurs interactions. Dans «The Grey Dog», nous voyons les soins en collaboration et les responsabilités réparties, le changement, le déclin dans les pouvoirs et leur représentation symbolique. Le nid vide est un thème qui revient dans «The Parakeet» et il comporte un magnifique refrain plein d’amour et bourru à propos d’un homme tel que vu par sa femme: la vieille femme le regardait et se disait que c’était un fou, un vieux fou. Ce qui la déconcertait, c’est qu’il avait toujours été ainsi et qu’elle l’aimait tout de même3. «La Mi-carême» raconte la façon d’expliquer à de petits enfants les cris de douleur quand la mère accouche à la maison. La Mi-carême est une sorte de sorcière légendaire qui vole dans la chambre au moment de l’accouchement et bat la mère, ce qui explique ses cris d’angoisse. À son tour, la sage-femme prend son bâton et bat la Mi-carême, qui quitte la chambre à toute vitesse, laissant derrière elle un petit bébé. Le narrateur de l’histoire, le fils aîné des enfants, conclut l’histoire en disant que son père s’est penché sur le berceau. Quand il s’est relevé, jamais le fils n’avait vu son père si heureux ni l’air aussi jeune. Les écailles de hareng reluisaient sur ses bras. Il s’est frotté les mains et a secoué ses pieds chaussés de grosses bottes. Le garçon se dit alors que la Mi-carême aurait plutôt dû battre son père3. Le garçon a fait la connexion avec la réalité et nous, les lecteurs, avons un bref aperçu du moment où l’observation et la connaissance tombent en place et où un enfant fait sa sortie de l’âge de l’innocence. Les narrations, les intrigues, l’importance de l’écoute, l’importance des histoires et leur valeur dans une relation efficace entre patients et médecins sont-elles essentielles dans la pratique de la médecine? J’ai eu un patient au milieu de la cinquantaine en pleine crise d’identité et de questionnement sur sa

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Récits en médecine familiale | Commentaire raison d’être. Je lui ai demandé de revenir la semaine suivante et de me raconter ses tout premiers souvenirs. Il a progressé chronologiquement dans le récit de ses souvenirs durant des séances hebdomadaires de 15 minutes. Dès la sixième séance, il avait repris contact avec son histoire et s’était redécouvert. Pellucide veut dire laisser passer la lumière au maximum sans distorsion. Le mot signifie aussi facile à comprendre. Si nous écoutons attentivement les histoires de nos patients et demandons des questions pour clarifier leur récit, la narration et l’intrigue apparaîtront clairement et nous comprendrons: le moment pellucide. La pertinence du moment pellucide dans notre profession vient du fait qu’il peut dériver d’une histoire et mener à un récit écrit, ayant une pertinence beaucoup

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plus large. C’est cette pertinence que nous célébrons aujourd’hui: l’importance des histoires. Dr Cameron est médecin de famille en milieu rural à Sherbrooke, en NouvelleÉcosse. Intérêts concurrents Aucun déclaré Références 1. Frank AW. Why doctors’ stories matter. Can Fam Physician 2010;56:51-4 (ang), e39-42 (fr). 2. Clarke LE, Nisker J, rédacteurs. In our hands. On becoming a doctor. East Lawrencetown, NÉ: Pottersfield Press; 2007. 3. Ferron J. Tales from the uncertain country and other stories. Bednarski B, traductrice. Toronto, ON: McClelland and Stewart; 2010. 4. Pariser P. Throw me a line. Can Fam Physician 2011;57:71-2 (ang), e31-2 (fr). 5. Audet N. Le pouvoir de l’écoute. Can Fam Physician 2011;57:74-5 (fr), e35-6 (ang). 6. Doko M. Why are you here to see the doctor today? Can Fam Physician 2011;57:73 (ang), e33-4 (fr).

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AMS — Mimi Divinsky Awards |

Stories in Family Medicine

hese stories were collected as part of the Family Medicine in Canada: History and Narrative in Medicine Program, an ongoing project of the College of Family Physicians of Canada (CFPC), supported by donations to the Research and Education Foundation by Associated Medical Services (AMS). The program collects stories and historical narrative about family medicine in Canada for a publicly available online database. The AMS–Mimi Divinsky Awards honour the 3 best stories submitted to the database each year. Information about the AMS–Mimi Divinsky Awards is available at “CFPC Honours & Awards” on the CFPC website, www.cfpc.ca. The Stories in Family Medicine database is available at http://cfpcstories.sydneyplus.com.

Best English story by a family physician

Throw me a line Pauline Pariser

MD CCFP FCFP

is hands were huge: calloused and creased, stained a permanent gray. The way he was gripping the sides of the hospital bed, you’d think he was sliding down an icy mountain pass. I barely knew him. His wife was more familiar, booking regular appointments for herself and her children. She looked to me as if I were a genie that could grant her 3 wishes: that her husband, Pat, would stop smoking, that he wouldn’t work so hard, that he’d take more holidays. I saw Pat the odd time when his smoking turned an ordinary cold into a high-pitched wheeze. I’d grab the chance to encourage him to consider quitting his 30-year habit or at least to return for a physical. At 55, he was overweight, his blood pressure was mildly elevated, and he had a family history of heart disease. I remember telling him, “You’re at risk for a heart attack or stroke. Some things like your family history we can’t fix. But we can tackle the other risk factors bit by bit.” “Doctor, I appreciate what you’re trying to do for me. But see here, I’m set in my ways. Even if I dragged myself from clear across town, the kids need tuition paid and the wife’s fussy about the mortgage. I’m sorry. Best you spend your time with those more deserving,” he answered.

La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro de janvier 2011 à la page e31.

My heart sank when he spoke that way. I felt compelled to meet with him before or after work, to enlist our dietitian, our smoking cessation counselor, whatever it took. But I’d learned waving my good intentions in his face was not enough. At this point I could not motivate him to change. “If you reconsider, you know where I am,” I had said to him at that last office visit. Then late Friday afternoon the call came. He’d collapsed at work. Now, here we were in the CCU. “Twenty-five years as a machinist—same company,” he told me between gasps. “Never missed a day. Sometimes even worked the weekends.” The monitor continued in the background. Heart rate 120. Blood pressure 150/105. Q waves evident on the tracing. “Is the pain letting up at all?” I asked, watching him grimace. He shook his head from side to side. The morphine drip had been increased for the third time in the past half-hour. “Get this cement truck off my chest,” he told me. His eyes kept darting around the room, not finding a place to settle. I had the feeling that whatever he was thinking was contributing to his pain. “Can you tell me what you’re thinking about?” I asked. “My work. I’m thinking about my work. What if I can’t go back? Who’s going to look after my family? How the heck are they going to manage?”

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Stories in Family Medicine | AMS — Mimi Divinsky Awards “Try not to think about that now,” I said without conviction. Pathetic. As if telling a person how to think ever made much difference. I stood there helpless—concerned that without pain control he would extend his infarct. If only he could transform his internal monologue. Or at the very least distract himself. I wracked my brain for some ideas when suddenly I was inspired to try something with him that I had never done before with anyone. “Pat, I believe you can lessen your pain. Finding a way to relax can reduce muscle tension and allow your heart to rest and recover. Can you think of something that relaxes you?” “My work. My work relaxes me.” Disappointed, I tried again. “OK, but try and find something that puts you into a state of deep relaxation, where your body feels light and you have not a care in the world. Is there anything, anything at all, that makes you feel that way? Maybe a hobby?” “Ice fishing. I really like to go ice fishing.” “Then let’s do it. Take me ice fishing with you.” “Right now?” “Yes. Close your eyes,” I said, taking his hand. “First, describe the day,” I guided him. “Look up. What do you see? Is the sky a piercing blue?” He still looked pained. “Are there billowing clouds up there?” I prodded. “Is a light snow falling and sticking to your eyeglasses? Maybe the frozen lake is shimmering in the sunshine. How about the temperature? Is the air that dry, crispy cold that makes your nose tingle or so frigid you are wearing 2 layers of clothes?” He described his surroundings and told me what he was wearing—his favourite red toque, his parka with the fur-lined hood, his buckskin mitts. I asked him to smell the fire from the camp stove and feel the hot coffee warming his insides. He described the banter between him and his buddies. He heard the

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whooping from neighbouring huts when a fish was caught, and the sounds of the snowmobiles coming and going throughout the afternoon. He cut the hole in the ice, placed his line in the water, felt the wriggling of the fish and the triumphant slap against the icy ground. Around me the CCU staff were adjusting IV meds and checking monitors. I thought I heard someone snicker. I carried on. As he spoke I could hear his voice slow down. I felt his hand loosen its grip on mine. I watched him sink into the bedding. I turned to glance at his cardiac monitor. His heart rate had come down to 80 beats per minute and his blood pressure had fallen to 130/90. He opened his eyes. I told him I was going and would not be back until Monday morning. I left him with instructions. “Whenever you start to worry—about your work, your family, or your future—or start feeling pain, I want you to take yourself ice fishing.” He reassured me. “The way I’m feeling, no problem— you bet I will.” When I returned Monday morning, I checked with his nurse who told me he had been very stable all weekend. I approached his bed. He was sitting up, beaming. “How are you?” I asked him. “Doc, I’ve been ice fishing all weekend. I’ve been to some of the best fishing holes. Thank you.” “Don’t thank me. You were able to do this for yourself.” From that day I have never underestimated the power of the mind—how an ordinary guy was able to have an extraordinary effect on his recovery. Sometimes when I am frustrated by my own limitations or there are just too many tasks to master, I have closed my eyes and taken myself back to the corner of a bustling CCU to hold Pat’s hand and go off ice fishing. Dr Pariser is the physician lead of the Taddle Creek Family Health Team in downtown Toronto, Ont.

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Prix AMS— Mimi Divinsky |

Récits en médecine familiale

es récits ont été présentés dans le contexte du programme Histoire et narration en médecine familiale, un projet que poursuit le Collège des médecins de famille du Canada (CMFC) sur une base continue, grâce à un don versé à la Fondation pour la recherche et l’éducation par Associated Medical Services Inc. (AMS). Le programme recueille des récits et des narrations historiques au sujet de la médecine familiale au Canada qui sont inclus dans une base de données en ligne accessible au public. Les Prix AMS-Mimi Divinsky sont décernés aux rédacteurs des trois meilleurs récits présentés chaque année. Pour en savoir plus sur les Prix AMS-Mimi Divinsky, rendez-vous à la section du Programme des prix dans le site Web du CMFC à l’adresse www.cfpc.ca. La base de données sur les récits en médecine familiale se trouve à http://cfpcstories.sydneyplus.com.

Meilleur récit rédigé en anglais par un médecin de famille

Une pêche miraculeuse Pauline Pariser,

MD CCMF FCMF

l avait des mains comme des battoirs, calleuses et plissées, avec des taches grisâtres, indélébiles. À le regarder s’agripper aux montants de son lit d’hôpital, on aurait cru qu’il était en train de dévaler les pentes glacées d’un col de montagne. Il m’était pratiquement inconnu. Je connaissais mieux sa femme, qui prenait régulièrement rendez-vous pour elle-même et ses enfants. Elle me considérait comme un génie capable de réaliser ses trois vœux : que Pat, son mari, arrête de fumer, qu’il travaille moins, et qu’il prenne plus de vacances. Je l’avais déjà rencontré pour un simple rhume que son tabagisme avait fait dégénérer en symptômes respiratoires aigus. J’en avais profité pour l’encourager à cesser de fumer, une habitude vieille de 30 ans, ou au moins à revenir pour un examen physique. À 55 ans, il faisait de l’embonpoint, était légèrement hypertendu et avait des antécédents familiaux de maladie cardiaque. Je me souviens lui avoir dit : « Vous risquez une crise cardiaque ou un AVC. Nous ne pouvons rien contre certaines choses, comme vos antécédents familiaux, mais nous pouvons nous attaquer petit à petit aux autres facteurs de risque. » « Docteur, j’apprécie ce que vous essayez de faire pour moi. Mais voyez-vous, je suis fait comme ça. J’aurais This article is also in English on page 71.

beau me traîner jusqu’à votre bureau pour me faire soigner, faudrait quand même que je paye les frais de scolarité des enfants et l’hypothèque, qui inquiète tant ma femme. Je suis désolé. Vaut mieux consacrer votre temps à ceux qui le méritent davantage », m’a-t-il répondu. Mon cœur s’est serré en entendant ces mots. J’estimais de mon devoir de faire quelque chose : le voir avant ou après le travail, faire appel à notre diététiste, à notre conseiller en renoncement au tabac, faire tout ce qu’il fallait. Mais je voyais bien que pour l’instant, mes bonnes intentions ne suffiraient pas à le motiver à changer. « Si vous changez d’avis, vous savez où me trouver », lui avais-je dit lors de cette dernière visite à mon bureau. L’appel est finalement arrivé un vendredi en fin d’après-midi. Il s’était écroulé au travail. Nous nous sommes donc retrouvés à l’unité des soins intensifs. « Vingt-cinq ans comme machiniste – pour la même compagnie, m’a-t-il dit entre deux halètements. Jamais manqué une journée. Au boulot même le week-end parfois. » En arrière-fond, les bips du moniteur. Fréquence cardiaque : 120. Tension artérielle : 150/105. Des ondes Q décelables sur le tracé. « Est-ce que la douleur diminue un peu? » lui ai-je demandé en le regardant grimacer. Il a secoué la tête de gauche à droite. Au cours de la dernière demi-heure, sa dose de morphine avait été augmentée à trois reprises.

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Récits en médecine familiale | Prix AMS— Mimi Divinsky « Enlevez ce camion de ciment qui m’écrase la poitrine », a-t-il ajouté. Son regard balayait la pièce sans répit, sans trouver d’endroit où se poser. J’avais l’impression que l’objet de ses pensées, quel qu’il fût, contribuait à sa douleur. « Pouvez-vous me dire à quoi vous pensez, lui ai-je demandé. – À mon travail. Je pense à mon travail. Qu’arriverat-il si je ne peux reprendre le boulot? Qui va s’occuper de ma famille? Comment diable vont-ils se débrouiller? – Essayez de ne pas penser à cela maintenant », ai-je répliqué sans conviction. Pathétique! Comme si le fait de dire à quelqu’un de penser à autre chose avait jamais fait la moindre différence. Je restais là, impuissante – préoccupée parce que si on ne soulageait pas sa douleur, l’infarctus allait progresser. Si seulement il pouvait transformer son monologue intérieur. Ou à tout le moins le distraire. Je me creusais la cervelle pour trouver une idée quand j’eus une inspiration et décidai d’essayer avec lui quelque chose que je n’avais jamais essayé avec personne. « Pat, je crois que vous pouvez faire diminuer votre douleur. Trouver une façon de relaxer peut atténuer la tension musculaire et permettre à votre cœur de se reposer et de récupérer. Pouvez-vous penser à quelque chose qui vous détend? – Mon travail. Mon travail me détend. » Désappointée, j’essayai de nouveau. « OK, mais cherchez quelque chose qui vous plonge dans un état de profonde relaxation, qui vous donne l’impression que votre corps est léger, que vous n’avez plus aucun souci. Y a-t-il quelque chose, n’importe quoi, qui vous donne cette impression? Un passe-temps peut-être? – La pêche sur la glace. J’aime vraiment pêcher sur la glace. – Dans ce cas, allons-y. Amenez-moi à la pêche sur la glace avec vous. – Maintenant? – Oui. Fermez les yeux, lui dis-je en prenant sa main. Premièrement, décrivez-moi la journée. Je le guidais. Levez les yeux. Que voyez-vous? Le ciel est-il parfaitement bleu? » Il avait toujours l’air de souffrir. « Y a-t-il des nuages?, insistai-je. Tombe-t-il une petite neige qui colle aux verres de vos lunettes? La surface du lac gelé brille peut-être sous les rayons du soleil? Quel temps fait-il? Fait-il un froid sec, mordant, qui vous pique les joues et vous force à vous emmitoufler dans plusieurs épaisseurs de vêtements? » Il me décrivit ce qui l’entourait et ce qu’il portait – sa tuque rouge préférée, sa parka avec un capuchon bordé de fourrure, ses mitaines en daim.

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Je lui demandai de sentir l’odeur du feu dans le poêle de sa cabane de pêche et la chaleur qu’il ressentait en buvant un bon café bien chaud. Il décrivit les plaisanteries échangées avec ses compagnons de pêche. Il entendit les cris de joie des pêcheurs dans les autres cabanes quand ils prenaient un poisson et le vrombissement incessant des motoneiges qui allaient et venaient tout l’après-midi. Il découpa un trou dans la glace, jeta sa ligne à l’eau, sentit les frétillements du poisson et entendit le claquement triomphal d’une prise que l’on jette sur le sol gelé. Autour de moi, le personnel de l’unité des soins intensifs ajustait la médication intraveineuse et surveillait les moniteurs. J’ai cru entendre quelqu’un ricaner. Je poursuivis. Pendant qu’il parlait, j’ai senti son débit ralentir. Sa main a relâché sa prise sur la mienne. J’ai vu son corps se détendre dans le lit. Je jetai un regard au moniteur cardiaque. Son pouls était descendu à 80 battements par minute et sa tension artérielle était revenue à 130/90. Quand il a ouvert les yeux, je lui ai dit que je partais et que je ne reviendrais pas avant lundi matin. Avant de partir, je lui ai donné des directives. « Chaque fois que vous commencerez à vous faire du souci – à propos de votre travail, de votre famille ou de votre avenir – ou quand vous commencerez à ressentir de la douleur, je veux que vous partiez à la pêche sur la glace. » Il m’a rassurée. « Avec comment je me sens, pas de problème – sûr que je vais y aller. » Quand je suis retournée le voir le lundi matin, son infirmière m’a dit que son état avait été très stable pendant tout le week-end. Je me suis approchée de son lit. Il était assis, rayonnant. « Comment allez-vous?, lui ai-je demandé. – Docteure, j’ai pêché tout le week-end. J’ai trouvé des trous fantastiques. Merci. – Ne me remerciez pas. Vous avez pu faire cela tout seul. » Depuis, je n’ai jamais sous-estimé la puissance de l’esprit – comment un gars ordinaire avait été capable d’avoir un effet extraordinaire sur sa guérison. Parfois, quand je suis frustrée par mes propres limites ou qu’il y a tout simplement trop de tâches à maîtriser, je ferme les yeux et je retourne dans une unité de soins intensifs achalandée, je prends la main de Pat et ensemble, nous allons pêcher sur la glace. Dre Pariser est médecin responsable de l’équipe de médecine familiale de Taddle Creek, dans le centre-ville de Toronto, Ont.

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AMS — Mimi Divinsky Awards | Stories in Family Medicine Best story by a medical student

Why are you here to see the doctor today? Magbule Doko

nock, knock. Take a breath. Hand on the knob. Meet and greet. Then comes the line: “So, why are you here to see the doctor today?” Behind every door lies a story. Knock, knock. So, why are you here to see the doctor today? The patient explains that he wishes to have bariatric surgery. I discuss the risks and benefits. I talk about the paperwork to be filled out. I notice in the chart that he has a past medical history of depression. I ask him about it and how the medications are working. He states that recently he lost his job and has been so depressed. His children are succeeding at school. He is worrying how he will pay for their university tuitions. He told me that he recently attempted suicide. His story is so sad. Why do some have depression? Good luck, bad luck? He has so many issues going on. Where do I start? He was thinking of suicide because of financial difficulties. Is he still suicidal? Need to tease that out. I need to let him know of the social supports in the community. I feel like I want to just tell him that everything is going to be OK. But I keep my cool and continue. Knock, knock. So, why are you here to see the doctor today? An elderly gentleman has come to the office for a reassessment of his peripheral neuropathy. I review the history of the current illness with him; do a thorough neurological exam. He is a type 2 diabetic. As I continue with the interview, I ask him about his home life. He takes care of his wife. He can barely take care of himself. He tells me that his wife has bipolar disorder. There are moments when he is verbally abused by her. He begins to cry because he doesn’t want to blame her. He loves her. I have never seen an old man cry. It is so touching. I am holding back tears. He loves his wife so much that he was hesitant to bring this up. He has caregiver burnout. This man can’t care for himself. He hardly has any sensation in his feet. He looks like he is a very kind person with a warm heart. I want to tell him that. Why does he have to deal with this? If only I could cure all his problems with a tap of a wand. But I can only tackle his problems one at a time. Knock, knock.

La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro de janvier 2011 à la page e33.

So, why are you here to see the doctor today? A young married couple have come in today because last week they had a positive pregnancy test result. This week it was negative. She had her period. I take a history regarding infertility. I talk to them about lab tests we can do to assess fertility. They have been trying ever since their first son died 5 months ago. He was only 2 years old. He passed from a rare disease. Why them? Look how strong they are even in these circumstances. Their child passed so recently. Are they still mourning? Have they come to terms with what has happened? Are they ready to have another child so quickly? It is hard to get pregnant after losing a child. I feel so helpless. I begin to get angry that their child was taken from them. It is too late. The only thing I can do is comfort them and encourage their efforts. Knock, knock. So, why are you here to see the doctor today? This patient has come to review her bloodwork results. Looks like high cholesterol. Risk assessment reveals she is at high risk because her parents had heart attacks and strokes at young ages. She is currently taking no medications. On physical exam she has high blood pressure, which was also present at her last visit. I tell her that she has hypertension and hyperlipidemia. Then I explain to her the long-term risks of these disorders if she does not take action. I then tell her that she must start 3 different pills and take them for the rest of her life. Then I pass her the Kleenex. This woman came into the office today thinking she was perfectly healthy. No previous medical history. No medications. Now in 2 minutes she has 2 diagnoses and 3 lifelong medications. I had to break it to her. Was I too harsh? She had to know. As her doctor I have to help her prevent morbidity and early mortality. Her tears were tears of realization. I feel like I did a good job. But I forgot to consider how this would affect her. I gave her words of motivation. Behind every door lies a story. People come to their doctors because they need someone to trust. They need someone to tell them that everything’s going to be all right and they will get through it. Their stories are more than medical problems. The problems become part of their existence, and doctors should realize that they need to treat the person not just the disease. Mrs Doko is a medical student at the University of Western Ontario in London.

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Le Médecin de famille canadien

Récits en médecine familiale | Prix AMS — Mimi Divinsky

Meilleur récit rédigé par un étudiant en médecine

Qu’est-ce qui vous amène à consulter le médecin aujourd’hui?

Magbule Doko

oc, toc! On prend une respiration, la main sur la poignée de porte. On fait les présentations d’usage puis vient la phrase : « Alors qu’est-ce qui vous amène à consulter le médecin aujourd’hui? » Derrière chaque porte close, il y a une histoire. Toc, toc! Qu’est-ce qui vous amène à consulter le médecin aujourd’hui? Le patient m’explique qu’il veut subir une chirurgie bariatrique. Je discute des risques et des avantages. Je parle aussi des formalités administratives. Je constate au dossier qu’il a des antécédents médicaux de dépression. Je le questionne à ce sujet et sur l’efficacité de ses médicaments. Il me dit qu’il a récemment perdu son emploi et qu’il a été très déprimé. Ses enfants ont de bons résultats scolaires et il se demande maintenant comment il fera pour payer les frais de scolarité à l’université. Il me dit qu’il a récemment tenté de se suicider. Son histoire est bien triste. Pourquoi certaines personnes souffrent-elles de dépression? Est-ce le fruit du hasard? Ses difficultés sont tellement nombreuses; par où vais-je commencer? Il a songé au suicide à cause de ses difficultés financières. Est-il toujours suicidaire? Il faut que j’explore ça. Je dois l’informer des réseaux de

soutien social dans sa communauté. J’aimerais tellement lui dire que tout ira bien, mais je garde mon sang froid et je continue. Toc, toc! Qu’est-ce qui vous amène à consulter le médecin aujourd’hui? Un homme âgé est venu au bureau pour une réévaluation de sa neuropathie périphérique. Je passe en revue avec lui l’histoire de la maladie actuelle et je fais un examen neurologique complet. Il a un diabète de type 2. Au fil de la consultation, je le questionne sur sa vie à la maison. Il prend soin de son épouse alors qu’il peut à peine s’occuper de lui-même. Il me dit que son épouse souffre d’un trouble bipolaire. Il lui arrive même d’être victime de violence verbale. Il se met à pleurer parce qu’il ne veut pas la blâmer : il l’aime. Je n’ai jamais vu pleurer un vieil homme. C’est très émouvant : j’ai peine à retenir mes larmes. Il aime tellement son épouse qu’il est réticent à aborder ce sujet. C’est un aidant qui souffre d’épuisement. Cet homme peut difficilement prendre soin de lui-même. Il a une perte de sensibilité aux deux pieds. Cet homme me semble bon et avoir grand cœur. Je veux le lui dire. Pourquoi doit-il vivre cela? Si seulement je pouvais résoudre ses problèmes avec une baguette magique. Mais je peux seulement aborder ses problèmes, un à la fois. Toc, toc!

This article is also in English on page 73.

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Prix AMS— Mimi Divinsky | Récits en médecine familiale Qu’est-ce qui vous amène à consulter le médecin aujourd’hui? Un jeune couple me consulte aujourd’hui parce qu’un test de grossesse effectué la semaine dernière est revenu positif. Cette semaine, il est négatif : elle a ses menstruations. Je fais l’histoire de l’infertilité. Je leur parle des tests de laboratoire que nous pouvons faire pour évaluer la fertilité. Elle tente d’être enceinte depuis le décès de leur premier enfant il y a 5 mois. Il n’avait que 2 ans et est décédé des suites d’une maladie rare. Pourquoi eux? Ils sont très courageux en dépit des circonstances. Leur enfant est décédé tout récemment. Sontils toujours endeuillés? Ont-ils fait la paix avec ce qui leur est arrivé? Sont-ils prêts à avoir un autre enfant dès maintenant? Il est difficile de vivre une autre grossesse après avoir perdu un enfant. Je me sens tellement impuissante. J’éprouve de la colère du fait qu’ils ont perdu leur enfant. Mais il est trop tard. La seule chose que je puisse faire, c’est de les réconforter et de les encourager dans leurs efforts. Toc, toc! Qu’est-ce qui vous amène à consulter le médecin aujourd’hui? Cette patiente est venue pour le compte rendu de ses résultats sanguins. Il semble que son taux de cholestérol soit élevé. L’évaluation du risque révèle qu’elle est à risque élevé parce que ses parents ont fait des crises cardiaques et des accidents vasculaires cérébraux en bas âge. Présentement, elle ne prend aucun médicament. L’examen physique indique qu’elle souffre d’hypertension artérielle, également présente lors de la

dernière visite. Je lui dis qu’elle souffre d’hypertension et d’hyperlipidémie. Je lui explique ensuite les risques à long terme de ces conditions si elle n’agit pas dès maintenant. Je lui dis qu’elle doit commencer à prendre 3 médicaments différents et qu’elle devra les prendre pour le reste de ses jours. Puis, je lui donne la boîte de papiers-mouchoirs. Cette femme qui est entrée dans le bureau aujourd’hui se pensait en bonne santé. L’histoire médicale antérieure était négative et elle ne prenait aucun médicament. Maintenant, en moins de 2 minutes, elle reçoit deux diagnostics et 3 médicaments à prendre durant toute sa vie. Et j’ai dû le lui annoncer. Ai-je été trop brusque? Il fallait qu’elle le sache. Comme médecin, il faut que je l’aide à prévenir la morbidité et la mortalité précoce. Ses larmes étaient des larmes de prise de conscience face à cette dure réalité. Je pense avoir fait un bon travail. Mais j’ai oublié de considérer comment elle en serait affectée. Je lui ai exprimé des mots d’encouragement. Derrière chaque porte close, il y a une histoire. Les gens viennent consulter leur médecin parce qu’ils ont besoin de quelqu’un à qui ils peuvent faire confiance. Ils ont besoin qu’on leur dise que tout ira bien et qu’ils vont s’en sortir. Leurs histoires vont bien au-delà des problèmes médicaux. Les problèmes font partie de leur vie et il est important que les médecins réalisent qu’ils doivent traiter non seulement la maladie mais la personne. Madame Doko est étudiante en médecine à l’Université de Western Ontario à London.

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Prix AMS — Mimi Divinsky | Récits en médecine familiale

Meilleur récit rédigé en français par un médecin de famille

Le pouvoir de l’écoute Nicole Audet

MD MA CCMF FCMF

orsque je pense aux meilleurs moments de ma carrière d’enseignante en médecine familiale, c’est le nom d’Élise qui me vient immédiatement en tête. Six mois avant ses examens de certification, mes collègues et moi lui reprochions son manque d’empathie. Certains professeurs l’avaient vue interrompre les explications de ses patients. D’autres se plaignaient qu’elle n’explorait pas leurs inquiétudes ou encore qu’elle avait du mal à structurer ses entrevues. À notre avis, Élise ne possédait pas les habiletés requises pour devenir un médecin de famille. Malgré ses bonnes connaissances, Élise risquait d’échouer son stage si la situation ne s’améliorait pas rapidement. À ce moment-là, je supervisais les résidents derrière un miroir. Après chaque séance, je leur donnais une rétroaction pour les aider à corriger leur technique d’entrevue. La première fois que j’ai observé Élise, elle a commencé la rencontre sans même se présenter. Le patient n’a pas eu le temps de formuler ses attentes ni de poser des questions. C’est Élise qui parlait. Après avoir posé le bon diagnostic, elle a prescrit une médication au patient sans lui expliquer la posologie ni l’aviser des effets indésirables potentiels.

Après l’entrevue, j’ai dit à Élise que sa performance ne répondait pas aux normes attendues. J’ai revu avec elle la technique de l’entrevue médicale centrée sur le patient. Elle m’a écoutée en silence. Je suis rentrée chez moi bouleversée. Je voulais aider Élise à se ressaisir à temps pour ses examens finaux. J’ignorais comment m’y prendre. Le même soir, le film L’Opus de M. Holland était diffusé à la télévision. Une scène m’a fascinée. M. Holland rencontre Gertrude, une jeune clarinettiste malhabile qui rêve de faire partie de l’harmonie. M. Holland lui demande de jouer une pièce facile. Au premier essai, sa performance médiocre ne décourage pas le professeur. Il lui dit de poser son instrument, puis ils parlent de choses et d’autres. Ils rigolent. L’étudiante se détend. Puis, il lui demande de jouer le même passage en fermant les yeux. Son interprétation est presque parfaite. Elle repart fière d’elle et se taille une place de choix dans l’orchestre. Pourrais-je réussir la même chose avec Élise ? La semaine suivante, j’ai convoqué Élise dans mon bureau une heure avant la clinique. Nous avons discuté en prenant un café. Elle m’a confié qu’elle venait de la région éloignée où j’avais pratiqué dix ans plus tôt. En parlant des magnifiques lacs et rivières, elle m’a dit qu’elle adorait aller à la pêche avec son père. Je lui ai demandé de fermer les yeux et de s’imaginer dans la chaloupe avec son père.

The English translation of this article is available at www.cfp.ca on the table of contents for the January 2011 issue on page e35.

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Récits en médecine familiale | Prix AMS— Mimi Divinsky -Bouges-tu ? -Non, je dois rester tranquille. -Parles-tu ? -Non, mon père dit que le silence est très important pour attraper des poissons. -Attrapes-tu des poissons ? -Oui, mon panier est plein. -Élise, la médecine c’est comme la pêche. Les poissons sont les inquiétudes des patients et ils se présentent sous forme de symptômes physiques ou psychologiques. Ton rôle comme médecin consiste à questionner le patient dans le but d’attraper les poissons. Pour y arriver, tu prépares ton attirail. Tu places un appât au bout de ta ligne et tu la lances à l’eau. Tu la laisses descendre à la bonne profondeur. En silence, tu attends que les poissons mordent à l’hameçon. Sans juger ni menacer, tu crées un climat de confiance et tu laisses le patient se dévoiler à son rythme. Après notre conversation, j’ai regardé Élise interroger un patient. Après lui avoir demandé l’objet de sa visite, elle a fait une longue pause pour écouter la réponse. Elle a exploré chacun des problèmes du patient. Elle a réussi à découvrir toutes les appréhensions du patient tout en le soignant avec rigueur. Élise

est entrée dans la salle de supervision en souriant. Elle m’a dit qu’elle était très fière d’elle et qu’elle avait bien aimé le patient et son histoire. Après cette rencontre, Élise a réussi à combler les faiblesses que nous avions observées. Un mois après ses examens de certification, Élise est venue me voir. -Dre Audet, je voulais vous remercier. J’ai eu cinq notes Hautement certifiable à mes examens et c’est grâce à vous. -Pourquoi dis-tu cela ? -Le jour de l’examen, je suis arrivée une heure trop tôt. Un professeur m’a envoyée bêtement de m’asseoir dans un coin. Au lieu de m’en faire, j’ai fermé les yeux. Je suis retournée pêcher dans la chaloupe avec mon père. En silence, j’ai préparé mon attirail. Ça m’a calmée. Quand je suis entrée dans les cinq salles, j’ai attrapé tous les poissons des patients. À la fin de sa résidence, Élise est partie pratiquer dans sa ville natale. Je ne l’ai jamais revue, mais je pense souvent à elle lorsque j’enseigne le pouvoir de l’écoute à mes étudiants. Dre Audet est chef de l’unité de médecine familiale à l’ Hôpital Cité de la Santé de Laval en Québec.

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Best French story by a family physician

The power of listening Nicole Audet

MD MA CCMF FCMF

hen I think back on the best moments of my career teaching family medicine, the name Élise immediately comes to mind. Six months before her Certification exams, my colleagues and I were dismayed by her lack of empathy. Some instructors had seen her interrupt her patients’ explanations. Others complained that she didn’t go far enough in uncovering their concerns or that she had trouble structuring her interviews. In our opinion, Élise didn’t have the skills she needed to become a family physician. Despite a good knowledge base, Élise was running the risk of failing her rotation if the situation didn’t improve quickly. At that time, I supervised students from behind a oneway mirror. After each session, I gave them feedback to help them improve their interview techniques. The first time that I observed Élise, she began the interview without even introducing herself. The patient didn’t have the time to communicate his expectations or to ask questions. Élise was doing all the talking. After making the correct diagnosis, she prescribed the patient medication without explaining the dosage regimen or informing the patient of any potential adverse effects. After the interview, I told Élise that her performance did not meet the standards. I reviewed patient-centred interview techniques with her. She listened in silence.

I went home stunned; I wanted to help Élise to turn the situation around before her final exams, but I didn’t know how. That night, Mr Holland’s Opus was on TV. I was fascinated by one scene in the film where Mr Holland meets Gertrude, a young, awkward clarinettist who dreams of playing in the school orchestra. Mr Holland asks her to play an easy piece. Her mediocre performance on her first try doesn’t discourage him. He asks her to put down her instrument and then they talk about many things. They laugh. She begins to relax. He asks her to play the same piece again, with her eyes closed. Her interpretation is nearly perfect. She leaves, proud of herself, and having earned an important position in the orchestra. Could I do the same with Élise? The following week, I called Élise into my office an hour before the clinic. We had a coffee and chatted. She told me that she came from a remote region where I had practised a decade earlier. Recalling the magnificent lakes and rivers, she told me that she loved fishing with her father. I asked her to close her eyes and picture herself in the boat with her father. “Are you moving?” “No, I have to stay still.” “Are you talking?” “No, my father says that silence is very important to catching fish.” “Are you catching any fish?”

Cet article se trouve aussi en français à la page 74.

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“Yes, my basket is full.” “Élise, practising medicine is like fishing. The fish are the patients’ concerns, and they come in the form of physical or psychological symptoms. Your role as a physician is to ask the patient questions in order to catch the fish. To do this, you prepare your tackle. You put the bait on your hook and you cast your line into the water. You let it drop to just the right depth. You wait silently for the fish to bite the hook. Without judgment or threats, you create an atmosphere of trust and you let the patient open up at his own pace.” After our conversation, I watched Élise interview a patient. After asking the patient for the purpose of the visit, she paused to listen to the answer. She explored each of the patient’s problems. She was able to find out about each of the patient’s concerns while carefully providing care. She was smiling when she came into the supervision room. She told me that she was very proud of herself and had enjoyed meeting the patient

and taking his history. After this meeting, Élise was able to overcome the weaknesses that we had observed. One month after her Certification exams, Élise came to see me. “Dr Audet, I want to thank you. I earned five superior certificant scores on my exams and it is all thanks to you.” “Why do you say that?” “On the day of the exam, I got there an hour early. An instructor stupidly told me to sit in a corner. Instead of stressing about it, I closed my eyes. I was back in the boat, fishing with my father. I silently prepared my tackle. It calmed me. When I went into the five rooms, I caught every one of the patients’ fish.” At the end of her residency, Élise left to practise in her hometown. I never saw her again, but I often think of her when I teach my students about the power of listening. Dr Audet is the Head of the Family Medicine Unit at l’ Hôpital Cité de la Santé de Laval in Quebec.

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2010 Manuscript Reviewers | Évaluateurs de manuscrits en 2010 Thank you, reviewers

he Editorial Advisory Board and staff of Canadian Family Physician wish to express their gratitude to the following people for their participation in the review process during 2010 and to all others who have volunteered to review but who have not yet been sent manuscripts. Canadian Family Physician now has more than 500 family physicians and other specialists participating in the journal’s peer-review process.

Merci aux évaluateurs

e Conseil consultatif de rédaction et le Médecin de famille canadien désirent remercier les personnes suivantes qui ont évalué des manuscrits au cours de l’année 2010, ainsi que celles s’étant portées volontaires pour le faire mais à qui nous n’avons pas encore envoyé de manuscrits. Le Médecin de famille canadien compte maintenant 500 médecins de famille et spécialistes participant au processus d’évaluation externe.

A Ossama Abbas, Boston, Mass Omar Abou-Hinin, Madrid, Spain Alexandre Ackaoui, Verdun, Qué Robert Adam, Hamilton, Ont Amanda J. Adams, Markham, Ont Donald Addington, Calgary, Alta Halil Akbulut, Ankara, Turkey Fatih Akcay, Erzurum, Turkey Zekeriya Akturk, Erzurum, Turkey Tareef Alaama, London, Ont Kannayiram Alagiakrishnan, Edmonton, Alta Fahad Alkherayf, Ottawa, Ont Michael Allan, Edmonton, Alta Tim Allen, Merrickville, Ont Gary Altman, Winnipeg, Man Jennifer Ellen Anderson, Sooke, BC Evans Andrea, Montréal, Qué Deidre Andres, Saskatoon, Sask Anneke Andriessen, Malden, The Netherlands Sibyl Anthierens, Wilrijk, Belgium

B Jason Bailey, Ottawa, Ont Lesley Bainbridge, Vancouver, BC Jana Maria Bajcar, Toronto, Ont Marcel Baltzan, Montréal, Qué Adrian Baranchuk, Kingston, Ont Zoe Barnett, Hamilton, Ont Daniele Behn Smith, Edmonton, Alta Neil Bell, Edmonton, Alta Anne-Pauline Bellanger, Besançon, France Eric Ian Benchimol, Toronto, Ont Whitney Blair Berta, Toronto, Ont Nazim Ercument Beyhun, Erzurum, Turkey

Julia Joy Bickford, London, Ont Yousef Binamer, Montréal, Qué Anne Biringer, Toronto, Ont Kathryn A. Birnie, Halifax, NS Richard Birtwhistle, Kingston, Ont Lisa Dawn Bishop, St John’s, Nfld Noemi Bitterman, Haifa, Israel Regis Blais, Montréal, Qué Sylvain Blanchet, Québec, Qué Beau Gordon Blois, Truro, NS Juan Javier Bolaños-Vergaray, Madrid, Spain Andre Bonneau, Laval, Qué Mark Ram Borganokar, St John’s, Nfld Neil J. Bosomworth, Princeton, BC Giselle Bourgeois-Law, Winnipeg, Man Rupinder Brar, Vancouver, BC Herbert Brill, Hamilton, Ont Robert J. Brison, Kingston, Ont Gordon Brock, Témiscaming, Qué Jason Brunetta, Toronto, Ont Jennifer Bryan, Halifax, NS Sandy Buchman, Toronto, Ont Philip Burge, Kingston, Ont Nancy Byatt, Worcester, Mass

C Eric Cadesky, Vancouver, BC Stewart Cameron, Halifax, NS Robin Gordon Carter, Portage la Prairie, Man Penny Cash, Kelowna, BC Andrew Cave, Edmonton, Alta Cathy Cervin, Halifax, NS Roger Chafe, St John’s, Nfld Nathalie Champoux, Montréal, Qué Irene Ah Wing Chan, Vancouver, BC

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Li-Hsin Chang, Guelph, Ont Gideon Charach, Tel-Aviv, Israel Yingming Amy Chen, Vaughan, Ont Chris Childs, Bedford, NS Nevio Cimolai, Vancouver, BC Carole Cohen, Toronto, Ont James Robin Conway, Smiths Falls, Ont Divanise Suruagy Correia, Maceió, Brazil Maria Costantino, Naples, Italy Lizebeth Cox, London, Ont Paulo Ricardo Criado, São Paulo, Brazil

D Christopher John Dainton, Toronto, Ont A. George Davidson, Vancouver, BC Kenneth Shawn Davison, Victoria, BC Martin Dawes, Vancouver, BC George L. Deagle, Hazelton, BC Wilber Deck, Gaspé, Qué Dianne Delva, Halifax, NS Christine De Maria, Montréal, Qué Hakan Demirci, Bursa, Turkey Catherine Deri Armstrong, Ottawa, Ont Jacques Desroches, Saint Pie, Qué Irfan Dhalla, Toronto, Ont Shafik Dharamsi, Vancouver, BC Bonnie M. Dobbs, Edmonton, Alta Martha L. Donnelly, Vancouver, BC Rebecca Janet Douglass, Hamilton, Ont Neil Drummond, Calgary, Alta Eliane F. Duarte-Franco, Montréal, Qué Ruth Ellen Dubin, Kingston, Ont

Évaluateurs de manuscrits en 2010 | 2010 Manuscript Reviewers Ann Duggan, Ottawa, Ont Pauline Sara Duke, St John’s, Nfld

E William Eaton, St John’s, Nfld William Ehman, Nanaimo, BC Catherine T. Elliott, Vancouver, BC Christopher Ellis, Al Ain, Abu Dhabi Charl Els, Edmonton, Alta Ruth Elwood-Martin, Vancouver, BC John M. Embil, Winnipeg, Man Francisco Escobar-Rabadán, Albacete, Spain Elizabeth Estey, Toronto, Ont Jeremy Etherington, Vancouver, BC

F Alejandra Farias Godoy, Burnaby, BC John Feightner, London, Ont Hillel M. Finestone, Ottawa, Ont Jonathan A.E. Fleming, Vancouver, BC Marie-Josee Fleury, Verdun, Qué Nigel Flook, Edmonton, Alta Guillaume Foldes-Busque, Lévis, Qué Kevin R. Forward, Halifax, NS Kathleen Frame, Toronto, Ont José François, Winnipeg, Man Christopher Frank, Kingston, Ont Jennifer Ewen Frank, Appleton, Wis Frederick Donald Fraser, Hamilton, Ont Christopher John Fries, Winnipeg, Man Jessica Fulton, Toronto, Ont

G Romayne Gallagher, Vancouver, BC Alberto López García-Basteiro, Barcelona, Spain Rudy Gasparelli, Wawa, Ont David Gass, Halifax, NS Gulsum Gencoglan, Manisa, Turkey Lia Gentil, Sherbrooke, Qué Samer Ghosn, Beirut, Lebanon, Julie Ellen Gilbert, Toronto, Ont Manuel Gil-Mosquera, Madrid, Spain Marshall Godwin, St John’s, Nfld Elisabeth Gold, Halifax, NS François Goulet, Rigaud, Qué I. Neil Grant, Manama, Bahrain William B. Grant, San Francisco, Calif Inese G. Grava-Gubins, Mississauga, Ont

Michael Edward Green, Kingston, Ont Allan Kevin Grill, Toronto, Ont Shirley Gross, Edmonton, Alta Stefan C.W. Grzybowski, Vancouver, BC Claudio Guarneri, Messina, Sicily Ian Gwynne-Robson, Lower Hutt, New Zealand

Nazan Karaoglu, Konya, Turkey Claire Kendall, Ottawa, Ont Emad Khawajah, Amman, Jordan Kenneth Kirkwood, London, Ont Michael Robert Kolber, Peace River, Alta Gerald Konrad, Winnipeg, Man Julie Kosteniuk, Saskatoon, Sask Jyoti Atul Kotecha, Kingston, Ont

Gayle Halas, Winnipeg, Man Christine E. Harrison, Ottawa, Ont Bart Harvey, Toronto, Ont Lydia B. Hatcher, Mount Pearl, Nfld Todd Hatchette, Halifax, NS C. Nicole Hawkins, Kingston, Ont Brian Hennen, Dartmouth, NS John Hoey, Port Perry, Ont Marcus Hollander, Victoria, BC Colin Kent Honish, Meadow Lake, Sask Roderick S. Hooker, Dallas, Tex Jessica Hopkins, Hamilton, Ont Jason Hosain, Saskatoon, Sask Roberta I. Howlett, Toronto, Ont Yanyan Huang, Shanghai, China John C. Hudec, Sydney, NS Tracy Hussey, Hamilton, Ont Liana Hwang, Calgary, Alta Ilene Hyman, Toronto, Ont

Miriam Lacasse, Québec, Qué Nisha Lakhi, Brooklyn, NY Christopher Lam, Victoria, BC Robert Lam, Toronto, Ont Donald B. Langille, Halifax, NS Richard G.B. Langley, Halifax, NS Joseph Lee, Kitchener, Ont Patricia Pui Shuen Lee, London, Ont Vikram Lekhi, Calgary, Alta Marianne Lemay, Victoriaville, Qué Barbara Pauline Lent, London, Ont Fok-Han Edmund Leung, Toronto, Ont Kevin Leung, Richmond Hill, Ont Lawrence Koon Chit Leung, Kingston, Ont Mark Leung, Toronto, Ont Lawrence Loh, Toronto, Ont Benjamin Longo-Mbenza, Mthatha, South Africa Diane Janet Lu, Kingston, Ont Dave Ludwick, Edmonton, Alta John T. Lysack, Calgary, Alta

I Steven Iliffe, London, United Kingdom Syed A. Imran, Halifax, NS Noah Michael Ivers, Toronto, Ont

J Liisa Jaakkimainen, Toronto, Ont Marc Jamoulle, Bruxelles, Beglium Magdalena Janus, Hamilton, Ont Jabir Jassam, Nepean, Ont Phyllis Jensen, Edmonton, Alta David Charles Jones, Edmonton, Alta John Michael Jordan, London, Ont Karen L. Juce, Hamiota, Man Pieter Josef Jugovic, Toronto, Ont Hans W. Jung, Ottawa, Ont

K Janusz Kaczorowski, Vancouver, BC Meldon Kahan, Toronto, Ont Mike Kalisiak, Edmonton, Alta Nili Kaplan-Myrth, Ottawa, Ont VOL 57: JANUARY t JANVIER 2011

M Anne-Marie MacLellan, Montréal, Qué Paul MacPherson, Ottawa, Ont Parker John Magin, Callaghan, Australia Donna P. Manca, Edmonton, Alta Jerry M. Maniate, Toronto, Ont Michèle Marchand, Montréal, Qué Carmel Mary Martin, Ottawa, Ont Danielle Martin, Toronto, Ont Ian Martin, Vancouver, BC Anne McCarthy, Ottawa, Ont Lynn McCleary, St Catharines, Ont Elizabeth McGregor, Calgary, Alta Brendan McIntosh, Ottawa, Ont Andrew McIvor, Hamilton, Ont Meredith Anne McKague, Saskatoon, Sask Nora McKee, Saskatoon, Sask

| Canadian Family Physician

Le Médecin de famille canadien

2010 Manuscript Reviewers | Évaluateurs de manuscrits en 2010 Peter Metcalfe, Edmonton, Alta Colleen J. Metge, Winnipeg, Man Baukje Miedema, Fredericton, NB Bernard Millette, Montréal, Qué Saroj K. Mishra, Rourkela, India Rahim Moineddin, Toronto, Ont Frank Molnar, Ottawa, Ont Wendy R. Mooney, Winnipeg, Man Ainsley Elizabeth Moore, Hamilton, Ont Pascale Morin, Sherbrooke, Qué Patricia Kathleen Morley-Forster, London, Ont Laura Muldoon, Ottawa, Ont Andries Johannes Muller, Warman, Sask Donatus Mutasingwa, Toronto, Ont

N Elsie Nahum, Toronto, Ont Louise Nasmith, Toronto, Ont Adam Newman, Kingston, Ont Eileen Nicolle, Markham, Ont Jason Xin Nie, Toronto, Ont Kendall Noel, Ottawa, Ont

O Ivy Oandasan, Toronto, Ont Jeremy O’Brien, Toronto, Ont John S. Ogrodniczuk, Vancouver, BC Cagatay Oktenli, Istanbul, Turkey Doug Oliver, Hamilton, Ont Wim Opstelten, Utrecht, The Netherlands Taofiq Olusegun Oyedokun, Saskatoon, Sask

P Beata Patasi, Ottawa, Ont Alan Pavilanis, Montréal, Qué Lauretta R. Pereles, Calgary, Alta Zvi Howard Perry, Be’er Sheva, Israel Navindra Persaud, Toronto, Ont Allan Peterkin, Toronto, Ont Paul Stephen Philbrook, Mississauga, Ont Jane Philpott, Toronto, Ont

Gilles Pineau, Outremont, Qué Gilles Plourde, Sherbrooke, Qué

R Brodie Ramin, Ottawa, Ont Jose Manuel Ramirez-Aranda, Monterrey, Mexico Vivian R. Ramsden, Saskatoon, Sask Mohana Ratnapalan, Toronto, Ont Lynda Redwood-Campbell, Hamilton, Ont Shmuel Reis, Haifa, Israel J. Barrie Ross, Halifax, NS Dominique M. Rouleau, Montréal, Qué Margo Rowan, Orleans, Ont Brian H. Rowe, Edmonton, Alta Evelyn T. Rubin, Toronto, Ont Grant Russell, Melbourne, Australia Bridget L. Ryan, London, Ont

S Doron Sagman, Toronto, Ont Shreyas Saligram, Pittsburgh, Pa Ginetta Salvalaggio, Edmonton, Alta Karen Cecilia Schliep, Salt Lake City, Utah Karen Schultz, Kingston, Ont Andrea Scobie, Halifax, NS Adrienne Scott, Montréal, Qué Ian Scott, Vancouver, BC Rachelle Seguin, East Falmouth, Mass Peter Selby, Toronto, Ont Maida J. Sewitch, Montréal, Qué Shahram Shams Tabrizi, West Vancouver, BC M. Zakaria Siddiqui, Omaha, Neb Christopher Sikora, Edmonton, Alta Manoj Singh, West Chester, Ohio Jeffrey Sisler, Winnipeg, Man Scott D. Smith, Kingston, Ont Beth Sproule, Toronto, Ont Sarah Natassia Stabler, Vancouver, BC

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William Ben Strean, Edmonton, Alta Patrick Joseph Sullivan, London, Ont Maureen Leah Sullivan-Bentz, Ottawa, Ont Michelle Sutherland, Regina, Sask John Sykiniotis, Montréal, Qué

T Aaron M. Tejani, Burnaby, BC Deanna Elaine Telner, Toronto, Ont Roanne Thomas-MacLean, Saskatoon, Sask James M. Thompson, Charlottetown, PEI Patricia Ting, Edmonton, Alta Ellen Toth, Edmonton, Alta Fred G. Tudiver, Johnson City, Tenn

V Stan H.M. Van Uum, London, Ont Grisell Vargas-Schaffer, Montréal, Qué J. Charles Victor, Toronto, Ont

W Sara Wainberg, Toronto, Ont Shayna Watson, Kingston, Ont Amanda Noelle Webb, Halifax, NS Amanda Dinah Welsh, St John’s, Nfld Elizabeth Francis Wenghofer, Sudbury, Ont Colin White, Vancouver, BC Marc White, Vancouver, BC Cynthia Whitehead, Toronto, Ont Thomas W. Wilson, Saskatoon, Sask Karen Elizabeth Wood, Saskatoon, Sask

Y Ming-Tso Yan, Taipei, Taiwan

Z John Zeber, San Antonio, Tex Rebecca Zur, Toronto, Ont

CAREERS/CLASSIFIED FAMILY MEDICINE/GP 2010 Classified Advertising Rates & Information Fast Facts

Ad Rates

t Title: Canadian Family Physician (CFP)

Text only: 'JSTU XPSET FBDI "EEJUJPOBM XPSET .JOJNVN DIBSHF #PY OVNCFS *OEJWJEVBM $'1$ NFNCFST SFDFJWF EJTDPVOU

t Type: 1FFS SFWJFXFE NFEJDBM KPVSOBM t Frequency: UJNFT QFS ZFBS t Circulation: 0WFS 000 t Audience: 7JSUVBMMZ PG GBNJMZ QIZTJDJBOT BOE SFTJEFOUT JO GBNJMZ NFEJDJOF QSPHSBNT JO $BOBEB t Format: HMPTTZ QFSGFDU CPVOE DPMPVS UISPVHI PVU /8 Y ÂŁ t Now on the web! :PVS QSJOU BE JODMVEFT '3&& FYQPTVSF PO PVS XFCTJUF www.cfp.ca Ad deadline: UI PG UIF NPOUI QSFDFEJOH NPOUI PG JTTVF Date published: UI PG NPOUI Visa, MasterCard, and AMEX accepted.

Classified Display Ad Rates Full Page 2 /3 Vert 2 /3 Horiz Â˝ Vert Â˝ Horiz 1 /3 Vert 1 /3 Horiz 1 /3 Island Âź Horiz Âź Island 1 /6 Vert 1 /8

Y Â&#x203A; Â&#x203A; Y Â&#x203A; Y / Â&#x17E; Y Â&#x203A; Y ÂŁ /8 Y Â&#x203A; Y Â&#x203A; Â&#x203A; Y ÂŁ Y Â&#x203A; Â&#x17E; Y ÂŁ /8 Y ÂŁ / Y /

Telephone Beth Carter at: 905 629-0900, ext 246 or 800 387-6197, ext 246

Add colour to your display ad! For full colour add:

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Âź Page or less 1 /3 Page Â˝ Page 2 /3 Page Full Page Pantone (PMS) colours

$MBTTJmFE BEWFSUJTJOH JT OPU DPNNJTTJPOBCMF CFP SFTFSWFT UIF SJHIU UP SFGVTF BOZ BEWFSUJTFNFOU BU JUT TPMF EJTDSFUJPO

FULL PAGE 7" x 9-1/2"

$575 2/3 page vertical: 4-1/2" x 9-1/2" horizontal: 7" x 6-1/3"

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1/3 page island: 4-1/2" x 4-3/4"

$1 080

1/3 page v: 2-1/8" x 9-1/2" h: 7" x 3-1/2"

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$830

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$465

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Circulation: Approx. 25 000. CFP accepts classified ads in the following categories: Positions Vacant; Positions Wanted; Locum Tenens; For Sale or Rent; Conferences; Miscellaneous. Rates: Full page: 2/3 page: 1/2 page: 1/3 page: 1/4 page: 1/6 page: 1/8 page:

$2,735 2,120 1,600 1,080 830 575 465

(Please visit www.cfp.ca click Advertisers for detailed specifications and dimensions.) Colour: 1/4 page or less, $119; 1/3 page, $189; 1/2 page, $279; 2/3 page, $349; full page, $399. (Pantone colours extra.) Text only: First 50 words, $2.25 each. Additional words, $2.00. (Min. charge, $90.00) Add a confidential box number: $10.00. Names and addresses of advertisers using box numbers are held in strict confidence. No telephone enquiries are accepted. Individual CFPC members receive 25% off the cost of any classified ad. Deadlines: 10th of the month preceding month of issue; telephone orders accepted, subject to written confirmation. While CFP attempts to screen ads for misrepresentation, it cannot assume responsibility for claims or offers made in advertisements. Readers are urged to investigate thoroughly any opportunities advertised. CFP reserves absolutely the right to decline or withdraw any advertisement at its sole discretion. CFP complies with the provisions of the Ontario Human Rights Code 1990. No advertising agency commission is paid on classified ads. An official publication of …

Canadian Family Physician Classified ads 2630 Skymark Ave Mississauga, ON L4W 5A4 905 629-0900 ext 246 800 387-6197 ext 246 Fax: 905 629-0893 E-mail: Web: http://www.cfp.ca

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classifieds@cfpc.ca

means of reaching every family Canadian Family Physician (CFP) is a peer-reviewed medical journal published monthly by the College of Family Physicians of Canada and distributed to all family physicians and family medicine residents in Canada.

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CLASSIFIED ADS

Your most economical and efficient physician in Canada!

800-387-6197

104*5*0/4 7"$"/5 r 1045&4 7"$"/54 Summerland, BC — family physician 2.5 - 3 d/week practice available with 3 other excellent GPs. All enjoy the many offerings of this area: mountain biking, cycling, beaches, skiing, and Okanagan wine! Fully computerized, very well run business. No OBS/ER. Shared inpatient weekends and call. Other work opportunities available if more desired. Contact Dr Brent Harrold 250 4944219 or e-mail bcchar@shaw.ca. (110103) Vancouver, BC — general practitioners. Group of eight established locations with opportunities for family, walkin or specialist physicians. Fulltime, part-time or locums. We provide all the administrative and operational support. Send CVs to: Denning Health Group, 215 - 12975 84th Ave., Surrey, BC V3W 1B3, fax 604 572-8658. Telephone enquiries to Paul Foster, toll free, 888 208-9211 or e-mail pfoster@denninghealth.ca. (090802R) Aurora, Ont — full-time/parttime family/walk-in physicians needed for new collaborative practice. New grads welcome. Minimum guarantee $125 per hour. Flexible hours, 85/15 split, no overhead for first 3 months. Physicians with existing practice also welcome. All relocation expenses covered. EMR, lab on-site, Allied health. Please call 416 839-2767 or e-mail enhanced care@hppinc.ca. (100802)

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Brampton, Ont — family and walk-in physicians needed for new fully equipped medical clinic. Practice stress-free in a busyplaza located in a family friendly area. 80/20 split. Try a shift without paying any overhead. EMR,lab, pharmacy on-site. Option for equity if desired. Contact Sagar at 416 456-0292 or e-mail sagar2600@hotmail.com. (110105) Etobicoke/Toronto, Ont — stateof-the-art Multidisciplinary Multicultural Medical Centre run and owned by medical doctor looking for family physician(s) to join family practice. Full- or parttime work available, flexible hours with attractive terms. New building, full EMR. Walk-in available. IMG and new graduates welcome. To discuss opportunities contact Dr Oleg Klipitch 416 277-9109, fax 416 521-7216 or e-mail oklipitch@gmail.com (101213) Lansdowne, Ont — beautiful Thousand Islands. Rural but not remote! Fall 2010. Office practice, full-time or part-time. Turnkey operation, your existing roster 1100 patients, with room for patient growth, in community based clinic. Working with another FP and NP. Collegial 10 member FHO share call. Near Kingston, Brockville, Ottawa. Signing bonus. See listing on hfojobs.ca. Contact jberbmd@earth link.net 613 659-2533. (100816) London, Ont — new medical clinic NOW OPEN. Adelaide Medical Centre. Excellent high traffic location with free parking. Opportunity to do family medicine, walk-in clinic

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or a mix of both. Excellent fee-split, high income potential. New state of the art clinic, EMR based. Please contact Shawna at 519 850-6937 or adelaidemedical@hotmail.com for a tour today. (100903) Merrickville, Ont — take over existing family practice with option to expand, available early 2011. Flexible remuneration options: FHO or CCM, turn-key opportunity with full EMR, staff and another MD. Overhead negotiable. Hospital privileges/OB/ER/GP anesthesia possible. Fifty minutes from Ottawa. Potential on-site childcare. Contact pkmcgregor@gmail.com. (101201) Manitoulin Island, Ont — Little Current Medical Associates is looking for a full-time physician to round out our group of six physicians. We are a teaching practice in a near northern rural setting. Our area is renowned as a sailing and canoeing paradise, but most importantly, we have designed our group to allow for a nice balance of lifestyle

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and clinical practice. The remuneration package is excellent and the colleagues supportive and amiable. We are part of a family health team and have a well functioning and collaborative practice style. Meaningful practice in a cutting edge group with superior remuneration. Call us and leave the mundane behind. Dr Ken Barrs or Dr Dieter Poenn 705 3680350 or e-mail kbarrs@sympatico.ca or dpoenn@manitoulin.net. (100813) Niagara Falls, Ont — URGENT CARE NIAGARA. Opening for full-time or part-time experienced MDs to join core group of physicians servicing busiest Urgent Care/Walk-in centres in the region. Better financial remuneration possible than FHG/FHN. Competitive split. State-of-the-art facilities and systems with electronic medical records, great staff and fun place to work in the heart of Niagara. Possibility of extended time off on rotating basis with other physicians if desired. Sign on bonus may be available. Call Medical Director at 905 464-7820 www.urgentcare niagara.com/doctors.htm (080422)

MÉDECINS RECHERCHÉS Temiskaming Shores et Kirkland Lake, Ontario Une équipe dynamique de soins de santé primaire et de prévention recherche deux médecins. - Horaire de travail flexible. - Suivi des patients hospitalisés requis. - Travail à la salle d’urgence optionnel. - Salaire très compétitif avec avantages sociaux. - Six semaines de vacances payées et formation continue. - Prime d’éloignement disponible. Communauté francophone dynamique, un milieu de vie exceptionnel, d’excellentes écoles et des services récréatifs à portée de main. Fatigué du stress de la ville, amateur de plein air et à la recherche d’un milieu de pratique et de vie de haute qualité, alors venez vous joindre à nous.

090502

Communiquer sans plus tarder avec Jocelyne Maxwell, directrice générale, 705 647-5775.

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ANNONCES CLASSÉES Le moyen le plus économique et efficace pour rejoindre tous les médecins de famille au Canada! Le Médecin de famille canadien (MFC) est une revue médicale évaluée par des pairs et publiée chaque mois par le Collège des médecins de famille du Canada. Elle est distribuée à tous les médecins de famille et résidents en médecine familiale au Canada. Tirage: plus de 25 000 Le MFC accepte des annonces classées dans les catégories suivantes: Postes vacants; demandes de postes; remplaçants; à vendre ou à louer; congrès; divers Tarifs: Pleine page: 2 735 $ 2/3 page: 2 120 $ 1/2 page: 1 600 $ 1/3 page: 1 080 $ 1/4 page: 830 $ 1/6 page: 575$ 1/8 page: 465 $ (Veuillez visiter le site web à l’adresse www.cfp.ca cliquez sur Advertisers pour consulter les spécifications et les dimensions détaillées.) Couleurs: 1/4 page ou moins, 119 $; 1/3 page, 189 $; 1/2 page, 279 $; 2/3 page, 349 $; pleine page, 399 $. (Frais additionnels pour couleurs Pantone) Texte seulement: 50 premiers mots, 2,25 $ par mot. 2,00 $ par mot additionnel (tarif minimal, 90,00 $) Ajouter une boîte-réponse confidentielle: 10,00 $ Le nom et l’adresse des annonceurs qui utilisent des boîtes-réponses sont gardés entièrement confidentiels. Aucun demande de renseignements par téléphone n’est acceptée. Rabais de 25 % sur le coût des annonces classées pour les membres du CMFC à titre individuel. Dates limites: le 10 du mois précédant le mois de parution; commandes téléphoniques acceptées, sous réserve d’une confirmation par écrit. Quoique Le MFC tente constamment de déceler la publicité trompeuse, il n’assume aucune responsabilité pour les déclarations ou les offres faites dans les annonces classées. Nous incitons donc les lecteurs à étudier attentivement les offres annoncées avant de s’engager. Le MFC se réserve le droit absolu de refuser ou de retirer les annonces, à sa discrétion. Le MFC respecte les dispositions du Code des droits de la personne de l’Ontario (1990). Aucune commission d’agence n’est versée sur les annonces classées. Une publication officielle du …

Le Médecin de famille canadien Annonces classées 2630, avenue Skymark Mississauga (Ontario) L4W 5A4 905 629-0900, poste 246 800 387-6197, poste 246 Télécopieur: 905 629-0893 Courriel: Web: http://www.cfp.ca

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104*5*0/4 7"$"/5 r 1045&4 7"$"/54 Mississauga, Ont — part-time/ full-time family practice/walkin available. Ability to take over a family practice and join a FHG. Many patients looking for a new family doctor. Work in a positive practice environment with support from the other MDs. Lab, pharmacy, foot clinic, optometry on site. E-mail doctorsearch@hotmail.com or call 416 844-8340 for more info. (100803)

090802

Mississauga, Ont — family group practice clinic. Seeking a family physician for possible long-term association. University of Toronto and Queen’s Family Practice Teaching Site. Part of FHG. Flexible scheduling. Young practice with on-site lab. On call optional. Call Diana 905 5072133 or e-mail ryychen@rogers.com. (110102) Ottawa, Ont — 70:30 or better (based on hours and commitment)

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for family medicine practice or walk-in clinic or locum work. ITS ALL ABOUT GOOD INCOME AND LIFESTYLE! Flexible hours, EMR, specialty and nurse support, no call, no administrative worries, rapidly expanding South Ottawa, earn bonuses by joining our FHO and NON OHIP income. Outstanding opportunity for new doctor learning the ropes, wanting part-time hours or more flexibility, or retiring/solo doctor wanting group. Please contact Faiza at 613 692-5433 or e-mail khc@doctor.com. (100705) Toronto, Ont — South Riverdale Community Health Centre requires a part-time family physician (two days a week). You will have an opportunity to work in a supportive multidisciplinary team environment to provide comprehensive primary health care and health promotion to clients of all ages, on and off-site, including home visits, shelter outreach and on-call services. For

EMERGENCY PHYSICIANS The Norfolk General Hospital is a 106 bed community hospital in Simcoe, Ontario serving a catchment area of 60,000 residents. The Town of Simcoe with a population of 15,000 residents is located just minutes from the sandy shores of Lake Erie with ample recreational, residential and educational opportunity. Simcoe is conveniently located within 60 minutes from Hamilton and within 80 minutes of London. There is twenty-four hour on-call service provided in General Surgery, Internal Medicine, Anaesthesia and Obstetrics at the Norfolk General Hospital. The Emergency Department has an annual caseload of approximately 27,000 unscheduled patient visits per annum. Remuneration is through the Alternate Funding Agreement. Commencing in July 2009, a full-time Physician Assistant was recruited to work in our Emergency Department for a two year trial basis. In November 2009, the Norfolk General Hospital was designated an official teaching site for medical students and residents from the Faculty of Health Sciences at McMaster University. Full-time and part-time Emergency Physicians are required. Certification in ATLS and ACLS is mandatory and certification in PALS is preferable. New graduates are welcomed. For additional information, please contact:

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Dr. John Rosati (email: jrosati@sympatico.com) Dr. Paul Medve (email: pwmedve@me.com) Telephone: 519-426-0750 ext: 2310

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more information please visit our website srchc.com or contact: Kathleen Foley, Manager Health Services, South Riverdale Community Health Centre 416 461-1925. (100512) Toronto, Ont — come join our busy family practice. We offer an attractive split with the provision of full administrative support. Full and part-time opportunities. Long standing patient population, walk-ins and interesting population specific clinics. Call 416 362-8611 extension 314 or e-mail andrea.duncan@seidenhealth.com.(100120) Toronto, Ont — associate for busy family practice west Toronto. Great office, view of Lake Ontario, near St. Joseph’s Health Center. Flexible hours, no on call, suitable financial arrangements could be worked out, interest in CAM or psychotherapy helpful, FHG. E-mail melborins@hotmail.com. (100601) Toronto, Ont — suburban community family physician practice seeks associate. Established practice of 3 GPs in FHG. Start with roster of 700, no evenings. No EMR at this time. Contact Dr Elaine Ling at 416 720-2269 or Dr Neil Edwards at 416 574-6875. E-mail neil.edwards@rogers.com. (100908) Toronto, Ont — open a solo/group or join a managed care practice (EMR provided) in new, modern medical centre, with medical laboratory and fully digital diagnostic imaging services on site. Minutes from Highways 401/404/DVP. Free parking. TTC stop. Close to North York General and Sunnybrook Hospitals. Telephone Idelta 416 449-2166, fax 416 449-2543, or e-mail idelta@alphainc.org. (090511)

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.*4$&--"/&064 r %*7&34 Greater Toronto or Ottawa,Ont — family or ER physicians. New enhanced OHIP fees and bonuses. Part or full-time home visits with MedVisit. Afternoons, evenings or weekends (no overnight call). Net $200/hour. Experienced drivers available. Contact Dr Tom Burko 416 631-0298 (or 800 355-6668) or e-mail drburko@medvisit.ca. Website www.medvisit.ca/doctors. (091214) Visit MDWork.com to access over 700 up-to-date Canadian physician vacancies. Save time and simplify your job or locum search with all jobs on one comprehensive site. Know your options — find the best position for you at MDWork.com (100820) Going EMR? Need to scan your patient records? Find out how we can do it for free. Contact Sid Soil at DOCUDAVIT SOLUTIONS today at 888 781-9083, extension 105, or e-mail ssoil@docudavit.com. (090618) DOCUdavit Medical Solutions — retiring, moving or closing your practice? DOCUdavit Medical Solutions provides free patient record storage with no hidden costs. Contact Sid Soil at DOCUdavit Solutions today at 888 7819083, extension 105 or ssoil@docudavit.com. (070712) CLOSING YOUR PRACTICE? — For retiring & relocating family physicians and estates. Compliant free patient record storage and closure consulting from Canada’s most trusted facility. Call RSRS at 888 563-3732, extension 221 or visit us at www.rsrs.com. Since 1997. (090822)

Life s better here

'03 4"-& r © 7&/%3&

-0$6. 5&/&/4 r 3&.1-"¬"/54 FAMILY PRACTICE LOCUM REQUIRED — Busy walkin / Family Practice in Whitby, Ontario. Locum Jan 12 - Feb 3, 2011. Split negotiable. More permanent association possible. Call 905 434-1662. (101216) Kitchener, Ont — maternity locum starting April 2011. King Street, close to Grand River hospital, St. Mary’s Hospital and Kitchener downtown. Office of 3 GPs. Free parking. Very friendly and young practice. Excellent support staff. Three to four days/wk, flexible work hours, excellent educated patient base, one evening until 7 pm. Over phone on-call one week/month (VERY light). No OB or ER. Compensation competitive. Option to join FHO/be eligible for FHO incentives. Duration 3 to 9 months (negotiable). Contact Dr Nazneed Mirza at srkhan128@ yahoo.com or 519 573-9843. (101214)

Wanted: A Family Physician Who Loves the Outdoors Nestled along a pristine lakeshore of Upper Arrow Lake in South Central B.C. is the charming community of Nakusp. Hot Springs amid spectacular mountain scenery. Rivers. Lakes. Take a recreation vacation out your back door! Come enjoy a collegial practice in the relaxing rural community of Nakusp! It’s Better Here!

Visit www.betterhere.ca to find out why. Nakusp 1-877-522-9722

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physicianrecruitment @ interiorhealth.ca

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110106

Surrey, BC — for sale 3000 square foot commercial space. Approved for pharmacy and medical clinic. Located 152nd and 68th Avenue, adjoining new Sikh Temple and commerical plaza. Call Aman at 604 572-4201 or 604 6571376 or e-mail aman@terragrp.ca. (100804)

080320

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Life. Career. Balance.

Experience it. Only at Southlake. By far, some of the highest physician satisfaction scores in the healthcare field. Recent data by NRC Picker confirm that we are well on our way to providing the premium practice environment that you deserve: 95.8% of our physicians rate Southlake a quality hospital for their medical practice 94.4% of our physicians rate Southlake as a positive place to work At Southlake, we’ve created something special… A big city hospital that hasn’t lost its community heart. A place where teamwork is the norm and new leaders are continually discovered. An environment where you can put your skills to work today, while advancing towards your goals for tomorrow. A collegial workplace focused on achieving work-life balance. If you are committed to excellence, passionate about making a difference, and looking for a place where your career can flourish, come join us. Newmarket is located in York Region, part of the Central LHIN, on the northern edge of the Greater Toronto Area, allowing easy access to city activities as well as a short distance to cottage country and ski resorts. Residents of York Region enjoy access to an array of real estate options and public and private schools, making the area a choice location for many young families.

Family Medicine Clinical Teachers

110110

Within the new, state-of-the-art academic environment of our Southlake Family Medicine Teaching Unit, in association with the Southlake Family Health Team and the Department of Family and Community Medicine, University of Toronto, you will practise comprehensive family medicine, supervise and support residents, develop curriculum, and provide didactic teaching. We offer access to a personal office space and two dedicated exam rooms, two assigned residents to each teacher, the support of a full-time social worker, two full-time nurses, a full-time nurse practitioner and a part-time dietitian, and access to sophisticated on-site AV equipment for observed teaching. You will also have the use of a fully equipped electronic health record system, take on a University of Toronto faculty appointment, and have a teaching commitment of two halfdays per week for direct resident supervision. Experienced family physicians and new graduates willing to develop their teaching skills are welcome and supported in faculty development. Preference will be given to applicants who are and will continue practising primary care obstetrics.

When fully implemented, Southlake’s Resident Program will have 18 residents practising and training as part of Southlake’s Family Medicine Teaching Unit. We welcome physicians who want to be part of our vision for healthcare. To join our dedicated team, please forward a letter of interest along with your curriculum vitae, to: Anne Marie Graham Administrative Director Southlake Family Health Team Tel: 905-853-3103, ext. 2020 E-mail: agraham@southlakeregional.org We thank everyone for their interest; however, only those selected for an interview will be contacted.

www.southlakeregional.org

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FAMILY AND WALK-IN PHYSICIANS NEEDED

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PHYSICIANS

o Very busy walk-in clinic in Etobicoke has shifts available. o On-site Pharmacy, Lab, Radiology, Specialists. o Great patient population o Room to add 2 full-time/part-time family physician o New Grads welcome o Competitive split

Alberta and Ontario Wellpoint Health is one of Canada’s fastest growing healthcare companies and requires physicians for family practice, and occupational medicine. We offer a turnkey operation for our physicians, utilization of EMR systems, and offer a competitive package that can include: large signing bonus, company car allowance, company paid vacations, and student loan repayment plans! All interested physicians contact:

Please contact: Clinic Director 905-270-6213 etobicokefamilyphysicians@yahoo.com

Sunil Sharma Tel 647 637-2233 Email sunil.sharma@wellpointhealth.ca

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ANNUAL SCIENTIFIC ASSEMBLIES, CONFERENCES & EVENTS Alberta College of Family Physicians ASA Place: Rimrock Resort Hotel Banff, AB Date: Feb 24- 26, 2011 Contact: Peggy Maher peggy.maher@acfp.ca

Saskatchewan College of Family Physicians ASA Place: Delta Hotel, Regina, SK Date: Sept 15 - 17, 2011 Lois Hislop scfp@shaw.ca

Manitoba College of Family Physicians ASA Place: Victoria Inn & Conference Centre Winnipeg, MB Date: April 7 - 9, 2011 Contact: Kari MacKinnon kmackinnon@mcfp.mb.ca

British Columbia College of Family Physicians ASA Place: Hyatt Regency, Vancouver, BC Date: Oct 15 - 16, 2011 Ian Tang ian.tang@bccfp.bc.ca Quebec College of Family Physicians ASA and CFPC’s Family Medicine Forum Place: Palais des congres de Montreal Montreal, Quebec Date: Nov 3 - 5, 2011 Contact: Nicole Cloutier cqmf@bellnet.ca

101204

106 B '(& SGI $0

110101

Nova Scotia College of Family Physicians ASA Place: White Point Beach Resort Queen’s County, South Shore Date: June 2 - 3, 2011 Contact: Cathie Caroll admin@nsfamdocs.com

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Monitoring and Laboratory Tests Response should be monitored by periodic measurements of blood glucose and HbA1c levels. Assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter. ADVERSE REACTIONS For complete information on adverse reactions, please also consult the supplemental product information section.

(as saxagliptin hydrochloride) Tablets, 5 mg Oral Antihyperglycemic Agent/ DPP-4 inhibitor/Incretin Enhancer

Prescribing Summary Patient Selection Criteria INDICATIONS AND CLINICAL USE ONGLYZA (saxagliptin) is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a sulfonylurea, when metformin or the sulfonylurea used alone, with diet and exercise, does not provide adequate glycemic control. Geriatrics (≥ 65 years of age): No dosage adjustment is required based on age, however greater sensitivity of some older individuals cannot be ruled out (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION). Pediatrics (< 18 years of age): Safety and effectiveness of ONGLYZA in pediatric patients have not been established. Therefore, ONGLYZA should not be used in this patient population. CONTRAINDICATIONS Patients who have had a history of any serious hypersensitivity to this drug or to any ingredient in the formulation or to another DPP-4 inhibitor.

Safety Information WARNINGS AND PRECAUTIONS For complete information on warnings and precautions, please also consult the supplemental product information section. General ONGLYZA (saxagliptin) should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Endocrine and Metabolism A lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia when used in combination with ONGLYZA (see SUPPLEMENTAL PRODUCT INFORMATION – ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). Special Populations Pregnant Women: There are no adequate and well-controlled studies in pregnant women. As animal reproduction studies are not always predictive of human response, ONGLYZA is not recommended for use in pregnancy. Nursing Women: Saxagliptin is secreted in the milk of lactating rats. It is not known whether saxagliptin is excreted in human milk. Therefore, ONGLYZA should not be used by a woman who is nursing. Pediatrics (< 18 years of age): Safety and effectiveness of ONGLYZA in pediatric patients have not been established. Therefore, ONGLYZA should not be used in this patient population. Geriatrics (≥ 65 years of age): Of the total number of subjects (N=4148) studied in controlled clinical safety and efficacy studies of ONGLYZA, 634 (15.3%) patients were 65 years and over, of which 59 (1.4%) patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Saxagliptin and its major metabolite are known to be eliminated in part by the kidney. Renal function should be assessed prior to initiating ONGLYZA and periodically thereafter in geriatric patients because they are more likely to have decreased renal function. Care should be taken in prescribing ONGLYZA in this population based on renal function (see WARNINGS and PRECAUTIONS AND DOSAGE AND ADMINISTRATION). Cardiovascular – Patients with Congestive Heart Failure: A limited number of patients with history of congestive heart failure participated in clinical studies with ONGLYZA. In clinical trials, ONGLYZA patients with NYHA Class III or IV congestive heart failure were excluded. Patients with history of congestive heart failure were included in small number (in total: 2% of patients exposed to ONGLYZA in clinical trials). Use in this population is not recommended. Hepatic Insufficiency: There are limited clinical data in patients with hepatic impairment taking multiple doses of ONGLYZA. The use of ONGLYZA in patients with moderate to severe hepatic impairment is not recommended. Renal Impairment: No dosage adjustment is recommended for patients with mild renal impairment. Clinical experience with ONGLYZA in patients with moderate or severe renal insufficiency including those with end-stage renal disease (ESRD) requiring hemodialysis is limited. Use in these patients is not recommended. Assessment of renal function is recommended prior to initiation of ONGLYZA, and periodically thereafter (see DOSAGE AND ADMINISTRATION).

Adverse Drug Reaction Overview ONGLYZA (saxagliptin) was generally well tolerated in controlled clinical studies as an add-on to metformin and as an add-on to sulfonylurea with the overall incidence of adverse events similar to that reported with placebo. In a placebo-controlled clinical study of patients receiving ONGLYZA 5 mg or placebo as an add-on to metformin, the incidence of serious adverse events was 9.9% and 5.6% respectively. The most commonly reported adverse events, reported regardless of causality and more common with ONGLYZA than placebo, were nasopharyngitis and bronchitis. Discontinuation of therapy due to adverse events occurred in 7.3% and 4.5% of patients, respectively. In a placebo-controlled clinical study of patients receiving ONGLYZA 5 mg or placebo as an add-on to sulfonylurea (glyburide), the incidence of serious adverse events was 3.6% and 5.6% respectively. The most commonly reported adverse events, reported regardless of causality and more common with ONGLYZA than placebo, were hypoglycaemia and urinary tract infection. Discontinuation of therapy due to adverse events occurred in 4.7% and 3.4% of patients, respectively. DRUG INTERACTIONS For complete information on drug interactions, please also consult the supplemental product information section. The metabolism of saxagliptin is primarily mediated by P450 3A4/5 (CYP3A4/5). In in vitro studies, saxagliptin and its major pharmacologically active metabolite neither inhibited nor induced CYP3A4. In addition, in in vitro studies, saxagliptin and its major pharmacologically active metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, nor induced CYP1A2, 2B6, 2C9. Therefore, saxagliptin is unlikely to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is neither a significant inhibitor of P-glycoprotein (P-gp) nor an inducer of P-gp, and is unlikely to cause interactions with drugs that utilize these pathways. The in vitro protein binding of saxagliptin and its major metabolite in human serum is below measurable levels. Thus, protein binding would not have a meaningful influence on the pharmacokinetics of saxagliptin or other drugs. Drug-Drug Interactions Effect of other drugs on saxagliptin In studies conducted in healthy subjects, the pharmacokinetics of saxagliptin and its major metabolite were not meaningfully altered by metformin, glyburide, pioglitazone, digoxin, simvastatin, diltiazem, ketoconazole, omeprazole, aluminum hydroxide + magnesium hydroxide + simethicone combination, or famotidine. These drugs are considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Effect of saxagliptin on other drugs In studies conducted in healthy subjects, saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, pioglitazone, digoxin, simvastatin, diltiazem, or ketoconazole. ONGLYZA is considered unlikely to cause a clinically meaningful interaction with these drugs. To report suspected side effects: By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789 Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance@hc-sc.gc.ca

Administration DOSAGE AND ADMINISTRATION Dosing Considerations ONGLYZA (saxagliptin) may be taken with or without food. Recommended Dose and Dosage Adjustment The recommended dose of ONGLYZA is 5 mg once daily. Renal Impairment: Use of ONGLYZA in patients with moderate to severe renal impairment, including patients with end stage renal disease requiring hemodialysis is not recommended. Hepatic Impairment: Use of ONGLYZA in patients with moderate to severe hepatic impairment is not recommended due to lack of clinical experience with this patient population. Pediatrics (<18 years of age): Safety and effectiveness of ONGLYZA in pediatric patients have not been established. Therefore, ONGLYZA should not be used in this patient population. Geriatrics (≥65 years of age): No dosage adjustment for ONGLYZA is required based solely on age (see WARNINGS AND PRECAUTIONS). Missed Dose If a dose of ONGLYZA is missed, it should be taken as soon as the patient remembers. A double dose of ONGLYZA should not be taken on the same day.

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Le Médecin de famille canadien

Supplemental Product Information

Number of Patients (%) Add-on to Metformin

ADVERSE REACTIONS

Body system/Organ Class Adverse Event

Saxagliptin 5 mg N=191

Placebo N=179

Saxagliptin 5 mg N=253

Placebo N= 267

6 (3.1)

4 (2.2)

6 (2.4)

2 (0.7)

Microalbuminuria

5 (2.6)

4 (2.2)

3 (1.2)

2 (0.7)

Nephrolithiasis

4 (2.1)

3 (1.7)

4 (1.5)

4 (2.2)

5 (2.0)

7 (2.6)

Cough

7 (3.7)

9 (5.0)

14 (5.5)

16 (6.0)

Pharyngolaryngeal pain

5 (2.6)

3 (1.7)

3 (1.2)

4 (1.5)

Rash

6 (3.1)

5 (2.8)

1 (0.4)

2 (0.7)

Alopecia

4 (2.1)

1 (0.4)

Pruritus

3 (1.6)

1 (0.6)

2 (0.8)

6 (2.2)

9 (4.7)

12 (6.7)

21 (8.3)

13 (4.9)

Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Depression

The incidence of adverse reactions, reported regardless of causality assessment, in ≥ 2 % of patients treated with either ONGLYZA 5 mg or placebo as an add-on to metformin or add-on to sulfonylurea (glyburide) are shown in Table 1. Table 1: Adverse Reactions (Regardless of Investigator Assessment of Causality) in the Add-on to Metformin Study and in Add-on to Sulfonylureab Study (24-week Short Term Study and the Long Term Extension) Reported in ≥ 2% of Patients Treated with Either ONGLYZA 5 mg or Placebo in at Least One Study a

Number of Patients (%) Add-on to Metformin Body system/Organ Class Adverse Event

Number of Patients (%) Add-on to Sulfonylurea

Saxagliptin 5 mg N=191

Placebo N=179

Anemia

11 (5.8)

3 (1.7)

2 (0.8)

3 (1.1)

Eosinophilia

6 (3.1)

1 (0.4)

4 (2.1)

1 (0.4)

Diarrhea

14 (7.3)

23 (12.8)

13 (5.1)

23 (8.6)

Dyspepsia

11 (5.8)

8 (4.5)

9 (3.6)

7 (2.6)

Toothache

8 (4.2)

11 (6.1)

8 (3.2)

8 (3.0)

Abdominal pain

7 (3.7)

2 (1.1)

6 (2.4)

4 (1.5)

Abdominal pain upper

7 (3.7)

5 (2.8)

10 (4.0)

8 (3.0)

Nausea

7 (3.7)

8 (4.5)

4 (1.6)

4 (1.5)

Vomiting

7 (3.7)

7 (3.9)

4 (1.6)

4 (1.5)

Constipation

5 (2.6)

3 (1.7)

2 (0.8)

3 (1.1)

Gastroesophageal reflux disease

4 (2.1)

1 (0.6)

2 (0.8)

6 (2.2)

Gastritis

2 (1.0)

2 (1.1)

5 (2.0)

8 (3.0)

Saxagliptin 5 mg N=253

Placebo N= 267

Blood and lymphatic system disorders

Cardiac disorders Coronary artery disease Gastrointestinal disorders

General disorders and administration site conditions

Number of Patients (%) Add-on to Sulfonylurea

Renal and urinary disorders

Dysuria Respiratory, thoracic, and mediastinal disorders

Skin and subcutaneous tissue disorders

Vascular disorders Hypertension

a The mean duration of exposure to double-blind study medication, including exposure after the initiation of rescue medication, was 75 weeks (Standard Deviation = 34) for ONGLYZA 5 mg plus metformin and 68 weeks (Standard Deviation = 35) for placebo plus metformin groups. b The mean duration of exposure to double-blind study medication, including exposure after the initiation of rescue medication, was 50 weeks (Standard Deviation = 17) for ONGLYZA 5 mg plus glyburide and 48 weeks (Standard Deviation = 17) for placebo plus uptitrated glyburide groups. Rash-related adverse events in the add-on to metformin study (24-week short-term and long-term extension) were reported in 4.2% and 2.8% of patients who received ONGLYZA 5 mg and placebo, respectively. In the add-on to sulfonylurea study (24-week short-term and long-term extension) rash-related events were reported in 1.6 % and 1.1% of patients who received ONGLYZA 5 mg and placebo, respectively. In a pooled analysis of the 24-week placebo-controlled clinical trials, hypersensitivity-related events, such as urticaria and facial edema were reported in 1.5% and 0.4% of patients who received ONGLYZA 5 mg and placebo, respectively. None of these events in patients who received ONGLYZA required hospitalization or were reported as life-threatening by the investigators. One ONGLYZA-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema. In the short-term 24-week add-on to sulfonylurea study (glyburide 7.5 mg), the overall incidence of hypoglycemia was higher for ONGLYZA 5 mg versus placebo (14.6% versus 10.1%). The incidence of confirmed hypoglycemic events, defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤ 2.8 mmol/L, was similar for ONGLYZA 5 mg treated group (0.8%) and placebo group (0.7%). In the long-term extension of the add-on to sulfonylurea study, the overall incidence of hypoglycemia was similar for ONGLYZA 5 mg (19.8%) versus uptitrated sulfonylurea plus placebo (19.8% versus 18.4%). The adverse event of hypertension was reported in more patients on ONGLYZA 5 mg plus glyburide (8.3%) versus placebo plus glyburide (4.9%) in the add-on to sulfonylurea trial. Analysis of the mean systolic and diastolic blood pressure values did not reveal clinically meaningful changes. Serious Adverse Reactions (reported in < 2% of patients) and Adverse Reactions of Interest* (reported in < 2% of patients and in at least 2 patients), Regardless of Investigator Assessment of Causality and Frequency > Placebo, in the Add-on to Metformin and Add-on to Sulfonylurea Studies (24-week short-term and the long-term extensions) * System Organ Classes were considered to be of interest based on the adverse event profile of the DPP-4 inhibitor class of drugs, non-clinical data for saxagliptin, as well as the patient population. Blood and lymphatic system disorders*: eosinophilia, lymphopenia, iron deficiency anemia, normochromic normocytic anemia Cardiac disorders*: coronary artery disease, left ventricular hypertrophy, atrioventricular block first degree, bundle branch block left, mitral valve incompetence, myocardial ischemia, palpitations, ventricular extrasystoles, acute myocardial infarction, atrioventricular block complete, cardiac failure congestive, cardiogenic shock Gastrointestinal disorders: abdominal pain, diarrhea, salivary gland mass, vomiting Hepatobiliary disorders: cholecystitis acute, cholecystitis Immune system disorders*: hypersensitivity, sarcoidosis Infections and infestations: cellulitis orbital, clostridium difficile colitis, urosepsis, diverticulitis Injury, poisoning and procedural complications: road traffic accident, ankle fracture, fall, gastrointestinal injury, incisional hernia, limb injury, skin laceration Investigations*: aspartate aminotransferase increased, c-reactive protein increased, electrocardiogram repolarisation abnormality, blood cholesterol increased, blood pressure increased, electrocardiogram abnormal, lymphocyte count decreased Metabolism and nutrition disorders: dehydration Musculoskeletal and connective tissue disorders: arthralgia, osteoarthritis Neoplasms benign, malignant and unspecified (including cysts and polyps): myelodysplastic syndrome Nervous system disorders: altered state of consciousness, dizziness Renal and urinary disorders: calculus ureteric, calculus urinary Respiratory, thoracic and mediastinal disorders: hemoptysis, pulmonary embolism Skin and subcutaneous tissue disorders*: rash, alopecia, dermatitis atopic, hyperhidrosis, rash papular, skin lesion, dermatitis contact, dermatitis, dry skin, seborrhoeic dermatitis, urticaria Surgical and medical procedures: sterilization

Edema peripheral

11 (5.8)

9 (5.0)

5 (2.0)

7 (2.6)

Chest pain

5 (2.6)

2 (1.1)

4 (1.6)

3 (1.1)

Fatigue

5 (2.6)

7 (3.9)

8 (3.2)

3 (1.1)

Asthenia

2 (1.1)

5 (2.0)

8 (3.0)

Influenza

22 (11.5)

23 (12.8)

16 (6.3)

26 (9.7)

Nasopharyngitis

21 (11.0)

19 (10.6)

24 (9.5)

27 (10.1)

Bronchitis

18 (9.4)

11 (6.1)

8 (3.2)

7 (2.6)

Upper respiratory tract infection

17 (8.9)

14 (7.8)

22 (8.7)

22 (8.2)

Urinary tract infection

15 (7.9)

12 (6.7)

35 (13.8)

29 (10.9)

Sinusitis

10 (5.2)

9 (5.0)

4 (1.6)

3 (1.1)

Gastroenteritis

5 (2.6)

3 (1.7)

7 (2.8)

7 (2.6)

Tooth infection

5 (2.6)

3 (1.7)

2 (0.8)

2 (0.7)

Gastroenteritis viral

4 (2.1)

2 (1.1)

1 (0.4)

Pharyngitis

2 (1.0)

4 (2.2)

19 (7.5)

14 (5.2)

Viral infection

1 (0.5)

4 (2.2)

4 (1.6)

6 (2.2)

Pharyngotonsillitis

1 (0.5)

1 (0.6)

5 (2.0)

10 (3.7)

3 (1.6)

1 (0.6)

7 (2.6)

Blood creatine phosphokinase increased

4 (2.1)

2 (1.1)

8 (3.2)

4 (1.5)

Alanine aminotransferase increased

1 (0.5)

4 (2.2)

4 (1.6)

3 (1.1)

Hypoglycemia

17 (8.9)

18 (10.1)

50 (19.8)

49 (18.4)

Hypertriglyceridemia

6 (3.1)

2 (1.1)

9 (3.6)

5 (1.9)

Dyslipidemia

3 (1.6)

4 (2.2)

11 (4.3)

10 (3.7)

Platelets: ONGLYZA did not demonstrate a clinically meaningful or consistent effect on platelet count in the double-blind, controlled clinical safety and efficacy trials. An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to ONGLYZA is not known.

Infections and infestations

Injury, poisoning, and procedural complications Limb Injury Investigations

Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders

Abnormal Hematologic and Clinical Chemistry Findings Absolute Lymphocyte Counts: A dose-related mean decrease in absolute lymphocyte count was observed with ONGLYZA. From a baseline absolute lymphocyte count of approximately 2200 cells/µL, a mean decrease of approximately 100 cells/µL relative to placebo was observed in a pooled analysis of the placebo-controlled clinical studies. The proportion of patients who were reported to have a lymphocyte count ≤ 750 cells/ µL was 1.5% in the ONGLYZA 5 mg group and 0.4% in the placebo group. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of ONGLYZA on lymphocyte counts in patients with lymphocyte abnormalities (e.g. human immunodeficiency virus) is unknown.

Arthralgia

16 (8.4)

9 (5.0)

17 (6.7)

20 (7.5)

DRUG INTERACTIONS

Back pain

15 (7.9)

16 (8.9)

16 (6.3)

17 (6.4)

Drug-Drug Interactions

Osteoarthritis

8 (4.2)

4 (2.2)

2 (0.8)

7 (2.6)

Myalgia

6 (3.1)

4 (2.2)

6 (2.4)

5 (1.9)

Pain in extremity

6 (3.1)

13 (7.3)

12 (4.7)

18 (6.7)

Exostosis

4 (2.1)

2 (1.1)

1 (0.4)

Musculoskeletal pain

4 (2.1)

9 (5.0)

4 (1.6)

9 (3.4)

Muscle spasms

3 (1.6)

4 (2.2)

3 (1.2)

4 (1.5)

Headache

17 (8.9)

20 (11.2)

25 (9.9)

19 (7.1)

Dizziness

8 (4.2)

9 (5.0)

3 (1.2)

11 (4.1)

Parasthesia

2 (1.1)

1 (0.4)

6 (2.2)

8 (4.2)

5 (2.8)

5 (2.0)

4 (1.5)

Effect of other drugs on saxagliptin Metformin: Coadministration of a single dose of saxagliptin (100 mg) and metformin (1000 mg), an OCT-1 and OCT-2 substrate, decreased the Cmax of saxagliptin by 21%; however, the AUC was unchanged. Therefore, metformin is considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Meaningful interactions of ONGLYZA with other OCT-1 and OCT-2 substrates would not be expected. Glyburide: Coadministration of a single dose of saxagliptin (10 mg) and glyburide (5 mg), a CYP2C9 substrate, did not affect the pharmacokinetics of saxagliptin. Therefore, glyburide is considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Meaningful interactions of ONGLYZA with other CYP2C9 substrates would not be expected. Pioglitazone: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and pioglitazone (45 mg), a CYP2C8 (major) and CYP3A4 (minor) substrate, did not alter the pharmacokinetics of saxagliptin. Therefore, pioglitazone is considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Meaningful interactions of ONGLYZA with other CYP2C8 substrates would not be expected. Digoxin: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and digoxin (0.25 mg), a P-gp substrate, did not alter the pharmacokinetics of saxagliptin. Therefore, digoxin is considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Meaningful interactions of ONGLYZA with other P-gp substrates would not be expected. Simvastatin: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and simvastatin (40 mg), a CYP3A4/5 substrate, increased the Cmax of saxagliptin by 21%; however, the AUC of saxagliptin was unchanged. Therefore, simvastatin is considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Meaningful interactions of ONGLYZA would not be expected with other substrates of CYP3A4/5.

Nervous system disorders

Psychiatric disorders Anxiety

Canadian Family Physician t Le Médecin de famille canadien

| VOL 57: JANUARY t JANVIER 2011

Diltiazem: Coadministration of a single dose of saxagliptin (10 mg) and diltiazem (360 mg long-acting formulation at steady state), a moderate inhibitor of CYP3A4/5, increased the Cmax and AUC for saxagliptin by 63% and 109%, respectively. This coadministration was also associated with 44% and 34% decreases in Cmax and AUC(INF) values, respectively of its major metabolite. Therefore, diltiazem is considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Meaningful interactions of ONGLYZA with other moderate CYP3A4/5 inhibitors would not be expected. Ketoconazole: Coadministration of a single dose of saxagliptin (100 mg) and ketoconazole (200 mg every 12 hours at steady state), a potent inhibitor of CYP3A4/5 and P-gp, increased the Cmax and AUC for saxagliptin by 62% and 145 % respectively. This coadministration was also associated with 95% and 88% decreases in Cmax and AUC(INF) values, respectively of its major metabolite. Following co-administration of a single dose of saxagliptin at 20 times the recommended dose (100 mg) with ketoconazole, transient flu-like symptoms and a transient decrease in absolute lymphocyte count were observed. Additionally, transient decreases in absolute lymphocyte count were observed without any flu-like symptoms following co-administration of a single dose of saxagliptin at 4 times the recommended dose (20 mg) with ketoconazole. CYP3A4/5 Inducers: The effects of CYP3A4/5 inducers on the pharmacokinetics of saxagliptin have not been studied. However, the coadministration of saxagliptin and CYP3A4/5 inducers such as carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampin may result in decreased plasma concentrations of saxagliptin and increased concentrations of its major metabolite. Omeprazole: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and omeprazole (40 mg), a CYP2C19 (major) and CYP3A4 substrate, an inhibitor of CYP2C19, and an inducer of MRP-3, did not alter the pharmacokinetics of saxagliptin. Therefore, omeprazole is considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Meaningful interactions of ONGLYZA with other CYP2C19 inhibitors or MRP-3 inducers would not be expected. Aluminum hydroxide + magnesium hydroxide + simethicone: Coadministration of a single dose of saxagliptin (10 mg) and a liquid containing aluminum hydroxide (2400 mg), magnesium hydroxide (2400 mg), and simethicone (240 mg) decreased the Cmax of saxagliptin by 26%; however, the AUC of saxagliptin was unchanged. Therefore, meaningful interactions of ONGLYZA with antacid and antigas formulations of this type would not be expected. Famotidine: Administration of a single dose of saxagliptin (10 mg) three hours after a single dose of famotidine (40 mg), an inhibitor of hOCT-1, hOCT-2, and hOCT-3, increased the Cmax of saxagliptin by 14%; however, the AUC of saxagliptin was unchanged. Therefore, famotidine is considered unlikely to cause a clinically meaningful interaction with ONGLYZA. Meaningful interactions of ONGLYZA would not be expected with other inhibitors of hOCT-1, hOCT-2, and hOCT-3. Effect of saxagliptin on other drugs Metformin: Coadministration of a single dose of saxagliptin (100 mg) and metformin (1000 mg), an OCT-1 and OCT-2 substrate, did not alter the pharmacokinetics of metformin in healthy subjects. Therefore, ONGLYZA is considered unlikely to cause a clinically meaningful interaction with metformin. ONGLYZA is not an inhibitor of OCT-1 and OCT-2- mediated transport. Glyburide: Coadministration of a single dose of saxagliptin (10 mg) and glyburide (5 mg), a CYP2C9 substrate, increased the plasma Cmax of glyburide by 16%; however, the AUC of glyburide was unchanged. Therefore, ONGLYZA is considered unlikely to cause a clinically meaningful interaction with glyburide. ONGLYZA does not meaningfully inhibit CYP2C9- mediated metabolism. Pioglitazone: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and pioglitazone (45 mg), a CYP2C8 substrate, increased the plasma Cmax of pioglitazone by 14%; however, the AUC of pioglitazone was unchanged. Therefore, ONGLYZA is considered unlikely to cause a clinically meaningful interaction with pioglitazone. ONGLYZA does not meaningfully inhibit or induce CYP2C8-mediated metabolism. Digoxin: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and digoxin (0.25 mg), a P-gp substrate, did not alter the pharmacokinetics of digoxin. Therefore, ONGLYZA is considered unlikely to cause a clinically meaningful interaction with digoxin. ONGLYZA is not an inhibitor or inducer of P-gp-mediated transport. Simvastatin: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and simvastatin (40 mg), a CP3A4/5 substrate, did not alter the pharmacokinetics of simvastatin. Therefore, ONGLYZA is considered unlikely to cause a clinically meaningful interaction with simvastatin. ONGLYZA is not an inhibitor or inducer of CYP3A4/5-mediated metabolism. Diltiazem: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and diltiazem (360 mg long-acting formulation at steady state), a moderate inhibitor of CYP3A4/5, increased the plasma Cmax of diltiazem by 16%; however, the AUC of diltiazem was unchanged. Therefore, ONGLYZA is considered unlikely to cause a clinically meaningful interaction with diltiazem. Ketoconazole: Coadministration of a single dose of saxagliptin (100 mg) and multiple doses of ketoconazole (200 mg every 12 hours at steady state), a potent inhibitor of CYP3A4/5 and P-gp, decreased the geometric means for Cmax and AUC(INF) of ketoconazole by 16 % and by 13% respectively, relative to those observed following administration of 200 mg ketoconazole q 12 h alone. Drug-Food Interactions There are no known interactions with food. Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism may give rise to modest increases in plasma levels of saxagliptin. Drug-Herb Interactions Interactions with herbal products have not been established. Drug-Laboratory Interactions Interactions with laboratory tests have not been established. Drug-Lifestyle Interactions No studies of the effects of ONGLYZA on the ability to drive and use machines have been performed. However, ONGLYZA is not expected to affect the ability to drive and use machines.

OVERDOSAGE

Index to Advertisers Index des annonceurs

Astellas

NovoNordisk Victoza .......................... 4–5 PI ........................ 103–104

Protopic ..................... 24–25 PI ........................ 115–117

Nycomed Tecta ......................... 57/59 PI ........................ 113–114

AstraZeneca Crestor Bootlug................. 7 Corporate .................. 14–15 Onglyza ............................. 2

Pfizer Pharmaceuticals Aricept............................. 10 PI ............................ 93–95 Pristiq ....................... 22–23 PI ........................ 100–102

PI ............................ 87–88 Boehringer Ingelheim Pradax ............................IFC PI ........................ 108–112

Purdue Pharma BuTrans ..................... 40–41 PI ............................ 98–99 Targin ........................ 52–53 PI ........................ 105–107

CFPC Honours & Awards ... 44/51 Leo Pharma Dovobet............................. 8 PI .................................. 90

Scotiabank Small Business Campaign .................... IBC

MD Practice Solutions ..................... 39

Takeda Canada Inc. Dexilant ............................. 6 PI ............................ 91–92

Merck Frosst Canada Januvia .........................OBC

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status. Saxagliptin and its major metabolite are removed by hemodialysis (23% of dose over 4 hours). For management of a suspected drug overdose, contact your regional Poison Control Centre.

… *PI - Prescribing Information

ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action Saxagliptin is a potent, selective, reversible, competitive, DPP-4 inhibitor. Saxagliptin demonstrates selectivity for DPP-4 versus other DPP enzymes, including DPP-8 and DPP-9. Saxagliptin has extended binding to the DPP-4 active site, prolonging its inhibition of DPP-4. Saxagliptin exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones, including glucagon-like peptide-1 (GLP-1). The concentration of active (intact) GLP-1 incretin hormone is increased. Incretin hormones are released by the intestine throughout the day and concentrations are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. The concentration of GLP-1 is reduced in patients with type 2 diabetes but saxagliptin increases active GLP-1 concentration. By increasing active GLP-1 concentration, saxagliptin increases postprandial insulin release and decreases postprandial glucagon concentrations in the circulation in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels may lead to lower hemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations.

My grandma doesn’t have arthritis. But I do. So does 1 out of every 1,000 children under 16.

Product Monograph available on request. Last revised 14 September 2009.

Please help us fund research for better treatments.

ONG069E Bristol-Myers Squibb Canada, Montreal, Quebec H4S 0A4 and AstraZeneca Canada Inc. Mississauga, Ontario L4Y 1M4 ONGLYZA is a registered trademark of Bristol-Myers Squibb Company used under license by Bristol-Myers Squibb Canada Co.

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rebound psoriasis when discontinuing corticosteroids after prolonged periods of use (see ADVERSE REACTIONS). MONITORING AND LABORATORY TESTS Treatment with Dovobet ® in the recommended amounts (See DOSAGE AND ADMINISTRATION) does not generally result in changes in laboratory values. In patients using greater than the recommended weekly maximum of 100 g of Dovobet ®, patients at risk of hypercalcemia, and patients with marginally elevated serum calcium levels, serum calcium should be monitored at suitable intervals.

Prescribing Summary Patient Selection Criteria THERAPEUTIC CLASSIFICATION Topical Antipsoriatic Agent Vitamin D Analogue/Corticosteroid INDICATIONS AND CLINICAL USE Dovobet ® ointment is indicated for the topical treatment of psoriasis vulgaris for up to 4 weeks. Dovobet ® should not be used on the face. SPECIAL POPULATIONS Pregnant Women: The safety of calcipotriol and/or topical corticosteroids for use during pregnancy has not been established. Although studies in experimental animals have not shown teratogenic effects with calcipotriol, studies with corticosteroids have shown teratogenic effects. The use of Dovobet ® is not recommended in pregnant women. Nursing Women: The safety of calcipotriol and/or topical corticosteroids for use in nursing women has not been established. It is not known whether calcipotriol can be excreted in breast milk or if topical application of corticosteroids can lead to sufficient systemic absorption to produce detectable quantities in breast milk. The use of Dovobet ® is not recommended in nursing women. Pediatrics (<18 years of age): There is no clinical trial experience with the use of Dovobet ® in children. Children may demonstrate greater susceptibility to systemic steroid-related adverse effects due to a larger skin surface area to body weight ratio as compared to adults. CONTRAINDICATIONS Known hypersensitivity to any of the ingredients of Dovobet ® ointment. NOT FOR OPHTHALMIC USE. Not for the treatment of viral, fungal or bacterial skin infections, tuberculosis of the skin, syphilitic skin infections, chicken pox, eruptions following vaccinations, and in viral diseases such as herpes simplex, varicella and vaccinia.

WARNINGS AND PRECAUTIONS General Due to the content of calcipotriol, hypercalcaemia may occur if the maximum weekly dose (100 g) is exceeded. Serum calcium is quickly normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are followed (see Monitoring and Laboratory Tests). The safety of calcipotriol and/or topical corticosteroids for use with children or pregnant or lactating women has not been established. (See SUPPLEMENTAL SAFETY INFORMATION; Special Populations). Skin Dovobet ® should not be used on the face since this may give rise to itching and erythema of the facial skin. Patients should be instructed to wash their hands after each application of Dovobet® in order to avoid inadvertent transfer to the face. Should facial dermatitis develop in spite of these precautions, Dovobet ® therapy should be discontinued. Prolonged use of corticosteroid-containing preparations may produce striae or atrophy of the skin or subcutaneous tissues. Therefore, it is recommended that corticosteroid treatment be interrupted periodically, and that one area of the body be treated at a time. Topical corticosteroids should be used with caution on lesions of the face, groin and axillae as these areas are more prone to atrophic changes than other areas of the body. If skin atrophy occurs, discontinue treatment. There may be a risk of Canadian Family Physician t Le Médecin de famille canadien

DRUG INTERACTIONS There is no experience of concomitant therapy with other antipsoriatic drugs.

Administration Dosing Considerations Dovobet® is FOR TOPICAL USE ONLY. Not for ophthalmic use. There is no clinical trial experience with the use of Dovobet ® in children. Recommended Dose and Dosage Adjustment Dovobet® should be applied topically to the affected areas once daily for up to 4 weeks. After satisfactory improvement has occurred, the drug can be discontinued. If recurrence takes place after discontinuation, treatment may be reinstituted. The maximum recommended adult dose of Dovobet® ointment is 100 g per week.

SUPPLEMENTAL PRODUCT INFORMATION OTHER POTENTIAL ADVERSE REACTIONS

Prolonged use of corticosteroid-containing preparations may produce striae or atrophy of the skin or subcutaneous tissues. Topical corticosteroids should be used with caution on lesions of the face, groin and axillae as these areas are more prone to atrophic changes than other areas of the body. If skin atrophy occurs, discontinue treatment. Topical corticosteroids can cause the same spectrum of adverse effects associated with systemic steroid administration, including adrenal suppression. Adverse effects associated with topical corticosteroids are generally local and include: dryness, itching, burning, local irritation, striae, atrophy of the skin or subcutaneous tissues, telangiectasia, hypertrichosis, folliculitis, skin hypopigmentation, allergic contact dermatitis, maceration of the skin, miliaria, or secondary infection. If applied to the face, acne rosacea or perioral dermatitis can occur. In addition, there are reports of the development of pustular psoriasis from chronic plaque psoriasis following reduction or discontinuation of potent topical corticosteroid products.

SUPPLEMENTAL SAFETY INFORMATION Carcinogenesis

Calcipotriol when used in combination with ultraviolet radiation (UVR) may enhance the known skin carcinogenic effect of UVR. (See TOXICOLOGY, Carcinogenicity, in the Product Monograph).

Safety Information

MOST COMMON ADVERSE REACTIONS In clinical trials, the most common adverse reaction associated with Dovobet ® was pruritus. Pruritus was usually mild and no patients were withdrawn from treatment. Calcipotriol is associated with local reactions such as transient lesional and perilesional irritation. Rare cases of hypersensitivity reaction have been reported. To report an adverse reaction please notify Health Canada at 1-866-234-2345 or LEO Pharma Inc. at 1-800-263-4218.

Endocrine and Metabolism

Application on large areas of damaged skin, under occlusive dressings, or in skin folds should be avoided since it increases systemic absorption of corticosteroids and the risk of adverse effects such as adrenal suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycaemia and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids. Occlusive dressings should not be applied if body temperature is elevated. All of the adverse effects associated with systemic use of corticosteroids, including adrenal suppression, may also occur following topical administration of corticosteroid-containing products such as Dovobet ®, especially in children.

Missed Dose

If a dose is missed, the patient should apply Dovobet ® as soon as he/she remembers and then continue on as usual.

Overdosage

Due to the calcipotriol component of Dovobet ® (calcipotriol and betamethasone dipropionate), excessive administration (i.e. more than the recommended weekly amount of 100 g) may cause elevated serum calcium, which rapidly subsides when treatment is discontinued. In such cases, it is recommended to monitor serum calcium levels once weekly until they return to normal. Excessive or prolonged use of topical corticosteroids can suppress pituitary-adrenal function, resulting in secondary adrenal insufficiency and manifestations of hypercorticoidism, including Cushing’s disease. Recovery is usually prompt and complete upon steroid discontinuation. In cases of chronic toxicity, slow withdrawal of corticosteroids is recommended.

AVAILABLE DOSAGE FORMS Dosage Form: Ointment (faintly translucent white to yellowish ointment). Strength: 50 mcg/g calcipotriol and 0.5 mg/g betamethasone (as dipropionate). Packaging: Available in 60 g and 120 g lacquered aluminium tubes (equipped with an aluminium membrane). Store at 5° to 25°C. For easy application: do not refrigerate (this is to prevent rubbing and pulling of delicate skin). Use within 12 months of first opening the tube.

Product monograph available upon request. For further information, please contact Medical Information at LEO Pharma Inc. 1-800-263-4218. ® Registered trademark of LEO Pharma A/S used under license and distributed by LEO Pharma Inc., Thornhill, ON.

| VOL 57: JANUARY t JANVIER 2011

LEO Pharma Inc. Thornhill, Ontario L3T 7W8 www.leo-pharma.com/canada

Safety Information

Prescribing Summary

This is a condensed version of the Product Monograph. For complete information, please refer to the Product Monograph available at www.takedacanada.com or by writing to Takeda Medical Affairs at 6750 Century Avenue, Suite 400, Mississauga, Ontario, L5N 2V8.

Patient Selection Criteria

THERAPEUTIC CLASSIFICATION H+, K+ - ATPase Inhibitor INDICATIONS AND CLINICAL USE DEXILANT (dexlansoprazole) is indicated in adults 18 years of age and older for healing of all grades of EE for up to 8 weeks, maintaining healing of EE for up to 6 months, and the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks. No dosage adjustment is necessary for elderly patients (> 65 years of age). The safety and effectiveness of DEXILANT in pediatric patients (< 18 years of age) have not been established. CONTRAINDICATIONS Patients who are hypersensitive to this drug or to any ingredient in the formulation. DEXILANT should not be concomitantly administered with atazanavir. (See DRUG INTERACTIONS) SPECIAL POPULATIONS Pregnant Women: There are no adequate or well-controlled studies in pregnant women with DEXILANT. Exposure in clinical trials was very limited. DEXILANT should not be administered to pregnant women unless the expected benefits outweigh the potential risks. See REPRODUCTION AND TERATOLOGY in the Product Monograph. Nursing Women: It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole (the racemate) and its metabolites are excreted in the milk of rats. As many drugs are excreted in human milk, DEXILANT should not be given to nursing mothers unless its use is considered essential. See REPRODUCTION AND TERATOLOGY in the Product Monograph. Pediatrics (<18 years of age): Safety and effectiveness of DEXILANT in pediatric patients have not been established. Geriatrics (> 65 years of age): In clinical studies of DEXILANT, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. No dosage adjustment is necessary for elderly patients. See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions in the Product Monograph. Hepatic Impairment: No dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A maximum daily dose of 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment. See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions in the Product Monograph. Renal Impairment: No dosage adjustment is necessary for patients with renal impairment. See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions in the Product Monograph.

WARNINGS AND PRECAUTIONS General Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis.” After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile. Carcinogenesis and Mutagenesis Dexlansoprazole was positive in the Ames test for mutagenicity in bacteria. In an in vitro chromosome aberration test using Chinese hamster lung cells, dexlansoprazole was considered positive based on equivocal data in which the percentage of cells with aberrant chromosomes increased slightly but did not reach the preset criteria for a positive response. Dexlansoprazole was negative in the in vivo mouse micronucleus test. Lansoprazole is a racemic mixture of R- and S-enantiomers. Following administration of lansoprazole in humans and animals, the major component circulating in plasma is dexlansoprazole, the R-enantiomer of lansoprazole. Therefore, the carcinogenic potential of dexlansoprazole was assessed using existing lansoprazole studies. See TOXICOLOGY in the Product Monograph. Lansoprazole treatment for 2-years was associated with hyperplasia and neoplasms (carcinoids) of enterochromaffin-like cells (ECL cells) in the stomach of conventional rats and mice. These proliferations are related to prolonged hypergastrinemia secondary to gastric acid suppression. Benign tumors of the testis (interstitial cell adenomas in rats and rete testis adenomas in mice) were secondary to an inhibitory effect on testosterone synthesis at high doses in these species. Hepatocellular adenomas and carcinomas were increased in the livers of mice related to induction of CYP enzymes leading to increased liver weights. Genitourinary Testicular interstitial cell adenoma occurred in 1 of 30 rats treated with 50 mg/kg/day of lansoprazole (13 times the recommended human dose based on body surface area) in a one-year toxicity study. See TOXICOLOGY, Carcinogenicity in the Product Monograph. These changes are associated with endocrine alterations which have not been, to date, observed in humans. VOL 57: JANUARY t JANVIER 2011

ADVERSE REACTIONS Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The safety of DEXILANT was evaluated in 4548 patients in controlled and uncontrolled clinical studies (30 mg, 60 mg, and 90 mg), including 863 patients treated for at least 6 months and 282 patients treated for one year. Patients ranged in age from 18 to 90 years (median age 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian and 3% other races. Six randomized controlled clinical trials were conducted for the treatment of erosive esophagitis, maintenance of healed erosive esophagitis, and symptomatic GERD, which included 896 patients on placebo, 2621 patients on DEXILANT 30 mg or 60 mg and 1363 patients on lansoprazole 30 mg. The following adverse events were reported to have a possible or definite treatment-relationship to DEXILANT in 1% or more of the treated patients in placebo and positive-controlled clinical trials (Tables 1 and 2, respectively). Numbers in parentheses indicate the percentage of the adverse events reported. Table 1: Incidence of possibly or definitely treatment-related adverse events in placebo controlled studies

Body system Adverse event Gastrointestinal disorders Diarrhea Abdominal pain Nausea Flatulence Constipation Nervous system disorders Headache

Placebo (N=896) n (%)

DEXILANT 30 mg and 60 mg (N=1399) n (%)

17 (1.9) 14 (1.6) 16 (1.8) 5 (0.6) 9 (1.0)

52 (3.7) 37 (2.6) 31 (2.2) 25 (1.8) 15 (1.1)

21 (2.3)

31 (2.2)

Table 2: Incidence of possibly or definitely treatment-related adverse events in active controlled clinical trials

Body system Adverse event Gastrointestinal disorders Diarrhea Abdominal pain Nausea Nervous system disorders Headache

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DEXILANT 60 mg (N=2621) n (%)

Lansoprazole 30 mg (N=1363) n (%)

44 (3.2) 21 (1.5) 14 (1.0)

28 (2.1) 19 (1.4) 18 (1.3)

16 (1.2)

19 (1.4)

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In placebo-controlled studies, gastrointestinal adverse reactions other than constipation occurred at a higher incidence for DEXILANT than placebo. In active-controlled studies, diarrhea occurred at a higher incidence for DEXILANT than lansoprazole. The incidence of other common adverse reactions for DEXILANT were similar to or lower than placebo or lansoprazole. For adverse events with a frequency of < 1%, see SUPPLEMENTAL PRODUCT INFORMATION. To report an adverse event, you may notify Health Canada by phone at 1-866-234-2345 or by toll-free fax at 1-866-678-6789. DRUG INTERACTIONS: SEE SUPPLEMENTAL PRODUCT INFORMATION.

Administration

Recommended Dose and Dosage Adjustment HEALING OF EROSIVE ESOPHAGITIS The recommended adult oral dose of DEXILANT (dexlansoprazole) for the healing of erosive esophagitis is 60 mg given once daily for up to 8 weeks. MAINTENANCE OF HEALED EROSIVE ESOPHAGITIS The recommended adult oral dose of DEXILANT (dexlansoprazole) for the maintenance of healed erosive esophagitis is 30 mg given once daily. In patients who had moderate or severe erosive esophagitis, a maintenance dose of 60 mg may be used. Controlled studies did not extend beyond 6 months. SYMPTOMATIC NON-EROSIVE GASTROESOPHAGEAL REFLUX DISEASE (GERD) The recommended adult oral dose of DEXILANT (dexlansoprazole) for symptomatic non-erosive GERD is 30 mg given once daily for 4 weeks. No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). No dosage adjustment is necessary for elderly patients or for patients with renal impairment. Missed Dose If a capsule is missed at its usual time, it should be taken as soon as possible. But if it is too close to the time of the next dose, only the prescribed dose should be taken at the appointed time. A double dose should not be taken. Administration DEXILANT can be taken without regard to food or the timing of food. DEXILANT should be swallowed whole with plenty of water. Alternatively, DEXILANT capsules can be opened and administered by opening capsule, sprinkling intact granules on one tablespoon of applesauce, and swallowing immediately.

Supplemental Product Information ADVERSE REACTIONS: For Adverse Drug Reaction Overview and Adverse Reactions with a frequency of ≥1%, see Adverse Reaction in the SAFETY INFORMATION section. Less Common Clinical Trial Adverse Drug Reactions (< 1%) Other adverse reactions that were reported for DEXILANT (30 mg, 60 mg or 90 mg) in controlled studies at an incidence of less than 1% are listed below by body system: Blood and Lymphatic System Disorders: anemia, lymphadenopathy Cardiac Disorders: acute myocardial infarction, angina, arrhythmia, bradycardia, edema, palpitations, tachycardia Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo

Endocrine Disorders: goiter Eye Disorders: eye irritation, eye swelling Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis, gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defecation, paresthesia oral, proctitis, rectal hemorrhage, vomiting General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly Immune System Disorders: hypersensitivity Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, upper respiratory tract infection, viral infection, vulvo-vaginal infection Injury, Poisoning and Procedural Complications: overdose, procedural pain, sunburn Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/ increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increased Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia Nervous System Disorders: altered taste, convulsion, dizziness, memory impairment, migraine, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes Renal and Urinary Disorders: dysuria, micturition urgency Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritus, rash, skin lesion, urticaria Vascular Disorders: deep vein thrombosis, hot flush, hypertension Additional adverse reactions that were reported for DEXILANT (60 mg or 90 mg) in a longterm uncontrolled study included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, decreased hemoglobin, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperglycemia, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decreased, neutropenia, oral soft tissue disorder, rectal tenesmus, restless legs syndrome, somnolence, thrombocythemia, tonsillitis. Post-Market Adverse Drug Reactions Adverse reactions have been identified during post-marketing surveillance of DEXILANT. As these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye Disorders: blurred vision Gastrointestinal Disorders: oral edema General Disorders and Administration Site Conditions: facial edema Immune System Disorders: anaphylactic shock (requiring emergency intervention), Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal) Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness Skin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitis OVERDOSAGE For management of a suspected drug overdose, consult your regional poison control centre. There have been no reports of significant overdose of DEXILANT. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. DRUG INTERACTIONS Drug-Drug Interactions Drugs with pH-Dependent Absorption Pharmacokinetics DEXILANT causes inhibition of gastric acid secretion. DEXILANT is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, DEXILANT should not be co-administered with atazanavir. It is theoretically possible that DEXILANT may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., Ampicillin esters, digoxin, iron salts, ketoconazole). Cytochrome P 450 Interactions DEXILANT is metabolized, in part, by CYP2C19 and CYP3A4. See ACTION AND CLINICAL PHARMACOLOGY, Metabolism in the Product Monograph. In vitro studies have shown that DEXILANT is not likely to inhibit CYP isoforms 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Furthermore, clinical drug-drug interaction studies have shown that DEXILANT does not affect the pharmacokinetics of diazepam, phenytoin, or theophylline. Warfarin In a study of 20 healthy subjects, co-administration of DEXILANT 90 mg once daily for 11 days with a single 25 mg oral dose of warfarin on day 6 did not result in any significant differences in the pharmacokinetics of warfarin or INR compared to administration of warfarin with placebo. However, there have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors (PPIs) and warfarin concomitantly. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

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Concomitant Use of Antacids with DEXILANT No formal drug-drug interaction studies were conducted with DEXILANT and antacids. Drug interactions studies were performed with the racemate lansoprazole and antacids. Simultaneous administration of lansoprazole with aluminum and magnesium hydroxide or magaldrate results in lower peak plasma levels, but does not significantly reduce bioavailability. Antacids may be used concomitantly if required. In clinical trials, antacids were administered concomitantly with lansoprazole delayed-release capsules. In a singledose crossover study when 30 mg of lansoprazole was administered concomitantly with one gram of sucralfate in healthy volunteers, absorption of lansoprazole was delayed and its bioavailability was reduced. The value of lansoprazole AUC was reduced by 17% and that for Cmax was reduced by 21%. In a similar study when 30 mg of lansoprazole was administered concomitantly with 2 grams of sucralfate, lansoprazole AUC and Cmax were reduced by 32% and 55%, respectively. When lansoprazole dosing occurred 30 minutes prior to sucralfate administration, Cmax was reduced by only 28% and there was no statistically significant difference in lansoprazole AUC. Therefore, lansoprazole should be administered at least 30 minutes prior to sucralfate. It would be expected that similar results would be seen with DEXILANT. Theophylline Although a study of the use of concomitant theophylline and dexlansoprazole did not reveal any changes in the pharmacokinetics or pharmacodynamics of theophylline, individual patients should monitor their theophylline level while taking the two drugs concomitantly. Tacrolimus Concomitant administration of dexlansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Clopidogrel Cytochrome P450 2C19 (CYP2C19) is responsible for the metabolism of clopidogrel to its active metabolite. Although in vitro metabolism studies have demonstrated that PPIs inhibit hepatic CYP2C19, the level of inhibition varies among PPIs, and it is unknown as to the amount other PPIs may interfere with clopidogrel. Various clinical drug-drug interaction studies have demonstrated that dexlansoprazole does not affect the pharmacokinetics of diazepam, phenytoin or R-warfarin, drugs that are metabolized by CYP2C19. Drug-Food Interactions DEXILANT can be taken without regard to food or timing of food. See ACTION AND CLINICAL PHARMACOLOGY in the Product Monograph. Drug-Herb Interactions Interactions with herbal products have not been established. Drug-Laboratory Tests Interactions with laboratory tests have not been established. Special Populations and Conditions Pediatrics: The pharmacokinetics of dexlansoprazole in patients under the age of 18 years have not been studied. Geriatrics: In a study of 12 male and 12 female healthy subjects who received a single oral dose of DEXILANT 60 mg, the terminal elimination half-life of dexlansoprazole was statistically significantly longer in geriatric subjects compared to younger subjects (2.23 and 1.5 hours, respectively). In addition, dexlansoprazole exhibited higher systemic exposure (AUC) in geriatric subjects (34.5% higher) than younger subjects. These differences were not clinically relevant. No dosage adjustment is necessary in geriatric patients. See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION. Gender: In a study of 12 male and 12 female healthy subjects who received a single oral dose of DEXILANT 60 mg, females had higher systemic exposure (AUC) (42.8% higher) than males. No dosage adjustment is necessary in patients based on gender. Hepatic Insufficiency: In a study of 12 patients with moderately impaired hepatic function who received a single oral dose of DEXILANT 60 mg, plasma exposure (AUC) of bound and unbound dexlansoprazole in the hepatic impairment group was approximately 2 times greater compared to subjects with normal hepatic function. This difference in exposure was not due to a difference in protein binding between the two liver function groups. No adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). See WARNINGS AND PRECAUTIONS in the Product Monograph. Renal Insufficiency: Dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole. Therefore, the pharmacokinetics of dexlansoprazole are not expected to be altered in patients with renal impairment, and no studies were conducted in subjects with renal impairment. See WARNINGS AND PRECAUTIONS in the Product Monograph. STORAGE AND STABILITY Store at room temperature (15° to 30°C). SPECIAL HANDLING INSTRUCTIONS None Full Product Monograph available upon request or online. July 2010. DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Canada, Inc.

Safety Information

Prescribing Summary Patient Selection Criteria THERAPEUTIC CLASSIFICATION: Cholinesterase inhibitor INDICATIONS AND CLINICAL USE ARICEPT (donepezil hydrochloride) is indicated for the symptomatic treatment of patients

with mild, moderate and severe dementia of the Alzheimer’s type. Efficacy of ARICEPT in patients with mild-to-moderate Alzheimer’s disease (AD) was established in two 24-week and one 54-week placebo-controlled trials. Efficacy in patients with severe AD was established in two 24-week/6-month placebo-controlled trials. ARICEPT tablets should only be prescribed by (or following consultation with) clinicians who are experienced in the diagnosis and management of AD. CONTRAINDICATIONS ARICEPT (donepezil hydrochloride) is contraindicated in patients with known hypersensitivity

to donepezil hydrochloride or to piperidine derivatives. SPECIAL POPULATIONS Use in pregnant or nursing women The safety of ARICEPT during pregnancy and lactation has not been established.

Therefore, it should not be used in women of childbearing potential or in nursing mothers unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus or the infant. Use in children

There are no adequate and well-controlled trials to document the safety and efficacy of ARICEPT in any illness occurring in children.Therefore, ARICEPT is not recommended for use in children. Use in elderly patients (≥65 years of age)

InAD patients,nausea,diarrhea,vomiting,insomnia,fatigue and anorexia increased with dose and age, and the incidence appeared to be greater in female patients. Since cholinesterase inhibitors as well as AD can be associated with significant weight loss, caution is advised regarding the use of ARICEPT in low body weight elderly patients, especially in those ≥85 years old. Use in elderly patients with comorbid disease There is limited safety information for ARICEPT in patients with mild-to-moderate or severe AD and significant comorbidity. The use of ARICEPT in AD patients with chronic illnesses

common among the geriatric population should be considered only after careful risk/benefit assessment and include close monitoring for adverse events (AEs). Caution is advised regarding the use of ARICEPT doses above 5 mg in this patient population. In severe AD, the possibility of comorbid vascular disease and risk factors for vascular AEs and mortality should be considered. Use in patients with vascular dementia

Three clinical trials, each of 6 months duration, were conducted to evaluate the safety and efficacy of ARICEPT for the symptomatic treatment of individuals meeting the NINDS-AIREN criteria for probable or possible vascular dementia (VaD). The NINDS-AIREN criteria are designed to identify patients with dementia that appears to be due solely to vascular causes, and to exclude patients with AD. ARICEPT was not shown to be an effective treatment for patients with VaD in 2 of these clinical trials. The safety profile from these controlled clinical trials in VaD patients indicates that the rate of occurrence of treatment-emergent AEs overall was higher in VaD patients (86%) than in AD patients (75%).This was seen in both ARICEPT-treated subjects and placebo-treated subjects, and may relate to the greater number of comorbid medical conditions in the VaD population. In 2 of the clinical trials, there was a higher rate of mortality among patients treated with ARICEPT, during double-blind treatment; this result was statistically significant for 1 of these 2 trials. For the 3 VaD studies combined, the mortality rate in the ARICEPT group (1.7%, 25/1,475) was numerically higher than in the placebo group (1.1%, 8/718), but this difference was not statistically significant (see Supplemental Product Information below). There is no evidence of an increased risk of mortality when ARICEPT is used in patients with mild-to-moderate AD.

WARNINGS AND PRECAUTIONS Cardiovascular Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important to patients with “sick sinus syndrome” or other supraventricular cardiac conduction conditions. In clinical trials in AD, most patients with serious cardiovascular conditions were excluded. Patients, such as those with controlled hypertension (DBP<95 mmHg), right bundle branch blockage, and pacemakers, were included. Therefore, caution should be taken in treating patients with active coronary artery disease and congestive heart failure. Syncopal episodes have been reported in association with the use of ARICEPT. It is recommended that ARICEPT should not be used in patients with cardiac conduction abnormalities (except for right bundle branch block) including “sick sinus syndrome” and those with unexplained syncopal episodes. Gastrointestinal Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) including high doses of acetylsalicylic acid (ASA), should be monitored for symptoms of active or occult gastrointestinal bleeding. Clinical studies of ARICEPT have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding (see ADVERSE REACTIONS section). ARICEPT, as a predictable consequence of its pharmacological properties, has been shown to produce, in controlled clinical trials in patients with AD, diarrhea, nausea and vomiting. These effects, when they occur, appear more frequently with the 10 mg dose than with the 5 mg dose. In most cases, these effects have usually been mild and transient, sometimes lasting 1 to 3 weeks and have resolved during continued use of ARICEPT (see ADVERSE REACTIONS section). Treatment with the 5 mg/day dose for 4-6 weeks prior to increasing the dose to 10 mg/day is associated with a lower incidence of gastrointestinal intolerance. Genitourinary

Although not observed in clinical trials of ARICEPT, cholinomimetics may cause bladder outflow obstruction. Hepatic

There is limited information regarding the pharmacokinetics of ARICEPT in hepaticallyimpaired AD patients. Close monitoring for AEs in patients with hepatic disease being treated with ARICEPT is therefore recommended. Neurologic Seizures: Some cases of seizures have been reported with the use of ARICEPT in clinical

trials and from spontaneous Adverse Reaction reporting. Cholinomimetics can cause a reduction of seizure threshold, increasing the risk of seizures. However, seizure activity may also be a manifestation of AD. The risk/benefit of ARICEPT treatment for patients with a history of seizure disorder must therefore be carefully evaluated. ARICEPT has not been studied in patients with Parkinsonian features.The efficacy and safety of ARICEPT in these patients are unknown. Peri-operative considerations Anesthesia: ARICEPT, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-

type muscle relaxation during anesthesia. Renal

There is limited information regarding the pharmacokinetics of ARICEPT in renally-impaired AD patients. Close monitoring for AEs in patients with renal disease being treated with ARICEPT is therefore recommended. Respiratory

Because of their cholinomimetic action, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. ARICEPT has not been studied in patients under treatment for these conditions and should therefore be used with particular caution in such patients. ADVERSE REACTION SERIOUSNESS AND INCIDENCE Mild-to-moderate Alzheimer’s disease

A total of 747 patients with mild-to-moderate AD were treated in controlled clinical studies with ARICEPT (donepezil hydrochloride). Of these patients, 613 (82%) completed the studies. The mean duration of treatment for all ARICEPT groups was 132 days (range 1-356 days). The rates of discontinuation from controlled clinical trials of ARICEPT due to AEs for the ARICEPT 5 mg/day treatment groups were comparable to those of placebo-treatment groups at approximately 5%. The rate of discontinuation of patients who received the 10 mg/day dose after only a 1-week initial treatment with 5 mg/day ARICEPT was higher at 13% (see Table 1). The most common AEs, defined as those occurring at a frequency of at least 5% in patients

receiving 10 mg/day and twice the placebo rate, are largely predicted by ARICEPT’s cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia. These AEs were often of mild intensity and transient, resolving during continued ARICEPT treatment without the need for dose modification. There is evidence to suggest that the frequency of these common AEs may be affected by the duration of treatment with an initial 5 mg daily dose prior to increasing the dose to 10 mg/day (see Table 2 and Supplemental Product Information below). Severe Alzheimer’s disease

A total of 573 patients with severe AD were treated in controlled clinical studies with ARICEPT. Of these patients, 441 (77%) completed the studies.The duration of double-blind treatment in all studies was 24 weeks. The mean duration of treatment for all ARICEPT groups was 148.4 days (range 1-231 days). The mean daily dose of ARICEPT was 7.5 mg/day. In clinical trials of patients with severe AD, most patients with significant comorbid conditions were excluded. The use of ARICEPT in AD patients with chronic illnesses common among the geriatric population should be considered only after careful risk/benefit assessment and should include close monitoring for AEs. In controlled clinical trials in severe AD, the rate of discontinuation due to AEs was 11.3% in patients treated with ARICEPT, compared to 6.7% in the placebo group. The most common AEs that led to discontinuation, more often in patients treated with ARICEPT than placebo, were diarrhea, nausea, vomiting, urinary tract infection, decreased appetite, and aggression. Each of these AEs led to discontinuation of less than 2% of patients treated with ARICEPT. The incidence profile for AEs for severe AD was similar to that of mild-to-moderate AD (see Table 4). The most common AEs, defined as those occurring at a frequency of at least 5% in patients and twice the placebo rate, were vomiting, diarrhea, nausea, and aggression. Overall, the majority of AEs were judged by the investigators to be mild or moderate in intensity. Results from the controlled clinical trials indicate that the incidence of AEs, such as vomiting, urinary tract infection, urinary incontinence, pneumonia, falls, decreased appetite, aggression, restlessness, hallucination and confusion, may be higher in ARICEPTand placebo-treated patients with severe AD than in patients with mild-to-moderate AD. Postmarket adverse drug reactions

Voluntary reports of AEs temporally associated with ARICEPT that have been received since market introduction that are not listed above, and for which there is inadequate data to determine the causal relationship with the drug, include the following: abdominal pain, cholecystitis, convulsions, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, pancreatitis, and rash. DRUG INTERACTIONS Concomitant use with other drugs Use with anticholinergics: Because of their mechanism of action, cholinesterase inhibitors

have the potential to interfere with the activity of anticholinergic medications. Use with cholinomimetics and other cholinesterase inhibitors: A synergistic effect may be

expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists, such as bethanechol. Use with other psychoactive drugs: Few patients in controlled clinical trials received neuroleptics, antidepressants or anticonvulsants. There is thus limited information concerning the interaction of ARICEPT with these drugs. Drug-drug interactions

Pharmacokinetic studies, limited to short-term, single-dose studies in young subjects, evaluated the potential of ARICEPT for interaction with theophylline, cimetidine, warfarin and digoxin administration. No significant effects on the pharmacokinetics of these drugs were observed. Similar studies in elderly patients were not done (see Supplemental Product Information below). Health Canada may be notified by phone of serious or unexpected reaction to this drug at: 1-866-234-2345.

Administration Dosing considerations ARICEPT (donepezil hydrochloride) or ARICEPT RDT should only be prescribed by (or following

consultation with) clinicians who are experienced in the diagnosis and management of AD. Special populations: The use of ARICEPT in AD patients with chronic illnesses common among the geriatric population should be considered only after careful risk/benefit assessment and include close monitoring for AEs. It is recommended that ARICEPT be used with caution in these patient populations.AEs are more common in individuals of low body weight, in patients ≥85 years old and in females. Recommended dose and dosage adjustment Adults: The recommended initial dose of ARICEPT or ARICEPT RDT is 5 mg taken once daily.

Therapy with the 5 mg dose should be maintained for 4-6 weeks before considering a dose increase, in order to avoid or decrease the incidence of the most common adverse reactions to the drug (see ADVERSE REACTIONS section) and to allow plasma levels to reach steady state.

Based on clinical judgement, the 10 mg daily dose may be considered following 4-6 weeks of treatment at 5 mg/day. The maximum recommended dose is 10 mg taken once daily. Following initiation of therapy or any dosage increase, patients should be closely monitored for AEs. Special populations: AEs are more common in individuals of low body weight, in patients ≥85 years old and in females. In elderly women of low body weight, the dose should not exceed 5 mg/day. In a population of cognitively-impaired individuals, safe use of this and all other medications may require supervision. Administration ARICEPT should be taken once daily in the morning or evening. It may be taken with or

without food. ARICEPT tablets should be swallowed whole with water. ARICEPT RDT should be placed on the tongue and allowed to disintegrate before swallowing with water.

Study References 1. ARICEPT/ARICEPT RDT Product Monograph, Pfizer Canada Inc., June 2007. Supplemental Product Information WARNINGS AND PRECAUTIONS Use in pregnant and nursing women Teratology studies conducted in pregnant rats at doses of up to 16 mg/kg/day and in pregnant rabbits at doses of up to 10 mg/kg/day did not disclose any evidence for a teratogenic potential of ARICEPT. Use in elderly patients (≥65 years of age) In controlled clinical studies with 5 and 10 mg ARICEPT in patients with mild-to-moderate AD, there were 536 patients between the ages of 65 to 84, and 37 patients aged ≥85 years treated with ARICEPT. In controlled clinical trials of patients with severe AD, there were 158 patients who were ≤74 years of age, 276 patients between the ages of 75 and 84, and 139 patients aged ≥85 years treated with ARICEPT. Use in patients with vascular dementia Mortality rates in ARICEPT vascular dementia clinical trials Study Placebo ARICEPT 5 mg p-valuex ARICEPT 10 mg p-valuex 307 3.5% (7/199) 1.0% (2/198) 0.17 2.4% (5/206) 0.57 308 0.5% (1/193) 1.9% (4/208) 0.37 1.4% (3/215) 0.62 319 0% (0/326) 1.7% (11/648) 0.02 * NA Combined 1.1% (8/718) 1.7% (25/1,475) 0.35 * No 10 mg ARICEPT treatment arm in Study 319. x p-values are for 5 mg donepezil vs. placebo and 10 mg donepezil vs. placebo. The majority of deaths in patients taking either ARICEPT or placebo appear to have resulted from various vascular-related causes, which may be expected in this elderly, fragile, population with comorbid vascular disease. In the 3 combined VaD clinical trials, there were similar proportions of patients with serious AEs in both treatment groups (approximately 15%), and similar proportions of patients with serious cardiovascular or cerebrovascular AEs (non-fatal and fatal, approximately 8%).The proportion of patients who had a fatal cardiovascular or cerebrovascular AE was numerically higher in the ARICEPT group than in the placebo group, but this difference was not statistically significant across the 3 trials. ADVERSE REACTIONS Mild-to-moderate Alzheimer’s disease The most common AEs leading to discontinuation, defined as those occurring in at least 2% of patients and at twice the incidence seen in placebo patients, are shown in Table 1. Table 1. Most frequent adverse events in patients with mild-to-moderate Alzheimer’s disease leading to withdrawal from controlled clinical trials by dose group Dose group Placebo 5 mg/day ARICEPT 10 mg/day ARICEPT Number of patients randomized 355 350 315 Events/% discontinuing Nausea 1% 1% 3% Diarrhea 0% <1% 3% Vomiting <1% <1% 2% An open-label study was conducted with 269 patients who received placebo in the 15- and 30-week studies.These patients received a 5 mg/day dose for 6 weeks prior to initiating treatment with 10 mg/day. The rates of common AEs were lower than those seen in controlled clinical trial patients who received 10 mg/day after only a 1-week initial treatment period with a 5 mg daily dose, and were comparable to the rates noted in patients treated only with 5 mg/day. See Table 2 for a comparison of the most common AEs following 1- and 6-week initial treatment periods with 5 mg/day ARICEPT. Table 2. Comparison of rates of adverse events in patients with mild-to-moderate Alzheimer’s disease treated with 10 mg/day after 1 and 6 weeks of initial treatment with 5 mg/day 1-week 6-week No initial treatment initial treatment initial treatment with 5 mg/day with 5 mg/day Adverse event Placebo 5 mg/day 10 mg/day 10 mg/day (n=315) (n=311) (n=315) (n=269) Nausea 6% 5% 19% 6% Diarrhea 5% 8% 15% 9% Insomnia 6% 6% 14% 6% Fatigue 3% 4% 8% 3% Vomiting 3% 3% 8% 5% Muscle cramps 2% 6% 8% 3% Anorexia 2% 3% 7% 3% The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behaviour, and the kinds of patients treated may differ. Table 3 lists treatment-emergent signs and symptoms (TESS) that were reported in at least 2% of patients from placebo-controlled clinical trials who received ARICEPT, and for which the rate of occurrence was greater for ARICEPT than placebo-assigned patients. In general, AEs occurred more frequently in female patients and with advancing age.

Table 3. Mild-to-moderate Alzheimer’s disease: Adverse events reported in controlled clinical trials in at least 2% of patients receiving ARICEPT and at a higher frequency than placebo-treated patients Body system/Adverse events Placebo n=355 ARICEPT n=747 Percent of patients with any adverse event 72 74 Body as a whole Headache 9 10 Pain, various locations 8 9 Accident 6 7 Fatigue 3 5 Cardiovascular system Syncope 1 2 Digestive system Nausea 6 11 Diarrhea 5 10 Vomiting 3 5 Anorexia 2 4 Hemic and lymphatic system Ecchymosis 3 4 Metabolic and nutritional Weight decrease 1 3 Musculoskeletal system Muscle cramps 2 6 Arthritis 1 2 Nervous system Insomnia 6 9 Dizziness 6 8 Depression <1 3 Abnormal dreams 0 3 Somnolence <1 2 Urogenital Frequent urination 1 2 Other adverse events observed during clinical trials in mild-to-moderate Alzheimer’s disease During the premarketing phase, ARICEPT has been administered to over 1,700 individuals with mild-to-moderate AD for various lengths of time during clinical trials worldwide. Approximately 1,200 patients have been treated for at least 3 months, and more than 1,000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months and 115 patients treated for over 1 year. The range of patient exposure is from 1 to 1,214 days. Treatment-emergent signs and symptoms that occurred during 3 placebo-controlled clinical trials and 2 open-label trials of patients with mild-to-moderate AD were recorded as AEs by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the studies were integrated and the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary and event frequencies were calculated across all studies.These categories are used in the listing below.The frequencies represent the proportion of 900 patients from these trials experiencing that event while receiving ARICEPT. All AEs occurring at least twice are included. AEs already listed in Tables 2 and 3 are not repeated here (i.e., events occurring at an incidence >2%). Also excluded are COSTART terms too general to be informative, or events less likely to be drug-caused. Events are classified by body system and listed as occurring in ≥1% and <2% of patients (i.e., in 1/100 to 2/100 patients: frequent) or in <1% of patients (i.e., in 1/100 to 1/1,000 patients: infrequent). These AEs are not necessarily related to ARICEPT treatment, and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a whole: (≥1% and <2%) influenza, chest pain, toothache; (<1%) fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, head pressure, listlessness. Cardiovascular system: (≥1% and <2%) hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; (<1%) angina pectoris, postural hypotension, myocardial infarction, premature ventricular contraction, arrhythmia, AV Block (1st degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thromboses. Digestive system: (≥1% and <2%) fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; (<1%) eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer. Endocrine system: (<1%) diabetes mellitus, goiter. Hemic & lymphatic system: (<1%) anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia. Nutritional disorders: (≥1% and <2%) dehydration; (<1%) gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase. Musculoskeletal system: (≥1% and <2%) bone fracture; (<1%) muscle weakness, muscle fasciculation. Nervous system: (≥1% and <2%) delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, libido increased, restlessness, abnormal crying, nervousness, aphasia; (<1%) cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing, seizures. Respiratory system: (≥1% and <2%) dyspnea, sore throat, bronchitis; (<1%) epistaxis, postnasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring. Skin and appendages: (≥1% and <2%) abrasion, pruritus, diaphoresis, urticaria; (<1%) dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer. Special senses: (≥1% and <2%) cataract, eye irritation, blurred vision; (<1%) dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes. Urogenital system: (≥1% and <2%) urinary incontinence, nocturia; (< 1%) dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis. Long-term safety for mild-to-moderate Alzheimer’s disease Patients were exposed to ARICEPT in 2 open-label extension mild-to-moderate AD studies (n=885) of over 2 years. In 1 of the studies, 763 patients who previously completed 1 of 2 placebo-controlled studies of 15 or 30 weeks duration continued to receive ARICEPT and were evaluated for safety and neuropsychological evaluations for up to 152 weeks; the safety profile of ARICEPT in this extension study remained consistent with that observed in placebo-controlled trials. Following 1 and 2 years of treatment, 76% (n=580) and 49% (n=374) of these patients, respectively, were still receiving therapy (cumulative weeks 48 and 108). Severe Alzheimer’s disease Table 4 lists treatment-emergent signs and symptoms (TESS) that were reported in at least 2% of patients from placebo-controlled clinical trials who received ARICEPT, and for which the rate of occurrence was greater for ARICEPT than placebo-assigned patients. Table 4. Severe Alzheimer’s disease: Adverse events reported in controlled clinical trials in at least 2% of patients receiving ARICEPT and at a higher frequency than placebo-treated patients Body system/Adverse events Placebo n=465 ARICEPT n=573 Percent of patients with any adverse event 74 81 Gastrointestinal Diarrhea 4 10 Vomiting 4 8 Nausea 3 6 Fecal incontinence 1 2 General Pyrexia 1 2 Chest pain 0 2 Infections and infestations Urinary tract infection 7 8 Nasopharyngitis 6 8 Pneumonia 3 4

Body system/Adverse events Placebo n=465 ARICEPT n=573 Percent of patients with any adverse event 74 81 Injury, poisoning, procedural complications Fall 9 10 Contusion 2 4 Skin laceration 1 2 Investigations Blood creatine phosphokinase increased 1 2 Metabolism and nutrition Anorexia 2 4 Decreased appetite 1 3 Dehydration 1 2 Musculoskeletal and connective tissue Back pain 2 3 Osteoarthritis 1 2 Nervous system Headache 3 5 Somnolence 0 2 Psychiatric Aggression 2 5 Insomnia 3 4 Restlessness 2 3 Hallucination 1 2 Confusional state 1 2 Renal and urinary Urinary incontinence 2 3 Respiratory Cough 1 2 Skin Eczema 1 2 Vascular Hypertension 1 2 A frequency of 0 has been used when frequencies were <0.5%. Other AEs that occurred with an incidence of at least 2% in ARICEPT-treated patients, and at an equal or lower rate than in placebotreated patients, included: abdominal pain, fatigue, gastroenteritis, excoriation, dizziness, anxiety and depression. Long-term safety for severe Alzheimer’s disease In Study 315, which was a 24-week, randomized, placebo-controlled study in severe AD patients, at the end of double-blind treatment, 229 patients entered open-label ARICEPT treatment for up to an additional 12 weeks. Therefore, at the end of the open-label phase, 111 patients had received up to 36 weeks of ARICEPT treatment and 118 patients had received up to 12 weeks of ARICEPT treatment. The most commonly affected body systems, types and frequencies of AEs reported during 12 weeks of open-label ARICEPT treatment were similar to what was observed during 24 weeks of double-blind treatment. Gastrointestinal AEs (diarrhea, nausea, vomiting, anorexia) were reported at a higher frequency in patients who received up to 12 weeks of ARICEPT treatment. Other AEs reported at higher frequencies in patients treated with ARICEPT for up to 12 weeks included infection, insomnia, pneumonia, fever, dizziness, hypertension, asthenia, tremor, pharyngitis, hallucinations, convulsions and cysts. In patients treated with ARICEPT for up to 36 weeks, accidental injury, urinary incontinence and urinary tract infections were reported at higher frequencies. DRUG INTERACTIONS Drug-drug interactions Drugs highly bound to plasma proteins: Drug displacement studies have been performed in vitro between donepezil, a highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. Donepezil at concentrations of 0.3-10 µg/mL did not affect the binding of furosemide (5 µg/mL), digoxin (2 ng/mL) and warfarin (3 µg/mL) to human albumin. Similarly, the binding of donepezil to human albumin was not affected by furosemide, digoxin and warfarin. Effect of ARICEPT on the metabolism of other drugs: In vitro studies show a low rate of donepezil binding to CYP 3A4 and CYP 2D6 isoenzymes (mean Ki about 50-130 µM), which, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interferences. In a pharmacokinetic study involving 18 healthy volunteers, the administration of ARICEPT at a dose of 5 mg/day for 7 days had no clinically significant effect on the pharmacokinetics of ketoconazole. No other clinical trials have been conducted to investigate the effect of ARICEPT on the clearance of drugs metabolized by CYP 3A4 (e.g., cisapride, terfenadine) or by CYP 2D6 (e.g., imipramine). It is not known whether ARICEPT has any potential for enzyme induction. Effect of other drugs on the metabolism of ARICEPT: Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. In a pharmacokinetic study, 18 healthy volunteers received 5 mg/day ARICEPT together with 200 mg/day ketoconazole for 7 days. In these volunteers, mean donepezil plasma concentrations were increased by about 30%-36%. Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin and phenobarbital) could increase the rate of elimination of ARICEPT. Pharmacokinetic studies demonstrated that the metabolism of ARICEPT is not significantly affected by concurrent administration of digoxin or cimetidine. Drug-food interactions Food does not have an influence on the rate and extent of donepezil hydrochloride absorption. Drug-herb interactions Interactions with herbal products have not been established. Drug-laboratory interactions Interactions with laboratory tests have not been established. SYMPTOMS AND TREATMENT OF OVERDOSE Symptoms: Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Treatment: The elimination half-life of ARICEPT (donepezil hydrochloride) at recommended doses is approximately 70 hours. Thus, in the case of overdose, it is anticipated that prolonged treatment and monitoring of adverse and toxic reactions will be necessary. As in any case of overdose, general supportive measures should be utilized. Tertiary anticholinergics, such as atropine, may be used as an antidote for ARICEPT overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response.Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether ARICEPT and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity observed in animals included: reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, fasciculation, and lower body surface temperature. Product Monograph available on request.

Buprenorphine transdermal delivery system

Prescribing Summary Patient Selection Criteria THERAPEUTIC CLASSIFICATION: !ENKNHQ(LMD=PJNF INDICATIONS AND CLINICAL USE Adults BuTrans- 2>CEIPLKIEGNLPQOIMLJHPIBMDQEMOFG3QNJ NLHNFMOPHQAKI7 OGPQBMLM=PBPLOQKAQEPIJNJOPLOQEMNLQKAQBKHPIMOPQNLOPLJNO?QNLQMHCDOJQIP'CNINL=QFKLONLCKCJ KENKNHQMLMD=PJNMQAKIQMLQP1OPLHPHQEPINKHQKAQONBP@Q Geriatrics (> 65 years of age): &LQ PDHPID?Q EMONPLOJ<Q BuTrans BM?Q GM;PQ MDOPIPH EGMIBMFK6NLPONFJQHCPQOKQEKKIQAMOQJOKIPJ<QBCJFDPQ:MJONL=QKIQMDOPIPHQFDPMIMLFPQ2JPPQDOSAGE AND ADMINISTRATION3@Q-GPIPAKIP<QNOQBM?Q>PQMEEIKEINMOP<QMFFKIHNL=QOKQFDNLNFMDQ CH=BPLO<QOK NLNONMOPQOGPJPQEMONPLOJQKLQOGPQDK:PJOQM;MNDM>DPQBuTrans JOIPL=OGQ:NOGQHKJPQONOIMONKLQOKQMFGNP;P JMONJAMFOKI?QEMNLQIPDNPAQ:NOGQMFFPEOM>DPQJNHPQPAAPFOJ@QPediatrics (< 18 years of age): -GP JMAPO?QMLHQPAANFMF?QKAQBuTrans GMJQLKOQ>PPLQJOCHNPHQNLQOGPQEPHNMOINFQEKECDMONKL@Q-GPIPAKIP<QCJP KAQBuTrans NJQLKOQNLHNFMOPHQNLQEMONPLOJQCLHPIQ9*Q?PMIJQKAQM=P@ CONTRAINDICATIONS: BuTrans- 2>CEIPLKIEGNLPQOIMLJHPIBMDQEMOFG3QNJQFKLOIMNLHNFMOPHQNL7 /MONPLOJQ :GKQ MIPQ G?EPIJPLJNON;PQ OKQ OGNJQ HIC=Q KIQ OKQ ML?Q NL=IPHNPLOQ NLQ OGPQ AKIBCDMONKLQ KI FKBEKLPLOQKAQOGPQFKLOMNLPI@Q KIQMQFKBEDPOPQDNJONL=QKAQP1FNENPLOJ<QJPPQOGPQDOSAGE FORMS< COMPOSITION AND PACKAGING JPFONKLQKAQOGPQ/IKHCFOQ KLK=IMEG5Q /MONPLOJQ:GKQGM;PQNDPCJQKAQML?QO?EP5 /MONPLOJQ:NOGQJCJEPFOPHQJCI=NFMDQM>HKBPLQ2P@=@<QMFCOPQMEEPLHNFNONJQKIQEMLFIPMONONJ35 /MONPLOJQ:NOGQBNDH<QNLOPIBNOOPLOQKIQJGKIOQHCIMONKLQEMNLQOGMOQFMLQKOGPI:NJPQ>PQBMLM=PH5 -GPQBMLM=PBPLOQKAQMFCOPQEMNL<QNLFDCHNL=QCJPQNLQKCO EMONPLOQKIQHM?QJCI=PINPJ5 -GPQ BMLM=PBPLOQ KAQ EPIN KEPIMON;PQ EMNLQ 2JPPQ WARNINGS AND PRECAUTIONS< Perioperative Considerations35 /MONPLOJQ:NOGQMFCOPQMJOGBMQKIQKOGPIQK>JOICFON;PQMNI:M?<QMLHQJOMOCJQMJOGBMONFCJ5 /MONPLOJQ:NOGQMFCOPQIPJENIMOKI?QHPEIPJJNKL<QPDP;MOPHQFMI>KLQHNK1NHPQDP;PDJQNLQOGPQ>DKKH<QMLH FKIQECDBKLMDP5 /MONPLOJQ:NOGQMFCOPQMDFKGKDNJBQKIQMDFKGKDQHPEPLHPLFP<QHPDNINCBQOIPBPLJ<QMLHQFKL;CDJN;P HNJKIHPIJ5 /MONPLOJQ:NOGQJP;PIPQ% "QHPEIPJJNKL<QNLFIPMJPHQFPIP>IKJENLMDQKIQNLOIMFIMLNMDQEIPJJCIP<QMLH GPMHQNL CI?5 /MONPLOJQOM6NL=QBKLKMBNLPQK1NHMJPQ2 (!3QNLGN>NOKIJQ2KIQ:NOGNLQ9.QHM?JQKAQJCFGQOGPIME?35 KBPLQHCINL=QEIP=LMLF?<QDM>KCIQMLHQHPDN;PI?QKIQ>IPMJO APPHNL=5Q !ENKNHQHPEPLHPLOQEMONPLOJQMLHQAKIQLMIFKONFQ:NOGHIM:MDQOIPMOBPLO5Q /MONPLOJQJCAAPINL=QAIKBQB?MJOGPLNMQ=IM;NJ5Q /MONPLOJQ:GKQGM;PQJP;PIPQGPEMONFQNLJCAANFNPLF?@

Safety Information WARNINGS AND PRECAUTIONS: PLPIMD BuTransâ&#x201E;˘ (buprenorphine transdermal patch) should ONLY be prescribed to patients who require continuous opioids for pain management. Initiation doses higher than the 5 mg patch should not be used in opioid naĂŻve patients (see DOSAGE AND ADMINISTRATION â&#x20AC;&#x201C; Patients Not Already Taking Opioids [Opioid NaĂŻve]). BuTrans is not indicated for use in children under 18 years of age, as dosage requirements for the safe and efficacious use of BuTrans have not been established for this patient population. BuTrans should only be prescribed by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of respiratory depression including the use of opioid antagonists. Since serum buprenorphine concentrations decline gradually after patch removal (approximately 50% in 12 hours [range 10-24 h]), patients who have experienced serious adverse events should be monitored for at least 24 hours after BuTrans removal or until the adverse reaction has subsided. Due to the formation of a subcutaneous depot of buprenorphine, not only does continued exposure occur after patch removal but, in the case of removal prior to attainment of peak buprenorphine exposure, buprenorphine plasma levels may continue to increase after removal of BuTrans patches. As with other CNS depressants, patients who have received BuTrans should be monitored especially for signs of respiratory depression until a stable maintenance dose is reached. BuTrans patches are intended for transdermal use on intact

Canadian Family Physician t Le MĂŠdecin de famille canadien

skin only; use on compromised skin can lead to increased exposure to buprenorphine. Placing BuTrans in the mouth, chewing it, swallowing it, or using it in any way other than indicated may cause choking or overdose that could result in death. /MONPLOJQJGKCDHQ>PQFMCONKLPHQLKOQOKQFKLJCBPQMDFKGKDQ:GNDPQCJNL=QBuTrans MJQNOQBM?QNLFIPMJPQOGP FGMLFPQKAQP1EPINPLFNL=QHML=PIKCJQJNHPQPAAPFOJ@Q NJ6QKAQ LNLOPLONKLMDQ&LFIPMJPQKAQ IC=Q 1EKJCIP Patients with Fever: (QEGMIBMFK6NLPONFQJOCH?QJGK:PHQLKQMDOPIMONKLQKAQ>CEIPLKIEGNLPQEDMJBM FKLFPLOIMONKLJQ NLQ JC> PFOJQ :NOGQ BNDHQ AP;PIQ NLHCFPHQ >?Q PLHKOK1NLQ MHBNLNJOIMONKL@Q K:P;PI< >PFMCJPQNLFIPMJPHQ>DKKHQADK:QOKQOGPQJ6NLQBM?QPLGMLFPQM>JKIEONKL<QEMONPLOJQ:NOGQJP;PIPQAP>INDP NDDLPJJQJGKCDHQ>PQBKLNOKIPHQAKIQJNHPQPAAPFOJQMLHQBM?QIP'CNIPQHKJPQMH CJOBPLO@QApplication of External Heat: GNDPQ:PMINL=QOGPQBuTrans OIMLJHPIBMDQEMOFG<QEMONPLOJQJGKCDHQ>PQMH;NJPHQOK M;KNHQP1EKJNL=QOGPQBuTrans JNOPQOKQP1OPILMDQGPMOQJKCIFPJ<QJCFGQMJQGPMONL=QEMHJ<QPDPFOINFQ>DML6POJ< GPMOPHQ:MOPIQ>PHJ<QGPMOQKIQOMLLNL=QDMBEJ<QGKOQ:MOPIQ>KOODPJ<QGKOQ>MOGJ<QJMCLMJ<QGKOQ:GNIDEKKD JEMQ>MOGJQMLHQJCL>MOGNL=<QMJQMLQNLFIPMJPQNLQM>JKIEONKLQKAQ>CEIPLKIEGNLPQBM?QKFFCIQMLHQIPJCDO NLQ JPINKCJQ BPHNFMDQ FKLJP'CPLFPJ@Q Accidental Exposure to BuTrans: "PINKCJQ BPHNFMD FKLJP'CPLFPJ<QNLFDCHNL=QHPMOG<QBM?QKFFCIQNAQEPKEDPQMIPQMFFNHPLOMDD?QP1EKJPHQOKQ>CEIPLKIEGNLP OIMLJHPIBMDQ EMOFG@Q 1MBEDPJQ KAQ MFFNHPLOMDQ P1EKJCIPQ NLFDCHPQ OIMLJAPIQ KAQ MQ >CEIPLKIEGNLP OIMLJHPIBMDQ EMOFGQ :GNDPQ GC==NL=<Q JGMINL=Q MQ >PH<Q KIQ BK;NL=Q MQ EMONPLO@ Acute Abdominal Conditions (JQ :NOGQ KOGPIQ KENKNHQ IPFPEOKIQ M=KLNJOJ<Q OGPQ MHBNLNJOIMONKLQ KAQ BuTrans BM? K>JFCIPQ OGPQ HNM=LKJNJQ KIQ FDNLNFMDQ FKCIJPQ NLQ EMONPLOJQ :NOGQ MFCOPQ M>HKBNLMDQ FKLHNONKLJ@ Cardiovascular Hypotensive Effects: BuTrans JGKCDHQ >PQ MHBNLNJOPIPHQ :NOGQ FMCONKLQ OK EMONPLOJQMOQINJ6QAKIQG?EKOPLJNKL@Q CEIPLKIEGNLP<QDN6PQKOGPIQKENKNHJ<QBM?QFMCJPQJP;PIPQG?EKOPLJNKL NLQ EMONPLOJQ :NOGQ HPEDPOPHQ >DKKHQ ;KDCBPQ KIQ MAOPIQ M=PLOJQ MFONL=Q KLQ ;MJKBKOKIQ OKLPQ JCFGQ MJ EGPLKOGNM,NLPJQKIQ=PLPIMDQMLPJOGPONFJ@Q/MONPLOJQIPFPN;NL=QBuTrans MJQOGPNIQANIJOQMIKCLH OGP FDKF6 KENKNHQBM?Q>PQMOQNLFIPMJPHQINJ6QKAQG?EKOPLJNKLQKIQKIOGKJOMONFQJ?LFKEP<QJNBNDMIQOKQOGMOQJPPLQ:NOG KOGPIQKENKNHJ@ Concomitant Use of CYP3A4 Inhibitors -GPQFKLFKBNOMLOQCJPQKAQBuTrans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oncomitant Use of CYP3A4 Inducers -GPQNLOPIMFONKLQ>PO:PPLQ>CEIPLKIEGNLPQMLHQ% /+(.QPL,?BPQNLHCFPIJQGMJQLKOQ>PPL JOCHNPH@Q %K MHBNLNJOIMONKLQ KAQ BuTrans MLHQ PL,?BPQ NLHCFPIJQ 2P@=@<Q EGPLK>MI>NOMD< FMI>MBM,PENLP<QEGPL?OKNL<QMLHQINAMBENL3QFKCDHQDPMHQOKQNLFIPMJPHQFDPMIMLFPQ:GNFGQBN=GOQIPJCDO NLQIPHCFPHQPAANFMF?@QDependence/Tolerance BuTrans can produce drug dependence of the opiate type. Diversion of buprenorphine has been reported. CEIPLKIEGNLPQNJQMQEMIONMDQ KENKNHQM=KLNJO@Q%GIKLNFQCJPQKAQ>CEIPLKIEGNLPQFMLQIPJCDOQNLQOGPQHP;PDKEBPLOQKAQMQDNBNOPHQHP=IPPQKA EG?JNFMDQHPEPLHPLFP@Q NOGHIM:MDQ2M>JONLPLFPQJ?LHIKBP3<QNJQ=PLPIMDD?QBNDH<Q>P=NLJQMAOPIQO:KQHM?J MLHQBM?QDMJOQCEQOKQO:KQ:PP6J@Q PEKIOJQKAQEG?JNFMDQHPEPLHPLFPQMLHQ:NOGHIM:MDQJ?LHIKBPQ:NOG BuTrans OIPMOBPLOQMIPQCLFKBBKL@ BuTrans JGKCDHQLKOQ>PQEIPJFIN>PHQAKIQEMONPLOJQ:NOGQ6LK:L EG?JNFMDQHPEPLHPLFPQKLQKOGPIQKENKNHJ@Q CPQOKQNOJQMLOM=KLNJOQFKBEKLPLOQBuTrans BM?QLKOQJC>JONOCOP AKIQKOGPIQKENKNHJQNLQJCFGQEMONPLOJ@Q%MCONKLQJGKCDHQ>PQP1PIFNJPHQ:GPLQEIPJFIN>NL=QBuTrans OKQEMONPLOJ 6LK:LQOKQGM;P<QKIQJCJEPFOPHQKAQGM;NL=<QEIK>DPBJQ:NOGQKOGPIQHIC=QKIQMDFKGKDQM>CJPQKIQJPINKCJQBPLOMD NDDLPJJ@ BuTrans GMJQ LKQ MEEIK;PHQ CJPQ NLQ OGPQ BMLM=PBPLOQ KAQ MHHNFON;PQ HNJKIHPIJ@Q (DD >CEIPLKIEGNLPQEIKHCFOJQGM;PQJKBPQEKOPLONMDQAKIQKENKNHQM>CJPQMLHQHPEPLHPLFP@Q K:P;PI<QIPEKIOJ KAQ M>CJPQ :NOGQ BuTrans MIPQ CLFKBBKL@Q -GPQ HP;PDKEBPLOQ KAQ MHHNFONKLQ OKQ KENKNHQ MLMD=PJNFJQ NL EIKEPID?QBMLM=PHQEMONPLOJQ:NOGQEMNLQGMJQ>PPLQIPEKIOPHQOKQ>PQCLFKBBKL<Q:GNFGQNJQFKLJNJOPLOQ:NOG OGPQFDNLNFMDQOINMDQIPJCDOJQMLHQEKJO BMI6PONL=QP1EPINPLFPQAKIQBuTrans@Q%MIPACDQ IPFKIH 6PPENL=Q KA EIPJFIN>NL=QNLAKIBMONKL<QNLFDCHNL=Q'CMLONO?<QAIP'CPLF?<QMLHQIPLP:MDQIP'CPJOJQNJQJOIKL=D?QMH;NJPH@ /MONPLOJQ JGKCDHQ >PQ MH;NJPHQ OKQ EIKEPID?Q JOKIPQ MLHQ HNJEKJPQ KAQ OGPQ EIKHCFO@ Hepatic/Biliary/Pancreatic PFMCJPQ>CEIPLKIEGNLPQNJQP1OPLJN;PD?QBPOM>KDN,PHQ>?QOGPQDN;PI< OGPQMFON;NO?QKAQBuTrans BM?Q>PQNLFIPMJPHQMLH8KIQP1OPLHPHQNLQOGKJPQNLHN;NHCMDJQ:NOGQNBEMNIPH GPEMONFQACLFONKLQKIQOGKJPQIPFPN;NL=QKOGPIQM=PLOJQ6LK:LQOKQHPFIPMJPQGPEMONFQFDPMIMLFP@Q/MONPLOJ :NOGQJP;PIPQGPEMONFQNBEMNIBPLOQBM?QMFFCBCDMOPQ>CEIPLKIEGNLPQHCINL=QBuTrans OIPMOBPLO@ %KLJNHPIMONKLQKAQMDOPILMOPQOGPIME?QJGKCDHQ>PQ=N;PL<QMLHQBuTrans JGKCDHQLKOQ>PQCJPHQNLQJCFG EMONPLOJQ2JPPQSpecial Populations5QHepatic Impairment3@Q CEIPLKIEGNLPQGMJQ>PPLQJGK:LQOK NLFIPMJPQNLOIMFGKDPHKFGMDQEIPJJCIP<QMJQHKQKOGPIQKENKNHJ<QMLHQFMCJPQJEMJBQKAQOGPQ"EGNLFOPIQKA !HHNQMLHQJGKCDHQ>PQCJPHQ:NOGQFMCONKLQNLQEMONPLOJQ:NOGQ>NDNMI?QOIMFOQHNJPMJP<QNLFDCHNL=QMFCOP EMLFIPMONONJ@Q!ENKNHJQBM?QMDJKQFMCJPQMLQNLFIPMJPQNLQJPICBQMB?DMJPQFKLFPLOIMONKL@QImmune Allergic Reactions: %MJPJQKAQMFCOPQMLHQFGIKLNFQG?EPIJPLJNON;NO?QOKQ>CEIPLKIEGNLPQGM;PQ>PPL IPEKIOPHQNLQFDNLNFMDQOINMDJQNLQKOGPIQ>CEIPLKIEGNLPQBMI6POPHQEIKHCFOJ@Q-GPQBKJOQFKBBKLQJN=LJ MLHQJ?BEOKBJQNLFDCHPQIMJGPJ<QGN;PJQMLHQEICINOCJ@Q%MJPJQKAQ>IKLFGKJEMJB<QML=NKLPCIKONFQPHPBM MLHQMLMEG?DMFONFQJGKF6QGM;PQ>PPLQIPEKIOPH@Q(QGNJOKI?QKAQG?EPIJPLJNON;NO?QOKQ>CEIPLKIEGNLPQKI ML?QFKBEKLPLOQKAQOGPQAKIBCDMONKLQNJQMQFKLOIMNLHNFMONKLQOKQBuTrans CJP@QNeurologic Interaction with Other Central Nervous System Depressants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ead Injury and Increased Intracranial Pressure: BuTrans JGKCDH

| VOL 57: JANUARY t JANVIER 2011

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piate Withdrawal Effects Buprenorphine is a partial agonist at the µ-opioid receptor and chronic administration produces dependence of the opiate type, characterized by withdrawal upon abrupt discontinuation or rapid taper. The withdrawal syndrome is generally milder than seen with full agonists and may be delayed in onset. Peri-operative Considerations BuTrans NJQFKLOIMNLHNFMOPHQAKIQEPIN KEPIMON;PQEMNLQIPDNPA@Q&LQOGP FMJPQKAQEDMLLPHQFGKIHKOKB?QKIQKOGPIQEMNL IPDNP;NL=QKEPIMONKLJ<QEMONPLOJQJGKCDHQLKOQ>PQOIPMOPHQ:NOG BuTrans AKIQ MOQ DPMJOQ .*Q GKCIJQ >PAKIPQ OGPQ KEPIMONKLQ MLHQ BuTrans JGKCDHQ LKOQ >PQ CJPHQ NLQ OGP NBBPHNMOPQEKJO KEPIMON;PQEPINKH@Q-GPIPMAOPIQNAQBuTrans NJQOKQ>PQFKLONLCPHQMAOPIQOGPQEMONPLOQIPFK;PIJ AIKBQ OGPQ EKJO KEPIMON;PQ EPINKH<Q MQ LP:Q HKJM=PQ JGKCDHQ >PQ MHBNLNJOPIPHQ NLQ MFFKIHMLFPQ :NOGQ OGP FGML=PHQLPPHQAKIQEMNLQIPDNPA@Q-GPQINJ6QKAQ:NOGHIM:MDQNLQKENKNH OKDPIMLOQEMONPLOJQJGKCDHQ>PQMHHIPJJPH MJQFDNLNFMDD?QNLHNFMOPHQ2JPPQOpiate Withdrawal Effects3@ -GPQMHBNLNJOIMONKLQKAQMLMD=PJNFJQNLQOGP EPIN KEPIMON;PQEPINKHQJGKCDHQ>PQBMLM=PHQ>?QGPMDOGFMIPQEIK;NHPIJQ:NOGQMHP'CMOPQOIMNLNL=QMLH P1EPINPLFPQ2P@=@<Q>?QMLQMLPJOGPJNKDK=NJO3Q2JPPQCONTRAINDICATIONS3@QPotential for Abuse and Diversion BuTrans EMOFGPJQFKLOMNLQMQDMI=PQMBKCLOQKAQMQEKOPLOQKENKNH<Q>CEIPLKIEGNLP<Q:GNFG MDKL=Q:NOGQKOGPIQKENKNHJQGMJQEKOPLONMDQAKIQM>CJPQMLHQMJJKFNMOPHQINJ6QKAQAMOMDQK;PIHKJPQHCPQOK IPJENIMOKI?QHPEIPJJNKL@Q-GPQGN=GQ>CEIPLKIEGNLPQFKLOPLOQNLQBuTrans EMOFGPJQBM?Q>PQMQOMI=POQAKI M>CJPQMLHQHN;PIJNKL<Q:NOGQMDOPILMON;PQIKCOPJQKAQMHBNLNJOIMONKLQEKOPLONMDD?QIPJCDONL=QNLQK;PIHKJPQHCP OKQ CLFKLOIKDDPHQ HPDN;PI?Q KAQ OGPQ KENKNH@Q -GNJQ INJ6Q JGKCDHQ >PQ FKLJNHPIPHQ :GPLQ EIPJFIN>NL=Q KI HNJEPLJNL=QBuTrans NLQJNOCMONKLJQ:GPIPQOGPQGPMDOGFMIPQEIKAPJJNKLMDQNJQFKLFPILPHQM>KCOQNLFIPMJPH INJ6QKAQBNJCJP<QM>CJPQKIQHN;PIJNKL@Q%KLFPILJQM>KCOQM>CJP<QMHHNFONKLQMLHQHN;PIJNKLQJGKCDHQLKO EIP;PLOQOGPQEIKEPIQBMLM=PBPLOQKAQEMNL@Q/MONPLOJQJGKCDHQ>PQMJJPJJPHQAKIQOGPNIQFDNLNFMDQINJ6JQAKI KENKNHQM>CJPQKIQMHHNFONKLQEINKIQOKQ>PNL=QEIPJFIN>PHQKENKNHJ@Q(DDQEMONPLOJQIPFPN;NL=QKENKNHJQJGKCDHQ>P IKCONLPD?QBKLNOKIPHQAKIQJN=LJQKAQBNJCJPQMLHQM>CJP@Q"NLFPQBuTransBM?Q>PQHN;PIOPHQAKIQLKL BPHNFMD CJP<QFMIPACDQIPFKIHQ6PPENL=QKAQEIPJFIN>NL=QNLAKIBMONKL<QNLFDCHNL=Q'CMLONO?<QAIP'CPLF?<QMLHQIPLP:MD IP'CPJOJQ NJQ JOIKL=D?Q MH;NJPH@Q /IKEPIQ MJJPJJBPLOQ KAQ OGPQ EMONPLO<Q EIKEPIQ EIPJFIN>NL=Q EIMFONFPJ< EPINKHNFQIP P;MDCMONKLQKAQOGPIME?<QMLHQEIKEPIQHNJEPLJNL=QMLHQJOKIM=PQMIPQMEEIKEINMOPQBPMJCIPJ OGMOQ GPDEQ OKQ DNBNOQ M>CJPQ KAQ KENKNHQ HIC=JQ 2JPPQ Dependence/Tolerance3@Q Psychomotor Impairment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uTrans JGKCDHQLKOQHIN;PQKIQKEPIMOP HML=PIKCJQBMFGNLPI?QCLDPJJQOGP?QMIPQOKDPIMLOQOKQOGPQPAAPFOJQKAQOGPQHIC=@QRespiratory Depression (JQ :NOGQ KOGPIQ EKOPLOQ KENKNHJ<Q FDNLNFMDD?Q JN=LNANFMLOQ IPJENIMOKI?Q HPEIPJJNKLQ BM?Q KFFCIQ NLQ EMONPLOJ IPFPN;NL=Q>CEIPLKIEGNLP@Q"KBPQFMJPJQKAQHPMOGQHCPQOKQIPJENIMOKI?QHPEIPJJNKLQGM;PQ>PPLQIPEKIOPH< EMIONFCDMID?Q:GPLQMHHNFOJQGM;PQNLOIM;PLKCJD?QM>CJPHQ>CEIPLKIEGNLP<QCJCMDD?QNLQFKB>NLMONKLQ:NOG >PL,KHNM,PENLPJ<QKIQ:NOGQFKLFKBNOMLOQMHBNLNJOIMONKLQKAQ>CEIPLKIEGNLPQ:NOGQKOGPIQHPEIPJJMLOJQJCFG MJQMDFKGKDQKIQKOGPIQKENKNHJ@Q!ENKNHJ<QNLFDCHNL=Q>CEIPLKIEGNLP<QJGKCDHQ>PQCJPHQ:NOGQFMCONKLQNLQEMONPLOJ :NOGQFKBEIKBNJPHQIPJENIMOKI?QACLFONKLQ2P@=@<QFGIKLNFQK>JOICFON;PQECDBKLMI?QHNJPMJP<QFKIQECDBKLMDP< HPFIPMJPHQIPJENIMOKI?QIPJPI;P<QG?EK1NM<QG?EPIFMELNMQKIQEIP P1NJONL=QIPJENIMOKI?QHPEIPJJNKL3<QNLQOGP PDHPID?QMLHQNLQHP>NDNOMOPHQEMONPLOJ@Q/MIONFCDMIQFMCONKLQNJQMH;NJPHQNAQBuTrans NJQOKQ>PQMHBNLNJOPIPHQOK EMONPLOJQOM6NL=<QKIQIPFPLOD?QIPFPN;NL=<QHIC=JQ:NOGQ% "8IPJENIMOKI?QHPEIPJJMLOQPAAPFOJ@ IN THE CASE OF OVERDOSE, THE PRIMARY MANAGEMENT SHOULD BE THE REESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OF RESPIRATION, IF REQUIRED. NALOXONE MAY NOT BE EFFECTIVE IN REVERSING ANY RESPIRATORY DEPRESSION PRODUCED BY BUPRENORPHINE (see OVERDOSAGE). PJENIMOKI?QHPEIPJJNKLQNJQMQINJ6QKAQJOMIONL= KENKNHQM=KLNJOQBPHNFMONKLJ<QPJEPFNMDD?QNLQPDHPID?<QHP>NDNOMOPHQEMONPLOJ@Q PJENIMOKI?QHPEIPJJNKLQCJCMDD? AKDDK:JQDMI=PQNLNONMDQHKJPJQNLQLKL OKDPIMLOQEMONPLOJ<QKIQ:GPLQKENKNHJQMIPQ=N;PLQNLQFKL CLFONKLQ:NOGQKOGPI M=PLOJQOGMOQHPEIPJJQIPJENIMONKL@Q (DOGKC=GQBuTransNJQMQEMIONMDQKENKNHQM=KLNJO<Q>CEIPLKIEGNLPQBM?QFMCJP G?EK;PLONDMONKLQMOQMLMD=PJNFQHKJPJ<QPJEPFNMDD?QNLQEMONPLOJQ:GKQGM;PQMLQCLHPID?NL=QECDBKLMI?QFKLHNONKLQKI :GKQIPFPN;PQCJCMDQHKJPJQKAQKENKNHJQKIQKOGPIQ% "QHIC=JQMJJKFNMOPHQ:NOGQG?EK;PLONDMONKLQNLQMHHNONKLQOK BuTrans 2JPPQ DRUG INTERACTIONS IP=MIHNL=Q OGPQ CJPQ KAQ FKLFKBNOMLOQ % "Q MFON;PQ HIC=J3@ %KBEMIMON;PQPAAPFOJQKAQBuTrans GM;PQLKOQ>PPLQP;MDCMOPH<Q>COQNLQFDNLNFMDQOINMDJQ2CEQOKQHKJPJQKA BuTrans .4QBF=8GI3<QIPJENIMOKI?QAMNDCIPQ:MJQIPEKIOPHQMJQMQIMIPQMH;PIJPQP;PLOQ2N@P@<Q 4@9 <Q>COQMO DPMJOQ NLQ BKIPQ OGMLQ 9Q EMONPLOQ JPPQ ADVERSE REACTIONS 3@Q &AQ IPJENIMOKI?Q HPEIPJJNKLQ AIKB BuTrans KFFCIJ<QNOQBM?QEPIJNJOQ>P?KLHQOGPQIPBK;MDQKAQOGPQEMOFG@Q/MONPLOJQ:NOGQG?EK;PLONDMONKL JGKCDHQ>PQK>JPI;PHQAKIQMOQDPMJOQJP;PIMDQGKCIJQMLHQCLONDQOGPNIQIPJENIMOKI?QIMOPQGMJQIPFK;PIPH@Q&L EMONPLOJQ:NOGQIPJENIMOKI?QHPEIPJJNKL<QJ?BEOKBMONFQOIPMOBPLOQAKDDK:NL=QJOMLHMIHQNLOPLJN;PQFMIP BPMJCIPJQJGKCDHQ>PQNLJONOCOPHQ2JPPQOVERDOSAGE3@QUse in Patients with Chronic Pulmonary Disease: CEIPLKIEGNLPQJGKCDHQ>PQCJPHQ:NOGQFMCONKLQNLQEMONPLOJQ:NOGQFGIKLNFQECDBKLMI?QHNJPMJP< EMONPLOJQ:NOGQHPFIPMJPHQIPJENIMOKI?QIPJPI;PQMLHQKOGPIJQ:NOGQEKOPLONMDD?QFKBEIKBNJPHQIPJENIMONKL@ KIBMDQMLMD=PJNFQHKJPJQKAQKENKNHJQBM?QACIOGPIQHPFIPMJPQIPJENIMOKI?QHIN;PQNLQOGPJPQEMONPLOJQOKQOGP EKNLOQKAQIPJENIMOKI?QAMNDCIP@Q

Special Populations Special Risk Groups: JPQ KAQ BuTrans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regnant Women: -GPIPQMIPQLKQHMOMQAIKBQOGPQCJPQKAQBuTrans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uTrans JGKCDHQLKOQ>PQCJPHQHCINL=QEIP=LMLF?QKIQNL :KBPLQ KAQ FGNDH>PMINL=Q EKOPLONMDQ :GKQ MIPQ LKOQ CJNL=Q PAAPFON;PQ FKLOIMFPEONKL@ Labour and Delivery: -GPQJMAPO?QKAQBuTrans =N;PLQHCINL=QDM>KCIQMLHQHPDN;PI?QGMJQLKOQ>PPLQPJOM>DNJGPH@ Nursing Women: CEIPLKIEGNLPQGMJQ>PPLQHPOPFOPHQNLQDK:QFKLFPLOIMONKLJQNLQGCBMLQBND6<QOGCJ LCIJNL=Q BKOGPIJQ OIPMOPHQ :NOGQ BuTrans JGKCDHQ LKOQ >IPMJO APPHQ KIQ OGPQ CJPQ KAQ BuTrans HCINL= DMFOMONKLQJGKCDHQ>PQM;KNHPH@QGender: KQHNAAPIPLFPJQNLQEDMJBMQ>CEIPLKIEGNLPQFKLFPLOIMONKLJ :PIPQHPOPFOPHQ>PO:PPLQBMDPJQMLHQAPBMDPJQOIPMOPHQ:NOGQBuTrans@QGeriatrics (> 65 years of age): -GPQEGMIBMFK6NLPONFQEIKANDPQKAQBuTrans NJQJNBNDMIQNLQGPMDOG?QPDHPID?QMLHQ?KCL=PIQMHCDO JC> PFOJ@Q DHPID?Q JC> PFOJQ OIPLHPHQ OK:MIHQ GN=GPIQ EDMJBMQ FKLFPLOIMONKLJQ KAQ >CEIPLKIEGNLP NBBPHNMOPD?QMAOPIQIPBK;MDQKAQBuTrans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ediatrics (< 18 years of age): BuTrans GMJQLKOQ>PPLQJOCHNPHQNLQFGNDHIPLQMLHQNJQLKOQNLHNFMOPH AKIQEMONPLOJQDPJJQOGMLQ9*Q?PMIJQKAQM=P@Q-GPQJMAPO?QMLHQPAANFMF?QKAQBuTrans NLQFGNDHIPLQGM;PQLKOQ>PPL PJOM>DNJGPH@ Renal Impairment: (QEGMIBMFK6NLPONFQJOCH?QJGK:PHQOGMOQEGMIBMFK6NLPONFQEMIMBPOPIJ AKIQ>CEIPLKIEGNLPQ:PIPQJNBNDMIQNLQEMONPLOJQ:NOGQJP;PIPQIPLMDQNBEMNIBPLOQFKBEMIPHQ:NOGQLKIBMDQMHCDOJ@ -GNJQJOCH?QFKLANIBPHQ:NOGQBCDONEDP HKJPQCJP<QOGMOQOGPQMFFCBCDMONKLQKAQ>CEIPLKIEGNLPQBPOM>KDNOPJQHNH LKOQHPFIPMJPQOGPQFDPMIMLFPQKAQOGPQEMIPLOQBKDPFCDPQNLQFGIKLNFQCJP@Q-GPIPAKIP<QLKQJEPFNMDQHKJPQMH CJOBPLO KAQ >CEIPLKIEGNLPQ NJQ LPFPJJMI?Q NLQ EMONPLOJQ :NOGQ IPLMDQ NBEMNIBPLO@ Hepatic Impairment: &LQ M EGMIBMFK6NLPONFQJOCH?QCONDN,NL=QNLOIM;PLKCJQ>CEIPLKIEGNLP<QOGPIPQ:PIPQLKQHNAAPIPLFPJQNLQFDPMIMLFP KAQ>CEIPLKIEGNLPQ>PO:PPLQBNDHQOKQBKHPIMOPQGPEMONFMDD?QNBEMNIPHQJC> PFOJQIPDMON;PQOKQGPMDOG?QMHCDO JC> PFOJ@Q-GPJPQHMOMQJGK:QLKQLPPHQAKIQHKJM=PQMH CJOBPLOQ:GPLQCJNL=QBuTrans NLQEMONPLOJQ:NOGQBNDH OKQ BKHPIMOPQ GPEMONFQ NBEMNIBPLO@ /MONPLOJQ :NOGQ JP;PIPQ GPEMONFQ NBEMNIBPLOQ BM?Q MFFCBCDMOP >CEIPLKIEGNLPQHCINL=QBuTrans OIPMOBPLO@Q%KLJNHPIMONKLQKAQMDOPILMOPQOGPIME?QJGKCDHQ>PQ=N;PL< MLHQBuTrans JGKCDHQLKOQ>PQCJPHQNLQJCFGQEMONPLOJ@Q ADVERSE REACTIONS Adverse Drug Reaction Overview "PINKCJQMH;PIJPQHIC=QIPMFONKLJ :GNFGQBM?Q>PQMJJKFNMOPHQ:NOGQBuTrans- 2>CEIPLKIEGNLPQOIMLJHPIBMDQEMOFG3QOGPIME?QNLQFDNLNFMDQCJP MIPQOGKJPQK>JPI;PHQ:NOGQKOGPIQKENKNHQMLMD=PJNFJ<QNLFDCHNL=QIPJENIMOKI?QHPEIPJJNKLQ2PJEPFNMDD?Q:GPL CJPHQ:NOGQKOGPIQ% "QHPEIPJJMLOJ3QMLHQG?EKOPLJNKL@Q%MIPQBCJOQ>PQP1PIFNJPHQ:GPLQCJNL=QBuTrans NLQEMONPLOJQ:GKQMIPQCJNL=Q>PL,KHNM,PENLPJQKIQKOGPIQM=PLOJQ:NOGQ% "QMFON;NO?@Q-GPQMH;PIJPQHIC= IPMFONKLJQJPPLQKLQNLNONMONKLQKAQOGPIME?Q:NOGQBuTrans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uTrans :PIPQMLKIP1NM<QMEEDNFMONKL JNOPQPI?OGPBM<QMEEDNFMONKLQJNOPQEICINOCJ<QMJOGPLNM<QFKLJONEMONKL<QHN,,NLPJJ<QHI?QBKCOG<QGPMHMFGP< G?EPIGNHIKJNJ<QNLJKBLNM<QLMCJPM<QJKBLKDPLFPQMLHQ;KBNONL=@Q!ENKNH M=KLNJOQIPDMOPHQMH;PIJPQP;PLOJ OPLHQOKQIPHCFPQK;PIQONBP<QP1FPEOQAKIQFKLJONEMONKL@QClinical Trial Adverse Drug Reactions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dverse events ≥ 1% for parallel-design titration-to-effect clinical trials Q KAQ EMONPLOJQ KLQ C-IMLJ- Q 2L + 038Q Q KAQ EMONPLOJQ KLQ EDMFP>KQ 2L 0#937Q Ear and labyrinth disorders: ONLLNOCJ7Q9@+84@.@QEye disorders: ;NJNKLQ>DCIIPH7Q9@)84@.@QGastrointestinal disorders: FKLJONEMONKL7Q9+@)8)@.5QHNMIIGPM7Q+@989@ 5QHI?QBKCOG7Q$@989@)5QLMCJPM7Q00@$8$@$5QJOKBMFGQHNJFKBAKIO7 0@489@95Q;KBNONL=7Q99@089@)@QGeneral disorders and administration site conditions: MEEDNFMONKL

VOL 57: JANUARY t JANVIER 2011

| Canadian Family Physician

Le Médecin de famille canadien

JNOPQPI?OGPBM7Q$@989@)5QMEEDNFMONKLQJNOPQEMNL7Q9@)84@*5QMEEDNFMONKLQJNOPQEICINOCJ7Q9)@9899@ 5QMEEDNFMONKL JNOPQ;PJNFDPJ7Q9@4845QMJOGPLNM7Q9@+89@95QAMON=CP7Q)@989@95QEMNL7Q9@)8Q9@)5QEPINEGPIMDQPHPBM7Q$@.8+@.5 E?IP1NM7Q9@)84@.@QInfections and infestations: NLADCPL,M7Q9@+84@.5QJNLCJNONJ7Q9@484@.5QCINLMI?QOIMFO NLAPFONKL7Q0@#80@+@QInjury, poisoning and procedural complications: AMDD7Q+@*89@)5QJ6NLQDMFPIMONKL7 9@+89@9@QInvestigations: >DKKHQEIPJJCIPQNLFIPMJPH7Q9@484@.@QMetabolism and nutrition disorders: MLKIP1NM7Q0@484@*@QMusculoskeletal and connective tissue disorders: MIOGIMD=NM7Q0@489@ 5Q>MF6 EMNL7Q0@#89@)5Q KNLOQJ:PDDNL=7Q0@#84@*5QBCJFDPQJEMJBJ7Q9@+84@*5QBCJFCDMIQ:PM6LPJJ7Q9@484@.5QEMNLQNL P1OIPBNO?7Q 0@*80@+@Q Nervous system disorders: HN,,NLPJJ7Q 9#@+8$@$5Q GPMHMFGP7Q 9#@9899@)5 G?EKPJOGPJNM7Q 0@+84@*5Q BN=IMNLP7Q 9@484@*5Q EMIMPJOGPJNM7Q 0@484@*5Q OIPBKI7Q 0@484@.5Q JKBLKDPLFP7 9+@)8.@#@Q Psychiatric disorders: M=NOMONKL7Q 9@484@45Q ML1NPO?7Q 9@*84@*5Q HPEIPJJNKL7Q 9@+84@*5 HNJKINPLOMONKL7Q 9@484@.5Q NLJKBLNM7Q 0@*89@ 5Q LPI;KCJLPJJ7Q 9@484@.@Q Respiratory, thoracic and mediastinal disorders: FKC=G7Q 9@+84@.5Q H?JELPM7Q 0@*89@9@Q Skin and subcutaneous tissue disorders: G?EPIGNHIKJNJ7Q.@+89@95QEICINOCJ7Q.@984@*5QEICINOCJQ=PLPIMDN,PH7Q9@)84@*5QIMJG7Q0@489@9@ Adverse events â&#x2030;Ľ1% for crossover-design titration-to-effect clinical trials QKAQEMONPLOJQKLQ C-IMLJ- Q2L Q9.#38Q QKAQEMONPLOJQKLQEDMFP>KQ2L 9++37QCardiac disorders: EMDENOMONKLJ7Q +@.84@*@Q Ear and labyrinth disorders7Q ONLLNOCJ7Q 9@.845Q ;PION=K7Q 9@.84@ Gastrointestinal disorders: M>HKBNLMDQEMNLQCEEPI7Q+@.80@+5QFKLJONEMONKL7Q09@ 8Q9+@)5QHI?QBKCOG7 94@+89@)5Q =MJOIKPJKEGM=PMDQ IPADC1Q HNJPMJP7Q 9@.84@45Q LMCJPM7Q .)@ 89*@45Q ;KBNONL=7Q 9*@)8.@)@ General disorders and administration site conditions: MEEDNFMONKLQ JNOPQ >ICNJNL=7Q 9@.845 MEEDNFMONKLQJNOPQEMNL7Q0@989@)5QMEEDNFMONKLQJNOPQEICINOCJ7Q0)@+80.@*5QQMEEDNFMONKLQJNOPQIMJG7Q+@.8+@45 MJOGPLNM7Q 90@+8*@+5Q AMON=CP7Q @#8+@45Q NLADCPL,M DN6PQ NDDLPJJ7Q 0@9845Q EPINEGPIMDQ PHPBM7Q *@ 84@ Immune system disorders7QCIONFMINM7Q9@.84@QInfections and infestations: NLADCPL,M7Q0@989@)5 CINLMI?Q OIMFOQ NLAPFONKL7Q 0@984@Q Metabolism and nutrition disorders: MLKIP1NM7Q 9+@4899@ Musculoskeletal and connective tissue disorders: CJFCDKJ6PDPOMDQJONAALPJJ7Q9@.84@*5QB?MD=NM7 0@984@Q Nervous system disorders: dizziness: 0$@.8Q #@45Q GPMHMFGP7Q 99@#8#@45Q BN=IMNLP7 0@$89@)5Q EMIMPJOGPJNM7Q 9@.84@*5Q JKBLKDPLFP7Q 0.@48#@45Q OIPBKI7Q .@980@Q Psychiatric disorders: M=NOMONKL7Q 0@$89@)5Q ML1NPO?7Q 0@984@*5Q LN=GOBMIP7Q 9@.84@*@Q Skin and subcutaneous tissue disorders: PI?OGPBM7Q 9@.845Q G?EPIGNHIKJNJ7Q 9#@.8 @45Q EICINOCJ7Q 9@.84@Q Surgical and medical procedures: PLHKHKLONFQEIKFPHCIP7Q9@.84@QVascular disorders: GKOQADCJG7Q.@989@)@ Adverse events â&#x2030;Ľ 1% for patients shown to be tolerant and responsive to a BuTransâ&#x201E;˘ (5 â&#x20AC;&#x201C; 20 mcg/h) patch during a run-in period of 3 weeks maximum, prior to randomization Q KAQ EMONPLOJQ KLQ BuTransâ&#x201E;˘ 2L 9#.38Q Q KAQ EMONPLOJQ KLQ EDMFP>KQ 2L 9#037Q Gastrointestinal disorders: M>HKBNLMDQ EMNL5Q 9@0845Q FKLJONEMONKL7Q $@98)@0Q HNMIIGPM79@)8Q 9@)5Q HI?Q BKCOG7Q 0@*80@9 LMCJPM7Q *@ 8*@ 5Q ;KBNONL=7Q 0@984@ @Q General disorders and administration site conditions: MEEDNFMONKLQJNOPQPI?OGPBM7Q+@989@)5QMEEDNFMONKLQJNOPQEICINOCJ7Q.@#8+@.5QMEEDNFMONKLQJNOPQIMJG7Q0@984@#5 AMON=CP7Q0@)89@)5QEPINEGPIMDQPHPBM7Q+@.84@#@QInfections and infestations: CINLMI?QOIMFOQNLAPFONKL7 9@084@+@QMusculoskeletal and connective tissue disorders: >MF6QEMNL7Q0@)80@95QEMNLQNLQP1OIPBNO?7 9@089@0@QNervous system disorders: HN,,NLPJJ7Q#@98+@$@QPsychiatric disorders: ML1NPO?5Q9@084@+@ &LQ FDNLNFMDQ OINMDJQ NLQ :GNFGQ BuTrans :MJQ FKBEMIPHQ OKQ MFON;PQ FKLOIKDJ<Q P1EPFOPHQ KENKNHQ PAAPFOJ 2LMCJPM<Q;KBNONL=<QHI?QBKCOG<QEICINOCJ<QHN,,NLPJJ<QJKBLKDPLFP3<QKLQNLNONMONKLQKAQOGPIME?QNLQLKL OKDPIMLOQNLHN;NHCMDJ<QIPMFGPHQOGPNIQBM1NBCBQ9Q Q0QHM?JQMAOPIQBuTrans MEEDNFMONKLQMLHQCJCMDD? HPFIPMJPHQ:NOGQFKLONLCPHQCJP@Q Less Common Clinical Trial Adverse Drug Reactions (< 1%): !OGPIQDPJJQFKBBKLQ2 Q9 3 MH;PIJPQHIC=QIPMFONKLJQIPEKIOPHQMLHQFKLJNHPIPHQNLQML?Q:M?QIPDMOPHQOKQBuTrans- NLQIMLHKBN,PH FDNLNFMDQOINMDJQMIPQJCBBMIN,PHQNLQOGPQ/IKHCFOQ KLK=IMEGQ2see Adverse Reactions section in the Product Monograph3@ DRUG INTERACTIONS Overview Additive Effects of Other CNS Depressants: BuTrans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eurologic â&#x20AC;&#x201C; Interaction with Other Central Nervous System Depressants3@Q/MONPLOJQJGKCDHQMDJKQ>PQ:MILPHQOGMOQOGPJP FKB>NLMONKLJQ NLFIPMJPQ FPLOIMDQ LPI;KCJQ J?JOPBQ HPEIPJJNKLQ MLHQ FMLQ BM6PQ HIN;NL=Q ;PGNFDPJQ MLH KEPIMONL=Q BMFGNLPI?Q GM,MIHKCJQ 2JPPQ WARNINGS AND PRECAUTIONS<Q Psychomotor Impairment3@Q Drug-Drug Interactions CYP 3A4 Inhibitors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oncomitant Use of CYP3A4 Inhibitors3@Q -GPQ NLOPIMFONKLQ >PO:PPLQ >CEIPLKIEGNLPQ MLHQ % /+(.Q PL,?BP NLHCFPIJQ GMJQ LKOQ >PPLQ JOCHNPH@Q %K MHBNLNJOIMONKLQ KAQ BuTrans MLHQ PL,?BPQ NLHCFPIJQ 2P@=@< EGPLK>MI>NOMD<QFMI>MBM,PENLP<QEGPL?OKNL<QMLHQINAMBENL3QFKCDHQDPMHQOKQNLFIPMJPHQFDPMIMLFPQ:GNFG BN=GOQIPJCDOQNLQIPHCFPHQPAANFMF?@QMAO Inhibitors: (!QNLGN>NOKIJQNLOPLJNA?QOGPQPAAPFOJQKAQKENKNH HIC=JQ :GNFGQ FMLQ FMCJPQ ML1NPO?<Q FKLACJNKLQ MLHQ HPFIPMJPHQ IPJENIMONKL@Q CEIPLKIEGNLPQ NJ FKLOIMNLHNFMOPHQNLQEMONPLOJQIPFPN;NL=Q (!QNLGN>NOKIJQKIQ:GKQGM;PQCJPHQOGPBQ:NOGNLQOGPQEIP;NKCJQ9.

Canadian Family Physician t Le MĂŠdecin de famille canadien

HM?JQ 2JPPQ CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS3@Q Warfarin: -GP EKOPLONMDQP1NJOJQAKIQ& QPDP;MONKLQNLQEMONPLOJQ:GKQMIPQFKLFKBNOMLOD?QOM6NL=Q:MIAMINL@QAnesthetics: PHCFONKLJQNLQGPEMONFQ>DKKHQADK:QNLHCFPHQ>?QJKBPQ=PLPIMDQMLPJOGPONFJQ2GMDKOGMLP3QMLHQKOGPIQHIC=J BM?QIPJCDOQNLQMQHPFIPMJPHQIMOPQKAQGPEMONFQPDNBNLMONKLQKAQ>CEIPLKIEGNLP@QFlunitrazepam: PMOGJ GM;PQ >PPLQ IPEKIOPHQ NLQ OGPQ MHHNFOQ EKECDMONKLQ :GPLQ >CEIPLKIEGNLPQ :MJQ FKMHBNLNJOPIPHQ :NOG ADCLNOIM,PEMB@Q-GNJQMH;PIJPQHIC=QNLOPIMFONKLQFMLLKOQ>PQP1EDMNLPHQ>?QMQEGMIBMFK6NLPONFQHIC= HIC= NLOPIMFONKL@Q%MCONKLQBCJOQ>PQP1PIFNJPHQ:NOGQOGPQFKB>NLPHQCJPQKAQ>CEIPLKIEGNLPQMLHQADCLNOIM,PEMB MLHQMQHKJM=PQIPHCFONKLQNLQKLPQKIQ>KOGQHIC=JQJGKCDHQ>PQFKLJNHPIPH@QDrug-Herb Interactions &LOPIMFONKLJQ :NOGQ GPI>MDQ EIKHCFOJQ GM;PQ LKOQ >PPLQ PJOM>DNJGPH@Q Drug-Laboratory Interactions &LOPIMFONKLJQ:NOGQDM>KIMOKI?QOPJOJQGM;PQLKOQ>PPLQPJOM>DNJGPH.

Administration DOSAGE AND ADMINISTRATION: General BuTransâ&#x201E;˘ (buprenorphine transdermal patch) should only be prescribed by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of respiratory depression including the use of opioid antagonists. Dosing Considerations BuTrans NJQNLOPLHPHQOKQ>PQCJPHQAKIQOGPQFKLONLCMDQIPDPMJPQKAQ>CEIPLKIEGNLP OIMLJHPIBMDD?Q K;PIQ MQ $ HM?Q EPINKHQ EPIQ EMOFG<Q AKIQ OGPQ BMLM=PBPLOQ KAQ EPIJNJOPLOQ EMNLQ KA BKHPIMOPQNLOPLJNO?@QBuTrans FMLQ>PQCJPHQNLQPNOGPIQKENKNHQLM ;PQEMONPLOJQKIQEMONPLOJQEIP;NKCJD? OIPMOPHQ:NOGQ/ Q2MJQLPPHPH3QMLMD=PJNFJQ:GPLQOGPQMLMD=PJNFQIP'CNIPBPLOQGMJQEIK=IPJJPHQOKQM LPPHQAKIQFKLONLCKCJQKENKNHQMLMD=PJNM@QBuTrans HKJPJQBCJOQ>PQNLHN;NHCMDN,PHQ>MJPHQCEKLQOGP JOMOCJQKAQPMFGQEMONPLOQMLHQJGKCDHQ>PQMJJPJJPHQMOQIP=CDMIQNLOPI;MDJQMAOPIQMEEDNFMONKL@Q/IKEPI KEONBN,MONKLQKAQHKJPJQJFMDPHQOKQOGPQIPDNPAQKAQOGPQNLHN;NHCMD JQEMNLQJGKCDHQMNBQMOQOGPQIP=CDMI MHBNLNJOIMONKLQKAQOGPQDK:PJOQHKJPQKAQBuTrans :GNFGQEIK;NHPJQEMNLQIPDNPAQ:NOGQMFFPEOM>DPQJNHP PAAPFOJ@Q-GPQHKJM=PQKAQOGPQHIC=QBCJOQ>PQNLHN;NHCMDN,PHQMFFKIHNL=QOKQOGPQIPJEKLJPQMLHQOKDPIMLFP KAQOGPQEMONPLO@Q(LQNBEKIOMLOQAMFOKIQOKQ>PQFKLJNHPIPHQNLQHPOPIBNLNL=QOGPQMEEIKEINMOPQHKJPQNJQOGP P1OPLOQ KAQ EIP P1NJONL=Q KENKNHQ OKDPIMLFPQ 2JPPQ Conversion from Opioid or Fixed-Ratio Opioid/Non-Opioid Combination Drugs3@Q &LNONMONKLQ KLQ OGPQ DK:PJOQ M;MNDM>DPQ JOIPL=OGQ KA BuTrans :NOGQMEEIKEINMOPQHKJPQONOIMONKLQNJQJC==PJOPHQAKIQOGPQPDHPID?QMLHQKOGPIQ=IKCEJQHNJFCJJPH NLQWARNINGS AND PRECAUTIONS@Q-GPQEMOFGQJGKCDHQ>PQ:KILQAKIQ$QHM?JQ>PAKIPQFGML=NL=QOK MQLP:QEMOFGQMOQOGPQJMBPQHKJP@Q(QLP:QJ6NLQJNOPQJGKCDHQ>PQJPDPFOPHQ:GPLQFGML=NL=QOKQMQLP:QEMOFG@ (AOPIQOGPQEMOFGQNJQIPBK;PH<QMQ+ :PP6QNLOPI;MDQNJQIP'CNIPHQ>PAKIPQOGPQJMBPQJNOPQFMLQ>PQIP CJPH@ BuTrans JGKCDHQLKOQ>PQCJPHQNLQNLHN;NHCMDJQDPJJQOGMLQ.4Q6=QNLQ:PN=GO@QBuTrans BM?QGM;PQMDOPIPH EGMIBMFK6NLPONFJQHCPQOKQEKKIQAMOQJOKIPJ<QBCJFDPQ:MJONL=QKIQMDOPIPHQFDPMIMLFP@Q!ENKNHQMLMD=PJNFJ BM?Q>PQKLD?QEMIONMDD?QPAAPFON;PQNLQIPDNP;NL=QH?JPJOGPONFQEMNL<QEKJOGPIEPONFQLPCIMD=NM<QJOM>>NL= EMNLJ<QMFON;NO? IPDMOPHQEMNLQMLHQJKBPQAKIBJQKAQGPMHMFGP@Q-GMOQNJQLKOQOKQJM?QOGMOQEMONPLOJQ:NOG OGPJPQO?EPJQKAQEMNLQJGKCDHQLKOQ>PQ=N;PLQMLQMHP'CMOPQOINMDQKAQKENKNHQMLMD=PJNFJ<Q>COQNOQBM?Q>P LPFPJJMI?QOKQIPAPIQJCFGQEMONPLOJQMOQMLQPMID?QONBPQOKQKOGPIQAKIBJQKAQEMNLQOGPIME?@QBuTrans has potential for abuse and diversion (see WARNINGS AND PRECAUTIONS). Initial BuTrans Dose Selection BuTrans NJQHPJN=LPHQOKQMDDK:QAKIQKLFPQ:PP6D?QHKJNL=<QN@P@<QHKJNL=QP;PI?Q$QHM?J@ -IPMOBPLOQ:NOGQBuTrans JGKCDHQ=PLPIMDD?Q>PQNLNONMOPHQMOQOGPQDK:PJOQM;MNDM>DPQHKJPQ2BuTrans 53@Q Patients Not Already Taking Opioids (Opioid-NaĂŻve) &LQJNOCMONKLJQ:GPLQNOQNJQFDNLNFMDD? NLHNFMOPHQOKQNLNONMOPQKENKNHQOGPIME?Q:NOGQMQBMNLOPLMLFPQ2MIKCLH OGP FDKF63QKENKNHQNLQMLQKENKNH LM ;PQ EMONPLO<Q FDNLNFMDQ OINMDJQ GM;PQ JGK:LQ OGMOQ JCFGQ EMONPLOJQ BM?Q JCFFPJJACDD?Q NLNONMOPQ KENKNH OGPIME?Q:NOGQBuTrans@QThe lowest dose available (BuTrans 5) should always be used as the initial dose and titrated as required. If the patient requires breakthrough medication, see Management of Breakthrough Pain section. Conversion from Opioid or Fixed-Ratio Opioid/Non-Opioid Combination Drugs BuTrans GMJQ>PPLQJOCHNPHQMJQMLQMDOPILMON;PQKENKNH MLMD=PJNFQNLQEMONPLOJQOM6NL=QCEQOKQ*4QB=QKAQKIMDQBKIEGNLP P'CN;MDPLOJQMQHM?@QSuch patients should be started on BuTrans 5 or BuTrans 10 and be provided with adequate breakthrough medication and titrated as required (JPP Management of Breakthrough Pain)@QPatch Application BuTrans JGKCDHQ>PQMEEDNPHQOKQLKL NIINOMOPH<QNLOMFOQJ6NLQKAQOGPQCEEPI KCOPIQMIB<QCEEPIQFGPJO<QCEEPIQ>MF6QKIQOGPQJNHPQKAQOGPQFGPJO@QBuTrans JGKCDHQ>PQMEEDNPHQOKQM IPDMON;PD?QGMNIDPJJQKIQLPMID?QGMNIDPJJQJ6NLQJNOP@Q&AQLKLPQMIPQM;MNDM>DP<QOGPQGMNIQMOQOGPQJNOPQJGKCDHQ>P FDNEEPH<QLKOQJGM;PL@QApplication site should be rotated whenever a patch is replaced or added. Application sites should be re-used at no less than 3-week intervals. &AQOGPQMEEDNFMONKL JNOPQBCJOQ>PQFDPMLPH<QNOQJGKCDHQ>PQHKLPQ:NOGQFDPMIQ:MOPIQKLD?@Q"KMEJ<QMDFKGKD<QKNDJ<QDKONKLJQKIQM>IMJN;P HP;NFPJQBCJOQLKOQ>PQCJPH@Q-GPQJ6NLQJNOPQBCJOQ>PQHI?Q>PAKIPQOGPQEMOFGQNJQMEEDNPH@QBuTrans JGKCDHQ>P NBBPHNMOPD?QMEEDNPHQMAOPIQIPBK;MDQAIKBQOGPQJPMDPHQEKCFG@Q KDDK:NL=QIPBK;MDQKAQOGPQEIKOPFON;PQDM?PI< OGPQ OIMLJHPIBMDQ EMOFGQ JGKCDHQ >PQ EIPJJPHQ ANIBD?Q NLQ EDMFPQ :NOGQ OGPQ EMDBQ KAQ OGPQ GMLHQ AKI MEEIK1NBMOPD?Q+4QJPFKLHJ<QBM6NL=QJCIPQOGPQFKLOMFOQNJQFKBEDPOP<QPJEPFNMDD?QMIKCLHQOGPQPH=PJ@Q&AQOGP PH=PJQKAQOGPQEMOFGQ>P=NLQOKQEPPDQKAA<QOGPQPH=PQBM?Q>PQOMEPHQHK:LQ:NOGQJCNOM>DPQJ6NLQOMEP@Q MOGNL=< JGK:PINL=QKIQJ:NBBNL=QJGKCDHQLKOQMAAPFOQOGPQEMOFG@Q GNDPQ:PMINL=QBuTrans<QEMONPLOJQJGKCDHQ>P MH;NJPHQOKQM;KNHQP1EKJNL=QOGPQEMOFGQJNOPQOKQHNIPFOQP1OPILMDQGPMOQJKCIFPJQ2JPPQWARNINGS AND PRECAUTIONS3@ Dose Titration /IKEPIQ KEONBN,MONKLQ KAQ HKJPJQ JFMDPHQ OKQ OGPQ IPDNPAQ KAQ OGP NLHN;NHCMD JQEMNLQJGKCDHQMNBQMOQIP=CDMIQMHBNLNJOIMONKLQKAQOGPQDK:PJOQHKJPQKAQFKLOIKDDPHQIPDPMJP >CEIPLKIEGNLPQ2BuTrans3Q:GNFGQ:NDDQMFGNP;PQOGPQK;PIMDDQOIPMOBPLOQ=KMDQKAQJMONJAMFOKI?QEMNL IPDNPAQ:NOGQMFFPEOM>DPQJNHPQPAAPFOJ@Q!LQM;PIM=P<QJOPMH? JOMOPQ>DKKHQDP;PDJQMIPQMFGNP;PHQMAOPIQ+ HM?J@Q It is recommended that doses of BuTrans be slowly titrated â&#x20AC;&#x201C; with dosage

| VOL 57: JANUARY t JANVIER 2011

adjustment generally separated by 7 days. The dose of BuTrans should not be increased before 3 days as the plasma concentrations continue to increase following application. Subsequent increases of BuTrans dosage must be individualized according to the pain relief and tolerance of the patient with adequate breakthrough pain medication, as required 2JPPQManagement of Breakthrough Pain3@Q&AQ>IPM6OGIKC=GQEMNLQIPEPMOPHD?QKFFCIJ MOQOGPQPLHQKAQOGPQHKJNL=QNLOPI;MDQNOQNJQ=PLPIMDD?QMLQNLHNFMONKLQAKIQMQHKJM=PQNLFIPMJPQIMOGPIQOGML BKIPQAIP'CPLOQMHBNLNJOIMONKLQKAQFKLOIKDDPHQIPDPMJPQ>CEIPLKIEGNLPQ2BuTrans3@QThe maximum recommended patch dose is 20 mcg/h every 7 days. -KQNLFIPMJPQOGPQHKJP<QOGPQEMOFGQOGMO NJQFCIIPLOD?Q>PNL=Q:KILQJGKCDHQ>PQIPBK;PH<QHNJEKJPHQKAQEIKEPID?<QMLHQOGPQLP1OQGN=GPIQJOIPL=OG KAQBuTrans JGKCDHQ>PQCJPH@Q(EEDNFMONKLQJNOPJQJGKCDHQ>PQIKOMOPHQ:GPLP;PIQMQEMOFGQNJQIPEDMFPHQKI MHHPH@Q(EEDNFMONKLQJNOPJQJGKCDHQ>PQIP CJPHQMOQLKQDPJJQOGMLQ+ :PP6QNLOPI;MDJ@Q&OQNJQIPFKBBPLHPH OGMOQLKQBKIPQOGMLQO:KQEMOFGPJQ>PQMEEDNPHQMOQOGPQJMBPQONBP@Q KQFGML=PQNLQHKJPQONOIMONKLQNJ IP'CNIPHQNLQEMONPLOJQ:NOGQIPLMDQNBEMNIBPLOQKIQBNDHQOKQBKHPIMOPQGPEMONFQNBEMNIBPLO@Q/MONPLOJ :NOGQJP;PIPQGPEMONFQNBEMNIBPLOQBM?QMFFCBCDMOPQ>CEIPLKIEGNLPQMLHQBuTrans JGKCDHQLKOQ>P CJPHQNLQJCFGQEMONPLOJ@ Management of Breakthrough Pain &LQ FDNLNFMDQ OINMDJQ :NOGQ BuTrans<Q MFPOMBNLKEGPLQ MLH MFPOMBNLKEGPLQ:NOGQFKHPNLPQFKB>NLMONKLJQ:PIPQCJPHQAKIQOGPQBMLM=PBPLOQKAQ>IPM6OGIKC=GQEMNL@ &AQPENJKHPJQKAQ>IPM6OGIKC=GQEMNLQMIPQPLFKCLOPIPHQ:NOGQMEEIKEINMOPQMH CJOBPLOJQKAQOGPQBuTrans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uTrans 04QBF=8GQP;PI?Q$QHM?J<QOGPQEMONPLOQJGKCDHQ>PQFKL;PIOPHQOKQMLQMDOPILMON;PQMIKCLH OGP FDKF6Q KENKNHQ M=KLNJO<Q MLHQ OGPQ HKJPQ KAQ OGPQ MDOPILMON;PQ MLMD=PJNFQ ACIOGPIQ ONOIMOPH<Q MJQ MEEIKEINMOP@ Managing Expected Opioid Adverse Experiences ML?Q EMONPLOJQ IPFPN;NL=Q KENKNHJ< PJEPFNMDD?QOGKJPQ:GKQMIPQKENKNHQLM ;P<Q:NDDQP1EPINPLFPQJNHPQPAAPFOJ@Q%DNLNFMDQOINMDJQGM;PQJGK:LQOGMO OGPJPQ PAAPFOJQ MIPQ BKJOQ >KOGPIJKBPQ HCINL=Q OGPQ NLNONMDQ MEEDNFMONKLQ MLHQ FMLQ >PQ BNLNBN,PHQ >? JOMIONL=QMOQBuTrans 5 MLHQ=IMHCMDD?QNLFIPMJNL=QOGPQHKJPQMJQLPPHPH@Q(DOGKC=GQOGPQJNHPQPAAPFOJ AIKBQ BuTrans MIPQ KAOPLQ OIMLJNPLO<Q JKBPQ BM?Q IP'CNIPQ OIPMOBPLO@Q (H;PIJPQ P;PLOJQ JCFGQ MJ FKLJONEMONKLQJGKCDHQ>PQMLONFNEMOPHQMLHQOIPMOPHQ:NOGQMQJONBCDMLOQDM1MON;PQMLH8KIQJOKKDQJKAOPLPI@ /MONPLOJQHKQLKOQCJCMDD?Q>PFKBPQOKDPIMLOQOKQOGPQFKLJONEMONL=QPAAPFOJQKAQKENKNHJ@Q!OGPIQKENKNH IPDMOPHQJNHPQPAAPFOJQJCFGQMJQJPHMONKLQMLHQLMCJPMQMIPQCJCMDD?QJPDA DNBNOPHQMLHQKAOPLQHKQLKOQEPIJNJO >P?KLHQOGPQANIJOQAP:QHM?J@Q&AQLMCJPMQEPIJNJOJQMLHQNJQCLMFFPEOM>DPQOKQOGPQEMONPLO<QOIPMOBPLOQ:NOG MLON PBPONFJQ KIQ KOGPIQ BKHMDNONPJQ BM?Q IPDNP;PQ OGPJPQ J?BEOKBJQ MLHQ JGKCDHQ >PQ FKLJNHPIPH@ Discontinuation of BuTrans Therapy (AOPIQ IPBK;MDQ KAQ BuTrans<Q EDMJBMQ FKLFPLOIMONKLJ HPFIPMJPQ=IMHCMDD?<QMLHQOGPQMLMD=PJNFQPAAPFOQNJQBMNLOMNLPHQAKIQMQFPIOMNLQMBKCLOQKAQONBP@Q-GNJ LPPHJQOKQ>PQFKLJNHPIPHQ:GPLQCJPQKAQBuTrans NJQOKQ>PQAKDDK:PHQ>?QKOGPIQKENKNHJ@Q(JQMQ=PLPIMDQICDP< MQJC>JP'CPLOQKENKNHQJGKCDHQLKOQ>PQMHBNLNJOPIPHQ:NOGNLQ0.QGKCIJQKAQIPBK;MDQKAQMQBuTrans EMOFG@ CEIPLKIEGNLPQFKLFPLOIMONKLJQHPFDNLP<QHPFIPMJNL=QMEEIK1NBMOPD?Q)4 QNLQ90QGKCIJQ2IML=PQ94 0. G3@ Safety and Handling -GPQ >CEIPLKIEGNLPQ FKLOMNLPHQ NLQ BuTrans NJQ JCEEDNPHQ NLQ JPMDPH OIMLJHPIBMDQEMOFGPJ@Q&AQOGPQMHGPJN;PQAIKBQOGPQHIC=QMFFNHPLOMDD?QFKLOMFOJQOGPQJ6NLQKOGPIQOGML NLOPLHPHQMEEDNFMONKLQJNOP<QOGPQMIPMQJGKCDHQ>PQ:MJGPHQ:NOGQ:MOPI@Q KQLKOQCJPQJKME<QMDFKGKDQKI KOGPIQJKD;PLOJQOKQIPBK;PQOGPQMHGPJN;PQ>PFMCJPQOGP?QBM?QPLGMLFPQOGPQM>JKIEONKLQKAQOGPQHIC=@ GPLQFGML=NL=QOGPQEMOFG<QIPBK;PQOGPQCJPHQBuTrans EMOFG<QAKDHQNOQK;PIQNOJPDA<QMLHQHNJFMIHQNO 2ADCJGQ HK:LQ OGPQ OKNDPOQ KIQ FKLJCDOQ :NOGQ MQ EGMIBMFNJOQ M>KCOQ KOGPIQ HNJEKJMDQ KEONKLJ3@ OVERDOSAGE (see Supplemental Product Information) For management of suspected drug overdose, contact your Regional Poison Control Centre.

Study References 9@Q BuTrans /IKHCFOQ KLK=IMEG<Q/CIHCPQ/GMIBM<Q P>ICMI?Q0494@ 0@Q/CIHCPQ/GMIBM<Q MIFGQ0.<Q0494@ Supplemental Product Information

Information for Physicians to Convey to Patients (QEMONPLOQNLAKIBMONKLQJGPPOQNJQNLFDCHPHQNLQOGPQEMF6M=PQKAQBuTrans EMOFGPJQHNJEPLJPHQOKQOGPQEMONPLO@ /MONPLOJQIPFPN;NL=QBuTrans EMOFGPJQJGKCDHQ>PQ=N;PLQOGPQAKDDK:NL=QNLJOICFONKLJQ>?QOGPQEG?JNFNML7 9@ /MONPLOJQJGKCDHQ>PQNLAKIBPHQOGMOQMFFNHPLOMDQNL=PJONKLQKIQCJPQ>?QNLHN;NHCMDJQ2NLFDCHNL=QFGNDHIPL3QKOGPIQOGMLQOGPQEMONPLOQAKIQ:GKBQNO :MJQKIN=NLMDD?QEIPJFIN>PH<QBM?QDPMHQOKQJP;PIP<QP;PLQAMOMD<QFKLJP'CPLFPJ@ 0@ /MONPLOJQJGKCDHQ>PQMH;NJPHQOGMOQBuTrans EMOFGPJQFKLOMNLQ>CEIPLKIEGNLP<QMLQKENKNHQEMNLQBPHNFNLP@ +@ /MONPLOJQJGKCDHQ>PQMH;NJPHQOGMOQPMFGQBuTrans EMOFGQBM?Q>PQ:KILQFKLONLCKCJD?QAKIQ$QHM?J<QMLHQOGMOQPMFGQEMOFGQJGKCDHQ>PQMEEDNPH OKQMQHNAAPIPLOQJ6NLQJNOPQMAOPIQIPBK;MDQKAQOGPQEIP;NKCJQOIMLJHPIBMDQEMOFG@ .@ /MONPLOJQJGKCDHQ>PQMH;NJPHQOGMOQOGPQMEEDNFMONKLQJNOPJQJGKCDHQ>PQIKOMOPHQ:GPLP;PIQMQEMOFGQNJQIPEDMFPH@Q(AOPIQOGPQEMOFGQNJQIPBK;PH<QM + :PP6QNLOPI;MDQNJQIP'CNIPHQ>PAKIPQOGPQJMBPQJNOPQFMLQ>PQIP CJPHQMJQMQJOIMOP=?QOKQEIP;PLOQJ6NLQNIINOMONKLQMLH8KIQIPHCFPQOGPQEKOPLONMD AKIQNLFIPMJPHQHIC=QM>JKIEONKL@ )@ /MONPLOJQJGKCDHQ>PQMH;NJPHQOGMOQBuTrans EMOFGPJQJGKCDHQ>PQMEEDNPHQOKQNLOMFO<QLKL NIINOMOPHQMLHQLKL NIIMHNMOPHQJ6NLQKLQMQADMOQJCIAMFPQJCFG MJQOGPQCEEPIQFGPJO<QCEEPIQ>MF6<QJNHPQKAQFGPJO<QKIQCEEPIQKCOPIQMIB@Q(HHNONKLMDD?<QEMONPLOJQJGKCDHQ>PQMH;NJPHQKAQOGPQAKDDK:NL=7 &LQEPIJKLJQ:NOGQFK=LNON;PQNBEMNIBPLO<QOGPQEMOFGQJGKCDHQ>PQECOQKLQOGPQCEEPIQ>MF6QOKQIPHCFPQOGPQFGMLFPJQOGMOQOGPQEMOFGQ:NDDQ>PQIPBK;PH MLHQEDMFPHQNLQOGPQBKCOG5 MNIQMOQOGPQMEEDNFMONKLQJNOPQJGKCDHQ>PQFDNEEPHQ2LKOQJGM;PH3QEINKIQOKQEMOFGQMEEDNFMONKL5 &AQOGPQJNOPQKAQBuTrans MEEDNFMONKLQBCJOQ>PQFDPMLJPHQEINKIQOKQMEEDNFMONKLQKAQOGPQEMOFG<QHKQJKQ:NOGQFDPMIQ:MOPI5 (DDK:QOGPQJ6NLQOKQHI?QFKBEDPOPD?QEINKIQOKQEMOFGQMEEDNFMONKL5 KQLKOQCJPQJKMEJ<QKNDJ<QDKONKLJ<QMDFKGKD<QKIQML?QKOGPIQM=PLOJQOGMOQBM?QNIINOMOPQOGPQJ6NLQKIQMDOPIQNOJQFGMIMFOPINJONFJ@

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"<Q%! /!"&-&! Q( Q/(% ( & QNLQOGPQ/IKHCFOQ KLK=IMEG3@Q

VOL 57: JANUARY t JANVIER 2011

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| Canadian Family Physician

Prescribing Summary Patient Selection Criteria Therapeutic Category: Antidepressant Action: Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Indications and Clinical Use Adults: PRISTIQÂŽ desvenlafaxine Extended-Release Tablets is indicated for: the symptomatic relief of major depressive disorder. The short-term efficacy of PRISTIQ extended-release tablets has been demonstrated in placebo-controlled trials of up to 8 weeks. Pediatrics (<18 years of age): PRISTIQ is not indicated for use in children under the age of 18. Safety and effectiveness in the pediatric population have not been established (see WARNINGS AND PRECAUTIONS, potential association with behavioural and emotional changes, including self-harm). CONTRAINDICATIONS P 6DG6?=272I:?6 >FDE ?@E 36 FD65 4@?4@>:E2?E=J :? A2E:6?ED E2<:?8 >@?@2>:?6 @I:52D6 :?9:3:E@CD $ &!D :?4=F5:?8 =:?6K@=:5 2? 2?E:3:@E:4 @C :? A2E:6?ED H9@ 92G6 E2<6? $ &!D H:E9:? E96 AC6465:?8 52JD 5F6 E@ E96 C:D< @7 D6C:@FD D@>6E:>6D fatal, drug interactions with selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) treatment or with other serotonergic drugs. These interactions have been associated with symptoms that include EC6>@C >J@4=@?FD 5:2A9@C6D:D ?2FD62 G@>:E:?8 O FD9:?8 5:KK:?6DD 9JA6CE96C>:2 H:E9 762EFC6D C6D6>3=:?8 ?6FC@=6AE:4 >2=:8?2?E DJ?5C@>6 D6:KFC6D C:8:5:EJ 2FE@?@>:4 :?DE23:=:EJ H:E9 A@DD:3=6 C2A:5 O F4EF2E:@?D @7 G:E2= D:8?D 2?5 >6?E2= DE2EFD changes that include extreme agitation progressing to delirium and coma. Based on the half-life of desvenlafaxine succinate, 2E =62DE 52JD D9@F=5 36 2==@H65 27E6C DE@AA:?8 56DG6?=272I:?6 DF44:?2E6 2?5 367@C6 DE2CE:?8 2? $ &! P JA6CD6?D:E:G:EJ E@ 56DG6?=272I:?6 DF44:?2E6 6IE6?565 C6=62D6 G6?=272I:?6 9J5C@49=@C:56 @C E@ 2?J 6I4:A:6?ED :? E96 desvenlafaxine formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section @7 E96 'C@5F4E $@?@8C2A9 SPECIAL POPULATIONS Pregnant Women: the safety of desvenlafaxine in human pregnancy has not been established. The extent of exposure to PRISTIQ in pregnancy during clinical trials was very limited. There are no adequate and well-controlled studies in pregnant women. Therefore, desvenlafaxine should be used during pregnancy only if the potential benefits justify the potential risks. If desvenlafaxine succinate is used until or shortly before birth, discontinuation effects in the newborn should be considered. Post-marketing reports indicate that some neonates exposed to SNRIs, SSRIs, or other newer antidepressants late in the E9:C5 EC:>6DE6C 92G6 56G6=@A65 4@>A=:42E:@?D C6BF:C:?8 AC@=@?865 9@DA:E2=:K2E:@? C6DA:C2E@CJ DFAA@CE 2?5 EF36 7665:?8 Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, 2A?62 D6:KFC6D E6>A6C2EFC6 :?DE23:=:EJ 7665:?8 5:7N 4F=EJ G@>:E:?8 9JA@8=J46>:2 9JA@E@?:2 9JA6CE@?:2 9JA6CC6O 6I:2 tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SNRIs, SSRIs and other newer antidepressants, or, possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see DRUG INTERACTIONS). When treating a pregnant woman with PRISTIQ during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Labour and Delivery: the effect of desvenlafaxine on labour and delivery in humans is unknown. PRISTIQ should be used during labour and delivery only if the potential benefits justify the potential risks. Nursing Women: 56DG6?=272I:?6 & 56D>6E9J=G6?=272I:?6 :D 6I4C6E65 :? 9F>2? >:=< 642FD6 @7 E96 A@E6?E:2= 7@C D6C:@FD adverse reactions in nursing infants from PRISTIQ, a decision should be made whether or not to discontinue nursing or to 5:D4@?E:?F6 E96 5CF8 E2<:?8 :?E@ 244@F?E E96 :>A@CE2?46 @7 E96 5CF8 E@ E96 >@E96C &?=J 25>:?:DE6C PRISTIQ to breastfeeding women if the expected benefits outweigh any possible risk. Pediatric: safety and effectiveness in patients less than 18 years of age have not been established. Geriatrics ( *65 years of age): of the 3,292 patients in clinical trials with PRISTIQ, 5% were 65 years of age or older. No overall differences in safety or efficacy were detected between these subjects and younger subjects; however in the short-term placebo-controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients *65 years of age compared to all adults treated with desvenlafaxine. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Dosing Considerations, Geriatrics and ACTION AND CLINICAL PHARMACOLOGY, Geriatrics). Greater sensitivity of some older individuals cannot be ruled out.

Safety Information WARNINGS AND PRECAUTIONS POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM. Pediatrics: Placebo-Controlled Clinical Trial Data Recent analyses of placebo-controlled clinical trial safety databases from Selective Serotonin Reuptake Inhibitors (SSRIs) and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

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The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among the drugs in the class. Adults and Pediatrics: Additional Data There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment. Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages especially when initiating therapy or during any change in dose or dosage regimen. This includes monitoring for agitation-type emotional and behavioural changes. Patients currently taking PRISTIQ should NOT be discontinued abruptly, due to risk of discontinuation symptoms (See WARNINGS and PRECAUTIONS, Discontinuation Symptoms, below). At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose, rather than an abrupt cessation, is recommended. (See Dosage and Administration). Concomitant Use of PRISTIQ with Venlafaxine Since desvenlafaxine is the major active metabolite of venlafaxine, concomitant use of PRISTIQ with products containing Venlafaxine is not recommended since the combination of the two will lead to additive desvenlafaxine exposure. Monitoring and Laboratory Tests Serum Lipids: :?4C62D6D :? 49@=6DE6C@= E@E2= 2?5 # # 2?5 EC:8=J46C:56D H6C6 @3D6CG65 :? D@>6 A2E:6?ED EC62E65 H:E9 56DG6?=272I:?6 DF44:?2E6 :? A=2463@ 4@?EC@==65 AC6 >2C<6E:?8 4=:?:42= EC:2=D A2CE:4F=2C=J H:E9 9:896C 5@D6D $62DFC6>6?E @7 serum lipid levels should be considered during treatment. Heart Rate and Blood Pressure: increases in heart rate and blood pressure were observed in some patients in clinical trials, A2CE:4F=2C=J H:E9 9:896C 5@D6D $62DFC6>6?E @7 3=@@5 AC6DDFC6 :D C64@>>6?565 AC:@C E@ :?:E:2E:?8 EC62E>6?E 2?5 C68F=2C=J during treatment with desvenlafaxine succinate (see ADVERSE REACTIONS, Vital Sign Changes). Self-Harm: rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen. (See WARNINGS AND PRECAUTIONS, POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM). Psychiatric Mania/hypomania: mania/hypomania may occur in a small proportion of patients with mood disorders who have received >65:42E:@? E@ EC62E 56AC6DD:@? :?4=F5:?8 56DG6?=272I:?6 DF44:?2E6 FC:?8 A92D6 2?5 A92D6 DEF5:6D >2?:2 H2D C6A@CE65 for approximately 0.1% of patients treated with PRISTIQ. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania. Neurologic Seizures: 42D6D @7 D6:KFC6D 92G6 366? C6A@CE65 :? AC6 >2C<6E:?8 EC:2=D H:E9 PRISTIQ 6DG6?=272I:?6 DF44:?2E6 D9@F=5 36 AC6D4C:365 H:E9 42FE:@? :? A2E:6?ED H:E9 2 D6:KFC6 5:D@C56C 6DG6?=272I:?6 92D ?@E 366? DJDE6>2E:42==J 6G2=F2E65 :? A2E:6?ED H:E9 2 D6:KFC6 5:D@C56C Serotonin Syndrome: as with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with desvenlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic ?6FC@EC2?D>:EE6C DJDE6>D DF49 2D EC:AE2?D D6C@E@?:? C6FAE2<6 :?9:3:E@CD D:3FEC2>:?6 $ &!D :?4=F5:?8 =:?6K@=:5 2? 2?E:3:@E:4 *E "@9? D .@CE JA6C:4F> A6C7@C2EF> 2?5 @C =:E9:F> 2?5 H:E9 5CF8D E92E :>A2:C >6E23@=:D> @7 D6C@E@?:? Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). If concomitant treatment with desvenlafaxine and other agents that may affect the serotonergic neurotransmitter system such as another SSRI, a Selective Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of desvenlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see DRUG INTERACTIONS, Serotonin Syndrome). Ophthalmologic Narrow Angle Glaucoma: mydriasis has been reported in association with desvenlafaxine; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see ADVERSE REACTIONS). Gastrointestinal Potential for Gastrointestinal Obstruction: because the PRISTIQ tablet does not appreciably change in shape in the gastrointestinal tract, PRISTIQ should not be administered to patients with pre-existing gastrointestinal narrowing (pathologic or iatrogenic, such as small bowel inflammatory disease, â&#x20AC;&#x153;short gutâ&#x20AC;? syndrome due to adhesions or decreased EC2?D:E E:>6 A2DE 9:DE@CJ @7 A6C:E@?:E:D 4JDE:4 N 3C@D:D 49C@?:4 :?E6DE:?2= AD6F5@ @3DECF4E:@? @C $64<6= D 5:G6CE:4F=F> +96C6 have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations, and very rare reports of obstructive symptoms associated with E96 FD6 @7 ?@?567@C>23=6 4@?EC@==65 C6=62D6 7@C>F=2E:@?D :? A2E:6?ED H:E9@FE <?@H? 82DEC@:?E6DE:?2= DEC:4EFC6 F6 E@ E96 controlled-release design, PRISTIQ tablets should only be used in patients who are able to swallow the tablets whole. (See DOSAGE AND ADMINISTRATION; Recommended Dose and Dosage Adjustment). ADVERSE REACTIONS The safety of PRISTIQ in major depressive disorder was evaluated in 3,292 patients exposed to at least one dose of PRISTIQ. +96 >@DE 4@>>@?=J @3D6CG65 25G6CD6 C624E:@?D :?4:56?46 @7 @C 8C62E6C 7@C E96 -* *) A@@=65 E@ >8 5@D6D 2?5 :?4:56?46 9:896C E92? A=2463@ :? -* *) EC62E65 $ A2E:6?ED :? D9@CE E6C> A=2463@ 4@?EC@==65 EC:2=D H6C6 ?2FD62 96252496 5CJ >@FE9 9JA6C9J5C@D:D 5:KK:?6DD :?D@>?:2 4@?DE:A2E:@? 564C62D65 2AA6E:E6 D@>?@=6?46 72E:8F6 EC6>@C and vomiting, and, in men, erectile dysfunction and ejaculation delayed.

| VOL 57: JANUARY t JANVIER 2011

Adverse Events Reported as Reasons for Discontinuation of Treatment in MDD Clinical Trials In the 8-week placebo-controlled, pre-marketing trials for MDD, 12% of the 1,834 patients who received PRISTIQ (50-400 mg/day) discontinued treatment due to an adverse experience, compared with 3% of the 1,116 placebo-treated patients in those trials. At the recommended dose of 50 mg, the discontinuation rate due to an adverse experience for PRISTIQ (4.1%) was similar to the rate for placebo (3.8%) and only 1% of patients discontinued due to nausea. The most common adverse reactions leading to discontinuation (i.e., leading to discontinuation in at least 2% and incidence higher than placebo) of the PRISTIQ-treated patients in short-term trials of up to 8 weeks were: nausea (4%); dizziness, headache and vomiting (2% each). To report adverse events: Wyeth Canada T 1-800-463-6001 F 1-866-463-6001 DRUG-DRUG INTERACTIONS Monoamine Oxidase Inhibitors: desvenlafaxine succinate is contraindicated in patients taking MAOIs. Desvenlafaxine succinate must not be used in combination with a monoamine oxidase inhibitor (MAOI), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of desvenlafaxine succinate, at least 7 days should be allowed after stopping desvenlafaxine succinate before starting an MAOI (see CONTRAINDICATIONS). Serotonin Syndrome: as with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with desvenlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, linezolid [an antibiotic which is a reversible non-selective MAOI], lithium, sibutramine, tramadol, or St. John’s Wort [Hypericum perforatum], with drugs which impair metabolism of serotonin (including MAOIs; see CONTRAINDICATIONS), or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see WARNINGS AND PRECAUTIONS). If concomitant treatment of desvenlafaxine with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of desvenlafaxine with serotonin precursors is not recommended. Central Nervous System (CNS) Active Agents The risk of using desvenlafaxine succinate in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when desvenlafaxine succinate is taken in combination with other CNS-active drugs. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when PRISTIQ is initiated or discontinued.

Administration

Switching Patients to or from a Monoamine Oxidase Inhibitor: at least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with desvenlafaxine succinate. In addition, based on the half-life of desvenlafaxine succinate, at least 7 days should be allowed after stopping desvenlafaxine succinate before starting an MAOI. Discontinuation of Therapy: a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. Discontinuation regimens should take into account the individual circumstances of the patient, such as duration of treatment and dose at discontinuation (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS). SUPPLEMENTAL PRODUCT INFORMATION Adverse Reactions in MDD Clinical Trials PRISTIQ was evaluated for safety in 3,292 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing trials, representing 1,289 patient-years of exposure. Among these 3,292 PRISTIQ-treated patients, 1,834 patients participated in 8-week, placebo-controlled trials at doses ranging from 50 to 400 mg/day. Of the total 3,292 subjects exposed to at least 1 dose of PRISTIQ, 1070 were exposed to PRISTIQ for greater than 6 months and 274 were exposed for 1 year. Adverse Reactions Occurring at an Incidence of *1% among PRISTIQ-treated Patients in Short-Term Placebo-controlled Trials The following adverse reactions (Table 2) occurred at *1% and are listed alphabetically by body system. Reported adverse events were classified using a standard MedDRA-based Dictionary terminology. Table 2: Adverse Reactions (*1% in Any PRISTIQ Group): Percentage of Subjects in Short-Term, Placebo-Controlled MDD Studies PRISTIQ

System Organ Class Preferred Term

Placeboa n=1116

50 mg b n=317

100 mgb n=424

200 mgb n=307

400 mgb n=317

50-400 mga n=1834

2 1

1 1

3 <1

2 1

3 2

2 1

Mydriasis <1 Vision blurred 1 Gastrointestinal disorders Nausea 11 Dry mouth 8 Constipation 4 Diarrhea 9 Vomiting 2 General disorders and administration site conditions Fatigue 4 Chills 1 Feeling jittery 1 Asthenia 1

2 3

2 4

6 4

4 4

22 11 9 11 3

26 17 9 9 4

36 21 10 7 6

41 25 14 5 9

32 20 11 8 6

7 1 1 1

7 <1 2 2

10 3 3 1

11 4 3 1

8 2 2 1

1 1

1 2

1 1

2 1

2 2

2 1

25 6 4 2 1 1 <1

20 13 4 2 2 1 <1

22 10 9 3 2 1 1

29 15 12 9 1 1 2

25 16 12 9 3 2 1

25 13 9 6 2 2 1

6 3 2 0 1 <1 1

9 3 2 <1 2 1 <1

12 5 3 2 3 1 1

14 4 2 2 3 1 2

15 4 4 6 2 2 2

12 4 3 2 2 1 1

4 1

10 1

11 1

18 2

21 <1

15 1

Cardiac disorders Palpitations Tachycardia Ear and labyrinth disorders Tinnitus Eye disorders

Investigations Blood pressure increased Weight decreased Metabolism and nutrition disorders

General PRISTIQ is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm). Recommended Dose and Dosage Adjustment Initial Treatment: the recommended dose of PRISTIQ (desvenlafaxine succinate) extended-release tablets is 50 mg once daily, with or without food. In clinical studies, no additional benefit was demonstrated at doses greater than 50 mg/day. In clinical studies, doses of 50-400 mg/day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg/day, and adverse events and discontinuations were more frequent at higher doses. If the physician, based on clinical judgment, decides a dose increase above 50 mg/day is warranted for an individual patient, the maximum dose should not exceed 100 mg/day. Patients should be periodically reassessed to determine the need for continued treatment. It is recommended that PRISTIQ be taken at approximately the same time each day. PRISTIQ tablets must be swallowed whole with liquids, and must not be chewed, divided or crushed. The medication is contained within a non-absorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice something that looks like a tablet in their stool. Due to the controlled-release design, PRISTIQ tablets should only be used in patients who are able to swallow the tablets whole. Missed Dose: a patient missing a dose should take it as soon as they remember to. If it is almost time for the next dose, the missed dose should be skipped. The patient should be cautioned against taking two doses concomitantly to “make up” for the missed dose. Discontinuing PRISTIQ: symptoms associated with discontinuation of PRISTIQ, other SNRIs and SSRIs have been reported (see WARNINGS AND PRECAUTIONS, Discontinuation Symptoms and ADVERSE REACTIONS, Discontinuation symptoms). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate. As the lowest dosage strength of PRISTIQ is 50 mg, it is recommended that dose reduction from 50 mg/day should proceed to 50 mg every other day before discontinuation. Dosing Considerations Patients with severe renal impairment and end-stage renal disease: the recommended dose in patients with severe renal impairment (24-hr CrCl <30 mL/min) or end-stage renal disease (ESRD) is 50 mg every other day. Because of individual variability in clearance in these patients, individualization of dosage may be desirable. Supplemental doses should not be given to patients after dialysis (see ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency). Use in patients with hepatic impairment: no dosage adjustment is necessary for patients with hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Hepatic Insufficiency).

Decreased appetite Musculoskeletal and connective tissue disorders Musculoskeletal stiffness Nervous system disorders Headache Dizziness Somnolence Tremor Paraesthesia Dysgeusia Disturbance in attention Psychiatric disorders Insomnia Anxiety Abnormal dreams Anorgasmia Libido decreased Orgasm abnormal Nervousness Renal and urinary disorders Urinary hesitation Respiratory, thoracic and mediastinal disorders Yawning Skin and subcutaneous tissue disorders Hyperhidrosis Rash Vascular disorders Hot flush

MDD=major depressive disorder. a. Includes data from all short-term, placebo-controlled studies including fixed-dose and flexible-dose studies. b. Only includes data from short-term, placebo-controlled, fixed-dose studies. Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities (MedDRA). Note: <1% indicates an incidence less than 0.5%, but greater than zero.

Geriatrics (*65 years of age) : no dosage adjustment is required solely on the basis of age; however, possible reduced clearance of PRISTIQ should be considered when determining dose (see ACTION AND CLINICAL PHARMACOLOGY, Geriatrics). VOL 57: JANUARY t JANVIER 2011

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101

SEXUAL FUNCTION ADVERSE REACTIONS Table 3 shows the incidence of sexual function adverse reactions that occurred in 1% or more of PRISTIQ-treated MDD patients in the 50 mg dose group (8-week, placebo-controlled, fixed and flexible-dose, pre-marketing clinical trials). Table 3: Sexual Dysfunction Adverse Reactions (*1% in Men or Women in Any PRISTIQ Group) During the On-Therapy Period: Percentage of Subjects in Short-Term, Placebo-Controlled MDD Studies Preferred Terma

Placebo b

DVS SR 50 mgc

DVS SR 100 mgc

DVS SR 200 mgc

DVS SR 400 mgc

DVS SR 50-400 mg b

Men only d Erectile dysfunction Ejaculation delayed Anorgasmia Libido decreased Ejaculation disorder Ejaculation failure Orgasm abnormal

1 <1 0 1 <1 0 0

3 1 0 4 0 1 0

6 5 3 5 1 0 1

8 7 5 6 2 2 2

11 6 8 3 5 2 3

7 5 4 4 2 1 1

Women only e Anorgasmia Libido decreased Orgasm abnormal

0 <1 <1

1 1 1

1 2 1

0 1 1

3 1 1

1 1 1

a. Medical Dictionary for Regulatory Activities (MedDRA) terms. b. Includes data from all short-term, placebo-controlled studies including fixed-dose and flexible-dose studies. c. Only includes data from short-term, placebo-controlled, fixed-dose studies. d. Percentage based on the number of men (placebo, n=403; DVS SR 50 mg, n=108; DVS SR 100 mg, n=157; DVS SR 200 mg, n=131; DVS SR 400 mg=154; DVS SR 50-400 mg, n=723). e. Percentage based on the number of women (placebo, n=713; DVS SR 50 mg, n=209; DVS SR 100 mg, n=267; DVS SR 200 mg, n=176; DVS SR 400 mg=163; DVS SR 50-400 mg, n=1111). ADVERSE DRUG REACTIONS - ALL MDD CLINICAL TRIALS A total of 3292 subjects were exposed to at least 1 dose of PRISTIQ ranging from 50 to 400 mg/day in MDD clinical trials. Long-term safety was evaluated in 1070 subjects in MDD who were exposed to desvenlafaxine succinate for at least 6 months (180 days) and 274 subjects in MDD who were exposed for 1 year (356 days). The following list is a list of MedDRA preferred terms that reflect adverse events that have been determined to be adverse drug reactions throughout the dose range studied (50 to 400 mg) during any premarketing MDD trials. Adverse reactions are categorized by system organ class and listed in order of decreasing frequency using the following definitions: Very common: *10% of patients Common: *1% and <10% of patients Uncommon: *0.1% and <1% of patients Rare: *0.01% and <0.1% of patients Very rare: <0.01% of patients Cardiac disorders: Common: palpitations, tachycardia. Ear and labyrinth disorders: Common: tinnitus. Eye disorders: Common: mydriasis, vision blurred. Gastrointestinal disorders: Very common: nausea, dry mouth, constipation; Common: vomiting, diarrhea. General disorders and administration site conditions: Very common: fatigue; Common: asthenia, chills, feeling jittery, irritability; Uncommon: drug withdrawal syndrome. Immune system disorders: Uncommon: hypersensitivity. Investigations: Common: weight decreased, weight increased, blood pressure increased; Uncommon: blood cholesterol increased, blood prolactin increased, blood triglycerides increased, liver function test abnormal. Metabolism and nutrition disorders: Very common: decreased appetite. Musculoskeletal, connective tissue, and bone disorders: Common: musculoskeletal stiffness. Nervous system disorders: Very common: headache, dizziness; Common: somnolence, tremor, disturbance in attention, paraesthesia, dysgeusia; Uncommon: syncope; Rare: convulsion, dystonia. Psychiatric disorders: Very common: insomnia; Common: orgasm abnormal, anorgasmia, anxiety, nervousness, libido decreased, abnormal dreams; Uncommon: depersonalization, hypomania. Renal and urinary disorders: Common: urinary hesitation; Rare: proteinuria. Reproductive system and breast disorders: Common: erectile dysfunction,* ejaculation delayed,* ejaculation disorder,* ejaculation failure*; Uncommon: sexual dysfunction. Respiratory, thoracic, and mediastinal disorders: Common: yawning; Uncommon: epistaxis. Skin and subcutaneous tissue disorders: Very common: hyperhidrosis; Common: rash. Vascular disorders: Common: hot flush; Uncommon: orthostatic hypotension. * Frequency is calculated based on men only. Ischemic cardiac adverse events: in clinical trials, there were uncommon reports of ischemic cardiac adverse events, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during desvenlafaxine treatment as compared to placebo (see WARNINGS AND PRECAUTIONS/Cardiovascular/ Cerebrovascular). Discontinuation Symptoms: adverse drug reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical trials at a rate of *5% include: dizziness, nausea, headache, irritability, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS). Orthostatic Hypotension: Of the 3,292 patients in clinical trials with PRISTIQ, 5% were 65 years of age or older. No overall differences in safety or efficacy were detected between these subjects and younger subjects; however, in the short-term placebo-controlled trials, there was a higher incidence of orthostatic hypotension in patients *65 years of age compared to patients <65 years of age treated with desvelafaxine. Greater sensitivity of some older individuals cannot be ruled out. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Dosing Considerations, Geriatrics and ACTION AND CLINICAL PHARMACOLOGY, Geriatrics). ECG Changes: electrocardiograms were obtained from 1,492 PRISTIQ-treated patients with major depressive disorder and 984 placebo-treated patients in clinical trials lasting up to 8 weeks. No clinically relevant differences were observed between PRISTIQ-treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval (see ACTION AND CLINICAL PHARMACOLOGY). A thorough QTc study was designed to assess the potential effect of 200 and 600 mg of PRISTIQ on QT interval prolongation. Table 4: Estimated and 90% Confidence Interval for QTc Changes from Time-Matched Baseline Relative to Placebo at Hour 8 after Dose with Different Heart Rate Corrections a Treatment

Fridericia’s QT Correction (ms)

Population QT Correction (ms)

PRISTIQ 200 mg

1.5 (-0.88, 3.88)

3.18 (0.87, 5.50)

PRISTIQ 600 mg b

-2.43 (-4.90, 0.04)

0.98 (-1.42, 3.38)

Moxifloxacin 400 mg (Active control)

10.80 (8.44, 13.16)

10.92 (8.62, 13.22)

Abnormal Hematologic and Clinical Chemistry Findings Serum Lipids Elevations in fasting serum total cholesterol, LDL cholesterol, and triglycerides occurred in the controlled trials. Some of these abnormalities were considered potentially clinically significant (see WARNINGS AND PRECAUTIONS, Serum Cholesterol Elevation and Monitoring and Laboratory Tests, Serum Lipids). The percentage of subjects who exceeded a predetermined threshold for values of outliers is represented in Table 5. Table 5: Proportion (%) of Subjects With Lipid Abnormalities of Potential Clinical Significance for All Short-Term, Placebo-Controlled Clinical Trials PRISTIQ

Canadian Family Physician t Le Médecin de famille canadien

50 mg n=317

100 mg n=424

200 mg n=307

400 mg n=317

50-400 mga n=1834

Total Cholesterol Increase *1.29 mmol/L and absolute value *6.75 mmol/L LDL Cholesterol Increase *1.29 mmol/L and absolute value *4.91 mmol/L Triglycerides *3.7 mmol/L

a. Includes data from all short-term, placebo-controlled studies including fixed-dose and flexible-dose studies. Proteinuria In placebo-controlled studies 6.4% of subjects treated with PRISTIQ, had treatment-emergent proteinuria. Proteinuria was usually of trace amounts, and was not associated with increases in BUN or creatinine or adverse events. The mechanism of the enhanced protein excretion is not clear but may be related to noradrenergic stimulation. Vital Sign Changes Tables 6 and 7 summarize the changes that were observed in placebo-controlled, short-term, premarketing trials with PRISTIQ in patients with MDD. Table 6: Mean Changes, Vital Signs, at Final On-Therapy for All Short-term, Fixed-dose Controlled Trials PRISTIQ Placebo

50 mg

100 mg

200 mg

400 mg

-1.4 -0.6

1.2 0.7

2.0 0.8

2.5 1.8

2.1 2.3

-0.3 0.0

1.3 -0.4

1.3 -0.6

0.9 -0.9

4.1 -1.1

Blood Pressure Supine systolic bp (mm Hg) Supine diastolic bp (mm Hg) Pulse rate Supine pulse (bpm) Weight (kg)

At the final on-therapy assessment in the 6-month, double-blind, placebo-controlled phase of a long-term trial in patients who had responded to PRISTIQ during the initial 12-week, open-label phase, there was no statistical difference in mean weight change between PRISTIQ- and placebo-treated patients. Table 7 provides the incidence of patients meeting criteria for sustained hypertension (defined as treatment-emergent supine diastolic blood pressure *90 mm Hg and *10 mm Hg above baseline for 3 consecutive visits). Table 7: Incidence (%) of Patients with Sustained Hypertension for All Short-Term Fixed-Dose Clinical Trials PRISTIQ Placebo Sustained hypertension

0.5

50 mg 1.3

100 mg 0.7

200 mg 1.1

400 mg 2.3

DRUG-DRUG INTERACTIONS Potential for other drugs to affect desvenlafaxine succinate (see also ACTION AND CLINICAL PHARMACOLOGY) Inhibitors of CYP3A4: CYP3A4 is a minor pathway for the metabolism of PRISTIQ. In a clinical study, ketoconazole (200 mg BID) increased the area under the concentration vs. time curve AUC of PRISTIQ (400 mg single dose) by about 43% and Cmax by about 8%. Concomitant use of PRISTIQ with potent inhibitors of CYP3A4 may result in higher concentrations of PRISTIQ. Inhibitors of other CYP enzymes: based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of desvenlafaxine. Potential for desvenlafaxine to affect other drugs (see also ACTION AND CLINICAL PHARMACOLOGY) Drugs metabolized by CYP2D6: clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. When desvenlafaxine succinate was administered at a dose of 100 mg daily in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased approximately 17%. When 400 mg of desvenlafaxine was administered (8 times the recommended 50 mg dose), the AUC of desipramine increased approximately 90%. Concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 may result in higher concentrations of that drug. Drugs metabolized by CYP3A4: in vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isozyme. In a clinical study, PRISTIQ (400 mg daily) was co-administered with a single 4 mg dose of midazolam (a CYP3A4 substrate). The AUC and Cmax of midazolam decreased by approximately 31% and 16%, respectively. Concomitant use of PRISTIQ with a drug metabolized by CYP3A4 may result in lower exposure to that drug. Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19: in vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes. P-glycoprotein transporter In vitro, desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter. The pharmacokinetics of desvenlafaxine are unlikely to be affected by drugs that inhibit the P-glycoprotein transporter and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter. Drug-Food Interactions Food does not alter the bioavailability of desvenlafaxine. Drug-Herb Interactions St. John’s Wort: in common with SSRI's, pharmacodynamic interactions between PRISTIQ and the herbal remedy St. John’s Wort may occur and may result in an increase in undesirable effects (see DRUG INTERACTIONS, Serotonin Syndrome). Drug-Lifestyle Interactions Ethanol: as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking desvenlafaxine succinate. For complete prescribing information please refer to the Product Monograph. PRISTIQ® Pfizer Products Inc., Pfizer Canada Inc., licensee TM Pfizer Inc., used under license © 2010 Pfizer Canada Inc., Kirkland, Quebec H9J 2M5

a. Mean (90% confidence intervals) b. The PRISTIQ doses of 200 and 600 mg were 2 and 6 times the maximum recommended dose, respectively.

102

Placeboa n=1116

| VOL 57: JANUARY t JANVIER 2011

observed in long term clinical trials. Because of limited clinical experience in patients who have cardiac conditions that might be worsened by an increase in heart rate, such as ischemic heart disease and tachyarrhythmia, caution should be observed in these patients. The incidence of a composite endpoint for all tachyarrhythmia in pooled clinical trials in diabetic patients was higher for VictozaÂŽ than for placebo.

Prescribing Summary THERAPEUTIC CLASSIFICATION Human Glucagon Like Peptide-1 (GLP-1)

Patient Selection Criteria INDICATIONS AND CLINICAL USE VictozaÂŽ is indicated for once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control in combination with: metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control and metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control. VictozaÂŽ should not be used in type 1 diabetes (formerly known as insulin-dependent diabetes mellitus or IDDM). CONTRAINDICATIONS VictozaÂŽ is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), patients who are hypersensitive to liraglutide or to any ingredient in the formulation and in pregnancy or breast-feeding women. SPECIAL POPULATIONS Pregnant Women: There have been no studies conducted in pregnant women with VictozaÂŽ. VictozaÂŽ should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment with liraglutide should be discontinued. Nursing Women: It is not known whether VictozaÂŽ is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for liraglutide in animal studies, women who are nursing should discontinue VictozaÂŽ treatment. Pediatrics (< 18 years of age): The safety and efficacy of VictozaÂŽ in pediatric patients has not been studied. VictozaÂŽ is not indicated in pediatric type 2 diabetes patients. Geriatrics (> 65 years of age): In the VictozaÂŽ clinical trials, a total of 797 (20%) of the patients were 65 years of age and over, of which 113 (2.8%) were 75 years of age and over. No differences in effectiveness were observed between subjects 65 years and over and younger subjects in the clinical studies. Patients > 70 years experienced more gastrointestinal side effects when treated with VictozaÂŽ.

Safety Information

PR Interval Prolongation: A prolongation of the mean PR interval of up to 10 ms was reported with VictozaÂŽ treatment in a clinical trial in healthy volunteers. In healthy volunteers and in patients with diabetes, the incidence of first degree atrioventricular (AV) block was higher with VictozaÂŽ than with placebo. The clinical significance of these changes is not fully known; however, because of limited clinical experience in patients with pre-existing conduction system abnormalities (e.g., marked first-degree AV block or second- or third-degree AV block) and heart rhythm disturbances (e.g., tachyarrhythmia), caution should be observed in these patients. General VictozaÂŽ should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. VictozaÂŽ should not be administered intravenously or intramuscularly. Endocrine and Metabolism Hypoglycemia Patients receiving VictozaÂŽ in combination with a sulfonylurea may have an increased risk of hypoglycemia. The risk of hypoglycemia can be lowered by reducing the dose of sulfonylurea. Pancreatitis In clinical trials conducted in adult patients with type 2 diabetes, very rare cases of pancreatitis were reported more frequently in the VictozaÂŽ-treated group than in the comparator-treated group (2.2 vs. 0.6 cases per 1000 subject-years). In the VictozaÂŽ-treated group one fatal case of necrotizing pancreatitis was observed. The causality relationship to VictozaÂŽ is unclear. After initiation of VictozaÂŽ and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, VictozaÂŽ and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, VictozaÂŽ should not be restarted. Use with caution in patients with a history of pancreatitis. ADVERSE REACTIONS Adverse Drug Reaction Overview: In long term clinical trials, the most common adverse drug reactions were gastrointestinal disorders, infections and nervous system disorders. Discontinuation of treatment due to adverse events was most common with VictozaÂŽ (7.8%) as compared to comparator treatments (3.4%). The difference was driven by withdrawals due to gastrointestinal disorders. Serious adverse events occurred in a similar proportion of patients treated with VictozaÂŽ (5.7%) as compared to other study treatments (5.6%), most commonly cardiac disorders (19.6 vs. 18.9 events per 1000 patient years respectively). You can report any suspected adverse reactions associated with the use of health products to the 1>141 ,979<1>35 'B?7B1= 2I ?>5 ?6 D85 6?<<?G9>7 G1IC - Report online at www.healthcanada.gc.ca/medeffect 1<< D?<< 6B55 1D

WARNINGS AND PRECAUTIONS

?=@<5D5 1 1>141 ,979<1>35 (5@?BD9>7 ?B= 1>4 61H D?<< 6B55 D? ?B =19< D? 1>141 ,979<1>35 'B?7B1= 51<D8 1>141 '?CD1< #?31D?B &DD1G1 &% " "

Serious Warnings and Precaution Risk of Thyroid C-cell Tumours O #9B17<ED945 31EC5C 4?C5 45@5>45>D 1>4 DB51D=5>D 4EB1D9?> 45@5>45>D D8IB?94 35<< tumours at clinically relevant exposures in both genders of rats and mice. It is unknown whether VictozaÂŽ 31EC5C D8IB?94 35<< DE=?EBC 9>3<E49>7 =54E<<1BI D8IB?94 31B39>?=1 $* 9> 8E=1>C 1C 8E=1> B5<5F1>35 3?E<4 >?D 25 BE<54 ?ED 2I 3<9>931< ?B >?>3<9>931< studies. O ,93D?J1ÂŽ 9C 3?>DB19>4931D54 9> @1D95>DC G9D8 1 @5BC?>1< ?B 61=9<I 89CD?BI ?6 $* 1>4 in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of D8IB?94 35<< DE=?EBC Patients should be counselled regarding the risk and symptoms of thyroid tumours. Cardiovascular Increase in Heart Rate: A 24 h time-averaged increase in mean heart rate of 7-8 bpm was reported with VictozaÂŽ treatment in a clinical trial in healthy volunteers undergoing C5B91< =?>9D?B9>7 > @1D95>DC G9D8 49125D5C 1 2@= 9>3B51C5 9> =51> @E<C5 B1D5 G1C

Administration DOSAGE AND ADMINISTRATION Dosing Considerations ?B 1<< @1D95>DC ,93D?J1ÂŽ is administered once daily at any time, independent of meals. VictozaÂŽ should be initiated with a dose of 0.6 mg once daily for at least one week. The 0.6 mg dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg once daily. Based on clinical response and after at least one week the dose can be increased to 1.8 mg once daily to achieve maximum efficacy for glycemic control. VictozaÂŽ can be added to existing metformin therapy. The current dose of metformin can be continued unchanged at the discretion of the physician. VictozaÂŽ can be added to combined metformin and sulfonylurea therapy. During clinical trials physicians were advised, at their discretion, to lower the dose of sulfonylurea to minimize the risk of unacceptable hypoglycemia.

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Administration Victoza® is administered once daily at anytime, independent of meals, and can be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site and timing can be changed if needed without dose adjustment.

Study References 1. Victoza® Product Monograph, Novo Nordisk Canada Inc., 2010. Supplemental Product Information WARNINGS AND PRECAUTIONS Carcinogenesis and Mutagenesis Risk of Thyroid C-Cell Tumors: In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 subject-years). Two additional cases of thyroid C-cell hyperplasia in Victoza®-treated patients and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one nonliraglutide-treated patient developed elevated calcitonin concentrations while on treatment. Monitoring and Laboratory Tests Regular self-monitoring of blood glucose is not needed in order to adjust the dose of Victoza®. However, when initiating treatment with Victoza® in combination with a sulfonylurea blood glucose self-monitoring may become necessary to reduce the dose of the sulfonylurea in order to reduce the risk of hypoglycemia. ADVERSE REACTIONS Clinical Trial Adverse Drug Reactions: For more details on treatment-emergent adverse events with frequency *1% from two 26 week combination trials 1572 and 1697 regardless of investigator assessment of causality, see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Table 1 in the Product Monograph. The two 26-week controlled clinical studies of Victoza® were LEAD 2-1572 for add on combination therapy with metformin and LEAD 5–1697 for add on combination therapy with metformin + sulfonylurea.

dyspepsia and constipation. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. Most episodes of nausea were mild or moderate in severity and declined over time. Withdrawals due to gastrointestinal adverse events occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients, mainly during the first 2 – 3 months of the trials. Immunogenicity: Approximately 50-70% of Victoza®-treated patients in pooled clinical trials of 26 weeks or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an under-estimated percentage of patients who developed antibodies. Cross reacting antibodies to native GLP-1 occurred in 6.9% of Victoza®-treated patients in a 52 week monotherapy trial and 4.8% of Victoza®-treated patients in 26 week combination therapy trials. Injection site reactions: Overall injection site reactions have been reported in approximately 2% of subjects receiving Victoza® in long-term controlled trials, most frequently bruising and pain. The rate of injection site disorders was 18.1, 27.6 and 37.6 events per 1000 subject-years of exposure for patients treated with liraglutide 0.6, 1.2 and 1.8 mg as compared to 34.0 and 14.9 events per 1000 subject-years of exposure for patients treated with placebo and active comparator. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions. None of these patients were tested positive for liraglutide antibodies. For more details on Serious Adverse Drug Reactions (SAEs) and Rare Adverse Drug Reactions of interest *0.1% and <1% from long term clinical trials, see ADVERSE REACTIONS, Less Common Clinical Trial Serious Adverse Drug Reactions (SAEs) and Rare Adverse Drug Reactions of interest *0.1% and <1% from long term clinical trials in the Product Monograph. Post-Market Adverse Drug Reactions Victoza® has been marketed since July 2009. As of 31 March 2010, Novo Nordisk has received 367 adverse drug reaction reports from market use of Victoza® comprising 767 adverse drug reactions of which 303 were non-serious reports and 64 were serious reports. Most adverse reactions were reported in the category of gastrointestinal disorders (235 non-serious, 62 serious of which 21 were serious unexpected events), general disorders and administrative site conditions (114 nonserious and 12 serious of which 9 were serious unexpected events), investigations (56 non-serious and 20 serious events of which 20 were serious unexpected events), nervous system disorders (57 non-serious and 10 serious of which 10 were serious unexpected events), skin and subcutaneous tissue disorder (31 non-serious and 5 serious of which 5 were serious unexpected events), metabolism and nutrition disorders (28 non-serious and 14 serious of which 14 were serious unexpected events), psychiatric disorders (14 non-serious and 9 serious of which 9 were serious unexpected events), musculoskeletal and connective tissue disorders (17 non-serious and 4 serious of which 4 were serious unexpected events), renal and urinary disorders (8 non-serious and 9 serious of which 9 were serious unexpected events), respiratory, thoracic and mediastinal disorders (8 non-serious and 4 serious of which 4 were serious unexpected events) and vascular disorders (4 non-serious and 6 serious of which 6 were serious unexpected adverse events). The adverse events reported do not change the safety profile for Victoza®.

Medullary thyroid cancer: Patients with MTC usually have calcitonin values >50 ng/L. In Victoza® clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one patient treated with Victoza® and no comparator-treated patients developed serum calcitonin >50 ng/L.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of patients treated with Victoza®, 0.3% of placebo-treated patients, and 0.5% of-active comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza®. The clinical significance of these findings is unknown.

Victoza® comes in a pre-filled disposable pen, comprising of a pen injector assembled with a cartridge (3 mL). Victoza® contains the following non-medicinal ingredients: disodium phosphate dihydrate, propylene glycol, phenol and water for injections.

Papillary thyroid cancer: In the completed trials the rates of papillary thyroid carcinoma were 1.9 and 0.6 (liraglutide vs. non-liraglutide) events per 1000 subjects-years of exposure. Papillary (follicular) thyroid cancers occurred at a higher frequency in the liraglutide clinical development programme than in the general Canadian population. Subjects included in the liraglutide clinical trial program underwent thyroid related assessments, leading to a high number of thyroidectomies. The majority of papillary carcinomas were incidental findings arising from thyroidectomies performed as a result of elevations in serum calcitonin; all but one of the papillary carcinomas were microcarcinomas of less than 1.0 cm. In subjects with pre-existing thyroid disease, the rates of thyroid neoplasms were comparable for liraglutide and placebo (28.8 per 1000 subject-years and 29.3 per 1000 subject-years; none in active comparator).

The cartridge is made of glass (type 1), containing a bromobutyl rubber closure shaped as a plunger and closed with a bromobutyl/ polyisoprene rubber closure. The pen injector is made of polyolefin and polyacetal. When incinerated these materials only result in non-toxic waste products (carbondioxide and water).

Neoplasms: In the intermediate and long-term trials, 115 treatment emergent neoplasm adverse events were reported and of these, 45 events were classified as malignant neoplasms. The proportion and rate (shown in brackets) of subjects with neoplasm adverse events (benign and malignant) was 1.8% (26.9 cases per 1000 subject-years), 1.2% (17.0 cases per 1000 subject-years) and 1.3% (25.3 cases per 1000 subject-years) for liraglutide, active comparator and placebo, respectively. The proportion and rate of subjects with malignant neoplasm adverse events was 0.8% (10.9 cases per 1000 subject-years), 0.5% (7.2 cases per 1000 subject-years) and 0.3% (6.3 cases per 1000 subject-years) for liraglutide, active comparator and placebo, respectively. Thyroid neoplasms were the most common neoplasm adverse events. The proportion and rate of subjects with benign thyroid neoplasms were higher for subjects treated with liraglutide compared to subjects treated with active comparator and placebo [liraglutide: 1.1% (16.0 cases per 1000 subject -years); active comparator: 0.6% (9.8 cases per 1000 subject-years); placebo: 1.0% (19.0 cases per 1000 subject-years)].

Victoza® multidose pen can deliver 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg. OVERDOSAGE For management of a suspected drug overdose, contact your regional Poison Control Centre. STORAGE AND STABILITY Victoza® should be stored in a refrigerator (2–8°C). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze Victoza® and do not use Victoza® if it has been frozen. After initial use of the Victoza® pen, the product can be stored for 30 days at room temperature (not above 30°C) or in a refrigerator (2–8°C). Complete Product Monograph is available upon request. For a copy of the Product Monograph, please contact: Novo Nordisk Canada Inc. 300-2680 Skymark Avenue Mississauga, Ontario L4W 5L6

Cardiovascular: Adverse events identified using a composite endpoint for all tachyarrhythmias in pooled intermediate and long term trials, including open label arms, occurred at rates of 16.5, 6.1, and 15.3 per 1000 subject-years in the liraglutide, placebo and active comparator groups. The respective proportions were 0.7, 0.2 and 0.7 per cent. The most commonly reported episodes of tachyarrhythmia were extrasystoles. The rate of pooled events of atrial fibrillation, atrial flutter, supraventricular tachycardia and supraventricular arrhythmia was 6.4 per 1000 subject-years in the liraglutide group and 5.6 per 1000 subject-years in the active comparator group; no events were reported in the placebo group. Rates of adverse events related to tachyarrhythmia reported as Serious Adverse Events were 2.7, 0 and 2.8 per 1000 subject-years in the Victoza®, placebo and active comparator groups respectively. In pooled long term trials, the rate of first-degree AV block was reported to be 2.6, 0 and 1.4 per 1000 subject-years in the liraglutide, placebo and active comparator groups.

Five additional cases of pancreatitis have subsequently been reported in clinical trials of Victoza®. One of these was a case of acute pancreatitis in a patient whose treatment remains blinded. The remaining 4 cases occurred in Victoza®-treated patients; 2 cases were acute pancreatitis, 1 case was chronic pancreatitis and 1 case was reported as “not acute”. Hypoglycemia: Major hypoglycemic episodes in the long-term phase 3 trials were rare (10 episodes in 9 subjects) and seven of these major episodes were reported when liraglutide was used in combination with glimepiride. Gastrointestinal adverse events: In pooled long term clinical trials, gastrointestinal adverse events were reported in 41% of Victoza®- treated patients and were dose related. Gastrointestinal adverse events occurred in 17% of comparatortreated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea,

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Pancreatitis: In clinical trials of Victoza® there were 7 cases of pancreatitis among Victoza®-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 subject-years). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. All events were serious except for one case of chronic pancreatitis in a patient treated with Victoza®. One fatal case of pancreatitis with necrosis was observed, in a Victoza®-treated patient.

10/5 mg, 20/10 mg, 40/20 mg

Prescribing Summary Patient Selection Criteria THERAPEUTIC CLASSIFICATION: Opioid Analgesic/Opioid Antagonist INDICATIONS AND CLINICAL USE: Adults: TarginÂŽ (oxycodone hydrochloride/naloxone hydrochloride) is a controlled release tablet having a dual therapeutic effect. The oxycodone component in TarginÂŽ is indicated for the relief of moderate to severe pain in adults who require continuous around-the-clock opioid analgesia for several days or more. The naloxone component in TarginÂŽ is indicated for the relief of opioid-induced constipation (OIC). Geriatrics (> 65 years of age): In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease and other drug therapy. The dosage should be adjusted to the intensity of the pain and the sensitivity of the individual patient. Pediatrics (< 18 years of age): The safety and efficacy of TarginÂŽ has not been studied in the pediatric population. Therefore, use of TarginÂŽ is not recommended in patients under 18 years of age. CONTRAINDICATIONS: TarginÂŽ (oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) is contraindicated in: .7J?;DJI M>E 7H; >OF;HI;DI?J?L; JE J>; 79J?L; IK8IJ7D9;I ENO9E:ED; EH D7BENED; EH other opioid analgesics or to any ingredient in the formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. 'D F7J?;DJI M?J> ADEMD EH IKIF;9J;: C;9>7D?97B =7IJHE?DJ;IJ?D7B E8IJHK9J?ED ; = bowel obstruction, strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type). :C?D?IJH7J?ED 8O J>; H;9J7B HEKJ; ?I 9EDJH7?D:?97J;: I;; WARNINGS AND PRECAUTIONS). .7J?;DJI M?J> IKIF;9J;: IKH=?97B 78:EC;D ; = 79KJ; 7FF;D:?9?J?I EH F7D9H;7J?J?I .7J?;DJI M?J> C?B: ?DJ;HC?JJ;DJ EH I>EHJ :KH7J?ED F7?D J>7J 97D 8; C7D7=;: M?J> EJ>;H pain medications. 2>; C7D7=;C;DJ E< 79KJ; F7?D ?D9BK:?D= KI; ?D EKJF7J?;DJ EH :7O IKH=;H?;I 2>; C7D7=;C;DJ E< F;H?EF;H7J?L; F7?D .7J?;DJI M?J> 79KJ; 7IJ>C7 EH EJ>;H E8IJHK9J?L; 7?HM7O 7D: IJ7JKI 7IJ>C7J?9KI .7J?;DJI M?J> 79KJ; H;IF?H7JEHO :;FH;II?ED ;B;L7J;: 97H8ED :?EN?:; B;L;BI ?D J>; 8BEE: and cor pulmonale. .7J?;DJI M?J> 79KJ; 7B9E>EB?IC :;B?H?KC JH;C;DI 7D: 9EDLKBI?L; :?IEH:;HI .7J?;DJI M?J> I;L;H; ",1 :;FH;II?ED ?D9H;7I;: 9;H;8HEIF?D7B EH ?DJH79H7D?7B FH;IIKH; and head injury. .7J?;DJI J7A?D= CEDE7C?D; EN?:7I; + - ?D>?8?JEHI EH M?J>?D :7OI E< IK9> J>;H7FO 4EC;D M>E 7H; 8H;7IJ <;;:?D= FH;=D7DJ EH :KH?D= B78EKH 7D: :;B?L;HO -F?E?: :;F;D:;DJ F7J?;DJI 7D: <EH D7H9EJ?9 M?J>:H7M7B JH;7JC;DJ .7J?;DJI M?J> CE:;H7J; JE I;L;H; >;F7J?9 ?CF7?HC;DJ ">?B: .K=> "B7II ! "

Safety Information WARNINGS AND PRECAUTIONS: General TarginÂŽ (oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) should be swallowed whole. Taking broken, chewed, dissolved or crushed TarginÂŽ tablets could lead to the rapid release and absorption of a potentially fatal dose of oxycodone. TarginÂŽ should not be administered rectally due to the possible increased systemic availability of naloxone by this route and the potential for the occurrence of severe withdrawal effects (see CONTRAINDICATIONS). TarginÂŽ 40/20 mg tablets are for use in opioid tolerant patients only (see also DOSAGE AND ADMINISTRATION). A single dose greater than 40 mg of oxycodone, or total daily doses greater than 80 mg of oxycodone, may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS). Patients for whom TarginÂŽ is prescribed should not give TarginÂŽ to anyone else as such inappropriate use may have severe medical consequences, including death. TarginÂŽ should not be used to treat patients with constipation not related to opioid use. Patients should be cautioned not to consume alcohol while taking TarginÂŽ, as it may increase the chance of experiencing dangerous side effects. There is no clinical experience in patients with cancer associated

with peritoneal carcinomatosis or with sub-occlusive syndrome in advanced stages of digestive and pelvic cancers. Therefore, the use of TarginÂŽ in this population is not indicated. Gastrointestinal Diarrhea is a possible effect of naloxone. If severe or persistent diarrhea lasts for more than 3 days during treatment, patients should be advised to contact their physician. Abuse of Opioid Formulations If abused parenterally, intranasally or rectally by individuals dependent on opioid agonists, TarginÂŽ is expected to produce marked withdrawal symptoms â&#x20AC;&#x201C; because of the systemic opioid receptor antagonist characteristics of naloxone by these routes â&#x20AC;&#x201C; or to intensify withdrawal symptoms already present. TarginÂŽ consists of a dual polymer matrix intended for oral use only. Abuse can lead to overdose and death. This risk is increased when the tablets are crushed, dissolved, broken or chewed, and with concurrent consumption of alcohol or other CNS depressants. With parenteral abuse, the tablet excipients, especially talc, can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Dependence/Tolerance As with other opioids, tolerance and physical dependence may develop upon repeated administration of TarginÂŽ and there is a potential for development of psychological dependence. TarginÂŽ tablets should therefore be prescribed and handled with the degree of caution appropriate to the use of a drug with abuse potential. Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Opioids, such as oxycodone, should be used with particular care in patients with a history of alcohol and drug abuse. Drug abuse is usually not a problem in patients with pain in which opioids are appropriately indicated. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. Use in Drug and Alcohol Addiction TarginÂŽ is an agonist/antagonist combination product with no approved use in the management of addictive disorders. Neurologic Interaction with Other Central Nervous System Depressants: Oxycodone should be used with caution and in a reduced dosage during concomitant administration of other opioid analgesics, general anaesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants and other CNS depressants, including alcohol. Respiratory depression, hypotension and profound sedation or coma may result. Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest. Patients who are scheduled for chordotomy or other interruption of pain transmission pathways should not receive TarginÂŽ within 24 hours of the procedure. Head Injury: The respiratory depressant effects of oxycodone, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, oxycodone may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, oxycodone must be used with extreme caution and only if it is judged essential. Withdrawal Effects: Withdrawal symptoms may occur following abrupt discontinuation of therapy. These symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. In patients who are appropriately treated with opioid analgesics and who undergo gradual withdrawal from the drug, these symptoms are usually mild. Cardiovascular TarginÂŽ should be used with caution in patients with preexisting cardiovascular disease. Oxycodone administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume or concurrent administration of drugs, such as phenothiazines or certain anaesthetics. Oxycodone may produce orthostatic hypotension in ambulatory patients. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Respiratory Depression Oxycodone should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia. Such patients are often less sensitive to the stimulatory effects of carbon dioxide (CO2) on the respiratory centre and the respiratory depressant effects of oxycodone may reduce respiratory drive to the point of apnea. Pre- and PostOperative Use TarginÂŽ is contraindicated for perioperative use, within 24 hours before or after surgery. TarginÂŽ is not indicated for pain in the postoperative period if the pain is mild or not expected to persist for an extended period of time.In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with TarginÂŽ within 24 hours before or after the operation. Thereafter, if TarginÂŽ is to be continued after the patient recovers from the postoperative period, a new dose should be used in accordance with the changed need for pain relief. Psychomotor Impairment TarginÂŽ may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients using TarginÂŽ should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug. Patients should also be cautioned about the combined effects of TarginÂŽ with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol. Special Populations Special Risk Groups: Oxycodone should be administered with caution and in a reduced dosage to debilitated patients, and in patients with Addison's disease, cholelithiasis, hypothyroidism, toxic psychosis, pancreatitis, prostatic hypertrophy or urethral stricture. Nursing Women: Oxycodone passes into the breast milk. It is not known whether naloxone is excreted in human milk. Since the safety of TarginÂŽ in infants and newborns has not been studied, TarginÂŽ is contraindicated in nursing mothers. Pregnancy, Labour and Delivery: Oxycodone and naloxone pass into the placenta. TarginÂŽ is contraindicated during pregnancy, labour and delivery due to impaired uterine contractility and the risk of neonatal respiratory depression. There are no adequate data from the use of TarginÂŽ in pregnant women or during childbirth. Animal studies have not been performed with oxycodone and naloxone in combination. While

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animal reproduction studies have revealed no evidence of harm to the fetus due to oxycodone, safe use in pregnancy has not been established. Long-term administration of oxycodone during pregnancy may lead to withdrawal symptoms in the newborn. Geriatrics (> 65 years of age): In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The dosage should be adjusted to the lowest Targin® dose which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects. Pediatrics (< 18 years of age): Targin® has not been studied in children and is not recommended for patients less than 18 years of age. The safety and efficacy of Targin® in children have not been established. Hepatic Impairment:A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with hepatic impairment. Naloxone concentrations were affected to a higher degree than oxycodone. The clinical relevance of this is under investigation. Caution must be exercised when administering Targin® to patients with mild hepatic impairment. Targin® is contraindicated in patients with moderate and severe hepatic impairment (see CONTRAINDICATIONS). Renal Impairment:A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with renal impairment. Naloxone concentrations were affected to a higher degree than oxycodone. The plasma concentrations obtained in patients with mild, moderate and severe renal impairment are comparable to those in mildly hepatic impaired patients. The clinical relevance of this is under investigation, but caution should be exercised when administering Targin® to patients with renal impairment. “In Vitro” Dissolution Studies of Interaction with Alcohol In-vitro data show that in presence of ethanol, at concentrations up to 40%, the controlled-release characteristics of the Targin® formulation were maintained and no breakdown of the controlled release mechanism was observed. ADVERSE REACTIONS: Clinical Trial Adverse Drug Reactions The pre-marketing pivotal clinical program of Targin® (oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) included exposure to 520 patients. A summary of adverse events occurring at an incidence of 1% or more is given below which includes all events, whether considered by the clinical investigator to be related to the study drug or not (see CLINICAL TRIALS for methodological details of the trials). Nausea was a very common adverse effect in patients taking Targin®. Nausea is a common effect associated with other drugs with opioid-agonist activity and tends to reduce with time. Adverse effects, including constipation, diarrhea, fatigue, headache and hyperhidrosis, often observed with other drugs with opioid-agonist activity, were also seen with Targin® treatment. Adverse Event Reports in Targin® Pivotal Clinical Trials (*1%) (% of patients on Targin® (n = 520) / % of patients on Oxycodone CR (n = 446) / % of patients on Placebo * (n = 235): Ear and labyrinth disorders: vertigo 1.7/1.8/5.1. Gastrointestinal disorders: abdominal pain: 3.3/2.7/3.8; abdominal pain upper: 1.9/2.7/2.1; constipation: 6.5/10.5/8.9; diarrhea: 6.2/5.4/6.0; dry mouth: 2.5, 1.6, 2.1; dyspepsia: 1.4/3.4/3.0; flatulence: 1.2, 0.5, 0.9; nausea: 12.3/14.8/14.9; vomiting: 5.4/5.6/6.0. General disorders and administrative site conditions: asthenia: 1.4/0.0/0.9; chills: 1.2/0.7/0.9; drug withdrawal syndrome: 0.2/1.4/0.4; fatigue: 5.4/5.8/4.3; malaise: 0.2/0.7/1.7; edema peripheral: 1.7/1.8/0.0; pain: 2.3/1.6/2.1; pyrexia: 0.4/0.0/1.3. Infections and infestations: bronchitis: 1.5/1.1/0.0; cystitis: 0.2/1.4/1.3; gastroenteritis: 1.9/2.2/0.0; influenza: 1.2/1.6/0.4; nasopharyngitis: 2.9/4.7/4.3; sinusitis: 1.2/0.0/0.0; upper respiratory tract infection: 0.0/1.6/0.0; urinary tract infection: 3.5/2.2/1.3; viral infection: 1.5/1.4/1.3. Injury, poisoning and procedural complications: Contusion: 0.0/0.2/1.7. Investigations: blood cholesterol increased: 0.0/0.0/1.7; blood glucose increased: 1.9/0.2/0.4; blood triglycerides increased: 0.6/2.0/1.7; blood uric acid increased: 0.2/0.2/2.6; gamma-glutamyltransferase increased: 0.6/1.1/0.4; lymphocyte count decrease: 0.0/0.2/1.3. Metabolism and nutrition disorders: anorexia: 0.8/1.1/0.9; decreased appetite: 0.6/0.2/1.3; hyperglycemia: 1.2/1.4/0.0; hyperlipidemia: 1.2/0.2/0.0; hypertriglyceridemia: 1.4/0.2/1.3; hyperuricemia: 1.2/1.1/0.0. Musculoskeletal and connective tissue disorders:arthralgia: 1.5/2.2/2.1; back pain: 3.3/2.5/0.0; neck pain: 0.0/1.4/0.0; osteoarthritis: 1.2/1.6/0.0; pain in extremity: 1.5/1.1/0.0. Nervous system disorders: dizziness: 4.2/8.1/4.3; headache: 6.2/6.3/9.8; migraine: 1.4/0.2/0.4; sciatica: 1.5/0.0/0.0; somnolence: 1.2/1.1/0.0; tremor: 1.0/1.1/0.4. Psychiatric disorders: depression: 1.9/2.5/0.0; insomnia: 2.1/2.5/3.4; nervousness: 0.6/0.0/1.3; restlessness: 0.8/0.2/2.6; sleep disorder: 0.6/0.2/1.7. Skin and subcutaneous tissue disorders: hyperhidrosis: 6.5/4.3/6.4; pruritus: 2.9/4.0/3.0; rash: 1.2/0.5/0.0. Vascular disorders: hot flush: 1.0/2.0/0.9; hypertension: 0.6/1.4/1.7. * Placebo patients received immediate-release oxycodone or combination preparations with codeine 30mg as rescue medication in pivotal clinical trials. Less Common Clinical Trial Adverse Drug Reactions (< 1%): Other less common (< 1%) adverse drug reactions reported and considered in any way related to Targin® in randomized pivotal clinical trials are summarized in the Product Monograph (see Adverse Reactions section in the Product Monograph). To report a suspected adverse reaction, please contact: Purdue Pharma 575 Granite Court Pickering, ON Canada L1W 3W8 Tel: 905-420-6400 1-800-387-5349 DRUG INTERACTIONS Overview Interaction with Central Nervous System (CNS) Depressants Targin® (oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) should be dosed with caution and started in a reduced dosage (1/3 to 1/2 of the usual dosage) in patients who are currently taking other central nervous system depressants (e.g., alcohol, other opioids, sedatives, hypnotics, anti-depressants, sleeping aids, phenothiazines, neuroleptics, anti-histamines and anti-emetics), pyrazolidone and beta-blockers, as they may enhance the CNS-depressant effect (e.g., respiratory depression) of Targin®. Drug-Drug Interactions No interaction studies have been performed with Targin®. Administration with Mixed Activity Agonist/Antagonist Opioids

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Mixed activity agonist/antagonist opioid analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure µ-opioid agonist analgesic, such as the oxycodone in Targin®. In this situation, mixed activity agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients. Drugs Metabolized by Cytochrome P450 Isozymes In vitro metabolism studies indicate that no clinically relevant interactions are to be expected between oxycodone and naloxone. At therapeutic concentrations, Targin® is not expected to cause clinically relevant interactions with other concomitantly administered drugs metabolized over the CYP isomers CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Oxycodone is metabolized, in part, by CYP3A4 therefore caution is advised when Targin® is administered with CYP3A4 inhibitors/inducers. In addition, the likelihood of clinically relevant interactions between acetaminophen or acetylsalicylic acid and the combination of oxycodone and naloxone in therapeutic concentrations is minimal. MAO Inhibitors MAO inhibitors intensify the effects of opioid drugs which can cause anxiety, confusion and decrease respiration. Targin® is contraindicated in patients receiving MAO inhibitors or who have used them within the previous 14 days (see CONTRAINDICATIONS). Warfarin and Other Coumarin Anticoagulants Clinically relevant changes in International Normalized Ratio (INR or Quick-value) in both directions have been observed in individuals when oxycodone and coumarin anticoagulants are co-administered.

Administration DOSAGE AND ADMINISTRATION: Dosing Considerations: Targin® (oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) should be swallowed whole. Taking broken, chewed, dissolved or crushed Targin® tablets could lead to the rapid release and absorption of a potentially fatal dose of oxycodone. Patients who are currently taking oral oxycodone can be switched to Targin® based on an equivalent oxycodone dose. For conversion from other opioids/opioid preparations, patients should be initiated on the lowest available Targin® strength, provided with adequate rescue medication, with dose titration to achieve satisfactory pain relief with acceptable side effects. Targin® doses must be individualized and should be assessed at regular intervals. Targin® 40/20 mg tablets are for use in opioid tolerant patients only. A single dose greater than 40 mg of oxycodone, or total daily doses greater than 80 mg of oxycodone, may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids at equivalent doses (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS). Targin® is contraindicated for rectal administration (see CONTRAINDICATIONS). Targin® is contraindicated in the perioperative period, within 24 hours before or after surgery. Targin® is not indicated for pain in the postoperative period if the pain is mild or not expected to persist for an extended period of time. In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with Targin® within 24 hours before or after the operation. Thereafter, if Targin® is to be continued after the patient recovers from the post-operative period, a new dose should be used in accordance with the changed need for pain relief. In steady-state studies, the analgesic efficacy of Targin® is equivalent to the OxyContin® controlled release oxycodone formulation. In clinical studies with Targin®, only patients who had previously been dosed on oxycodone were switched to Targin®. To date, there is no clinical experience evaluating switching from other analgesics to Targin®. Targin® doses must be individualized based upon the status of each patient and should be assessed at regular intervals after application. Proper optimization of doses scaled to the individual’s pain should aim at the regular administration of the lowest dose of Targin® which provides pain relief. The dosage of the drug must be individualized according to the response and tolerance of the patient. Targin® should be taken at the determined dosage twice daily (every 12 hours) according to a fixed time schedule. Single doses should not exceed 40 mg oxycodone and 20 mg naloxone. The maximum daily dose of Targin® is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. For patients requiring higher doses of Targin®, administration of supplemental controlled-release oxycodone at the same time intervals should be considered. In the case of supplemental oxycodone dosing, the beneficial effect of naloxone on bowel function may be impaired. In general, the lowest effective opioid analgesic dose should be selected. After discontinuation of therapy with Targin®, with a subsequent switch to another opioid, symptoms associated with reduced bowel motility can be expected. The controlled release tablets may be taken with or without food with sufficient liquid (with 4 to 6 oz. of water). The empty matrix tablet remnants may be visible in the stool. Adults (over 18 years) Patients Not Receiving Opioids at the Time of Initiation of Targin ® Treatment (Opioid-Naïve) The usual initial adult dose for patients who have not previously received opioid analgesics is Targin® 10/5 mg every 12 hours. Patients Currently Receiving Opioids Patients who are currently taking oxycodone can be switched to Targin® based on an equivalent oxycodone dose. Discontinue all other around-the-clock oxycodone analgesic medications when Targin® therapy is initiated. In clinical studies with Targin®, only patients who had previously been dosed on oxycodone were switched to Targin®. Patients receiving other oral oxycodone formulations may be transferred to Targin® tablets at the same total daily dosage, equally divided into two 12-hourly Targin® tablet doses and reassessed with dose adjustments made accordingly. To date, there is no clinical experience to refer to for switching other opioid analgesics to Targin®. Patients already receiving oxycodone, and tolerant to the respiratory depressant effects, may be started on higher dose than the usual initial adult dose of 10/5 mg every 12 hours depending on their previous oxycodone dose. Not to exceed the maximum daily dose of Targin®, 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. For conversion from other opioids/opioid preparations, discontinue all other round-the-clock opioid analgesic preparations. Patients should be initiated on the lowest available Targin® strength, provided with adequate rescue

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medication, with dose titration to achieve satisfactory pain relief with acceptable side effects. Targin® doses must be individualized and should be assessed at regular intervals. Targin® should be gradually titrated until adequate pain relief and acceptable side effects have been achieved. The maximum daily dose of Targin® is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. Dose Titration Proper optimization of doses scaled to the relief of the individual's pain should aim at regular administration of the lowest dose of Targin® which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects. Dose adjustments may be made every 1-2 days until a stable dose is reached. Subsequent increases in Targin® dosage must be individualized according to the pain relief and tolerance of the patient with adequate rescue medication, as required (see Management of Breakthrough Pain section of the Product Monograph). If breakthrough pain repeatedly occurs at the end of the dosing interval it is generally an indication for a dosage increase rather than more frequent administration. The maximum daily dose of Targin® is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. Management of Breakthrough Pain Some patients taking Targin® according to a fixed time schedule may require immediate-release analgesics as "rescue" medication for breakthrough pain. Immediate-release oxycodone or combination preparations with codeine 30 mg may be given. Alternatively, non-opioid analgesics may be used. Targin® is a controlled release formulation and therefore is not intended for use as rescue medication. For the treatment of breakthrough pain with an immediate-release opioid, a single dose of “rescue medication” should approximate one sixth of the equivalent daily dose of oxycodone hydrochloride. The need for more than two rescue medication doses per day (24 hours) is usually an indication that the dose of Targin® requires upward adjustment. This adjustment may be made every 1-2 days until a stable dose is reached. The aim is to establish a patient-specific 12 hour dose that will maintain adequate analgesia and minimize side effects for as long as pain therapy is necessary. Reducing the dosing frequency from every 12 hours is not recommended. Managing Expected Opioid Adverse Experiences Many patients receiving opioids, especially those who are opioid-naïve, will experience side effects. Clinical trials have shown that these effects are generally most bothersome during initial treatment and can be minimized by starting Targin® at 10/5 mg every 12 hours and gradually increasing the dose as needed. Other opioid related side effects such as sedation and nausea are usually self-limited and often do not persist beyond the first few days. If nausea persists and is unacceptable to the patient, treatment with anti-emetics or other modalities may relieve these symptoms and should be considered. Missed Dose If the patient forgets to take one or more doses, they should take their next dose at the next scheduled time and in the normal amount. Discontinuation Careful and regular monitoring are required to establish required maintenance of treatment. When the patient no longer requires therapy with Targin®, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. Withdrawal symptoms may occur following abrupt discontinuation of therapy. These symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. In patients who are appropriately treated with opioid analgesics and who undergo gradual withdrawal from the drug, these symptoms are usually mild. If treatment discontinuation is required, the dose of opioid may be decreased as follows: one-half of the previous daily dose given every 12 hours or immediate release oxycodone every 6 hours for the first two days, followed by a 25% reduction every two days. OVERDOSAGE (see Supplemental Product Information) For management of suspected drug overdose, contact your Regional Poison Control Centre.

Study References 1. Pereira J, Bruera E et al. Alberta Hospice Palliative Care Resource Manual. A project of the Alberta Cancer Board with financial support provided by Alberta Cancer Foundation. Division of Palliative Care Medicine, University of Alberta, 2001:1-87. 2. Targin® Product Monograph, Purdue Pharma, March 2010. 3. Lowenstein O et al. Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: a randomized controlled trial. Expert Opin Pharmacother 2009;10(4):531-543. Supplemental Product Information Information for Physicians to Convey to Patients A patient information sheet should be provided when Targin® tablets are dispensed to the patient. Patients receiving Targin® should be given the following instructions by the physician: 1. Patients should be informed that accidental ingestion or use by individuals (including children) other than the patient for whom it was originally prescribed, may lead to severe, even fatal, consequences. 2. Patients should be advised that Targin® contains oxycodone, an opioid pain medicine. 3. Patients should be advised that Targin® should only be taken as directed. The dose of Targin® should not be adjusted without consulting with a physician. 4. Targin® should be swallowed whole (not broken, chewed, dissolved or crushed) due to the risk of fatal oxycodone overdose. 5. Patients should be warned not to administer Targin® by the rectal route, as severe withdrawal effects may occur. 6. Diarrhea is a possible effect of naloxone. Patients should be advised to contact their physician if the diarrhea is severe or persistent.

7. Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication. 8. Patients should not combine Targin® with alcohol or other central nervous system depressants (sleep aids, tranquilizers) because dangerous additive effects may occur resulting in serious injury or death. 9. Patients should be advised to consult their physician or pharmacist if other medications are being used or will be used with Targin®. 10. Patients should be advised that if they have been receiving treatment with Targin® and cessation of therapy is indicated, it may be appropriate to taper the Targin® dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. 11. Patients should be advised of the most common adverse reactions that may occur while taking Targin®: nausea, constipation, diarrhea, hyperhidrosis, fatigue, vomiting, headache and dizziness. 12. Patients should be advised that Targin® may cause drowsiness, dizziness, or lightheadedness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on Targin® or patients whose dose has been adjusted should be advised not to drive a car or operate machinery unless they are tolerant to the effects of Targin®. 13. Patients should be advised that Targin® is a potential drug of abuse. They should protect it from theft or misuse. 14. Patients should be advised that Targin® should never be given to anyone other than the individual for whom it was prescribed. 15. Patients should be advised that Targin® 40/20 mg is for use only in individuals tolerant to the effect of equivalent doses of oxycodone. 16. Women of childbearing potential who become or are planning to become pregnant should be advised to consult a physician prior to initiating or continuing therapy with Targin®. Women who are breast-feeding or pregnant should not use Targin®. 17. Patients should be advised that they may pass empty matrix tablet remnants in the stool, and that this should not be a concern since the analgesic medication, oxycodone, has already been released. ADVERSE REACTIONS Post-Market Adverse Drug Reactions In a two year non-interventional open-label, prospective, observational study (Study 9002) performed in Europe, 7,836 pain patients with severe pain for at least 4 months received Targin® and were monitored over a period of 4 weeks. Approximately 25% of the patients (n=1,963) were opioid naïve with the remaining 5,849 patients previously pre-treated with opioids. The most frequently reported adverse drug reactions in the total population were nausea (3.1%), constipation (3.1%), dizziness (2.4%), abdominal distension (1.9%), diarrhea (1.9%), abdominal pain (1.4%), vomiting (1.1%) and irregular bowel movements (1.1%). All these adverse drug reactions are consistent with the expected adverse event profile of the opioid analgesic class of drugs. (see Adverse Reactions section in the Product Monograph). OVERDOSAGE Symptoms Depending on the history of the patient, an overdose of Targin® (oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) may be manifested by symptoms that are either triggered by oxycodone (opioid receptor agonist) or by naloxone (opioid receptor antagonist). Symptoms of oxycodone overdose include miosis, respiratory depression, somnolence progressing to stupor, skeletal muscle flaccidity, bradycardia as well as hypotension. Coma, non-cardiogenic pulmonary oedema and circulatory failure may occur in more severe cases and may lead to a fatal outcome. Symptoms of a naloxone overdose alone are unlikely due to the low systemic availability of naloxone by the oral route. Withdrawal symptoms due to an overdose of naloxone should be treated symptomatically in a closely-supervised environment. Treatment Primary attention should be given to the establishment of adequate respiratory exchange through the provision of a patent airway and controlled or assisted ventilation. Clinical symptoms suggestive of an oxycodone overdose may be treated by the administration of opioid antagonists (e.g., naloxone 0.4-2 mg intravenously). Administration should be repeated at 2-3 minute intervals, as clinically necessary. It is also possible to apply an infusion of 2 mg naloxone in 500 mL of 0.9% sodium chloride or 5% dextrose (0.004 mg/mL naloxone). The infusion should run at a rate aligned to the previously administered bolus doses and to the patient's response. Consideration may be given to gastric lavage. Supportive measures (artificial ventilation, oxygen, vasopressors and infusions) should be employed, as necessary, to manage the circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Artificial ventilation should be applied if necessary. Fluid and electrolyte metabolism should be maintained. SPECIAL HANDLING INSTRUCTIONS: Store at Room Temperature (15-30°C). Keep in a cool dry place. Protect from light, heat and humidity. Keep Targin® out of sight and reach of children. DOSAGE FORMS AND PACKAGING: Targin® 10/5 mg are white, oblong tablets with a film coating, marked OXN on one side and 10 on the other. Targin® 20/10 mg are pink, oblong tablets with a film coating, marked OXN on one side and 20 on the other. Targin® 40/20 mg are yellow, oblong tablets with a film coating, marked OXN on one side and 40 on the other. All strengths will be available in blisters (10s, 14s, 20s, 28s, 30s, 50s, 56s, 60s, 98s and 100s) and opaque plastic bottles of 50, 60, 100 and 250’s (see DOSAGE FORMS, COMPOSITION AND PACKAGING in the Product Monograph). Targin® is a registered Trademark of Purdue Pharma

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Safety Information

Dabigatran Etexilate 110mg and 150mg Capsules Prescribing Summary

This is a condensed version of the Product Monograph. For complete information please refer to the Product Monograph available at www.boehringer-ingelheim.ca or by contacting Boehringer Ingelheim (Canada) Ltd., 5180 South Service Road, Burlington, Ontario, L7L 5H4. Patient Selection Criteria

THERAPEUTIC CLASSIFICATION: Anticoagulant INDICATIONS AND CLINICAL USE S Prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate. Geriatrics (>65 years of age): Clinical studies have been conducted in patients with a mean age >65 years. Safety and efficacy data are available (see CLINICAL TRIALS in the Product Monograph). Pharmacokinetic studies in older subjects demonstrate an increase in exposure to dabigatran in most of those patients, usually in association with age-related decline of renal function (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Renal Impairment). Pediatrics (<18 years of age): The safety and efficacy of PRADAX have not been established in children less than 18 years of age. Therefore, PRADAX is not recommended in this patient population. CONTRAINDICATIONS S Severe renal impairment (CrCl <30mL/ min) S Hemorrhagic manifestations, bleeding diathesis, or patients with spontaneous or pharmacological impairment of hemostasis S Lesions at risk of clinically significant bleeding, e.g., extensive cerebral infarction (hemorrhagic or ischemic) within the last 6 months, or active peptic ulcer disease with recent bleeding S Concomitant treatment with strong P-glycoprotein (P-gp) inhibitors, i.e., oral ketoconazole (see DRUG INTERACTIONS) S Known hypersensitivity to dabigatran or dabigatran etexilate or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. 108

WARNINGS AND PRECAUTIONS The following Warnings and Precautions are listed in alphabetical order. Bleeding As with all anticoagulants, PRADAX should be used with caution in circumstances associated with an increased risk of bleeding. Bleeding can occur at any site during therapy with PRADAX. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site. Patients at high risk of bleeding should not be prescribed PRADAX (see CONTRAINDICATIONS). Close clinical surveillance (looking for signs of bleeding or anemia) is recommended throughout the treatment period, especially if risk factors are combined. Table 1: Factors which increase hemorrhagic risk, as identified in clinical studies Factors increasing dabigatran plasma levels

Moderate renal impairment (30-50 mL/min CrCl)

Pharmacodynamic interactions

Acetylsalicylic acid

P-glycoprotein-inhibitor comedication NSAID Clopidogrel

Diseases/procedures with special hemorrhagic risks

Congenital or acquired coagulation disorders Thrombocytopenia or functional platelet defects Active ulcerative gastrointestinal disease Recent gastro-intestinal bleeding Recent biopsy or major trauma Recent intracranial hemorrhage Brain, spinal or ophthalmic surgery Bacterial endocarditis

Others

Age *75 years

The measurement of dabigatran-related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors. In patients who are bleeding, an aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT >80 sec at trough, i.e., when the next dose is due, is associated with a higher risk of bleeding (see Monitoring and Laboratory Tests). Should severe bleeding occur, treatment with PRADAX must be discontinued and the source of bleeding investigated promptly. Agents that may enhance the risk of hemorrhage should not be administered concomitantly with PRADAX, or, if necessary, should only be administered with caution (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetic Interactions in the Product Monograph). Treatments that should NOT be administered concomitantly with PRADAX due to increase in bleeding risk include: unfractionated heparin and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, bivalirudin, thrombolytic agents, GPIIb/ IIIa receptor antagonists, ticlopidine, sulfinpyrazone, and vitamin K antagonists

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such as warfarin. The concomitant use of PRADAX with the following treatments has not been studied and may increase the risk of bleeding: rivaroxaban, prasugrel, and the strong P-gp inhibitors itraconazole, tacrolimus, cyclosporine, ritonavir, tipranavir, nelfinavir and saquinavir. Unfractionated heparin may be administered at doses necessary to maintain a patent central venous or arterial catheter. In patients with atrial fibrillation treated for the prevention of stroke and systemic embolism, the co-administration of oral antiplatelet (including aspirin and clopidogrel) and NSAID therapies increases the risk of bleeding by about two-fold (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph). If necessary, co-administration of low-dose ASA, i.e., )100 mg daily with PRADAX may be considered for other indications than stroke prevention in atrial fibrillation. Note that in the RELY trial, there is no evidence that the addition of ASA or clopidogrel to dabigatran, or its comparator warfarin, improved outcomes in respect to stroke (see CLINICAL TRIALS, Stroke Prevention in Atrial Fibrillation in the Product Monograph). Treatment initiation with verapamil should be avoided in patients following orthopedic surgery who are already treated with PRADAX. Simultaneous initiation of treatment with PRADAX and verapamil should also be avoided at any time (see DRUG INTERACTIONS, P-glycoprotein inhibitors). Interaction with P-gp inducers The concomitant use of PRADAX with the strong P-gp inducer, rifampicin, reduces dabigatran plasma concentrations. Other P-gp inducers such as St. Johnâ&#x20AC;&#x2122;s Wort or carbamazepine are also expected to reduce dabigatran plasma concentrations, and should be co-administered with caution (see DRUG INTERACTIONS and Special Populations). Surgery/Procedural Interventions Patients on PRADAX who undergo surgery or invasive procedures are at increased risk for bleeding. In these circumstances, temporary discontinuation of PRADAX may be required. Pre-operative Phase In advance of invasive or surgical procedures PRADAX should be stopped temporarily due to an increased risk of bleeding. If possible, PRADAX should be discontinued at least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding (see DOSAGE AND ADMINISTRATION) or in major surgery where

complete hemostasis may be required, consider stopping PRADAX 2-4 days before surgery. Clearance of dabigatran in patients with renal insufficiency may take longer (see DOSAGE AND ADMINISTRATION, Renal). This should be considered in advance of any procedures. PRADAX is contraindicated in patients with severe renal dysfunction (CrCl <30 mL/min). Should acute renal failure occur before surgery is required, PRADAX should generally be stopped at least 5 days before major surgery. If acute intervention is required, PRADAX should be temporarily discontinued, due to increased risk of bleeding. Surgery or procedural interventions should be delayed if possible until at least 12 hours after the last dose of PRADAX, with risk of bleeding weighed against the urgency of the needed intervention. Peri-Operative Spinal/Epidural Anesthesia, Lumbar Puncture Procedures such as spinal anesthesia may require complete hemostatic function. In patients treated with PRADAX for VTE prevention following major orthopedic surgery and who undergo spinal or epidural anesthesia, or in whom lumbar puncture is performed in follow-up to surgery, the formation of spinal or epidural hematomas that may result in long-term or permanent paralysis cannot be excluded. In the case of these peri-spinal procedures, administration of the first dose of PRADAX should occur after hemostasis has been obtained and no sooner than 2 hours following puncture or removal of catheters related to these procedures. The risk of these rare events may be higher with post-operative use of indwelling epidural catheters or the concomitant use of other products affecting hemostasis. Accordingly, the use of PRADAX is not recommended in patients undergoing anesthesia with post-operative indwelling epidural catheters. Post-Procedural Period Resume treatment with PRADAX as soon as complete hemostasis is achieved. Renal PRADAX is contraindicated in cases of severe renal impairment (CrCl <30 mL/ min). Patients who develop acute renal failure while on PRADAX should discontinue such treatment. S Patients with atrial fibrillation treated for prevention of stroke and systemic embolism: Since no dose adjustment is necessary for most atrial fibrillation patients with moderate renal impairment (CrCl 30-50 mL/min), a standard daily dose of 300 mg, taken orally as one 150 mg capsule twice daily is recommended (see DOSAGE

AND ADMINISTRATION, Renal Impairment). Special Populations Pregnant Women: Since there are no studies of PRADAX in pregnant women, the potential risk in these patients is unknown. Animal reproductive studies did not show any adverse effects on fertility or postnatal development of the neonate. Women of child-bearing potential should avoid pregnancy during treatment with PRADAX and when pregnant, women should not be treated with PRADAX unless the expected benefit is greater than the risk. Nursing Women: Breast-feeding during treatment with PRADAX is not recommended. There are no clinical data available on the excretion of dabigatran into breast milk. Geriatrics (>65 years of age): Pharmacokinetic studies in older subjects demonstrate an increase in drug exposure; especially in those patients with age-related decline of renal function (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Renal Impairment). S Patients with atrial fibrillation treated for prevention of stroke and systemic embolism: Patients aged 80 years and above should be treated with a daily dose of 220 mg taken orally as one 110 mg capsule twice daily. This alternate dosing may also be considered for other geriatric patients (see DOSAGE AND ADMINISTRATION, Elderly). Use with caution. Pediatrics (<18 years of age): The safety and efficacy of PRADAX have not been established in children less than 18 years of age. Therefore, PRADAX is not recommended in this patient population. Patients of low body weight (<50 kg): Since limited data are available in these patients, PRADAX should be used with caution. Monitoring and Laboratory Tests At recommended doses of PRADAX, dabigatran prolongs coagulation time as measured by the activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT). In patients who are bleeding due to excess activity of dabigatran, these coagulation tests would be expected to be elevated and may be helpful in assessing anticoagulant activity of dabigatran, if necessary (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics in the Product Monograph). The aPTT is generally less sensitive to anticoagulant activity than either TT or ECT (see DRUG INTERACTIONS, Drug-Laboratory Interactions). However, the aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding, the aPTT test may be useful to assist in VOL 57: JANUARY t JANVIER 2011

determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT greater than 80 sec at trough (when the next dose is due) is associated with a higher risk of bleeding. In circumstances where there is no excess of anticoagulant activity, the utility of aPTT is limited in monitoring anticoagulant status of patients taking PRADAX. ADVERSE REACTIONS The safety of PRADAX has been evaluated overall in 22,126 patients. A total of 10,084 patients were exposed to at least one dose of dabigatran as study medication in four active-controlled clinical trials conducted to evaluate the safety and effectiveness of dabigatran etexilate in the prevention of venous thromboembolic events (VTE) following major elective orthopedic surgery. Of these, 5,419 were treated with 150 mg or 220 mg daily of PRADAX, while 389 received doses of less than 150 mg daily, and 1,168 received doses in excess of 220 mg daily. In the RELY trial investigating the prevention of stroke and systemic embolism in patients with atrial fibrillation, a total of 12,042 patients were exposed to PRADAX. Of these, 6,059 were treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily. About 21% of patients with atrial fibrillation treated with dabigatran and about 16% of patients treated with warfarin for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years) experienced adverse events considered related to treatment. Bleeding Bleeding is the most relevant side effect of PRADAX. Bleeding of any type or severity occurred in approximately 14% of patients treated short-term for elective hip or knee replacement surgery and in long-term treatment in 16.5% of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism. Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes. A summary description of major and total bleeding is provided in Table 2. Table 2 shows the number of patients experiencing major and total bleeding event rates during the treatment period in the RELY study, conducted in patients with atrial fibrillation. In Table 2, the category of major bleeds includes both life-threatening and non-life threatening bleeds. Within life-threatening, intracranial bleeds is a subcategory of life-threatening bleeds.

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Intracranial bleeds include intracerebral (hemorrhagic stroke), subarachnoid and subdural bleeds. For this reason, these events may be counted in multiple categories. Table 2: Frequency and annualized event rate (%) of bleeding events from the RELY trial Dabigatran etexilate 110 mg bid N (%)

Dabigatran etexilate 150 mg bid N (%)

Warfarin** N (%)

Patients randomized

6,015

6,076

6,022

Patient-years

11,899

12,033

11,794 421 (3.6)

Major bleeding event (MBE)*

342 (2.9)

399 (3.3)

Hazard ratio vs. warfarin (95% CI)

0.80 (0.70, 0.93)

0.93 (0.81, 1.07)

0.0026

0.3146

Life threatening MBE

p-value

147 (1.2)

179 (1.5)

Hazard ratio vs. warfarin (95% CI)

0.67 (0.54, 0.82)

0.80 (0.66, 0.98)

p-value Intra-cranial hemorrhage (ICH)+ Hazard ratio vs. warfarin (95% CI) p-value Any bleeding event a Hazard ratio vs. warfarin (95% CI) p-value

0.0001

0.0305

27 (0.2)

38 (0.3)

0.30 (0.19, 0.45)

0.41 (0.28, 0.60)

< 0.0001

1,754 (14.7)

1,993 (16.6)

0.78 (0.73, 0.83)

0.91 (0.85, 0.96)

< 0.0001

0.0016

218 (1.9)

90 (0.8)

2,166 (18.4)

*Adjudicated bleeds **Dose-adjusted warfarin to an INR of 2.0 – 3.0 + ICH consists of adjudicated hemorrhagic stroke and subdural and/or subarachnoid hemorrhage. aInvestigator-reported bleeding events

Major bleeding fulfilled one or more of the following criteria: S Bleeding associated with a reduction in hemoglobin of at least 20 grams per litre or leading to a transfusion of at least 2 units of blood or packed cells; S Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intraarticular bleeding or pericardial bleeding. Major bleeds were classified as lifethreatening if they fulfilled one or more of the following criteria: S Fatal bleed; symptomatic intracranial bleed; reduction in hemoglobin of at least 50 grams per litre; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of intravenous inotropic agents; a bleed that necessitated surgical intervention. Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Table 3: Common Adverse Reactions observed in *1% of dabigatran-treated patients with atrial fibrillation in the active- controlled trial, RELY 110

Bleeding and anemia*

Dabigatran etexilate 110 mg N (%)

Dabigatran etexilate 150 mg N (%)

Warfarin N (%)

5,983 (100)

6,059 (100)

5,998 (100) 825 (13.8)

599 (10.0)

747 (12.3)

Anemia

73 (1.2)

97 (1.6)

74 (1.2)

Epistaxis

66 (1.1)

67 (1.1)

107 (1.8)

Gastrointestinal hemorrhage

196 (3.3)

277 (4.6)

155 (2.6)

Urogenital hemorrhage

66 (1.1)

84 (1.4)

96 (1.6)

Gastrointestinal disorders*

735 (12.3)

772 (12.7)

220 (3.7)

Abdominal pain

135 (2.3)

134 (2.2)

15 (0.3)

Diarrhea

75 (1.3)

71 (1.2)

11 (0.2)

Dyspepsia

250 (4.2)

234 (3.9)

13 (0.2)

Nausea

58 (1.0)

73 (1.2)

12 (0.2)

*Aggregate incidence presented for all adverse reactions within the body system, including those reactions occurring <1% and not listed in the Table above.Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort), or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, gastrointestinal ulcer). Gastrointestinal (GI) hemorrhage occurred at a higher frequency with PRADAX compared to warfarin (see Table 3). GI adjudicated major bleeds were reported at 1.1%, 1.6%, and 1.1% (annualized rates) in the DE 110 mg, DE 150 mg and warfarin groups, respectively. GI life-threatening bleeds occurred with a frequency of 0.6%, 0.8% and 0.5% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. Any GI bleeds occurred with a frequency of 5.4%, 6.1% and 4.0% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. The underlying mechanism of the increased rate of GI bleeding has not been established (see CLINICAL TRIALS, Prevention of stroke and systemic embolism in patients with atrial fibrillation in the Product Monograph). Allergic reactions or drug hypersensitivity including urticaria, bronchospasm, rash and pruritus have been reported in patients who received dabigatran etexilate. Rare cases of anaphylactic reactions have also been reported.

Less Common Clinical Trial Adverse Drug Reactions (<1%) Observed with exposure to dabigatran 110 mg bid and 150 mg bid during the RELY trial, an active-controlled clinical trial for the prevention of stroke and systemic embolism in patients with atrial fibrillation: Blood and lymphatic system disorders: thrombocytopenia Vascular disorders: hematoma, hemorrhage Gastrointestinal disorders: gastrointestinal ulcer, gastroesophagitis, gastro-esophageal reflux disease, vomiting, dysphagia Hepatobiliary disorders: hepatic function abnormal/liver function test abnormal, hepatic enzyme increased Skin and subcutaneous tissue disorders: skin hemorrhage, urticaria, rash, pruritus Musculoskeletal and connective tissue and bone disorders: hemarthrosis Renal and urinary disorders: hematuria General disorders and administration site conditions: injection site hemorrhage, catheter site hemorrhage Injury, poisoning and procedural complications: incision site hematoma, traumatic hematoma, incision site hemorrhage Immune system disorder: drug hypersensitivity Respiratory disorders: hemoptysis, bronchospasm Nervous system disorders: intracranial hemorrhage For abnormal liver function tests reported in the RE-LY trial, please see Table 5. To report an adverse event, contact your

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Regional Adverse Reaction Monitoring Office at 1-866-234-2345, or contact: Boehringer Ingelheim (Canada) Ltd., Drug Safety at 1-800-263-5103 ext. 4603. DRUG INTERACTIONS Based on in vitro evaluation, neither dabigatran etexilate nor its active moiety, dabigatran, have been shown to be metabolized by the human cytochrome P450 system, nor did they exhibit effects on human CYP P450 isozymes. Concomitant use of PRADAX with treatments that interfere with hemostasis or coagulation increases bleeding risk (see WARNINGS AND PRECAUTIONS, Bleeding). Co-administration of PRADAX with other anticoagulants has not been adequately studied and is not recommended. In the RELY trial, conducted in patients with atrial fibrillation, a two-fold increase in major bleeding was seen in both dabigatran study treatment arms, as well as that of the comparator, warfarin, when ASA was administered concomitantly (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph; CLINICAL TRIALS, Stroke Prevention in Atrial Fibrillation in the Product Monograph; and DOSAGE AND ADMINISTRATION). Drug-Drug Interactions Transporter interactions: Dabigatran etexilate, but not dabigatran, is a substrate with moderate affinity for the efflux P-glycoprotein (P-gp) transporter. Therefore, potent P-glycoprotein inducers or inhibitors may be expected to impact exposure to dabigatran. P-glycoprotein inhibitors: P-gp inhibitors like verapamil, quinidine and amiodarone may be expected to increase systemic exposure to dabigatran, see Table 4 below. The strong P-glycoprotein inhibitor ketoconazole, when administered orally, is contraindicated (see CONTRAINDICATIONS). If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anemia), along with a sense of caution is required when dabigatran is co-administered with strong P-glycoprotein inhibitors. P-glycoprotein inducers: The concomitant use of PRADAX with the strong P-gp inducer rifampicin, reduces dabigatran plasma concentration. Other P-gp inducers such as carbamazepine and St John’s Wort are also expected to reduce the systemic exposure of dabigatran. Less potent inducers such as tenofovir can potentially reduce systemic exposure. Caution is advised when coadministering these drug products. P-glycoprotein substrates: Dabigatran etexilate is not expected to have a clinically meaningful interaction with P-glycoprotein substrates that do not also act as inhibitors or inducers of P-gp.

Table 4: Summary of Drug-Drug Interactions Proper name

Ref* Effect

Clinical comment

Amiodarone

Dabigatran exposure in healthy subjects was increased by 60% in the presence of amiodarone (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph).

Adjust dosing for patients treated for prevention of VTE after hip- or knee-replacement surgery to 150 mg daily PRADAX with amiodarone. Caution should be exercised.

Diminished clinical effect may occur, as may be expected for any drug resulting in an increase in gastric pH during PRADAX administration. PRADAX should be administered at least 2 hours before taking an antacid. Co-administration with PRADAX should be avoided within 24 hours after orthopedic surgery.

No dose adjustment is generally recommended for AF patients. Use with caution. Occasional testing of aPTT may be considered to rule out excessive anticoagulant effect.

Antacids (aluminium compounds, sodium bicarbonate, calcium and/or magnesium compounds, or combinations of these)

In population PK analyses, a reduction in dabigatran exposure by 35% was seen over the first 24 hours following surgery. Thereafter, (>24 hours after surgery), a reduction of about 11% was observed.

Atorvastatin

When dabigatran etexilate was No dose adjustment is co-administered with atorvastatin, recommended. exposure of atorvastatin, and atorvastatin metabolites were not significantly changed. Dabigatran concentrations were decreased about 20%.

Clarithromycin

Dabigatran exposure in healthy subjects was increased by about 15% in the presence of clarithromycin (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph).

No dose adjustment is recommended. Caution should be exercised.

Diclofenac

When dabigatran etexilate was co-administered with diclofenac, pharmacokinetics of both drugs appeared unchanged.

No dose adjustment is recommended. Use with caution (see WARNINGS AND PRECAUTIONS, Bleeding, Table 1.)

Digoxin

When dabigatran etexilate was co-administered with digoxin, no PK-interaction was observed.

No dose adjustment is recommended.

Ketoconazole

Dabigatran exposure was increased 150% after single and multiple doses of ketoconazole (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph).

Co-administration with PRADAX is contraindicated. (see CONTRAINDICATIONS).

Pantoprazole

When dabigatran etexilate was co-administered with pantoprazole, a decrease in dabigatran AUC of about 30 % was observed. In the Phase III study, RELY, PPI co-medication did not result in lower trough levels and on average only slightly reduced post-dose concentrations (-11%) (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph).

No dose adjustment is recommended. Diminished clinical effect may occur, as may be expected for any drug resulting in an increase in gastric pH during PRADAX administration.

Rifampicin

After 7 days of treatment with 600 mg rifampicin qd total dabigatran AUC0-' and Cmax were reduced by 67% and 66% compared to the reference treatment, respectively (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph).

Concomitant use of PRADAX with rifampicin should, in general, be avoided. Concomitant use would be expected to result in substantially diminished anticoagulant effect of PRADAX.

When dabigatran etexilate, given at 150 mg once daily, was co-administered with moderate doses of oral verapamil, the Cmax and AUC of dabigatran were increased, but the magnitude of this change varied depending on the timing of administration and the formulation of verapamil used (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph).

Dosing should be reduced to 150 mg PRADAX daily in patients treated for prevention of VTE after hip- or knee-replacement surgery who concomitantly receive dabigatran etexilate and verapamil. To minimize potential for interaction, PRADAX should be given at least two hours before verapamil. Caution should be exercised.

Dabigatran exposure in healthy subjects was increased by 53 % in the presence of quinidine.

Adjust dosing for patients treated for prevention of VTE after hip- or knee-replacement surgery to 150 mg daily PRADAX. Caution should be exercised.

Verapamil

Quinidine

Although no dose adjustment is recommended for AF patients, to minimize potential for interaction, PRADAX should be given at least two hours before verapamil. Caution should be exercised.

Although no dose adjustment is recommended for AF patients, to minimize potential for interaction, PRADAX should be given at least two hours before quinidine, if possible. Caution should be exercised.

*C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Food Interactions Food does not affect the bioavailability of PRADAX but delays the time-to-peak plasma concentrations by 2 hours. Drug-Herb Interactions Drug-herb interactions have not been investigated. Potent P-gp inducers such as St. Johnâ&#x20AC;&#x2122;s Wort (Hypericum perforatum) may be expected to affect systemic exposure of dabigatran. Co-administration of these products is not recommended. Drug-Laboratory Interactions No single test (aPTT, TT, ECT) is adequate to reliably assess the anticoagulant activity of dabigatran following PRADAX

administration. At therapeutic levels of dabigatran, thrombin time (TT) is the best measure of the pharmacodynamic effect of dabigatran because of its linear and sensitive relationship with dabigatran exposure (WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, in the Product Monograph). The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding, the aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT greater than 80 sec at trough (when the next dose is due) is associated with a higher risk of bleeding. Note that a PT (INR) test is not useful to assess the anticoagulant activity of PRADAX. Drug-Lifestyle Interactions No direct interaction between dabigatran etexilate and alcohol was demonstrated in animal models or has been hypothesized. The effect of PRADAX on the ability to drive and use machines has not been investigated. However, no such interaction is to be expected. Administration

v DOSAGE AND ADMINISTRATION PRADAX should be taken orally, with the entire capsule to be swallowed whole. The capsule should not be chewed, broken, or opened. PRADAX should be taken regularly, as prescribed, to ensure optimal effectiveness. All temporary discontinuations should be avoided, unless medically indicated. Recommended Dose and Dosage Adjustment S Prevention of stroke and systemic embolism in patients with atrial fibrillation: The recommended dose of PRADAX is 300 mg daily, taken orally as one 150 mg capsule twice a day. Elderly: S Prevention of stroke and systemic embolism in patients with atrial fibrillation: Patients aged 80 years and above should be treated with a dose of 220 mg of PRADAX daily, taken orally as one 110 mg capsule twice a day (see WARNINGS AND PRECAUTIONS, Geriatrics, and CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Tables 24 and 25, in the Product Monograph). S The usual recommended dose for most geriatric patients under the age of 80 years is 300 mg daily, taken orally as one 150 mg capsule twice a day (see VOL 57: JANUARY t JANVIER 2011

CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Tables 24 and 25, in the Product Monograph). However, in geriatric patients, especially those over the age of 75 with at least one other risk factor for bleeding (see WARNINGS AND PRECAUTIONS, Bleeding, Table 2), the administration of a dose of 220 mg of PRADAX daily, taken orally as one 110 mg capsule twice a day, may be considered. It should be noted, however, that the effectiveness of stroke prevention may be expected to be lessened with this dosage regimen, compared to that of the usual one of 300 mg of PRADAX daily. As with any anticoagulant, caution is required when prescribing PRADAX to the elderly (see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS, Bleeding). Patients at risk of bleeding: Prevention of stroke and systemic embolism in patients with atrial fibrillation: Patients with an increased risk of bleeding (see WARNINGS AND PRECAUTIONS, Bleeding, Table 1), should be closely monitored clinically (looking for signs of bleeding or anemia). In such patients, a dose of 220 mg, given as 110 mg twice daily may be considered. A coagulation test, such as aPTT (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests), may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. As for any anticoagulant, PRADAX is NOT indicated in patients at excessive risk of bleeding (see CONTRAINDICATIONS). Renal impairment: Following oral dosing with dabigatran etexilate, there is a direct correlation of systemic exposure to dabigatran with degree of renal impairment (see WARNINGS AND PRECAUTIONS, Renal). The kidneys account for 85% of dabigatran clearance. There are no data to support use in patients with severe renal impairment (CrCl <30 mL /min). Given the substantial increase in dabigatran exposure observed in this patient population, treatment with PRADAX is not recommended (see CONTRAINDICATIONS, and ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency in the Product Monograph). S Patients with atrial fibrillation treated for prevention of stroke and systemic embolism having moderate renal impairment (CrCl 30-50 mL/min): No dose adjustment is recommended (see CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Renal Impairment in the Product Monograph). Patients with moderate renal impairment (CrCl 30-50 mL/min) should be treated with a daily dose

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of PRADAX at 300 mg taken orally as one 150 mg capsule twice daily, with caution. Regular assessment of renal status is required in these patients (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Renal). A coagulation test, such as aPTT (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests), may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. Creatinine clearance can be estimated using the Cockroft-Gault formula as follows: Creatinine clearance (mL/min) = Males: (140-age (years)) x weight (kg) 72 x serum creatinine (mg/100mL) Females: 0.85 x (140-age (years)) x weight (kg) 72 x serum creatinine (mg/100mL) P-glycoprotein inhibitors: P-gp inhibitors like verapamil, quinidine, and amiodarone may be expected to increase systemic exposure to dabigatran. Combination use with oral ketoconazole is contraindicated (see CONTRAINDICATIONS). S Patients with atrial fibrillation treated for prevention of stroke and systemic embolism: No dose adjustment is recommended in patients concomitantly receiving amiodarone, quinidine or verapamil (see DRUG INTERACTIONS, Table 4, Summary of Drug-Drug Interactions; and ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic interactions in the Product Monograph). Patients should be treated with a daily dose of 300 mg PRADAX taken orally as one 150 mg capsule twice daily. To minimize potential for interaction, PRADAX should be given at least two hours before verapamil (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic interactions in the Product Monograph). Caution should be exercised. Close clinical surveillance is recommended. Drugs that increase gastric pH, such as antacids, protein pump inhibitors (PPI): Diminished clinical effect for antacids may occur (see DRUG INTERACTIONS, Table 4, Summary of Drug-Drug Interactions). Although no dosage adjustment is generally necessary, administer PRADAX at least two hours before antacids, if possible, to minimize interaction potential. No dose adjustment is required for pantoprazole or other PPIs. Concomitant antithrombotic use: Concomitant use of ASA or clopidogrel with PRADAX in patients with atrial fibrillation approximately doubled the risk of major bleed, irrespective of dose of PRADAX used. A similar increase was noted with such concomitant use with the study comparator, warfarin. These observations contrasted 112

with little apparent additional improvement in stroke and systemic embolic events with combined antithrombotic use and PRADAX (or warfarin). Concomitant use of PRADAX with an antithrombotic is not recommended for prevention of cardiogenic thromboembolic stroke in patients with atrial fibrillation. Concomitant use of ASA or other antiplatelet agents based on medical need to prevent myocardial infarction should be undertaken with caution. Close clinical surveillance is recommended. Acute myocardial infarction (AMI): Consideration should be given to discontinuing PRADAX in the setting of acute myocardial infarction should the treatment of myocardial infarction involve invasive procedures, such as percutaneous coronary revascularization, or coronary artery bypass surgery. Similar consideration should be given if thrombolytic therapy is to be initiated, because bleeding risk may increase. Patients with AMI should be treated according to current clinical guidelines for that disorder. In this setting, PRADAX may be resumed for the prevention of stroke and systemic embolism upon completion of these revascularization procedures. Children: Since PRADAX has not been investigated in patients <18 years of age, treatment is not recommended. Patient Body Weight: Population PK modelling shows that patients with a body weight of about 120 kg have about 20% lower drug exposure. Patients with a body weight of about 48 kg have about 25% higher drug exposure compared to patients with average weight. No dose adjustment deemed necessary. Switching from PRADAX treatment to parenteral anticoagulant: S In patients with atrial fibrillation treated for prevention of stroke and systemic embolism: wait 12 hours after the last dose of PRADAX before switching to a parenteral anticoagulant. Switching from parenteral anticoagulants treatment to PRADAX: If deemed medically appropriate, treatment with PRADAX should be initiated 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g., intravenous unfractionated heparin, [UFH]). Switching from Vitamin K antagonists to PRADAX: If deemed medically appropriate, PRADAX should only be started after Vitamin K antagonists have been discontinued, and the patient’s INR is found to be below 2.0. Cardioversion: Patients can be maintained on PRADAX while being cardioverted. Missed Dose: Prevention of stroke and systemic embolism in patients with atrial

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fibrillation: If the prescribed dose of PRADAX is not taken at the scheduled time, the dose should be taken as soon as possible on the same day. A forgotten PRADAX dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted. Patients should not take a double dose to make up for missed individual doses. For optimal effect and safety, it is important to take PRADAX regularly twice a day, at approximately 12-hour intervals. Administration PRADAX may be taken with food, or on an empty stomach with water. The capsule should be swallowed intact. It should not be opened, broken, or chewed (see ACTION AND CLINICAL PHARMACOLOGY in the full Product Monograph, Pharmacokinetics in the Product Monograph). SUPPLEMENTAL PRODUCT INFORMATION Adverse Reactions: Liver Function Tests: In the long-term RELY study, observed abnormalities of liver function tests (LFT) are presented below in Table 5. Table 5: Liver Function Tests in the RELY trial Dabigatran etexilate Dabigatran etexilate 110 mg twice daily 150 mg twice daily N (%) N (%) Total treated

Warfarin N (%)

5,983 (100.0)

6,059 (100.0)

5,999 (100.0)

ALT or AST >3xULN

118 (2.0)

106 (1.7)

125 (2.1)

ALT or AST >5xULN

36 (0.7)

45 (0.7)

50 (0.8)

ALT or AST >3xULN + Bilirubin >2xULN

11 (0.2)

14 (0.2)

21 (0.4)

OVERDOSAGE

There is no antidote to dabigatran etexilate or dabigatran. Doses of PRADAX beyond those recommended expose the patient to increased risk of bleeding. Excessive anticoagulation may require discontinuation of PRADAX. In the event of hemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route, adequate diuresis must be maintained. Appropriate standard treatment, e.g., surgical hemostasis as indicated and blood volume replacement, should be undertaken. In addition, consideration may be given to the use of fresh whole blood or the transfusion of fresh frozen plasma. As protein binding is low, dabigatran can be dialysed, although there is limited clinical experience in using dialysis in this setting. Activated prothrombin complex concentrates (e.g., FEIBA) or recombinant Factor VIIa or concentrates of coagulation factors II, IX or X, may be considered. There is some experimental evidence to support the role of these agents in reversing the anticoagulant effect of dabigatran but their usefulness in clinical settings has not yet been clearly demonstrated. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. All symptomatic treatment should be given according to the physician’s judgement. For management of a suspected drug overdose, contact your regional Poison Control Centre. Product Monograph is available upon request or at www.boehringer-ingelheim.ca Boehringer Ingelheim (Canada) Ltd. 5180 South Service Road Burlington, ON L7L 5H4

PRADAX™ is a trademark of Boehringer Ingelheim Pharma GmnH & Co. KG, used under license by Boehringer Ingelheim (Canada) Ltd. November 8, 2010

haematemesis, anaemia, or melaena) and when gastric ULCER IS SUSPECTED THE POSSIBILITY OF MALIGNANCY SHOULD BE EXCLUDED BEFORE THERAPY WITH 4%#4! (pantoprazole magnesium) is instituted since treatment with PANTOPRAZOLE MAGNESIUM MAY ALLEVIATE SYMPTOMS AND DELAY DIAGNOSIS &URTHER INVESTIGATION SHOULD BE CONSIDERED IF SYMPTOMS persist despite adequate treatment. $ECREASED GASTRIC ACIDITY DUE TO ANY MEANS INCLUDING proton pump inhibitors, increases gastric counts of BACTERIA NORMALLY PRESENT IN THE GASTROINTESTINAL TRACT 4REATMENT WITH PROTON PUMP INHIBITORS MAY LEAD TO SLIGHTLY INCREASED RISK OF GASTROINTESTINAL INFECTIONS such as Salmonella and Campylobacter AND POSSIBLY Clostridium difficile. Antibiotic Combination Therapy Pseudomembranous colitis has been reported with NEARLY ALL ANTIBACTERIAL AGENTS INCLUDING CLARITHROMYCIN AND AMOXICILLIN AND MAY RANGE IN SEVERITY FROM MILD to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. 4REATMENT WITH ANTIBACTERIAL AGENTS ALTERS THE NORMAL mORA OF THE COLON AND MAY PERMIT OVERGROWTH OF #LOSTRIDIA 3TUDIES INDICATE THAT A TOXIN PRODUCED BY Clostridium difficile IS A PRIMARY CAUSE OF hANTIBIOTIC ASSOCIATED colitisâ&#x20AC;?. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be INITIATED -ILD CASES OF PSEUDOMEMBRANOUS COLITIS USUALLY RESPOND TO DISCONTINUATION OF THE DRUG ALONE )N moderate to severe cases, consideration should be given TO MANAGEMENT WITH mUIDS AND ELECTROLYTES PROTEIN supplementation, and treatment with an antibacterial DRUG CLINICALLY EFFECTIVE AGAINST Clostridium difficile colitis. Carcinogenesis and Mutagenesis %FFECTS OF LONG TERM TREATMENT INCLUDE HYPERGASTRINEMIA

POSSIBLE ENTEROCHROMAFFIN LIKE %#, CELL HYPERPLASIA and carcinoid formation in the stomach, adenomas and CARCINOMAS IN THE LIVER AND NEOPLASTIC CHANGES IN THE THYROID In the rat, the mechanism leading to the formation of gastric carcinoids is considered to be due to the elevated GASTRIN LEVEL OCCURRING DURING CHRONIC TREATMENT 3IMILAR observations have also been made after administration OF OTHER ACID SECRETION INHIBITORS &OR FURTHER DETAILS SEE 4/8)#/,/'9 IN THE 0RODUCT -ONOGRAPH 3HORT TERM AND LONG TERM TREATMENT WITH PANTOPRAZOLE SODIUM IN A LIMITED NUMBER OF PATIENTS UP TO YEARS HAVE NOT RESULTED IN ANY SIGNIlCANT PATHOLOGICAL CHANGES IN GASTRIC OXYNTIC EXOCRINE CELLS Hepatic/Biliary/Pancreatic & Renal 0ANTOPRAZOLE MG DAILY IS NOT RECOMMENDED IN PATIENTS WITH SEVERE LIVER DISEASE &OR MORE DETAILS PLEASE SEE 3500,%-%.4!, 02/$5#4 ).&/2-!4)/. 4HE DAILY DOSE USED IN RENAL INSUFlCIENT PATIENTS AS A RULE

SHOULD NOT EXCEED THE RECOMMENDED DOSAGE REGIMENS 3EE 3500,%-%.4!, 02/$5#4 ).&/2-!4)/. Pantoprazole should not be used in combination treatment for the eradication of ( PYLORI in patients WITH SEVERE HEPATIC OR RENAL DYSFUNCTION SINCE CURRENTLY NO DATA ARE AVAILABLE ON THE EFFICACY AND SAFETY OF pantoprazole in combination treatment of these patients. ADVERSE REACTIONS Adverse Drug Reaction Overview 0ANTOPRAZOLE IS WELL TOLERATED -OST ADVERSE EVENTS have been mild and transient showing no consistent relationship with treatment. The following adverse EVENTS THE MOST FREQUENTLY REPORTED HAVE BEEN REPORTED IN INDIVIDUALS RECEIVING PANTOPRAZOLE SODIUM THERAPY MG ONCE DAILY IN CONTROLLED CLINICAL TRIALS OF AT LEAST 6 months duration: headache (2.1%), diarrhea (1.6%), ÂŽ

Prescribing Summary Patient Selection Criteria THERAPEUTIC CLASSIFICATION

H+, K+-ATPase Inhibitor

INDICATIONS AND CLINICAL USE

TECTA (pantoprazole magnesium) is indicated for the treatment of conditions where a reduction of gastric acid secretion is required, such as the following: s $UODENAL ULCER s 'ASTRIC ULCER s 2EmUX ESOPHAGITIS s 3YMPTOMATIC GASTRO ESOPHAGEAL REmUX DISEASE SUCH as, acid regurgitation and heartburn). s (ELICOBACTER PYLORI associated duodenal ulcer 0ANTOPRAZOLE IN COMBINATION WITH CLARITHROMYCIN AND EITHER AMOXICILLIN OR METRONIDAZOLE IS INDICATED FOR THE treatment of patients with an active duodenal ulcer who are ( PYLORI positive. Clinical trials using combinations of pantoprazole with appropriate antibiotics have indicated that such combinations are successful in eradicating ( PYLORI. ÂŽ

CONTRAINDICATIONS

0ATIENTS WHO ARE HYPERSENSITIVE TO THIS DRUG OR TO ANY ingredient in the formulation or component of the container. 0ANTOPRAZOLE LIKE ALL 00)S SHOULD NOT BE CONCURRENTLY administered with atazanavir 3EE $25' ).4%2!#4)/.3). SPECIAL POPULATIONS:

Geriatrics (> 65years of age): .O DOSAGE ADJUSTMENT IS RECOMMENDED BASED ON AGE 4HE DAILY DOSE USED IN ELDERLY PATIENTS AS A RULE SHOULD NOT EXCEED THE RECOMMENDED DOSAGE REGIMENS 3EE 3500,%-%.4!, 02/$5#4 ).&/2-!4)/. Pediatrics: 4HE SAFETY AND EFFECTIVENESS OF PANTOPRAZOLE IN CHILDREN HAVE NOT YET BEEN ESTABLISHED Pregnant Women: There are no adequate or well-controlled studies in PREGNANT WOMEN 3TUDIES IN ANIMALS HAVE SHOWN REPRODUCTIVE TOXICITY THE POTENTIAL RISK FOR HUMANS IS unknown. TECTA (pantoprazole magnesium) should not be administered to pregnant women unless the EXPECTED BENElTS OUTWEIGH THE POTENTIAL RISKS TO THE FETUS 3EE 2%02/$5#4)/. !.$ 4%2!4/,/'9 IN THE 0RODUCT -ONOGRAPH Nursing Women: ,IMITED DATA IS AVAILABLE AROUND PANTOPRAZOLE USE IN NURSING WOMEN 0ANTOPRAZOLE EXCRETION IN HUMAN MILK HAS BEEN DETECTED IN A STUDY OF A SINGLE NURSING MOTHER after a single 40 mg oral dose. The clinical relevance of THIS lNDING IS NOT KNOWN !NIMAL STUDIES HAVE SHOWN EXCRETION OF PANTOPRAZOLE IN BREAST MILK 0ANTOPRAZOLE should not be given to nursing mothers unless its use is believed to outweigh the potential risks to the infant. 3EE 2%02/$5#4)/. !.$ 4%2!4/,/'9 IN THE 0RODUCT -ONOGRAPH ÂŽ

Safety Information WARNINGS AND PRECAUTIONS

General )N THE PRESENCE OF ANY ALARM SYMPTOM E G SIGNIlCANT UNINTENTIONAL WEIGHT LOSS RECURRENT VOMITING DYSPHAGIA

VOL 57: JANUARY t JANVIER 2011

NAUSEA .O DIFFERENCES IN ADVERSE REACTIONS ARE EXPECTED BETWEEN PANTOPRAZOLE MAGNESIUM AND pantoprazole sodium. Clinical Trial Adverse Drug Reactions )N A SHORT TERM STUDY MG PANTOPRAZOLE MAGNESIUM TABLET ONCE DAILY FOR DAYS IN PATIENTS WITH '%2$ AND IN A TO WEEK CLINICAL TRIAL IN '%2$ PATIENTS THE ADVERSE EVENT PROlLE SEEN WITH 4%#4! (pantoprazole magnesium) 40 mg tablet was similar to that seen with the pantoprazole sodium 40 mg tablet. Adverse events have been recorded during controlled clinical investigations IN PATIENTS EXPOSED TO PANTOPRAZOLE SODIUM AS the single therapeutic agent for treatment of conditions requiring acid suppression. The following adverse reactions considered possibly, probably, or definitely related by the investigator have been reported in individuals receiving pantoprazole sodium therapy (20 mg or 40 mg once daily) in long-term clinical trials (duration of at least 6 months). There were a limited number of ( PYLORI positive patients IN THESE STUDIES AND THEREFORE DElNITIVE CONCLUSIONS WITH regard to long-term consequences of ( PYLORI infection AND ACID SUPPRESSIVE TREATMENT ON GASTRIC INmAMMATION in this sub-group cannot be made. Adverse drug reactions with a frequency of q 1% related to 40 mg pantoprazole sodium, assessed as possibly, probably or definitely related by the investigator ÂŽ

Preferred term

Number of patients

Percentage of patients

Headache

$IARRHOEA

1.603

.AUSEA

1.158

&OR ADVERSE EVENTS WITH A FREQUENCY OF SEE 3500,%-%.4!, 02/$5#4 ).&/2-!4)/. 4O REPORT AN ADVERSE EVENT YOU MAY NOTIFY .YCOMED Canada Inc., the manufacturer, at 1-866-295-4636, OR (EALTH #ANADA BY PHONE OR FAX DRUG INTERACTIONS: 3%% 3500,%-%.4!, 02/$5#4 ).&/2-!4)/.

Administration Recommended Dose and Dosage Adjustment DUODENAL ULCER

The recommended adult dose of TECTA (pantoprazole magnesium) for the oral treatment of duodenal ulcer is MG GIVEN ONCE DAILY IN THE MORNING (EALING USUALLY OCCURS WITHIN WEEKS &OR PATIENTS NOT HEALED AFTER THIS INITIAL COURSE OF THERAPY AN ADDITIONAL COURSE OF WEEKS is recommended. ÂŽ

GASTRIC ULCER

The recommended adult oral dose of TECTA (pantoprazole magnesium) for the oral treatment of GASTRIC ULCER IS MG GIVEN ONCE DAILY IN THE MORNING (EALING USUALLY OCCURS WITHIN WEEKS &OR PATIENTS NOT HEALED AFTER THIS INITIAL COURSE OF THERAPY AN ADDITIONAL course of 4 weeks is recommended. HELICOBACTER PYLORI ASSOCIATED ÂŽ

DUODENAL ULCER

0ANTOPRAZOLE #LARITHROMYCIN -ETRONIDAZOLE 4RIPLE #OMBINATION 4HERAPY 4HE RECOMMENDED DOSE FOR ( PYLORI ERADICATION IS TREATMENT FOR SEVEN DAYS WITH TECTA (pantoprazole magnesium) 40 mg together with CLARITHROMYCIN MG AND METRONIDAZOLE MG ALL TWICE DAILY ÂŽ

| Canadian Family Physician

Le MĂŠdecin de famille canadien

113

0ANTOPRAZOLE #LARITHROMYCIN !MOXICILLIN 4RIPLE #OMBINATION 4HERAPY 4HE RECOMMENDED DOSE FOR ( PYLORI ERADICATION IS TREATMENT FOR SEVEN DAYS WITH TECTA (pantoprazole magnesium) 40 mg together with CLARITHROMYCIN MG AND AMOXICILLIN MG ALL TWICE DAILY ÂŽ

SYMPTOMATIC GASTRO-ESOPHAGEAL REFLUX DISEASE (GERD)

The recommended adult oral dose for the treatment OF SYMPTOMS OF '%2$ INCLUDING HEARTBURN AND regurgitation, is TECTA (pantoprazole magnesium) MG ONCE DAILY FOR UP TO WEEKS )F SIGNIFICANT SYMPTOM RELIEF IS NOT OBTAINED IN WEEKS FURTHER investigation is required. ÂŽ

REFLUX ESOPHAGITIS

The recommended adult oral dose of TECTA PANTOPRAZOLE MAGNESIUM IS MG GIVEN ONCE DAILY IN THE MORNING )N MOST PATIENTS HEALING USUALLY OCCURS WITHIN WEEKS &OR PATIENTS NOT HEALED AFTER THIS INITIAL COURSE OF THERAPY AN ADDITIONAL WEEKS OF TREATMENT IS recommended. 0ATIENTS WITH HEALED GASTROESOPHAGEAL REmUX DISEASE

who require greater than usual maintenance doses OF 00)S TO AVOID RECURRENCE OF REmUX ESOPHAGITIS MAY consider 40 mg TECTA ONCE DAILY IN THE MORNING Missed Dose If a dose is forgotten, the missed dose should be taken as SOON AS POSSIBLE UNLESS IT IS CLOSE TO THE NEXT SCHEDULED dose. Two doses should never be taken at one time to MAKE UP FOR A MISSED DOSE PATIENTS SHOULD JUST RETURN TO the regular schedule. Administration TECTA (pantoprazole magnesium) is formulated as an enteric-coated tablet. A whole tablet should not be CHEWED OR CRUSHED AND SHOULD BE SWALLOWED WITH mUID in the morning either before, during, or after breakfast. Reconstitution: .OT !PPLICABLE ÂŽ

ÂŽ

Study References 1. TECTA 0RODUCT -ONOGRAPH 3EPTEMBER ÂŽ

Supplemental Product Information ADVERSE REACTIONS: &OR !DVERSE $RUG 2EACTION /VERVIEW AND !DVERSE 2EACTIONS WITH A FREQUENCY of q SEE !DVERSE 2EACTION IN THE 3!&%49 ).&/2-!4)/. SECTION Adverse drug reactions with a frequency of 0.1 to 1% related to 40 mg pantoprazole sodium #ARDIOVASCULAR 3YSTEM "LOOD 0RESSURE )NCREASED (YPERTENSION %#' Abnormal 'ASTROINTESTINAL $ISORDERS &LATULENCE !BDOMINAL $ISTENSION

!BDOMINAL 0AIN !BDOMINAL PAIN 5PPER ,OOSE 3TOOLS /ESOPHAGEAL 2EmUX !GGRAVATED 'ASTRIC 0OLYPS !BDOMINAL $ISCOMFORT !BDOMINAL 4ENDERNESS

#ONSTIPATION %RUCTATION 6OMITING $YSPEPSIA 'ASTROESOPHAGEAL 2EmUX

/ESOPHAGITIS 'ENERAL $ISORDERS &ATIGUE 0ERIPHERAL /EDEMA 0YREXIA (EPATOBILIARY $ISORDERS Alanine Aminotransferase Increased, Aspartate !MINOTRANSFERASE )NCREASED ,IVER &UNCTION 4ESTS !BNORMAL 4RANSAMINASES Increased ,ABORATORY 0ARAMETERS (YPERTRIGLYCERIDAEMIA -ETABOLIC AND .UTRITIONAL !PPETITE $ECREASED 7EIGHT )NCREASE .ERVOUS 3YSTEM $ISORDERS $YSGEUSIA

$IZZINESS -IGRAINE 6ERTIGO 2ESPIRATORY 3YSTEM Cough 3KIN AND 3UBCUTANEOUS 4ISSUE $ISORDERS 0RURITUS 2ASH 3PECIAL 3ENSES -OUTH $RY

Vision Blurred /THER .EOPLASM The following adverse reactions considered possibly, probably, or definitely related by the investigator have been reported in individuals receiving pantoprazole therapy (20 mg or 40 mg pantoprazole sodium once daily) in short-term clinical trials (duration of up to 3 months). Adverse Events with a frequency of 0.1 to 1% related to pantoprazole sodium 20 mg or 40 mg 'ASTROINTESTINAL $ISORDERS $IARRHOEA &LATULENCE .AUSEA #ONSTIPATION

Abdominal Pain .ERVOUS 3YSTEM $ISORDERS (EADACHE $IZZINESS 3KIN AND 3UBCUTANEOUS 4ISSUE $ISORDERS Pruritus In addition, the following adverse events considered unrelated, or unlikely related by the investigator have been reported in individuals receiving pantoprazole sodium therapy (20 mg or 40 mg once daily) in short-term and long-term clinical trials. Adverse Events with a frequency of >1%, 20 or 40 mg pantoprazole sodium )NmUENZA ,IKE )LLNESS (EADACHE $IARRHOEA Adverse Events with a frequency of 0.1 to 1%, 20 or 40 mg pantoprazole sodium

114

"RONCHITIS .AUSEA "ACK 0AIN !BDOMINAL 0AIN 5PPER 5PPER 2ESPIRATORY 4RACT )NFECTION .ON ACCIDENTAL )NJURY 3INUSITIS !BDOMINAL 0AIN $IZZINESS

!RTHRALGIA 6OMITING 0HARYNGITIS #HEST 0AIN 'ASTROENTERITIS $YSPEPSIA

5RINARY 4RACT )NFECTION %RUCTATION 0YREXIA #OUGH $EPRESSION (YPERTENSION

0AIN IN ,IMB #ONSTIPATION &ATIGUE /PERATION .ECK 0AIN .ASOPHARYNGITIS

!LANINE !MINOTRANSFERASE )NCREASED (AEMMORRHOIDS 0AIN &LATULENCE

6IRAL )NFECTION (YPERTRIGLYCERIDAEMIA 4OOTHACHE (YPERSENSITIVITY 2ASH

!BDOMINAL 0AIN ,OWER 0NEUMONIA !BDOMINAL $ISTENSION $YSPNOEA

-USCLE #RAMP 2HINITIS 0ERIPHERAL /EDEMA 4ONSOLITIS !NGINA 0ECTORIS

#HOLELITHIASIS 3INUS #ONGESTION )NmUENZA 6ERTIGO )NSOMNIA )NFECTION

/STEOARTHRITIS (YPERCHOLESTEROLAEMIA 0RURITIS %CZEMA 3LEEP $ISORDER

-IGRAINE !SPARTATE !MINOTRANSFERASE )NCREASED (YPERGLYCAEMIA

-USCULOSKELETAL $ISCOMFORT "LOOD 4RIGLYCERIDES )NCREASED -YOCARDIAL )NFARCTION 4ENDONITIS 7EIGHT )NCREASED 2ECTAL (AEMMORRHAGE #YSTITIS

.ASAL #ONGESTION !RTHRITIS #ONTUSION !BDOMINAL $ISCOMFORT %NTERITIS 4HE FOLLOWING 3ERIOUS !DVERSE %VENTS REGARDLESS OF CAUSALITY WERE REPORTED WITH A FREQUENCY OF IN EITHER MG OR MG 3EPSIS ! TOTAL OF PATIENTS WERE TREATED WITH TRIPLE COMBINATION THERAPY INCLUDING PANTOPRAZOLE SODIUM AND TWO ANTIBIOTICS !DVERSE EVENTS NOTED AT A FREQUENCY of greater than or equal to 1% when pantoprazole sodium was used in combination with antibiotics for the eradication of an ( PYLORI infection included the following: )N COMBINATION WITH CLARITHROMYCIN AND METRONIDAZOLE N "ODY AS A 7HOLE headache (1.8%), tiredness (1.1%) #ENTRAL AND 0ERIPHERAL .ERVOUS 3YSTEM dizziness (1.4%) 'ASTROINTESTINAL DIARRHEA NAUSEA

upper abdominal pain (1.9%), tongue pain (1.2%), loose stools (1.0%), BUCCAL INmAMMATION ,IVER "ILIARY HEPATIC ENZYMES INCREASED 3PECIAL 3ENSES bitter taste (4.0%), metallic taste (2.1%) )N COMBINATION WITH AMOXICILLIN AND CLARITHROMYCIN N "ODY AS A 7HOLE headache (1.8%), pain (1.0%) 3KIN AND !PPENDAGES EXANTHEMA 'ASTROINTESTINAL diarrhea (10.0%), bitter taste (3.0%), upper abdominal pain (1.4%), nausea (1.2%) 2EGARDLESS OF THE COMBINATION REGIMEN THE MOST FREQUENTLY REPORTED EVENTS WERE GASTROINTESTINAL SYSTEM DISORDERS FOLLOWED BY AUTONOMIC NERVOUS SYSTEM DISORDERS AND hBODY AS A WHOLEv OR GENERALIZED DISORDERS Abnormal Hematological & Clinical Chemistry findings 0LEASE REFER TO THE (EPATOBILIARY $ISORDERS AND ,ABORATORY 0ARAMETERS PORTIONS OF THE !$6%23% 2%!#4)/. SECTION THE !#4)/. #,).)#!, 0(!2-!#/,/'9 3PECIAL 0OPULATIONS #ONDITIONS SECTIONS OF THE 0RODUCT -ONOGRAPH AND THE 7!2.).'3 02%#!54)/.3 (EPATIC "ILIARY Pancreatic section. Post-Market Adverse Drug Reactions The following adverse events were reported in post-marketing use and causal relation to pantoprazole sodium treatment could not be ruled out. As the EVENTS WERE REPORTED SPONTANEOUSLY NO EXACT INCIDENCES CAN BE PROVIDED )NTERSTITIAL NEPHRITIS 3TEVENS *OHNSON 3YNDROME %RYTHEMA -ULTIFORME 4OXIC %PIDERMAL .ECROLYSIS ,YELL SYNDROME 0HOTOSENSITIVITY (YPONATRAEMIA (EPATOCELLULAR )NJURY *AUNDICE (EPATOCELLULAR &AILURE (ALLUCINATION #ONFUSION ESPECIALLY IN PRE DISPOSED PATIENTS AS WELL AS THE AGGRAVATION OF THESE SYMPTOMS IN THE CASE OF PRE EXISTENCE (YPOKINESIA !NTERIOR )SCHEMIC /PTIC .EUROPATHY 0ANCREATITIS )NCREASED 3ALIVATION 0ANCYTOPENIA 3PEECH $ISORDER %LEVATED #REATINE 0HOSPHOKINASE 2HABDOMYOLYSIS !LOPECIA !CNE %XFOLIATIVE $ERMATITIS .ERVOUSNESS 4REMOR 4INNITUS Paresthesia; Photophobia; Vertigo; Increased Appetite; Hematuria; Impotence; %OSINOPHILIA )N ADDITION THE FOLLOWING IDENTIlED ADVERSE DRUG REACTIONS HAVE BEEN REPORTED IN ORAL PANTOPRAZOLE SODIUM CLINICAL TRIALS IN ANY INDICATION AND IN ANY DOSAGE 5NCOMMON (EADACHE $IZZINESS .AUSEA 6OMITING !BDOMINAL $ISTENSION AND "LOATING #ONSTIPATION $RY -OUTH !BDOMINAL 0AIN AND $ISCOMFORT 2ASH %XANTHEMA %RUPTION 0RURITUS !STHENIA &ATIGUE AND -ALAISE ,IVER %NZYMES )NCREASED TRANSAMINASES G '4 3LEEP $ISORDERS 2ARE !GRANULOCYTOSIS $ISTURBANCES IN 6ISION "LURRED 6ISION 5RTICARIA !NGIOEDEMA -YALGIA !RTHRALGIA (YPERLIPIDAEMIAS AND ,IPID )NCREASES 7EIGHT #HANGES "ODY 4EMPERATURE )NCREASED /EDEMA 0ERIPHERAL (YPERSENSITIVITY INCLUDING !NAPHYLACTIC 2EACTIONS AND !NAPHYLACTIC 3HOCK "ILIRUBIN )NCREASED $EPRESSION AND ALL AGGRAVATIONS 6ERY RARE 4HROMBOCYTOPENIA ,EUKOPENIA $ISORIENTATION AND ALL AGGRAVATIONS OVERDOSAGE For management of a suspected drug overdose, consult your regional poison control centre. 3OME REPORTS OF OVERDOSAGE WITH PANTOPRAZOLE SODIUM HAVE BEEN RECEIVED .O CONSISTENT SYMPTOM PROlLE WAS OBSERVED AFTER INGESTION OF HIGH DOSES OF PANTOPRAZOLE SODIUM $AILY DOSES OF UP TO MG PANTOPRAZOLE SODIUM I V

and single doses of up to 240 mg i.v. administered over 2 minutes, have been administered and were well tolerated. 4REATMENT OF OVERDOSAGE SHOULD BE SUPPORTIVE AND SYMPTOMATIC 0ANTOPRAZOLE IS NOT REMOVED BY HEMODIALYSIS DRUG INTERACTIONS Overview 0ANTOPRAZOLE UNDERGOES EXTENSIVE HEPATIC METABOLISM VIA CYTOCHROME 0 MEDIATED OXIDATION FOLLOWED BY SULPHATE CONJUGATION VIA A 0HASE )) REACTION NON SATURABLE NON CYTOCHROME 0 DEPENDANT 0HARMACOKINETIC drug interaction studies in man did not demonstrate the inhibition of the OXIDATIVE METABOLISM OF THE DRUG .O INDUCTION OF THE #90 SYSTEM BY pantoprazole was observed during chronic administration of pantoprazole SODIUM WITH ANTIPYRINE AS A MARKER #HANGES IN ABSORPTION SHOULD BE taken into account when drugs whose absorption is pH dependent, e.g., KETOCONAZOLE ARE TAKEN CONCOMITANTLY It has been shown that co-administration of atazanavir 300mg/ ritonavir 100mg WITH OMEPRAZOLE MG ONCE DAILY OR ATAZANAVIR MG WITH LANSOPRAZOLE MG SINGLE DOSE TO HEALTHY VOLUNTEERS RESULTED IN A SUBSTANTIAL REDUCTION IN THE BIOAVAILABILITY OF ATAZANAVIR 4HE ABSORPTION OF ATAZANAVIR IS P( DEPENDENT Therefore all PPIs, including pantoprazole, should not be co-administered WITH ATAZANAVIR 3EE #/.42!).$)#!4)/.3 Drug-Drug Interactions 4HE MAGNESIUM CONTENT OF A MG TABLET IS NEGLIGIBLY LOW AND THUS FAR BELOW THE AMOUNT OF MAGNESIUM TAKEN WITH FOOD OR DIETARY SUPPLEMENTS .O DIFFERENCES IN DRUG DRUG INTERACTIONS ARE EXPECTED BETWEEN PANTOPRAZOLE magnesium and pantoprazole sodium. Pantoprazole sodium does not interact with carbamazepine, caffeine, DICLOFENAC NAPROXEN PIROXICAM ETHANOL GLIBENCLAMIDE METOPROLOL

Canadian Family Physician t Le MĂŠdecin de famille canadien

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ANTIPYRINE DIAZEPAM PHENYTOIN NIFEDIPINE THEOPHYLLINE DIGOXIN ORAL CONTRACEPTIVES OR CYCLOSPORINE #ONCOMITANT USE OF ANTACIDS DOES NOT AFFECT the pharmacokinetics of pantoprazole sodium. Clinical studies have shown that there is no pharmacokinetic interaction between pantoprazole sodium and the following antibiotic combinations: METRONIDAZOLE PLUS CLARITHROMYCIN METRONIDAZOLE PLUS AMOXICILLIN

AMOXICILLIN PLUS CLARITHROMYCIN )N A PRECLINICAL STUDY PANTOPRAZOLE SODIUM IN COMBINATION THERAPY WITH VARIOUS ANTIBIOTICS INCLUDING TETRACYCLINE CLARITHROMYCIN AND AMOXICILLIN was shown to have a potentiating effect on the elimination rate of Helicobacter PYLORI INFECTION 3EE -)#2/")/,/'9 Although no interaction during concomitant administration of warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of CHANGES IN ).2 HAVE BEEN REPORTED DURING CONCOMITANT TREATMENT IN THE post-marketing period. Therefore, in patients being treated with coumarin ANTICOAGULANTS MONITORING OF PROTHROMBIN TIME ).2 IS RECOMMENDED AFTER initiation, termination or during irregular use of pantoprazole. Drug-Food Interactions #ONSUMPTION OF FOOD DOES NOT AFFECT THE PHARMACOKINETICS !5# AND #MAX) OF PANTOPRAZOLE SODIUM 3EE (5-!. 0(!2-!#/,/'9 IN THE 0RODUCT -ONOGRAPH Drug-Laboratory Interactions There have been reports of false-positive results in urine screening tests FOR TETRAHYDROCANNABINOL 4(# IN PATIENTS RECEIVING MOST PROTON PUMP INHIBITORS INCLUDING PANTOPRAZOLE 4O SOME EXTENT A CROSS REACTIVITY OF PROTON PUMP INHIBITORS TO THE 4(# ASSAY IN THE /N4RAK 4ES4CARD 9 has been seen, THOUGH THIS MAY NOT BE LIMITED TO THIS SCREENING TEST )N ORDER TO VERIFY POSITIVE URINE SCREENING RESULTS A CONlRMATORY METHOD SHOULD BE CONSIDERED Other 'ENERALLY DAILY TREATMENT WITH ANY ACID BLOCKING MEDICINES OVER A LONG TIME E G LONGER THAN YEARS MAY LEAD TO MALABSORPTION OF CYANOCOBALAMIN CAUSED BY HYPO OR ACHLORHYDRIA 2ARE CASES OF CYANOCOBALAMIN DElCIENCY UNDER ACID BLOCKING THERAPY HAVE BEEN REPORTED IN THE LITERATURE AND SHOULD BE CONSIDERED IF RESPECTIVE CLINICAL SYMPTOMS ARE OBSERVED Special Populations and Conditions Pediatrics: 4HE SAFETY AND EFFECTIVENESS OF PANTOPRAZOLE IN CHILDREN HAVE NOT YET BEEN established. Geriatrics: !N INCREASE IN !5# AND #MAX FOR PANTOPRAZOLE OCCURS IN ELDERLY VOLUNTEERS WHEN COMPARED TO YOUNGER VOLUNTEERS AFTER CONSECUTIVE DAYS oral dosing with pantoprazole sodium 40mg. After a single oral dose of PANTOPRAZOLE SODIUM MG AN INCREASE IN !5# AND #MAX (26%) OCCURS IN ELDERLY VOLUNTEERS WHEN COMPARED TO YOUNGER VOLUNTEERS .O DOSE ADJUSTMENT IS RECOMMENDED BASED ON AGE 4HE DAILY DOSE IN ELDERLY PATIENTS

AS A RULE SHOULD NOT EXCEED THE RECOMMENDED DOSAGE REGIMENS Hepatic Insufficiency: 4HE HALF LIFE INCREASED TO BETWEEN AND H THE !5# INCREASED BY A FACTOR OF TO AND THE #MAX INCREASED BY A FACTOR OF IN PATIENTS WITH LIVER CIRRHOSIS COMPARED WITH HEALTHY SUBJECTS FOLLOWING ADMINISTRATION OF MG PANTOPRAZOLE SODIUM 3IMILARILY FOLLOWING ADMINISTRATION OF A MG DOSE

THE !5# INCREASED BY A FACTOR OF AND THE #MAX INCREASED BY A FACTOR OF IN PATIENTS WITH SEVERE LIVER CIRRHOSIS COMPARED WITH HEALTHY SUBJECTS Considering the linear pharmacokinetics of pantoprazole sodium, there is an INCREASE IN !5# BY A FACTOR OF IN PATIENTS WITH SEVERE LIVER CIRRHOSIS FOLLOWING ADMINISTRATION OF A MG DOSE COMPARED TO HEALTHY VOLUNTEERS following administration of a 40 mg dose. Renal Insufficiency: In patients with severe renal impairment, pharmacokinetic parameneters for PANTOPRAZOLE SODIUM WERE SIMILAR TO THOSE OF HEALTHY SUBJECTS .O DOSAGE ADJUSTMENT IS NECESSARY IN PATIENTS WITH RENAL IMPAIRMENT OR IN PATIENTS UNDERGOING HEMODIALYSIS AS THE DIFFERENCE IN !5#S BETWEEN PATIENTS WHO ARE DIALYZED AND THOSE WHO ARE NOT IS STORAGE AND STABILITY 3TORE AT Â&#x17D;# TO Â&#x17D;# IN THE RECOMMENDED PACKAGING SPECIAL HANDLING INSTRUCTIONS .ONE &ULL 0RODUCT -ONOGRAPH AVAILABLE AT WWW NYCOMED CA 3EPTEMBER Â&#x161; 2EGISTERED TRADEMARK OF .YCOMED 'MB( 5SED UNDER LICENCE 4-

Prescribing Summary Patient Selection Criteria Tacrolimus ointment, 0.03% and 0.1% (w/w) THERAPEUTIC CLASSIFICATION Topical Calcineurin Inhibitor INDICATIONS AND CLINICAL USE Treatment PROTOPIC, both 0.03% and 0.1% for adults and only 0.03% for children aged 2 to 15 years, is indicated as a second-line therapy for short and long-term intermittent-treatment of moderate to severe atopic dermatitis in nonimmunocompromised patients, in whom the use of conventional therapies are deemed inadvisable because of potential risks, or who are not adequately responsive to or intolerant of conventional therapies. Maintenance PROTOPIC is also indicated for maintenance therapy to prevent flares and prolong flare-free intervals in patients with moderate to severe atopic dermatitis experiencing a high frequency of flares (i.e., occurring 5 or more times per year) who have had an initial response (i.e., lesions cleared, almost cleared or mildly affected) with up to 6 weeks of treatment with twice daily PROTOPIC. Geriatric Use (* 65 years of age): In Phase 3 studies, 405 patients * 65 years old received PROTOPIC. The adverse event profile for these patients was consistent with that for other adult patients. Pediatric Use (2 to 15 years): PROTOPIC, 0.03% strength only, is indicated for use in children aged 2 to 15 years. The safety and efficacy of PROTOPIC have not been established in pediatric patients below 2 years of age, and its use in this age group is not recommended. CONTRAINDICATIONS PROTOPIC (tacrolimus ointment) is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the preparation.

Safety Information WARNINGS AND PRECAUTIONS Long-term safety of topical calcineurin inhibitors has not been established. Although a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including PROTOPIC ointment 0.1% and 0.03%. Therefore: D 87=37>8>< 5871 =/;6 ></ 80 =893-+5

calcineurin inhibitors including PROTOPIC ointment 0.1% and 0.03% should be avoided, and application limited to areas of involvement with atopic dermatitis. D #$"&"# 837=6/7= 3< 78= 37.3-+=/. 37 children less than 2 years of age. Only 0.03% PROTOPIC ointment is indicated for use in children 2-15 years of age. General: Prolonged systemic exposure to calcineurin inhibitors has been associated with an increased risk of infections, lymphomas and skin malignancies. These risks are associated with the intensity and duration of immunosuppression. Therefore, PROTOPIC should not be used in immunocompromised adults and children. While a causal relationship has not been established, cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including PROTOPIC. The use of PROTOPIC should be avoided on pre-malignant and malignant skin conditions. Some malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), may mimic atopic dermatitis. If signs and symptoms of atopic dermatitis do not improve within 6 weeks of twice daily treatment, PROTOPIC treatment should be discontinued and patients should be re-examined by their healthcare provider and their diagnosis be confirmed. Patients should minimize or avoid natural or artificial sunlight exposure during the course of treatment, even while PROTOPIC is not on the skin. It is not known whether PROTOPIC interferes with skin response to ultraviolet damage. Carcinogenesis and Mutagenesis: Prolonged use of calcineurin inhibitors for sustained immunosuppression in animal studies and systemic administration in transplant patients has been associated with an increased risk of lymphomas and skin malignancies. Although a causal relationship has not been established, cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including PROTOPIC, during post-marketing surveillance. Immune: In clinical studies, cases of lymphadenopathy were reported and were usually related to infections and noted to resolve upon appropriate antibiotic therapy. The majority of these cases had either a clear etiology or were known to resolve. Transplant patients receiving immunosuppressive regimens (e.g. systemic tacrolimus) are at increased risk for developing lymphoma; therefore, patients who receive PROTOPIC and who develop lymphadenopathy should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of PROTOPIC should be considered. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves. Immunocompromised Patients: The safety and efficacy of PROTOPIC in immunocompromised patients have not been studied. Renal Insufficiency: Post-marketing cases of acute

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renal failure have been reported in patients treated with PROTOPIC. Systemic absorption is more likely to occur in patients with epidermal barrier defects especially when PROTOPIC is applied to large body surface areas. Caution should also be exercised in patients predisposed to renal impairment. Sexual Function/Reproduction: Reproductive toxicology studies were not performed with tacrolimus ointment. Skin: The use of PROTOPIC may cause local symptoms of short duration, such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of PROTOPIC application and typically resolve as the lesions of atopic dermatitis heal. PROTOPIC has not been studied for its efficacy and safety in the treatment of clinically infected atopic dermatitis. Patients with atopic dermatitis are predisposed to superficial skin infections. Treatment with PROTOPIC may be associated with an increased risk of varicella zoster virus infection (chickenpox or shingles), herpes simplex virus infection, or eczema herpeticum. In the presence of infections, the balance of risks and benefits associated with PROTOPIC use should be evaluated. The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Despite the absence of observed phototoxicity in humans, PROTOPIC shortened the time to skin tumour formation in an animal photocarcinogenicity study. Therefore, it is prudent for patients to minimize or avoid natural or artificial sunlight exposure. The use of PROTOPIC in patients with Nethertonâ&#x20AC;&#x2122;s syndrome is not recommended due to the potential for increased systemic absorption of tacrolimus. The safety of PROTOPIC has not been established in patients with generalized erythroderma. SPECIAL POPULATIONS Pregnant Women: There are no studies on the use of PROTOPIC in pregnant women. Reproduction studies were carried out with systemically administered tacrolimus in rats and rabbits. Adverse effects on the fetus were observed mainly at oral dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights. No reduction in male or female fertility was evident. There are no adequate and well-controlled studies of systemically administered tacrolimus

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in pregnant women. Tacrolimus is transferred across the placenta. The use of systemically administered tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. PROTOPIC should be used during pregnancy only if the potential benefit to the mother justifies a potential risk to the fetus. Nursing Mothers: Although systemic absorption of tacrolimus following topical applications of PROTOPIC is minimal relative to systemic administration, it is known that tacrolimus is excreted in milk. Therefore, breast feeding should be avoided during use of PROTOPIC. Pediatrics: PROTOPIC 0.03% may be used in pediatric patients 2 years of age and older. The safety and efficacy of PROTOPIC have not been established in pediatric patients below 2 years of age, and its use in this age group is not recommended. Geriatrics (* 65 years of age): Four hundred and five (405) patients * 65 years old received PROTOPIC in Phase 3 studies. The adverse event profile for these patients was consistent with that for other adult patients. Drug Interactions: Formal topical drug interaction studies with PROTOPIC have not been conducted. Based on its minimal extent of absorption, interactions of PROTOPIC with systemically administered drugs cannot be ruled out, but are unlikely to occur. ADVERSE REACTIONS In normal volunteer dermal safety studies, PROTOPIC was neither phototoxic, nor photoallergenic, nor a contact sensitizer. Overall, 14,828 patients treated with PROTOPIC were evaluated in phase 3 studies. Treatment Clinical Trials with PROTOPIC Compared to Active Comparators: In three active comparator studies using topical corticosteroids with PROTOPIC, the duration of treatment was 3 weeks. In the adult study, the most common adverse events experienced were skin burning and pruritus, which were primarily applicationsite events caused by the medication. In total, 35.5% of patients in the 0.1% hydrocortisone butyrate group, 63.7% of patients in the 0.03% PROTOPIC group and 68.6% of patients in the 0.1% PROTOPIC group experienced an application-site adverse event. Both skin burning and pruritus tended to be brief; the occurrence of which decreased with time, lasting approximately 4-7 days. Other adverse events reported in this clinical trial included flu-like symptoms, folliculitis, headache, allergic reaction, skin erythema, maculopapular rash, nausea, diarrhea and paresthesia. None of these adverse events showed a significant difference in incidence among the treatment groups. Herpes simplex, a less common adverse reaction (<5%), was more frequent in patients treated with PROTOPIC compared to 0.1% hydrocortisone butyrate group. As in the adult study, skin burning and pruritus comprised the most common application site

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adverse events and tended to occur only during the first few days of treatment in this pediatric comparator study. In this study population, 21.1% of patients in the 1% hydrocortisone acetate group, 38.1% of patients in the 0.03% PROTOPIC group, and 36.6% of patients in the 0.1% PROTOPIC group experienced an application site adverse event. There was a marked decrease in the prevalence of skin burning over time, particularly in the PROTOPIC treatment groups. Pruritus also decreased over time in the PROTOPIC treatment groups but not in the hydrocortisone acetate group. The incidence of other adverse events that may be associated with treatment was similar among all study groups and included flu-like symptoms, fever, abdominal pain, increased cough, rhinitis, diarrhea and headache. Clinical Trials with PROTOPIC Compared to Vehicle Ointment: In the three 12-week vehicle-controlled clinical trials, the most common adverse events reported were application site incidences of skin burning (46%, 58%, 43%), pruritus (46%, 46%, 41%), skin erythema (25%, 28%, 12%), flu-like symptoms (23%, 31%, 28%) and headache (20%, 19%, 5%) in adult patients who received 0.03% or 0.1% PROTOPIC and paediatric patients who received 0.03% PROTOPIC, respectively. In open-label, long-term safety studies of up to 4 years’ duration, the adverse event profile of PROTOPIC was similar to the adverse event profile seen in pivotal Phase 3 studies. Maintenance: In the two Phase 3, multi-centre, double-blind, vehicle-controlled 12-month studies the nature and incidence of adverse events were consistent with the established safety profile of PROTOPIC. REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways: Report Online: www.healthcanada.gc.ca/ medeffect Call toll-free at: 1-866-234-2345 Complete a Canada Vigilance Reporting Form and: - Fax toll-free to: 1-866-678-6789, or - Mail to: Canada Vigilance Program Health Canada Postal Locator 0701C Ottawa, ON K1A 0K9 To report any suspected adverse reactions to this drug, you can notify Astellas Pharma Canada, Inc. at 1-888-338-1824.

Administration DOSAGE AND ADMINISTRATION Adult (age 16 and over): PROTOPIC (tacrolimus ointment) 0.03% and 0.1%. Paediatric (above 2 years of age): PROTOPIC (tacrolimus ointment) 0.03% only. Each affected region of the skin should be treated with PROTOPIC until lesions are cleared, almost cleared or mildly affected. Thereafter, patients who have a high frequency of

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flares (* 5 times per year) are considered suitable for maintenance treatment. At the first signs of recurrence (flares) of the disease symptoms, twice daily treatment should be re-initiated. The use of PROTOPIC under occlusion has not been studied; therefore occlusive dressings are not recommended. Treatment: PROTOPIC 0.03% and 0.1% should be applied topically morning and evening twice daily as a thin layer to affected areas of skin, including the face, neck and eyelids. If no improvement occurs after 6 weeks of therapy or in case of disease exacerbation, PROTOPIC therapy should be discontinued and patients should consult their physicians. Maintenance: Patients who have a high frequency of flares (* 5 times per year) and are responding to up to 6 weeks of acute treatment with tacrolimus ointment twice daily are suitable for maintenance treatment. PROTOPIC 0.03% or 0.1% should be applied once daily twice a week. There should be 2 to 3 days between applications (e.g., Monday and Thursday). PROTOPIC should be applied as a thin layer to the areas of the skin normally affected by atopic dermatitis (including the face, neck and eyelids). If signs of flares reoccur, twice daily treatment should be reinitiated (see Treatment). After 12 months, a review of the patient`s condition should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data for maintenance treatment beyond 12 months. In children, this review should include suspension of treatment to assess the need to continue this regimen and to evaluate the course of the disease. AVAILABILITY PROTOPIC (tacrolimus ointment) 0.03% (w/w) 30 gram laminate tube 60 gram laminate tube PROTOPIC (tacrolimus ointment) 0.1% (w/w) 30 gram laminate tube 60 gram laminate tube

Study References 1. PROTOPIC® Product Monograph, Astellas Pharma Canada, Inc. September 24, 2010. A phase 3, 12-month, multicentre, randomized, vehicle-controlled study evaluating the efficacy of twice-weekly maintenance application of 0.1% PROTOPIC ointment in adult patients (* 16 years) with moderate to severe eczema. Patients with active disease entered an openlabel period (OLP) during which they treated affected lesions with PROTOPIC ointment twice daily until improvement had reached a predefined score (Investigator’s Global Assessment [IGA] ) 2, i.e. clear, almost clear or mild disease) for a maximum of 6 weeks. If patients did not respond to treatment, they were discontinued from the study. Thereafter, patients entered a double-blind disease control period (DCP) for up to 12 months. Patients were randomized to receive 0.1% PROTOPIC ointment or vehicle, once a day twice weekly

on Mondays and Thursdays. If a disease exacerbation occurred, patients were treated with open-label PROTOPIC ointment twice daily for a maximum of 6 weeks until the IGA score returned to ) 2. Patients who did not achieve an IGA score of ) 2 were withdrawn from the study. Disease exacerbations (DE) were defined as an exacerbation requiring a “substantial therapeutic intervention,” defined as a DE with an IGA of 3-5 (i.e. moderate, severe and very severe disease) on the first day of the flare, and requiring more than 7 days treatment. Supplemental Product Information WARNINGS AND PRECAUTIONS Sexual Function/Reproduction: Reproductive toxicology studies were not performed with tacrolimus ointment. In studies of oral tacrolimus no impairment of fertility was seen in male and female rats. Tacrolimus, given orally at 1.0 mg/kg to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg, tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations. ADVERSE REACTIONS Adverse Drug Reaction Overview In normal volunteer dermal safety studies, PROTOPIC was neither phototoxic, nor photoallergenic, nor a contact sensitizer. Overall, 14,828 patients treated with PROTOPIC were evaluated in phase 3 studies. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Treatment Clinical Trials with PROTOPIC Compared to Vehicle Ointment: Table 1 describes the adjusted incidence of adverse events (*3%) pooled across the 3 identically designed 12-week, vehicle-controlled Phase 3 studies (two adult studies, one pediatric study). In open-label, long-term safety studies of up to 4 years’ duration, the adverse event profile of PROTOPIC was similar to the adverse event profile seen in pivotal Phase 3 studies. Less Common Clinical Trial Adverse Drug Reactions: Less common events occurring in 1% - 5% of patients in order of decreasing frequency include skin tingling, acne, folliculitis, hyperesthesia (sensitive skin, increased sensitivity to hot/cold temperature), alcohol intolerance (skin/facial flushing, redness, heat sensation), dyspepsia, myalgia, and cyst. The incidence of herpes zoster (chickenpox) occurred less frequently in patients treated with vehicle (0 cases) and PROTOPIC 0.1% (1 case) than in patients treated with PROTOPIC 0.03% (4 cases). Maintenance In the two Phase 3, multi-centre, double-blind, vehicle-controlled 12-month studies the nature and incidence of adverse events were consistent with the established safety profile of PROTOPIC. Table 2 describes the most frequently reported adverse events (*3%) that occurred in the Phase 3 study in adults. Table 3 describes the most frequently reported adverse events (*3%) that occurred in the Phase 3 study in pediatrics. Post-Market Adverse Drug Reactions The following adverse reactions have been reported from postmarketing surveillance for PROTOPIC ointment 0.1% and 0.03%. Since these events are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Central Nervous System: seizures Metabolism: alcohol intolerance Neoplasms: lymphomas, skin neoplasms (basal cell carcinoma, squamous cell carcinoma and melanoma) Infections: bullous impetigo, osteomyelitis, septicemia, local skin infection regardless of specific etiology Renal: Acute renal failure in patients with or without Nertherton’s syndrome, renal impairment Skin: rosacea SYMPTOMS AND TREATMENT OF OVERDOSE For management of a suspected drug overdose, contact your regional Poison Control Centre. PROTOPIC is not for oral use. Oral ingestion of PROTOPIC may lead to adverse effects associated with systemic administration of tacrolimus. If oral ingestion occurs, medical advice should be sought.

Product Monograph available on request. Astellas Pharma Canada, Inc., 675 Cochrane Drive, Suite 500 (West Tower), Markham, Ontario, L3R 0B8, 1 888 338 1824 http://www.astellas.com/ca/

Table 1: Incidence of Treatment Emergent Adverse Events (*3% in Any Treatment Group) COSTART Term

Adult Tacrolimus 0.03% (N=210) % 46 46 23 12 25 20 12 4 1 1 6 4 3 3 3 6 3 0 4 3 3 2 1 2 5 1 2 2 3 4 2 3 2 3 3 1 3 3 4 1 3 2 4 3 4 3 1 1 3

Vehicle (N=212) % Skin Burning* Pruritus* Flu-like symptoms* Allergic reaction Skin erythema Headache* Skin infection Fever Infection Cough increased Asthma Herpes simplex Pharyngitis Accidental injury Pustular rash Folliculitis* Rhinitis Otitis media Sinusitis* Diarrhea Urticaria Bronchitis Vomiting Maculopapular rash Rash* Abdominal pain Fungal dermatitis Gastroenteritis Alcohol intolerance* Acne* Skin disorder Vesiculobullous rash* Lymphadenopathy Nausea Skin tingling* Dyspesia* Dry skin Hyperesthesia* Peripheral edema Varicella zoster/Herpes zoster*,** Contact dermatitis Asthenia Insomnia Exfoliative dermatitis Dysmenorrhea Myalgia* Cyst* Arthralgia Paresthesia

26 37 19 8 20 11 11 4 1 2 4 4 3 4 2 1 4 4 1 3 3 0 0 2 1 3 0 1 0 2 2 3 2 4 2 1 7 1 2 0 1 1 3 3 2 0 0 1 1

Tacrolimus 0.1% (N=209) % 58 46 31 6 28 19 5 1 2 1 4 4 4 6 4 4 2 1 2 4 6 2 1 2 2 1 1 2 7 7 1 2 1 2 8 4 3 7 3 0 3 3 3 1 4 2 3 3 3

Vehicle (N=116) % 29 27 25 8 13 8 14 13 9 14 6 2 11 3 3 0 2 6 8 2 1 3 7 3 4 2 3 3 0 1 1 0 0 0 1 0 0 0 0 0 3 0 1 0 0 0 0 2 0

Pediatric Tacrolimus 0.03% (N=118) % 43 41 28 4 12 5 10 21 7 18 6 0 6 6 2 2 6 12 3 5 1 3 6 0 2 3 0 0 0 0 4 4 3 1 2 0 1 0 0 5 4 0 1 0 0 0 0 0 0

*May be reasonably associated with the use of PROTOPIC. **All the herpes zoster cases in the pediatric 12-week study were reported as chicken pox. Table 2: Incidence of Most Frequently Reported Adverse Events Table 3. Incidence of Most Frequently Reported Adverse Events (* 3%) Regardless of Relationship to Study Drug in the (* 3%) Regardless of Relationship to Study Drug in the Double-Blind Maintenance Treatment Phase of Study FG-506-06Double-Blind Maintenance Treatment Phase of Study FG-506-0640 (Adults) 41 (Pediatrics) MedDRA preferred term

Number of Patients Experiencing an Adverse Event (%) at a Frequency of * 3% PROTOPIC 0.1% Vehicle N=80 N=73

Application-site Application-site pruritus 14 (17.5) 11 (15.1) Application-site folliculitis 6 (7.5) 8 (11.0) Application-site irritation 4 (5.0) 6 (8.2) Application-site infection 6 (7.5) 3 (4.1) Herpes simplex 3 (3.8) 4 (5.5) Impetigo 3 (3.8) 4 (5.5) Non-application-site Nasopharyngitis * 11 (13.8) 6 (8.2) Headache 9 (11.3) 3 (4.1) Pruritus 4 (5.0) 4 (5.5) Influenza 3 (3.8) 4 (5.5) Herpes simplex 1 (1.3) 2 (2.7) Pharyngolaryngeal pain 0 4 (5.5) Pyrexia 1 (1.3) 2 (2.7) Respiratory tract infection viral 3 (3.8) 0 *The MedDRA preferred term “Nasopharyngitis” includes the lowest level terms “cold” and “cold symptoms”.

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MedDRA preferred term

Number of Patients Experiencing an Adverse Event (%) at a Frequency of * 3% PROTOPIC Vehicle 0.03% N=75 N=78

Application-site Application-site pruritus 12 (15.4) 8 (10.7) Impetigo 9 (11.5) 5 (6.7) Application-site infection 7 (9.0) 4 (5.3) Herpes simplex 3 (3.8) 1 (1.3) Skin papilloma 3 (3.8) 4 (4.0) Non-application-site Nasopharyngitis * 30 (38.5) 21 (28.0) Influenza 9 (11.5) 1 (1.3) Pyrexia 8 (10.3) 6 (8.0) Respiratory tract infection viral 2 (2.6) 2 (2.7) Cough 3 (3.8) 5 (6.7) Pruritus 8 (10.3) 3 (4.0) Rhinitis 2 (2.6) 4 (5.3) Gastroenteritis viral 5 (6.4) 3 (4.0) Headache 4 (5.1) 4 (5.3) Asthma 6 (7.7) 3 (4.0) Gastroenteritis 2 (2.6) 1 (1.3) Tonsillitis 5 (6.4) 4 (5.3) Bronchitis bacterial 3 (3.8) 0 Varicella 3 (3.8) 3 (4.0) Upper respiratory tract infection 5 (6.4) 3 (4.0) Vomiting 4 (5.1) 4 (5.3) Molluscum contagiosum 4 (5.1) 2 (2.7) Eczema infected 2 (2.6) 4 (5.3) Pharyngitis 1 (1.3) 3 (4.0) Abdominal pain 1 (1.3) 4 (5.3) Gastrointestinal infection 2 (2.6) 4 (5.3) Lice infestation 1 (1.3) 3 (4.0) Skin bacterial infection 1 (1.3) 4 (5.3) Diarrhea 4 (5.1) 0 *The MedDRA preferred term “Nasopharyngitis” includes the lowest level terms “cold” and “cold symptoms”.

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Les visages de la médecine familiale | The Faces of Family Medicine Continued from inside half-cover (IHC) Suite de la demi-page intérieure de la couverture

Heather Armson MD CCFP FCFP

Tout revient à la relation, à l’établissement d’un lien, d’une connexion et au développement du partage, de l’intérêt pour ce qui s’est passé et de la curiosité à propos de ce qui viendra. La médecine concerne souvent bien plus la discussion des problèmes que leur solution, car c’est la relation qui fait le médecin et non l’inverse. Dre Armson, aussi diplômée en psychologie et en éducation, comprend que les patients de sa pratique ont besoin d’elle, d’une personne avec qui ils peuvent avoir des liens pour pouvoir se rétablir ou tout au moins avoir un forum pour parler de leur problème. Dre Armson est si passionnée par les relations qu’elle enseigne aux résidents en difficulté la nature de la relation, la façon dont une personne en approche une autre, comment une personne peut en venir à apprendre des choses sur une autre qui vont au-delà des données et des faits médicaux et l’importance d’apprécier véritablement le fait que chaque rencontre est une possibilité de grandir, que même les plus difficiles rencontres enseignent aux médecins quelque chose à propos d’eux-mêmes. Un de ses patients souffre de multiples problèmes concomitants, greffé deux fois, amputé, sans compter les nombreuses infections, le genre de patient que les médecins évaluent en se fondant sur tant d’incertitude. C’est la relation qu’elle entretient avec cet homme atteint de maladies chroniques qui a fait une différence dans la vie de ce patient: il lui a affirmé et sa famille l’a confirmé que par le simple fait qu’elle connaisse ses circonstances, sa situation personnelle, ses difficultés et sa frustration face à un système qui lui inflige d’innombrables spécialistes, elle a changé sa vie en validant sa souffrance.

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Cette passion pour les relations s’est transformée en projet de formation scientifique. Dre Armson a enseigné à des médecins au Kenya l’importance des relations. Elle a d’abord dû établir des relations avec des médecins musulmans, dans un monde musulman à dominance masculine, mettre sur pied un système autosuffisant dans lequel ces médecins alimenteraient réciproquement leur curiosité scientifique et s’évalueraient mutuellement. Ces médecins ont dû apprendre la pratique fondée sur des données probantes et n’auraient pas pu le faire ni l’auraientils fait sans que Dre Armson n’ait établi avec eux une relation, relation qui est le cœur-même de la machine fondée sur des données probantes. Le programme continue encore et le fait qu’il se poursuive et qu’il soit continuellement évalué témoigne des relations qu’elle a favorisées et du genre de médecine qu’elle exerce.

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Dre Armson est professeure agrégée au Département de médecine familiale de l’University of Calgary en Alberta et directrice de la recherche au Programme d’apprentissage en petit groupe basé sur la pratique. Dr Armson is Associate Professor in the Department of Family Medicine at the University of Calgary in Alberta and Research Director of the Practice Based Small Group Learning Program.

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Photos: Terence Law, Calgary, Alta Texte | story: Shane Neilson MD CCFP, Erin, Ont

E ROJET DE LA PAGE COUVERTURE Le Médecin de famille canadien entreprend un projet visant à tracer le portrait de la médecine familiale au Canada. La page couverture de la revue mettra en vedette un médecin de famille choisi au hasard dans notre liste de membres. Un court texte donnera un bref aperçu de la personne et de sa pratique. Avec le temps, cette sélection aléatoire deviendra représentative, car les différences, rassemblées, feront ressortir ce que tous les médecins de famille ont en commun. VOL 57: JANUARY t JANVIER 2011

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Teaching Moment | Occasion d’enseignement

Clinical uncertainty Helping our learners Dale Guenter

MD MPH CCFP FCFP

Nancy Fowler

MD CCFP FCFP

Linda Lee

hat is the problem?

A resident comes to the preceptor to discuss a case. She is anxious, frustrated, and grasping for help. She has just been with a patient for a halfhour visit and feels she has no idea what the diagnosis is or what she can offer. The patient is also frustrated and increasingly demanding. As the discussion unfolds, it is apparent that the resident has begun to settle on a single working diagnosis, which has eliminated other possibilities too early, wants to order some tests that are likely unnecessary, and is beginning to speak about the patient in a tone that is condescending, alienating, and blaming. It seems likely that this encounter will end with considerable distress for both.

As teachers we come up against this scenario, or some version of it, all too often. It is difficult for the resident, but it is also difficult for most of us, as we have never developed a skill set or language to address this type of situation constructively. Our education is focused primarily on increasing our knowledge base, developing our skills in accessing the evidence, and refining our clinical reasoning, all in service of the false assumption that every clinical problem can be solved. This is not unique to primary care, but primary care is uniquely an environment of low disease probability and the undifferentiated presentation. The family physician is also in the position of remaining part of the patient’s clinical course indefinitely, unlike the specialist who might shrug and direct the patient back to the family physician. Clinical uncertainty, as well as physician intolerance of it, has been linked to increased test ordering and overall use of health resources,1,2 in spite of evidence that shows patients might not want somatic interventions.3 Anxiety with uncertainty has also been linked to lower workrelated satisfaction.4

Learners’ experience of uncertainty Learners in medicine are in a phase of rapid expansion of their knowledge base, developing sound clinical reasoning skills and understanding how to “be with” patients. But something we do not discuss a great deal is the role of perceived competence. As learners, we tend to avoid situations that will reveal our Cet article se trouve aussi en français à la page 123.

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uncertainty, or when avoiding it is impossible, we might either disguise it or reposition it as someone else’s problem. 5 The learner expends a great deal of effort maintaining the “cloak of competence,” a survival technique that would fit well into Maslow’s hierarchy of needs, as it might be translated for the jungle of medical training. As Fox explained in 1957, our uncertainty might be the result of limitations or ambiguities in the medical knowledge base, or our own incomplete mastery of that knowledge base.6 Much of our anxiety in our early careers stems from not knowing the difference.

Play of certainty and uncertainty in the clinical encounter From the moment we begin to engage with a patient’s predicament (eg, the nurse’s note on the chart says, “Headache”) until we consider this encounter complete, we pass through an emotional trajectory described as a clinical tension curve.7 Our tension and anxiety increase over the course of a clinical encounter not only in response to the revelation of data that are difficult to interpret or to synthesize. Other conditions such as the patient’s emotions, time pressures, provider fatigue, or cognitive overload aggravate the situation. Ultimately, we hope for a resolution that allows us to leave the encounter with less tension. In the best situation, this resolution might be a confident diagnosis, a management plan, or a reframing of the situation that will maintain engagement with the patient and relieve anxiety. In other words, resolution of an encounter comes by achieving a level of certainty that the provider and patient can hold with confidence. In the worst situation, we force a resolution by imposing or agreeing to an unnecessary test or prescription, blaming patients for our inability to explain what is going on, or taking shortcuts in clinical reasoning to arrive at an inadequate diagnosis. These responses, sometimes referred to as premature closure, are costly. They are the main cause of medical errors.8 They can leave patients feeling alienated or unheard. Our own anxieties, though briefly relieved, might return to haunt us that evening or when we see those patients’ names on our lists another day. Premature closure is a flailing attempt to impose a higher level of certainty on a situation than that situation is ready for.

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Teaching Moment Helping learners get better results A few simple strategies can improve the outcomes of these encounters for our patients and for our learners. (We believe they also improve satisfaction for the clinical teacher.) We have assembled these strategies from the literature and from our own experience as teachers. The research on effectiveness of teaching these approaches is thus far scant as far as we can determine. Tend to emotions. If we begin by encouraging our learners to have self-awareness of emotional response, and a deeper understanding of the triggers for that response, we set the foundation for better problem solving. By normalizing and probing (eg, “What are you feeling?” “This feeling is common,” and “What makes you feel this way?”) we begin to shed light on the web of factors that lead up to this unpleasant sensation. We can teach residents to check in with themselves when they notice the temperature rising in the moment of clinical tension. And more important, in doing this, we begin to shift the focus away from blaming patients as bad historians, somatizers, drug seekers, or malingerers to a focus on learners’ knowledge base, clinical reasoning, relationships with patients, and other pressures of the day that make these encounters a struggle. Slow down for clinical reasoning. If diagnoses or treatment plans are not obvious, learners might march through such cases too quickly. They might seek a pattern that fits with something they readily recognize. As the experienced clinician, you might be able to see patterns that they do not, or you might see that it is time to abandon pattern recognition and go back to the hard work of step-by-step hypothesis testing. In other words, the case might benefit from taking more time, reviewing the data in depth, surfacing a few new ideas, and going down a new reasoning path. 9 We need to emphasize for our learners the intellectual and relational rewards of seeking what is particular and unique about the individual in front of us, rather than seeking ways to slot him or her into a recognizable category. Explore certainty within uncertainty. We can have uncertainty without being uncertain. We might not know the exact diagnosis or have a complete explanation for what is going on, but there are still pieces of the problem about which we are certain. We might be certain that patients are safe and that their physical or mental conditions do not put them in danger. We might be certain about some aspects of the pathophysiology (eg, “You clearly have muscle spasm and some inflammation in a joint, I’m just not sure why it’s there”). And we might have certainty about what this is not. We need to teach our learners not to be

defeated by what they do not know, but to be skillful in identifying and describing what they do know and what they are confident about. Join with the patient. Once learners have taken time for the above steps, they are well positioned to move in relation with rather than to control the patient or the encounter. This draws on the familiar territory of patient-centred care, in which we seek to understand the expectations, feelings, and ideas held by patients. Patient-centred care, empathy, and a partnering style have been well scrutinized in research, and have proven to have positive effects on satisfaction and on health outcomes.10 We can remind learners to disclose their own uncertainty to the patient; to validate the patient’s symptoms and the emotional response of both patient and learner; to think out loud with the patient about the analytical process thus far and for the future; and to commit to “stay” with the patient’s journey over time as possibilities are explored or strategies to improve the situation are tried. In large part, this joining process involves reframing the problem together with the patient, so that it is less about arriving at a definitive diagnosis or treatment, and more about a partial explanation, a partial plan of action, and a commitment to be in it for the long haul. Achieve resolution (for today). It will seldom be possible to accomplish all of this in the moment of a single encounter. Thankfully, in family medicine we have many opportunities to return to the drawing board with learners and patients. For any encounter, we can introduce learners to some part of this approach and encourage them to tend to symptom management and function. This will achieve some resolution in clinical tension, and avoid errors, alienation, and unnecessary investigation or treatment. Dr Guenter is Associate Professor and Co-Director of McMaster Family Practice in the Department of Family Medicine at McMaster University in Hamilton, Ont. Dr Fowler is Associate Professor and Family Medicine Residency Program Director in the Department of Family Medicine at McMaster University. Dr Lee is Director of the Centre for Family Medicine Memory Clinic in Kitchener, Ont, and Assistant Professor in the Department of Family Medicine at McMaster University. Competing interests None declared References 1. Van der Weijden T, van Velsen M, Dinant GJ, van Hasselt CM, Grol R. Unexplained complaints in general practice: prevalence, patients’ expectations, and professionals’ test-ordering behavior. Med Decis Making 2003;23(3):226-31. 2. Allison JJ, Kiefe CI, Cook EF, Gerrity MS, Orav EJ, Centor R. The association of physician attitudes about uncertainty and risk taking with resource use in a Medicare HMO. Med Decis Making 1998;18(3):320-9. 3. Salmon P, Ring A, Dowrick CF, Humphris GM. What do general practice patients want when they present medically unexplained symptoms, and why do their doctors feel pressurized? J Psychosom Res 2005;59(4):255-60. 4. Bovier PA, Perneger TV. Stress from uncertainty from graduation to retirement—a population-based study of Swiss physicians. J Gen Intern Med 2007;22(5):632-8. Epub 2007 Mar 9. 5. Lingard L, Garwood K, Szauter K, Stern D. The rhetoric of rationalization: how students grapple with professional dilemmas. Acad Med 2001;76(Suppl 10):S45-7.

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Teaching Moment 6. Fox R. Training for uncertainty. In: Merton RK, Reader G, Kendall PL, editors. The student physician. Cambridge, MA: Harvard University Press; 1957. 7. Borrell-Carrió F, Epstein RM. Preventing errors in clinical practice: a call for self-awareness. Ann Fam Med 2004;2(4):310-6. 8. Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Arch Intern Med 2005;165(13):1493-9. 9. Moulton CE, Regehr G, Mylopoulos M, MacRae HM. Slowing down when you should: a new model of expert judgment. Acad Med 2007;82(Suppl 10):S109-16. 10. Seaburn DB, Morse D, McDaniel SH, Beckman H, Silberman J, Epstein R. Physician responses to ambiguous symptoms. J Gen Intern Med 2005;20(6):525-30.

TEACHING TIPS r $MJOJDBM VODFSUBJOUZ JT DPNNPO JO UIF GBNJMZ QSBDUJDF setting, and learning to recognize and manage it is an important skill for learners to develop. r 'BJMVSF PG MFBSOFST UP SFDPHOJ[F BOE EFBM XJUI DMJOJDBM uncertainty can lead to unsatisfactory and even harmful outcomes for both patients and learners. r 5FBDIFST DBO BQQMZ TJNQMF TUSBUFHJFT UP IFMQ MFBSOFST recognize and effectively deal with clinical uncertainty, including tending to emotions, slowing down clinical reasoning, exploring certainty within uncertainty, joining with the patient, and achieving resolution (at least for today). CONSEILS POUR L’ENSEIGNEMENT r - JODFSUJUVEF DMJOJRVF FTU DPVSBOUF FO QSBUJRVF GBNJMJBMF FU JM est important que les étudiants développent la capacité de la reconnaître et de la gérer. r © EÊGBVU EF SFDPOOBÏUSF M JODFSUJUVEF DMJOJRVF FU E Z GBJSF face, les étudiants peuvent finir par ressentir de l’insatisfaction, ce qui peut entraîner des conséquences nuisibles pour les patients et pour eux-mêmes. r -FT FOTFJHOBOUT QFVWFOU VUJMJTFS EF TJNQMFT TUSBUÊHJFT pour aider les étudiants à reconnaître l’incertitude clinique et à savoir y faire face, notamment en se préoccupant des émotions, en mettant un frein au raisonnement clinique, en explorant la certitude au sein de l’incertitude, en rejoignant le patient et en en arrivant à une entente (au moins pour aujourd’hui). Teaching Moment is a quarterly series in Canadian Family Physician, coordinated by the Section of Teachers of the College of Family Physicians of Canada. The focus is on practical topics for all teachers in family medicine, with an emphasis on evidence and best practice. Please send any ideas, requests, or submissions to Dr Allyn Walsh, Teaching Moment Coordinator, at walsha@mcmaster.ca.

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Mission

Canadian Family Physician (CFP), a peer-reviewed medical journal, is the official publication of the College of Family Physicians of Canada. Our mission is to ensure that practitioners, researchers, educators and policy makers are informed on current issues and in touch with the latest thinking in the discipline of family medicine; to serve family physicians in all types of practice in every part of Canada in both official languages; to advance the continuing development of family medicine as a discipline; and to contribute to the ongoing improvement of patient care.

Le Médecin de famille canadien (MFC), une revue médicale évaluée par des pairs, est la publication officielle du Collège des médecins de famille du Canada. Notre mission est d’informer les praticiens, les chercheurs, les enseignants et les décideurs au sujet des questions d’actualité et des courants de pensée les plus récents dans la discipline de la médecine familiale; d’être au service des médecins de famille dans les deux langues officielles, quel que soit leur genre de pratique, dans toutes les régions du Canada; de promouvoir le perfectionnement continu de la médecine familiale en tant que discipline; et de contribuer à l’amélioration constante des soins aux patients.

As the official publication of the College of Family Physicians of Canada, Canadian Family Physician has a role in disseminating information on the activities and objectives of the College.

Comme publication officielle du Collège des médecins de famille du Canada, Le Médecin de famille canadien contribue à diffuser des informations concernant les activités et le rôle du Collège.

The opinions expressed in articles and claims made in advertisements appearing in Canadian Family Physician or packaged as onserts with it are the opinions of the authors and advertisers, respectively, and do not imply endorsement by the College of Family Physicians of Canada. The College of Family Physicians of Canada does not assume liability or responsibility for any damages claimed as a result of any error or omission, or from the use or misuse of any information or advice published in Canadian Family Physician. No part of this publication may be reproduced in a retrieval system, or transmitted in any form or by any other means, electronic, mechanical, photocopying, recording or otherwise, without written permission from Canadian Family Physician. Copyright© the College of Family Physicians of Canada Subscriptions: College members in good standing receive Canadian Family Physician as a perquisite of membership. Others may subscribe. Canada: Individual Canadian physician $60 per year; individual, non-physician, $136 per year; Canadian institutional, $189 per year; single copy, $15. US and Mexico: Individual, US$199 per year; institutional, US$239 per year; single copy, US$20. Overseas: individual, US$229 per year; institutional, US$259 per year; single copy, US$25. In Canada, GST, HST and/or sales taxes extra where applicable. GST R108078023. For more information or to subscribe, go to www.cfp.ca and click on Subscribers. To order: Subscriptions, Canadian Family Physician, 2630 Skymark Ave, Mississauga, ON L4W 5A4; telephone 905 629-0900, extension 331; fax 905 629-0893, ma@cfpc.ca NOTE: All prescription drug advertisements in Canadian Family Physician have been precleared by the Pharmaceutical Advertising Advisory Board.

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Les opinions énoncées dans les articles et les déclarations dans la publicité apparaissant dans Le Médecin de famille canadien, ou qui font partie du même envoi postal, sont celles des auteurs et des annonceurs, respectivement, et ne sont pas nécessairement sanctionnées par le Collège des médecins de famille du Canada. Aucune partie de cette publication ne peut être reproduite par quelque moyen que ce soit, électronique ou mécanique, y compris enregistrement, archivage ou tout autre procédé de stockage, de traitement et de récupération d’information, sans la permission écrite du Médecin de famille canadien. Le Collège des médecins de famille n’assume aucune obligation ni responsabilité pour tout préjudice invoqué à la suite d’une erreur ou d’une omission ou découlant de l’utilisation bonne ou mauvaise de renseignements ou de conseils publiés dans Le Médecin de famille canadien. Copyright© le Collège des médecins de famille du Canada Abonnements: Les membres en règle du Collège des médecins de famille du Canada reçoivent Le Médecin de famille canadien à titre de privilège. Les autres personnes peuvent s’abonner. Canada: médecins canadiens à titre individuel, 60 $ par année; autres personnes à titre individuel, 136 $ par année; institutions canadiennes, 189 $ par année; à l’unité, 15 $. États-Unis et Mexique: abonnement individuel, 199 $US par année; institutionnel, 239 $US par année; à l’unité, 20 $US. Autres pays: individuel, 229 $US par année; institutionnel, 259 $US par année; à l’unité: 25 $US. Au Canada, la TPS, la TVH et/ou les taxes de vente sont en sus, là où elles s’appliquent. No de TPS: R108078023. Pour en savoir plus ou vous abonner, allez à www.cfp.ca et cliquez sur Subscribers. Pour placer une commande: Service des abonnements, Le Médecin de famille canadien, 2630, avenue Skymark, Mississauga, ON L4W 5A4; téléphone 905 629-0900, extension 331; Télécopieur 905 629-0893, ma@cfpc.ca NOTE: Toutes les annonces de produits pharmaceutiques sur ordonnance publiées dans le Médecin de famille canadien ont été approuvées par le Conseil consultatif de publicité pharmaceutique.

Teaching Moment |

Occasion d’enseignement

L’incertitude clinique Aider nos étudiants Dale Guenter

MD MPH CCFP FCFP

Nancy Fowler

MD CCFP FCFP

Linda Lee

uel est le problème?

Une résidente vient voir son précepteur pour discuter d’un cas. Elle est anxieuse, frustrée et a désespérément besoin d’aide. Elle vient de passer une demiheure avec un patient et elle a l’impression de n’avoir aucune idée du diagnostic à poser ni de ce qu’elle pourrait offrir. Le patient est aussi frustré et de plus en plus exigeant. À mesure que progresse la discussion, il est apparent que la résidente a commencé à se cramponner à un seul diagnostic, ce qui élimine trop vite d’autres possibilités, veut prescrire des analyses qui sont probablement inutiles et commence à parler du patient d’un ton condescendant, aliénant et ponctué de blâme. Il semble probable que cette rencontre se soldera par beaucoup de détresse de part et d’autre.

En tant qu’enseignants, nous sommes trop souvent témoins de ce scénario ou de l’une de ses variantes. C’est difficile pour le résident, mais aussi pour la plupart d’entre nous, puisque nous n’avons jamais développé un profil de compétences ou un langage pour faire face de manière constructive à ce genre de situation. Notre formation insiste surtout sur l’accroissement de notre base de connaissances, le perfectionnement de nos habiletés à accéder aux données probantes et le raffinement de notre raisonnement clinique, tous au service de la fausse hypothèse voulant que chaque problème clinique ait une solution. Cette situation n’est pas unique aux soins primaires, mais ces derniers sont un environnement particulièrement propice à la faible probabilité de maladie et aux présentations indifférenciées. Il est fort probable aussi que le médecin de famille demeure un élément stable et à long terme du cheminement clinique du patient, contrairement au spécialiste qui peut hausser les épaules et le renvoyer à son médecin de famille. L’incertitude clinique et l’intolérance des médecins à son égard ont été associées à une hausse du nombre d’analyses prescrites et de l’utilisation générale des ressources en santé1,2, en dépit des données scientifiques disant que les patients ne veulent pas nécessairement d’interventions somatiques3. L’anxiété créée par l’incertitude a aussi été associée à une satisfaction professionnelle moindre4.

L’expérience des étudiants quant à l’incertitude Les étudiants en médecine sont dans une phase This article is also in English on page 120.

MD MCLSC CCFP FCFP

d’expansion rapide de leur base de connaissances. Ils développent de bonnes habiletés en raisonnement clinique et comprennent comment «être avec» les patients. Cependant, une chose dont on ne discute pas beaucoup, c’est le rôle de la compétence perçue. En tant qu’étudiants, nous avons tendance à éviter les situations qui révèlent notre incertitude ou, quand c’est impossible de le faire, nous la déguisons ou la repositionnons comme étant le problème d’autrui5. L’étudiant déploie beaucoup d’efforts pour maintenir la «toge de la compétence», une technique de survie qui s’inscrirait bien dans la hiérarchie des besoins de Maslow, car elle se transpose aisément dans la jungle de la formation médicale. Comme l’expliquait Fox en 1957, notre incertitude pourrait être le résultat de nos limites, des ambigüités dans la base du savoir médical ou de notre maîtrise incomplète de cette base de connaissances6.Une grande partie de notre anxiété en début de carrière vient du fait que nous ne savons pas faire la distinction.

Le jeu de la certitude et de l’incertitude dans la rencontre clinique Du moment où nous prenons connaissance du problème du patient (p. ex. la note de l’infirmière dans le dossier dit «mal de tête») jusqu’à ce que nous jugions la rencontre terminée, nous traversons une trajectoire émotionnelle décrite comme une courbe de tension clinique7. Notre tension et notre anxiété augmentent durant la rencontre clinique, et ce n’est pas seulement en réaction à la révélation de données qui sont difficiles à interpréter ou à résumer. D’autres circonstances, comme les émotions du patient, les pressions liées au temps, la fatigue du médecin ou une surcharge cognitive, aggravent la situation. En bout de ligne, nous espérons qu’une solution nous permette de terminer la rencontre avec moins de tension. Dans le meilleur des scénarios, cette solution peut être un diagnostic posé en toute confiance, un plan thérapeutique ou une reformulation de la situation qui maintient l’engagement avec le patient et soulage l’anxiété. Autrement dit, la conclusion d’une rencontre vient de l’atteinte d’un degré de certitude que le médecin et le patient peuvent tous deux préserver en toute confiance. Dans les pires scénarios, nous forçons une solution en imposant ou en acceptant un test ou une prescription inutile, en blâmant le patient de notre incapacité d’expliquer ce qui se passe ou en prenant un raccourci dans le raisonnement clinique pour en arriver à un

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Occasion d’enseignement diagnostic erroné. Ces réactions, parfois appelées conclusions prématurées, coûtent cher. Elles sont la cause principale des erreurs médicales8. Elles peuvent faire en sorte que le patient se sente aliéné ou incompris. Nos propres anxiétés, quoique brièvement soulagées, peuvent revenir nous hanter en soirée ou un autre jour, quand nous verrons le nom du patient sur notre liste. La conclusion prématurée est une tentative, vouée à l’échec, d’imposer à une situation un plus grand degré de certitude qu’elle ne le mérite.

Aider les étudiants à obtenir de meilleurs résultats Quelques simples stratégies peuvent améliorer l’issue de ces rencontres pour nos patients et nos étudiants. (Nous croyons qu’elles rehaussent aussi la satisfaction du clinicien enseignant.) Nous avons cerné ces stratégies dans les ouvrages spécialisés et à partir de notre propre expérience en tant qu’enseignants. La recherche sur l’efficacité de l’enseignement de telles approches est limitée si l’on se fie au meilleur de nos connaissances. Se préoccuper des émotions. Si nous commençons par encourager nos étudiants à être conscients des réactions émotionnelles et à mieux comprendre ce qui déclenche ces réactions, nous établissons une base pour mieux résoudre les problèmes. En normalisant et en sollicitant une réponse (p. ex. «Que ressentez-vous?» «Ce sentiment est normal.» «Qu’est-ce qui vous fait sentir ainsi?»), nous commençons à mettre en lumière la panoplie de facteurs qui suscitent cette sensation désagréable. Nous pouvons enseigner aux résidents à s’examiner eux-mêmes quand ils se rendent compte que la température monte dans les moments de tension clinique. Avant tout, ce faisant, nous commençons à changer le focus du problème: au lieu de blâmer les patients de mal expliquer la chronologie des symptômes, d’être des somatisateurs, des quémandeurs de drogues ou des fainéants, on se concentre sur la base de connaissances des étudiants, le raisonnement clinique, les relations avec les patients et d’autres pressions de la journée qui compliquent ces rencontres. Ralentir le raisonnement clinique. Dans les cas où les diagnostics ou les plans thérapeutiques ne sont pas évidents, les étudiants pourraient procéder trop rapidement. Ils pourraient rechercher une tendance qui ressemble à ce qu’ils reconnaissent aisément. Étant le clinicien expérimenté, vous seriez capable de voir des tendances qu’ils ne voient pas ou pourriez savoir qu’il vaut mieux abandonner la reconnaissance des tendances pour en revenir au difficile travail de la mise à l’épreuve étape par étape des hypothèses. Autrement dit, le cas bénéficierait qu’on y accorde plus de temps, à revoir en profondeur les données, à ressortir de nouvelles idées pour

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adopter une nouvelle piste de raisonnement 9. Nous devons mettre en évidence pour nos étudiants les satisfactions intellectuelles et relationnelles procurées par la recherche de ce qui est particulier et unique dans la personne en face de nous, au lieu de chercher à la classer dans une catégorie reconnaissable. Explorer la certitude au sein de l’incertitude. Nous pouvons être incertains de notre incertitude. Nous ne connaissons peut-être pas le diagnostic exact ou nous ne pouvons pas expliquer complètement ce qui se passe, mais il y a quand même des parties du problème au sujet desquelles nous sommes certains. Nous pouvons être sûrs que le patient est en sécurité et que son problème physique ou mental ne le met pas en danger. Nous pouvons être certains à propos de certains aspects de la pathophysiologie (p. ex. «Vous avez clairement des spasmes musculaires et une certaine inflammation articulaire, mais je ne suis pas absolument sûr de la cause.»). Nous pouvons aussi avoir la certitude de ce que le problème n’est pas. Nous devons enseigner à nos étudiants à ne pas se sentir démolis par ce qu’ils ne savent pas, mais à plutôt être capables d’identifier et de décrire ce qu’ils savent effectivement et dont ils ont la certitude. Rejoindre le patient. Une fois que les étudiants ont pris le temps de suivre les étapes qui précèdent, ils sont bien placés pour passer à une relation avec le patient plutôt que de contrôler ou la rencontre. Cette mesure repose sur la notion familière des soins centrés sur le patient, où nous cherchons à comprendre les attentes, les sentiments et les idées des patients. Les soins centrés sur le patient, l’empathie et le style du partenariat ont fait l’objet de nombreuses recherches, et il est démontré qu’ils ont un effet positif sur la satisfaction et les résultats en matière de santé10. Nous pouvons rappeler aux étudiants d’avouer leur propre incertitude au patient, de valider les symptômes du patients et sa réaction émotionnelle ainsi que la leur, de réfléchir tout haut avec le patient à propos du processus analytique jusqu’à présent et pour l’avenir, et de s’engager à «rester» avec le patient pendant qu’on explore des possibilités ou des stratégies pour améliorer la situation. Ce processus de «rejoindre» le patient comporte une reformulation du problème, de concert avec le patient, de manière à ce que la stratégie cherche moins à en arriver à un diagnostic ou à un traitement définitif et davantage à trouver une explication partielle ou un plan d’action provisoire et de prendre l’engagement d’accompagner le patient durant tout ce temps. En venir à une entente (pour aujourd’hui). Il est rarement possible d’accomplir tout cela durant une seule rencontre. Heureusement, en médecine familiale, nous

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Occasion dâ&#x20AC;&#x2122;enseignement avons de nombreuses possibilitĂŠs de revoir la situation avec les ĂŠtudiants et les patients. Quelle que soit la rencontre, nous pouvons prĂŠsenter aux ĂŠtudiants certaines parties de cette approche et les encourager Ă se prĂŠoccuper de la prise en charge des symptĂ´mes et du fonctionnement. Cela permet dâ&#x20AC;&#x2122;attĂŠnuer dans une certaine mesure la tension clinique, dâ&#x20AC;&#x2122;ĂŠviter des erreurs, dâ&#x20AC;&#x2122;aliĂŠner le patient et de procĂŠder Ă des investigations ou Ă des traitements inutiles. Dr Guenter est professeur agrĂŠgĂŠ et codirecteur de la Pratique familiale McMaster au DĂŠpartement de mĂŠdecine familiale de la McMaster University Ă Hamilton, en Ontario. Dre Fowler est professeure agrĂŠgĂŠe et directrice du programme de rĂŠsidence en mĂŠdecine familiale au DĂŠpartement de mĂŠdecine familiale de la McMaster University. Dre Lee est directrice du Centre for Family Medicine Memory Clinic Ă Kitchener, en Ontario, et professeure adjointe au DĂŠpartement de mĂŠdecine familiale de la McMaster University. IntĂŠrĂŞts concurrents Aucun dĂŠclarĂŠ RĂŠfĂŠrences 1. Van der Weijden T, van Velsen M, Dinant GJ, van Hasselt CM, Grol R. Unexplained complaints in general practice: prevalence, patientsâ&#x20AC;&#x2122; expectations, and professionalsâ&#x20AC;&#x2122; test-ordering behavior. Med Decis Making 2003;23(3):226-31. 2. Allison JJ, Kiefe CI, Cook EF, Gerrity MS, Orav EJ, Centor R. The association of physician attitudes about uncertainty and risk taking with resource use in a Medicare HMO. Med Decis Making 1998;18(3):320-9. 3. Salmon P, Ring A, Dowrick CF, Humphris GM. What do general practice patients want when they present medically unexplained symptoms, and why do their doctors feel pressurized? J Psychosom Res 2005;59(4):255-60. 4. Bovier PA, Perneger TV. Stress from uncertainty from graduation to retirementâ&#x20AC;&#x201D;a population-based study of Swiss physicians. J Gen Intern Med 2007;22(5):632-8. Cyperpub. 9 mars 2007. 5. Lingard L, Garwood K, Szauter K, Stern D. The rhetoric of rationalization: how students grapple with professional dilemmas. Acad Med 2001;76(Suppl 10):S45-7. 6. Fox R. Training for uncertainty. Dans: Merton RK, Reader G, Kendall PL, rĂŠdacteurs. The student physician. Cambridge, MA: Harvard University Press; 1957. 7. Borrell-CarriĂł F, Epstein RM. Preventing errors in clinical practice: a call for self-awareness. Ann Fam Med 2004;2(4):310-6. 8. Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Arch Intern Med 2005;165(13):1493-9. 9. Moulton CE, Regehr G, Mylopoulos M, MacRae HM. Slowing down when you should: a new model of expert judgment. Acad Med 2007;82(Suppl 10):S109-16. 10. Seaburn DB, Morse D, McDaniel SH, Beckman H, Silberman J, Epstein R. Physician responses to ambiguous symptoms. J Gen Intern Med 2005;20(6):525-30.

CONSEILS POUR Lâ&#x20AC;&#x2122;ENSEIGNEMENT r - JODFSUJUVEF DMJOJRVF FTU DPVSBOUF FO QSBUJRVF GBNJMJBMF FU JM est important que les ĂŠtudiants dĂŠveloppent la capacitĂŠ de la reconnaĂŽtre et de la gĂŠrer. r ÂŠ EĂ&#x160;GBVU EF SFDPOOBĂ?USF M JODFSUJUVEF DMJOJRVF FU E Z GBJSF face, les ĂŠtudiants peuvent finir par ressentir de lâ&#x20AC;&#x2122;insatisfaction, ce qui peut entraĂŽner des consĂŠquences nuisibles pour les patients et pour eux-mĂŞmes. r -FT FOTFJHOBOUT QFVWFOU VUJMJTFS EF TJNQMFT TUSBUĂ&#x160;HJFT pour aider les ĂŠtudiants Ă reconnaĂŽtre lâ&#x20AC;&#x2122;incertitude clinique et Ă savoir y faire face, notamment en se prĂŠoccupant des ĂŠmotions, en mettant un frein au raisonnement clinique, en explorant la certitude au sein de lâ&#x20AC;&#x2122;incertitude, en rejoignant le patient et en en arrivant Ă une entente (au moins pour aujourdâ&#x20AC;&#x2122;hui). TEACHING TIPS r $MJOJDBM VODFSUBJOUZ JT DPNNPO JO UIF GBNJMZ QSBDUJDF setting, and learning to recognize and manage it is an important skill for learners to develop. r 'BJMVSF PG MFBSOFST UP SFDPHOJ[F BOE EFBM XJUI DMJOJDBM uncertainty can lead to unsatisfactory and even harmful outcomes for both patients and learners. r 5FBDIFST DBO BQQMZ TJNQMF TUSBUFHJFT UP IFMQ MFBSOFST recognize and effectively deal with clinical uncertainty, including tending to emotions, slowing down clinical reasoning, exploring certainty within uncertainty, joining with the patient, and achieving resolution (at least for today).

Occasion dâ&#x20AC;&#x2122;enseignement est une sĂŠrie trimestrielle publiĂŠe dans Le MĂŠdecin de famille canadien et coordonnĂŠe par la Section des enseignants du CollĂ¨ge des mĂŠdecins de famille du Canada -B TĂ&#x160;SJF QPSUF TVS EFT TVKFUT QSBUJRVFT FU T BESFTTF Ă&#x2020; UPVT MFT FOTFJHOBOUT FO NĂ&#x160;EFDJOF GBNJMJBMF FO JOTJTUBOU TVS MFT EPOOĂ&#x160;FT QSPCBOUFT FU MFT QSBUJRVFT exemplaires. Veuillez faire parvenir vos idĂŠes, vos demandes ou vos prĂŠsentations Ă Dre Allyn Walsh, coordonnatrice dâ&#x20AC;&#x2122;Occasion dâ&#x20AC;&#x2122;enseignement Ă walsha@mcmaster.ca.

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President’s Message | College

Collège

Epiphanies in family medicine Rob Boulay

MD CCFP

G ratitude bestows reverence, allowing us to

ast May, I had the incredible good fortune of being able to attend the WONCA (World Organization of Family Doctors) meeting held in Cancun, Mexico. It was an inspiring experience—family physicians from around the world meeting with the common goal of improving the care they deliver to their patients. But it was a series of events that occurred on a side trip to Belize that provided me with fodder for reflection about the day-to-day lives of family doctors in Canada.

after you go over a speed bump, then slowing down as you approach the next one, usually located about 500 m away. I thought to myself that this was akin to how our governments try to control health care spending, something I now refer to as the speed bump model of cost containment. There are many things that can be considered bumps in our health care highways; for example, billing numbers have been used in this way as an attempt to slow down increases in physician numbers and thus decrease escalating costs. Indeed, maybe I am just a speed bump myself, something a patient has to navigate to access health care. Or maybe we look at access to more specialized care as the biggest speed bump of all, where our patients must queue for what seems like ages before crawling through the system.

Unfamiliar waters

Safe passage

It began innocently enough. After the meeting, 3 couples, including my wife, Bernadette, and me, had planned to go to Belize, kayak out to a small island approximately 20 km from shore, and do some snorkeling and sightseeing. What could possibly go wrong? We arrived in Placencia after a grueling trip by van, then got a good night’s rest. Things did not look good the next morning. The weather had changed overnight and the sky was dark and somewhat ominous. We set out nonetheless, our guide leading the way in his motorboat. At about the 9-km mark, just after Bernadette exclaimed how much fun she was having, we zigged when we should have zagged and were capsized when a wave struck us broadside! At that moment, as we submerged and were ejected from our kayak, I was utterly thankful that we had a guide. The analogy struck me immediately. Having a guide while kayaking through unfamiliar waters was a lot like having a family doctor help you navigate through an unfamiliar health care experience. Our guide was able to pluck us out of the water and bring us to safety— not unlike what family doctors do for their patients each and every day. This was my first epiphany!

My final epiphany occurred just before we left for the airport to return home from Cancun. We had traveled back from Belize the day before, and, like a good traveler, I put our rather soggy passports (don’t forget our capsize) in the safe in our room. About an hour before the cab was to pick us up to go to the airport, I went to retrieve our passports and, lo and behold, the safe would not open. I could tell I was entering the correct code, as the mechanism seemed to go through its paces, but the lock would not release. After 40 or 50 tries, it became clear to me that I would have to call for help. (I never said I was quick!) The security guard who was dispatched to our room shrugged when I asked if he could open it, and I was eventually made to understand that maintenance had been called. Shortly thereafter, 4 rather large men equipped with crowbars, drills, sledgehammers, and chisels proceeded to decimate the poor wall safe. Forty-five minutes later, they proudly handed me our passports, and we had all of 5 minutes to spare before the cab picked us up. And what did this teach me about family medicine? Well, it demonstrated that it often takes teamwork to get the job done, and that health care does not always go as planned; we have to be ready for the unexpected and be prepared to work together with the ultimate goal of making sure our patients get the care and access they need. Life is full of moments that can change how you see the world. I can hardly wait for our next trip!

encounter everyday epiphanies, those transcendent moments of awe that change forever how we experience life and the world. John Milton

Bumps in the road My next epiphany occurred as I pondered on our drive to and from Belize. It seems that the Belizean government has decided to control vehicular speed on all their roads by using speed bumps—and lots of them. Driving in Belize consists of a repetitive cycle of speeding up

Cet article se trouve aussi en français à la page 127.

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College r Collège |

Message du président

Épiphanies en médecine familiale Rob Boulay La gratitude engendre le respect, nous permettant de vivre des épiphanies au quotidien, ces moments transcendants d’émerveillement qui changent pour toujours notre façon de voir la vie et le monde. John Milton (traduction libre)

n mai dernier, j’ai eu l’incroyable chance de pouvoir assister à la rencontre de WONCA (l’organisation mondiale des médecins de famille) qui se tenait à Cancun, au Mexique. Ce fut une expérience inspirante - des médecins de famille de tous les coins du monde se rencontrant dans le seul et même but d’améliorer les soins que nous offrons à nos patients. Mais, ce fut une série d’événements qui se sont produits au cours d’une visite complémentaire au Belize qui m’ont fourni matière à réflexion sur la vie au quotidien des médecins de famille au Canada.

MD CCFP

vitesse routière à l’aide de dos d’âne - beaucoup de dos d’âne. La conduite au Belize se résume à un cycle répétitif d’accélérations après avoir franchi un dos d’âne, puis de ralentissements à l’approche du suivant, à environ 500 m l’un de l’autre. Je me suis dit que c’était semblable à la façon dont nos gouvernements contrôlent les dépenses en soins de santé, ce que j’appelle le modèle du dos d’âne pour contenir les coûts. Il y a de nombreux obstacles sur les routes de notre secteur de la santé qui ressemblent à des dos d’âne; par exemple, les numéros de facturation sont utilisés à cette fin pour tenter de freiner la hausse du nombre de médecins et, de ce fait, ralentir l’escalade des coûts. En réalité, peut-être suis-je moi-même l’un de ces dos d’âne que doit franchir le patient pour accéder aux soins de santé. Il est aussi possible que l’accès à des soins plus spécialisés représente le plus gros dos d’âne de tous, là où nos patients doivent attendre en ligne pendant des éternités avant de se faufiler dans le système.

Eaux inconnues

Passage du coffret de sécurité

Tout a commencé assez candidement. Après la rencontre, 3 couples, dont mon épouse Bernadette et moi-même, avions planifié nous rendre au Belize pour une randonnée en kayak jusqu’à une île située à environ 20 km de la côte, afin de faire du snorkeling et visiter les lieux. Que pourraitil arriver de mal? Nous sommes arrivés à Placencia après un exténuant voyage en fourgonnette, puis nous avons pris une bonne nuit de repos. Le matin suivant, le temps n’était pas au beau fixe. La température avait changé pendant la nuit, et le ciel était sombre et plutôt menaçant. Nous sommes quand même partis, notre guide nous montrant le trajet en embarcation à moteur. À environ 9 km de la plage, juste après que Bernadette se soit exclamée qu’elle s’amusait beaucoup, nous avons pagayé à droite plutôt qu’à gauche et nous avons chaviré après qu’une vague nous ait frappés de travers! À ce moment précis, alors que nous étions submergés et éjectés du kayak, j’ai senti un vif sentiment de gratitude d’avoir un guide avec nous. L’analogie m’a immédiatement frappé. Avoir un guide alors qu’on fait du kayak en eaux inconnues, c’est comme avoir un médecin de famille qui vous aide à naviguer dans une expérience de soins de santé non familière. Notre guide nous a tirés de l’eau et amenés en lieux sûrs - un peu comme les médecins de famille font avec leurs patients au jour le jour. C’était ma première épiphanie!

Ma dernière épiphanie s’est produite juste avant notre départ pour l’aéroport de Cancun afin de rentrer chez nous. Nous étions revenus du Belize la veille et, comme tout bon voyageur, j’avais placé nos passeports plutôt détrempés (n’oubliez pas notre trempette) dans le coffret de sécurité de notre chambre. Environ une heure avant que le taxi vienne nous chercher pour aller à l’aéroport, je suis allé chercher nos passeports et, comble de surprise, le coffret ne s’ouvrait pas. Je savais que j’utilisais le bon code, parce que le mécanisme semblait répondre, mais la serrure ne cédait pas. Après 40 ou 50 tentatives, j’en suis venu à la conclusion qu’il me fallait demander de l’aide. (Je n’ai jamais dit que j’étais vite!) Le gardien de sécurité dépêché à notre chambre a secoué la tête quand je lui ai demandé s’il pouvait l’ouvrir et il m’a éventuellement fait comprendre qu’une équipe de l’entretien avait été appelée. Peu après, 4 hommes imposants munis de barres de fer, de perceuses, de masses et de ciseaux procédaient au démantèlement du pauvre coffret de sécurité. Trois quarts d’heure plus tard, ils me remettaient fièrement nos passeports et nous n’avions plus, en tout et pour tout, que 5 minutes avant l’arrivée de notre taxi. Qu’ai-je appris de l’expérience concernant la médecine familiale? La situation m’a démontré qu’il faut souvent un travail d’équipe pour venir à bout de la tâche et que les soins de santé ne se passent pas toujours comme prévu; nous devons être prêts à affronter l’imprévisible et à travailler ensemble dans le but ultime que nos patients obtiennent les soins et l’accès dont ils ont besoin. La vie est remplie de moments qui peuvent changer notre façon de voir le monde. J’ai vraiment hâte à notre prochain voyage!

Dos d’âne sur la route Mon épiphanie suivante a eu lieu alors que je réfléchissais à notre trajet aller-retour sur les routes du Belize. Il semble que le gouvernement du Belize ait décidé de contrôler la This article is also in English on page 126.

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Signes vitaux | College

Collège

Hommage à l’élite de la médecine familiale Cal Gutkin

MD CCMF(MU) FCMF, DIRECTEUR GÉNÉRAL ET CHEF DE LA DIRECTION

Prix Donald I. Rice

e Forum en médecine familiale 2010 à Vancouver, en Colombie-Britannique, a servi de magnifique arrièrescène aux hommages qu’ont rendus le Collège des médecins de famille du Canada (CMFC) et sa Fondation pour la recherche et l’éducation (FRE) aux récipiendaires de nos prix et bourses annuels. Les médecins de famille, les étudiants en médecine, les résidents en médecine familiale et les collègues dont les noms suivent ont été reconnus pour leurs exceptionnelles contributions aux soins cliniques, à l’enseignement, à la recherche, aux activités du Collège et aux initiatives du système de santé. Ils méritent notre admiration pour leurs réalisations individuelles et d’être fiers de représenter des milliers d’autres qui travaillent avec eux au quotidien dans les communautés de tous les coins du pays. Les prix et bourses du CMFC sont soutenus financièrement par des dons de membres et d’entreprises à la FRE. Nous remercions les généreux donateurs et nous félicitons les lauréats.

Dr Garey Mazowita, Vancouver, BC Ce prix, qui porte le nom de Dr Donald I. Rice, directeur général du CMFC de 1965 à 1985, rend hommage à un exceptionnel médecin de famille membre du CMFC pour ses contributions à l’enseignement et son leadership dans notre discipline. Il permet au récipiendaire de présenter ses expériences et ses points de vue, pendant une période de 2 ans, aux assemblées scientifiques des sections provinciales et aux conférences des départements de médecine familiale. Ce prix est financé par des dons versés par les membres au Fonds D.I. Rice de la FRE.

Prix Jean-Pierre Despins

Dr Cheryl Levitt, Hamilton, Ont Ce prix, à la mémoire du Dr Jean-Pierre Despins, président du CMFC de 1995 à 1996 et président du Conseil d’administration de la FRE de 1999 à 2000, honore un médecin de famille membre du CMFC qui est identifié comme un ardent défenseur et un porte-parole public de la médecine familiale, des médecins de famille et de leurs patients. Ce prix est financé par des dons versés par les membres au Fonds J-P Despins de la FRE.

Prix W. Victor Johnston

Dr Rob Wedel, Taber, Alta Ce prix porte le nom de D r W. Victor Johnston, premier directeur général du CMFC, de 1954 à 1964, et est remis en hommage à sa mémoire. Le lauréat est reconnu pour son leadership en médecine familiale au Canada ou internationalement et pour ses contributions continues et durables à notre spécialité. Il est appelé à prononcer l’allocution W. Victor Johnston lors de la collation des grades du CMFC.

Prix Ian McWhinney pour l’éducation en médecine familiale

Dr Robert Thirsk, Seabrook, Tex Ce prix reconnaît une personne exceptionnelle au Canada ou sur la scène internationale qui a contribué de façon significative, intellectuellement ou concrètement, à la santé et au bien-être des personnes au Canada ou dans le monde. Ce prix est financé par des dons de la Banque Scotia.

Dr Paul Grand’Maison, Sherbrooke, Qué Ce prix, nommé en l’honneur du Dr Ian McWhinney, le premier professeur et le premier directeur d’un département universitaire canadien de médecine familiale, soit à l’University of Western Ontario, de 1968 à 1987, est présenté à un professeur de médecine familiale dont les pairs et les étudiants reconnaissent la contribution remarquable à l’éducation en médecine familiale. Ce prix est financé par des dons versés par les membres au Fonds Ian McWhinney de la FRE.

Prix Reg L. Perkin des Médecins de famille canadiens de l’année

Chercheur de l’année en médecine familiale

Prix de Conférence CMFC/Banque Scotia en médecine familiale

Dr Ronald A. Wilson, Vancouver, BC Dr Karen Lundgard, Peace River, Atla Dr Carla Eisenhauer, Saskatoon, Sask Dr Anne Durcan, Winnipeg, Man Dr Catherine Faulds, London, Ont Dre Ruth Vander Stelt, Gatineau, Qué Dr Jennifer Hall, Saint John, NB Dr Charles Dewar, O’Leary, PEI Dr David MacNeil, Bedford, NS Dr Catherine Penney, St Anthony, Nfld Ces prix, nommés en l’honneur de Dr Reg L. Perkin, directeur général du CMFC de 1985 à 1996, rendent hommage à d’exceptionnels médecins de famille membres du CMFC qui personnifient les 4 principes de la médecine familiale par les contributions apportées dans les soins aux patients, à l’enseignement, à la recherche et au service communautaire. Ces prix sont financés par Santé Canada et des dons versés par Merck Frosst Canada Ltd.

Dr Rick Birtwhistle, Kingston, Ont Ce prix rend hommage à un chercheur en médecine familiale qui a joué un rôle central et qui a apporté des contributions inédites à la recherche en médecine familiale.

Prix pour l’ensemble des réalisations dans la recherche en médecine familiale

Dr Brian Dixon-Warren, Saturna Island, BC Dr William Andre Falk, Sidney, BC Dr John Hilditch, Victoria, BC Dr Michael Klein, Roberts Creek, BC Ces prix rendent hommage à des pionniers et à des leaders qui ont apporté d’importantes contributions à la recherche en médecine familiale durant leur carrière.

Membres honoraires

Dr Dana Hanson, Fredericton, NB Dr Nick Kates, Hamilton, Ont

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Hommage à l’élite de la médecine familiale | Signes vitaux Mr Sam Sullivan, Vancouver, BC Ce titre honorifique rend hommage aux personnes qui ne sont pas membres du CMFC mais qui se sont distinguées par leur contribution exceptionnelle au CMFC, à la médecine familiale, ou à la santé et au bien-être de la population au Canada et à l’étranger.

Prix AMS-Mimi Divinsky d’histoire et narration en médecine familiale

Meilleur récit en anglais par un médecin de famille: “Throw Me a Line,” par Dr Pauline Pariser, Toronto, Ont Meilleur récit en français par un médecin de famille: «Le pouvoir de l’écoute», par Dre Nicole Audet, Laval, Qué Meilleur récit par un résident en médecine familiale: “Why Are You Here to See the Doctor Today?” par Mrs Magbule Doko, Windsor, Ont Ces prix sont nommés en mémoire de Dre Mimi Divinsky pour son rôle de pionnière en médecine narrative au Canada. Ils sont financés par des dons versés par Associated Medical Services Inc.

Prix d’excellence du CMFC

Dr Elizabeth Bautista, Grand Falls–Windsor, Nfld Dr Gilbert Blanchard, Caraquet, NB Dr Risa Bordman, Thornhill, Ont Dre Suzanne Bouchard, Gatineau, Qué Dr Michael Caffaro, Hinton, Alta Dr Paul Caldwell, Cobourg, Ont Dr George Carruthers, Charlottetown, PEI Dr Sony Cejic, London, Ont Dr Catherine Cervin, Halifax, NS Dr Cyprian Enweani, Saskatoon, Sask Dr Muhammad Sohail Gandhi, Stayner, Ont Dr Rick Gibson, Dartmouth, NS Dr Lisa Graves, Sudbury, Ont Dr Katalin Ivanyi, Hamilton, Ont Dre Kirsten Johnson, Westmount, Qué Dr Karen L. Juce, Hamiota, Man Dr Tara Kiran, Toronto, Ont Dr Robert Lam, Toronto, Ont Dre Julie Langlois, Bathurst, NB Dr Leo Lanoie, Prince Albert, Sask Dr Gaétan Y. Lavoie, Matane, Qué Dr François Lehmann, Montréal, Qué Dr Mark MacKenzie, Chilliwack, BC Dr Joanne Maier, Brandon, Man Dre Andrea Moser, Huntsville, Qué Dr Susan Munro, Chatham, Ont Dr Stuart Murdoch, Barrie, Ont Dr Ashoor Nagji, Don Mills, Ont Dr Ieva Neimanis, Hamilton, Ont Dr Kendall Noel, Rockland, Ont Dr Gurdeep Parhar, Vancouver, BC Dr Nadia Plach, Hamilton, Ont Dr Mona Reck, Stratford, PEI Dr Ian M. Scott, Vancouver, BC Dr Jason A. Shack, Fort Frances, Ont Dr William Shannon, Peterborough, Ont Dr Eileen St. Croix, Gander, Nfld Dre Dominique Tessier, Montréal, Qué Dr Alain Vanasse, Sherbrooke, Qué Dr Samantha Winemaker, Hamilton, Ont Dr Joanne Young, North Vancouver, BC Les Prix d’excellence reconnaissent les membres du CMFC qui, au cours des 12 à 24 derniers mois, ont apporté des

contributions exceptionnelles dans les soins aux patients, le service communautaire, les établissements hospitaliers ou de soins de santé, les activités du Collège (national ou des sections), l’enseignement, la recherche ou d’autres éléments de la discipline de la médecine familiale.

PRIX RELIÉS AUX EXAMENS DE CERTIFICATION DU CMFC Prix Irwin Bean

Dr Eimad Elghol, Stephenville, Nfld

Prix Bob Robertson

Dr Jennifer Thomas, Ottawa, Ont Ces prix, nommés à la mémoire du D r Irwin Bean, président du CMFC (1962-1963) et premier président du Comité des examens du CMFC, et du Dr Bob Robertson, président du CMFC (1980-1981), sont décernés chaque année respectivement à la personne parmi le groupe des praticiens admissibles et à celle parmi les résidents en médecine familiale, qui ont obtenu le meilleur résultat à l’examen de Certification en médecine familiale.

PRIX AUX ÉTUDIANTS EN MÉDECINE Prix de leadership du CMFC pour les étudiants en médecine

Dr Aedes Scheer, University of British Columbia Dr Katie McIntyre, University of Calgary Dr Daniel McKennitt, University of Alberta Dr Sarah Liskowich, University of Saskatchewan Dr Trishia Penner, University of Manitoba Dr Katie Kauffeldt, Northern Ontario School of Medicine Dr Jacqueline Wolting, University of Western Ontario Dr Sanaz Zarinehbaf, McMaster University Dr Janice Bacher, University of Toronto Dr Yelena Chorny, Queen’s University Dr Amy Forbes, University of Ottawa Dre Isabelle Samson, Université Laval Dr Anthony Rizzuto, McGill University Dre Gabrielle Barbarese, Université de Montréal Dre Anne Pomerleau, Université de Sherbrooke Dr Nicole Fancy, Dalhousie University Dr Colin Newman, Memorial University of Newfoundland Ces prix reconnaissent les qualités de leadership d’exemplaires étudiants en médecine canadiens dans chacune des facultés de médecine au Canada, qui en sont à leur dernière année d’études prédoctorales. Ces prix sont financés par des dons de la Banque Scotia,.

Bourses d’études du CMFC pour les étudiants en médecine

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Signes vitaux | Hommage à l’élite de la médecine familiale Mme Évelyne Bourdua-Roy, Université Laval Ms Hallie Coltin, McGill University Mme Christine De Maria, Université de Montréal Mme Anouck C. Latrémouille, Université de Sherbrooke Mr Colin McCready, Dalhousie University Ms Heather O’Dea, Memorial University of Newfoundland Ces prix reconnaissent d’exemplaires étudiants en médecine canadiens, qui en sont à leur avant-dernière année d’études prédoctorales et qui ont démontré leur intérêt ou leur engagement à l’endroit de la médecine familiale. Ces prix sont financés par des dons de la Banque Scotia.

PRIX AUX RÉSIDENTS EN MÉDECINE FAMILIALE Prix commémoratif Murray Stalker

Dr Clarissa Burke, Hamilton, Ont Ce prix, à la mémoire de Dr Murray Stalker, le premier président du CMFC (1954-1955), reconnaît un exceptionnel résident en médecine familiale comme étant un potentiel leader de la discipline de la médecine familiale compte tenu de ses qualités de leadership, de sa réussite scolaire, de ses réalisations en recherche et de ses compétences en communication.

Prix de recherche pour les résidents en médecine familiale

Dr Amanda Flanagan, University of Ottawa Drs Marie-Ève Larivière, Marie-Ève Bergeron, Geneviève Desbiens et Juan Carlos Ochoa, Université Laval Ces prix reconnaissent les exceptionnelles réalisations en recherche de résidents en médecine familiale. Ces prix sont financés par des dons du Fonds en fiducie de la Professional Association of Internes and Residents of Ontario.

Prix Nadine St-Pierre

D Rachel Gough, Université de Montréal Ce prix, nommé à la mémoire de Dre Nadine St-Pierre, qui fut l’une des pionnières de l’élaboration de la version française de l’examen de Certification en médecine familiale, veut reconnaître un résident francophone et leader exceptionnel en médecine familiale. re

Prix de leadership du CMFC pour les résidents en médecine familiale

Dr Jennifer Parker, University of British Columbia Dr Kristine Bertsch, University of Calgary Dr Jamil Hirji, University of Alberta Dr Lena Derie-Gillespie, University of Saskatchewan Dr Kevin Earl, University of Manitoba Dr Tyler Christie, Northern Ontario School of Medicine Dr Clarissa Burke, University of Western Ontario Dr Nicole Green, McMaster University Dr Ritika Goel, University of Toronto Dr Jennifer Tong, Queen’s University Dr Richard Waldolf, University of Ottawa Dre Marie-Pierre Dumas, Université Laval Dr Marc Cotran, Université McGill Dre Isabelle Hébert, Université de Montréal Dre Myriam Champagne, Université de Sherbrooke Dr Amy Brennan, Dalhousie University Dr Sheldon Butt, Memorial University of Newfoundland Ces prix reconnaissent les compétences en leadership

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d’exceptionnels résidents seniors en médecine familiale de chacun des programmes de résidence en médecine familiale au Canada. Ils sont financés par des dons de la Banque Scotia.

Prix d’érudition du CMFC aux résidents en médecine familiale

Drs Susan Nouch et Jill Cunes, University of British Columbia Dr Brett Poulin, University of Calgary Dr Helene O’Connor, University of Alberta Drs Katherine Bisby, Conrad Veikle et Diana Hammond, University of Saskatchewan Dr Rehana Alarakhia, University of Manitoba Dr Tyler Christie, Northern Ontario School of Medicine Dr Emily Kelly, University of Western Ontario Drs Amy Bourns, Anusha Kathiravelu et Jeanne Yip, University of Toronto Dr Norma M. Charrière, Queen’s University Dr Amanda Flanagan, University of Ottawa D rs Geneviève Desbiens, Marie-Ève Bergeron, Juan Carlos Ochoa et Marie-Ève Larivière, Université Laval Dr André Jakubow, Université McGill Dre Myriam Mazza, Université de Montréal Drs Kevin Girard, Alexandre Dufour, Mélodie Pedneault, Marie-Anne Gagnon et Catherine Girard-Martel, Université de Sherbrooke Drs Philip Bock et Brian Milligan, Dalhousie University Dr Keith Short, Memorial University of Newfoundland Ces prix reconnaissent les meilleurs travaux d’érudition de résidents seniors en médecine familiale de chacun des départements universitaires de médecine familiale au Canada.

Bourses de développement en début de carrière

Dr Jonathan Kerr, Belleville, Ont Dr Michael Lee-Poy, Kitchener, Ont Ces prix reconnaissent d’exceptionnels médecins de famille durant les 5 premières années de pratique pour leurs habiletés en leadership en début de carrière. Ils sont financés par des dons de TD Meloche Monnex.

PRIX DU MÉDECIN DE FAMILLE CANADIEN Prix du Médecin de famille canadien pour le meilleur article de recherche originale

Dr Karen Tu, Toronto, Ont avec Ms Karen Cauch-Dudek et Dr Zhongliang Chen Les récipiendaires sont reconnus pour leur article de recherche originale, publié dans Le Médecin de famille canadien durant l’année précédente et jugé le meilleur de son genre.

PRIX POUR LA FORMATION MÉDICALE CONTINUE ET LE PERFECTIONNEMENT PROFESSIONNEL Bourses C. Robert Kemp en soins palliatifs

Dr Barbara Fischer, Whitecourt, Alta Dr Eileen Nicolle, Toronto, Ont Ces bourses, présentées en hommage à la mémoire de Dr C. Robert Kemp, un ancien président du Collège des médecins de famille de l’Ontario (1967-1968), soutiennent

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Hommage à l’élite de la médecine familiale | Signes vitaux la participation de médecins de famille à des programmes de formation continue en soins palliatifs. Ces bourses sont financées par des dons du Kemp Family Stoney Creek Fund de la Hamilton Community Foundation.

Bourse Hollister King pour la pratique familiale rurale

Dr Richard Claveau, Hearst, Ont Cette bourse, nommée à la mémoire du Dr Hollister King qui fut président du CMFC de 1977 à 1978, et directeur de la pratique familiale au Women’s College Hospital de Toronto, donne la possibilité à un médecin de famille en pratique d’acquérir ou de perfectionner des compétences spéciales dans la prestation de soins médicaux en milieu rural. Ce prix est financé par des dons versés par les membres au Fonds Hollister King de la FRE.

Bourses de développement professionnel continu et de formation médicale continue Janus

Prix Geeta Gupta pour l’équité et la diversité

Dr Peter Granger, Vancouver, BC Ce prix est nommé en l’honneur de Dre Geeta Gupta, médecin de famille dévouée envers les communautés minoritaires et ethniques. Ce prix reconnaît les réalisations d’un médecin de famille exceptionnel qui a fait preuve de leadership en soignant des patients ou des populations diversifiés. Ce prix est financé par des dons versés à la FRE par la Ben Topor Family Foundation par l’intermédiaire de la Fondation de la communauté juive de Montréal.

PRIX ET BOURSES EN RECHERCHE DU CMFC

Dre Marie-Hélène Boudreau, Québec, Qué Dr Vimal Kapoor, Toronto, Ont Dr Rahul Khosla, Nelson, BC Dr Nadia Knarr, Belleville, Ont Dr Allan Kopyto, Hamilton, Ont Dr Robert Lam, Toronto, Ont Dr Sophie Low-Beer, Vancouver, BC Dre Patricia Marchand, Trois-Rivières, Qué Dr Patrick Merrett, Montréal, Qué Dr Lili Mileva, Kingston, Ont Dr Christie Newton, Port Moody, BC Dr Danielle O’Keefe, St John’s, Nfld Dr Rick Penciner, Toronto, Ont Dr April Sanders, Vernon, BC Dr David Singleton, Rainy River, Ont Dr Trina Stewart, Summerside, PEI Grâce à ces bourses, le Projet Janus du CMFC appuie des médecins de famille dans la poursuite d’activités de développement professionnel continu en vue de répondre aux besoins en évolution de leurs patients et de leurs communautés. Ces bourses sont financées par des dons d’Associated Medical Services Inc. et de la Banque Scotia.

Bourse Janus pour des projets en santé internationale

Dr Jane Philpott, Stouffville, Ont Cette bourse aide un membre du CMFC impliqué dans des projets en soins de santé internationale au Canada ou à l’étranger qui fait la promotion de la médecine familiale à l’étranger. Les activités cliniques, l’enseignement, la recherche ou la participation à des conférences sont pris en compte. Cette bourse est financée par des dons du CMFC, d’Associated Medical Services Inc et de la Banque Scotia.

Bourses d’études du CMFC en santé des femmes

Dr Fay Sliwin, Toronto, Ont Ces bourses d’études sont décernées à des médecins de famille à l’appui d’activités de perfectionnement professionnel continu dans le domaine de la santé des femmes. Elles sont financées par des dons à Fondation pour la promotion de la santé sexuelle et génésique de la Société des obstétriciens et gynécologues du Canada.

Dr Lopita Banerjee, Brampton, Ont Dre Liny Laroche, Saint-Augustin-de-Desmaures, Qué Dr Naomi Lear, Toronto, Ont Dr Shehnaz Pabani, Sudbury, Ont Dr Aleksandar Radan, Goderich, Ont Dr Sarah Rice, Ottawa, Ont Dre Lucie Rochefort, Québec, Qué

Subventions de recherche Janus pour chercheurs seniors Dr Lisa Graves, Sudbury, Ont Dr Maureen Mayhew, Vancouver, BC Dr Leah Steele, Toronto, Ont

Subventions de recherche Janus pour chercheurs novices-intermédiaires Dre Chantal Guimont, Québec, Qué Dre Namta Gupta, Montréal, Qué Dr Jason Hosain, Saskatoon, Sask Dr Shayna Watson, Kingston, Ont

Subventions pour l’élaboration de propositions de projet de recherche Dr François Couturier, St-Lambert, Qué Dr Réjean Duplain, Trois-Rivières, Qué

Subvention de recherche D.M. Robb

Dre Christine Bourbonnière, Ottawa, Ont Cette subvention est nommée à la mémoire de Dr Douglas M. Robb, ancien président du Collège des médecins de famille du Nouveau-Brunswick, de 1979 à 1980. Ce prix appuie les activités de recherche d’un médecin de famille basé dans la communauté.

Prix du CMFC pour un article de recherche exceptionnel en médecine familiale

Dr Marshall Godwin, St John’s, Nfld avec Miu Lam, Richard Birtwhistle, Dianne Delva, Rachelle Seguin, Ian Casson et Susan MacDonald Ce prix reconnaît le meilleur article de recherche publié dans une revue nationale ou internationale durant l’année précédente, qui se fondait sur des recherches en médecine familiale réalisées par un membre du CMFC.

Prix de recherche du Collège des médecins de famille de la Colombie-Britannique (CMFCB)

Dr Lisa Mu, Vancouver, BC Dr Chris A. Whittington, Abbotsford, BC Ces prix appuient des recherches originales effectuées par

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Signes vitaux | Hommage à l’élite de la médecine familiale des médecins de famille membres du CMFCB, des résidents en médecine familiale au niveau postdoctoral ou des étudiants en médecine inscrits à l’University of British Columbia. Ces prix sont financés par le Research Awards Fund du CMFCB et la FRE.

TITRES DE FELLOW

Le titre honorifique de fellow du Collège des médecins de famille du Canada (FCMF) est conféré aux certifiés du CMFC qui ont fait preuve de leur engagement envers le développement professionnel continu et l’apprentissage permanent en maintenant leur adhésion en bonne et due forme et leur certification pendant un minimum de 10 années consécutives. Les noms des fellows du CMFC de 2010 se trouvent dans le site web du Collège à www.cfpc.ca/awards.

MEMBRES À VIE

Le titre de membre à vie est décerné aux médecins de famille de 70 ans ou plus qui ont été membres en règle pendant au moins 10 années consécutives immédiatement avant la date de leur nomination. Les noms des membres à vie du CMFC de 2010 se trouvent dans le site web du Collège à www.cfpc.ca/awards.

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Honouring the best of the best in family medicine | Vital Signs continued from page 136

CFPC CERTIFICATION EXAMINATION AWARDS

AMS–Mimi Divinsky Awards for History and Narrative in Family Medicine

Irwin Bean Award

Best English story by a family physician: “Throw Me a Line,” by Dr Pauline Pariser, Toronto, Ont Best French story by a family physician: “Le pouvoir de l’écoute,” by Dr Nicole Audet, Laval, Que Best story by a medical student: “Why Are You Here to See the Doctor Today?” by Mrs Magbule Doko, Windsor, Ont These awards are named in memory of the late Dr Mimi Divinsky for her role as a pioneer in narrative medicine in Canada. They are supported by donations from Associated Medical Services Inc.

CFPC Awards of Excellence

Dr Elizabeth Bautista, Grand Falls–Windsor, Nfld Dr Gilbert Blanchard, Caraquet, NB Dr Risa Bordman, Thornhill, Ont Dr Suzanne Bouchard, Gatineau, Que Dr Michael Caffaro, Hinton, Alta Dr Paul Caldwell, Cobourg, Ont Dr George Carruthers, Charlottetown, PEI Dr Sony Cejic, London, Ont Dr Catherine Cervin, Halifax, NS Dr Cyprian Enweani, Saskatoon, Sask Dr Muhammad Sohail Gandhi, Stayner, Ont Dr Rick Gibson, Dartmouth, NS Dr Lisa Graves, Sudbury, Ont Dr Katalin Ivanyi, Hamilton, Ont Dr Kirsten Johnson, Westmount, Que Dr Karen L. Juce, Hamiota, Man Dr Tara Kiran, Toronto, Ont Dr Robert Lam, Toronto, Ont Dr Julie Langlois, Bathurst, NB Dr Leo Lanoie, Prince Albert, Sask Dr Gaétan Y. Lavoie, Matane, Que Dr François Lehmann, Montreal, Que Dr Mark MacKenzie, Chilliwack, BC Dr Joanne Maier, Brandon, Man Dr Andrea Moser, Huntsville, Que Dr Susan Munro, Chatham, Ont Dr Stuart Murdoch, Barrie, Ont Dr Ashoor Nagji, Don Mills, Ont Dr Ieva Neimanis, Hamilton, Ont Dr Kendall Noel, Rockland, Ont Dr Gurdeep Parhar, Vancouver, BC Dr Nadia Plach, Hamilton, Ont Dr Mona Reck, Stratford, PEI Dr Ian M. Scott, Vancouver, BC Dr Jason A. Shack, Fort Frances, Ont Dr William Shannon, Peterborough, Ont Dr Eileen St. Croix, Gander, Nfld Dr Dominique Tessier, Montreal, Que Dr Alain Vanasse, Sherbrooke, Que Dr Samantha Winemaker, Hamilton, Ont Dr Joanne Young, North Vancouver, BC Awards of Excellence recognize CFPC members who in the past 12 to 24 months have made outstanding contributions to patient care, community service, hospital or health care institutions, the health care system, College activities (National or Chapter), teaching, research, or other elements of the discipline of family medicine.

Dr Eimad Elghol, Stephenville, Nfld

Bob Robertson Award

Dr Jennifer Thomas, Ottawa, Ont These awards, honouring the late Dr Irwin Bean, CFPC President from 1962 to 1963 and the first Chair of the CFPC’s Committee on Examinations, and the late Dr Bob Robertson, CFPC President from 1980 to 1981, are presented annually to the candidates who achieve the highest standing among practice-eligible candidates and family medicine residents, respectively, in the Certification Examination in Family Medicine.

MEDICAL STUDENT AWARDS CFPC Medical Student Leadership Awards

Dr Aedes Scheer, University of British Columbia Dr Katie McIntyre, University of Calgary Dr Daniel McKennitt, University of Alberta Dr Sarah Liskowich, University of Saskatchewan Dr Trishia Penner, University of Manitoba Dr Katie Kauffeldt, Northern Ontario School of Medicine Dr Jacqueline Wolting, University of Western Ontario Dr Sanaz Zarinehbaf, McMaster University Dr Janice Bacher, University of Toronto Dr Yelena Chorny, Queen’s University Dr Amy Forbes, University of Ottawa Dr Isabelle Samson, Laval University Dr Anthony Rizzuto, McGill University Dr Gabrielle Barbarese, University of Montreal Dr Anne Pomerleau, University of Sherbrooke Dr Nicole Fancy, Dalhousie University Dr Colin Newman, Memorial University of Newfoundland These awards recognize the leadership abilities of outstanding Canadian medical students in their final undergraduate year of study at each medical school. These awards are supported by donations from Scotiabank.

CFPC Medical Student Scholarships

Mr James Handel, University of British Columbia Mr Robert Pomerleau, University of Calgary Mr Harbir S. Gill, University of Alberta Ms Randi V. Ramunno, University of Saskatchewan Ms Zahra Abhari, University of Manitoba Mrs Kiersten Parr, Northern Ontario School of Medicine Mr Dax Biondi, University of Western Ontario Ms Jacqueline Green, McMaster University Ms Keely Johnston, University of Toronto Mr Nathaniel Charach, Queen’s University Ms Amanda Lohnes, University of Ottawa Ms Évelyne Bourdua-Roy, Laval University Ms Hallie Coltin, McGill University Ms Christine De Maria, University of Montreal Ms Anouck C. Latrémouille, University of Sherbrooke Mr Colin McCready, Dalhousie University Ms Heather O’Dea, Memorial University of Newfoundland These scholarships recognize outstanding Canadian medical students in their second-last undergraduate year of study who have demonstrated interest in, or commitment to, careers in family medicine. These awards are supported by donations from Scotiabank.

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Vital Signs | Honouring the best of the best in family medicine FAMILY MEDICINE RESIDENT AWARDS Murray Stalker Memorial Award

Dr Clarissa Burke, Hamilton, Ont This award, named in memory of the late Dr Murray Stalker, first CFPC President (1954 to 1955), recognizes an outstanding family medicine resident as a potential leader in the discipline of family medicine based on current leadership, academic standing, research accomplishments, and communication skills.

Research Awards for Family Medicine Residents

Dr Amanda Flanagan, University of Ottawa Drs Marie-Ève Larivière, Marie-Ève Bergeron, Geneviève Desbiens, and Juan Carlos Ochoa, Laval University These awards recognize the outstanding research achievements of family medicine residents. These awards are supported by donations from the Professional Association of Internes and Residents of Ontario Trust Fund.

Nadine St-Pierre Award

Dr Rachel Gough, University of Montreal This award, named in honour of the late Dr Nadine St-Pierre, who was instrumental in the development of the Frenchlanguage version of the Certification Examination in Family Medicine, recognizes an outstanding Francophone family medicine resident leader.

Dr Jennifer Parker, University of British Columbia Dr Kristine Bertsch, University of Calgary Dr Jamil Hirji, University of Alberta Dr Lena Derie-Gillespie, University of Saskatchewan Dr Kevin Earl, University of Manitoba Dr Tyler Christie, Northern Ontario School of Medicine Dr Clarissa Burke, University of Western Ontario Dr Nicole Green, McMaster University Dr Ritika Goel, University of Toronto Dr Jennifer Tong, Queen’s University Dr Richard Waldolf, University of Ottawa Dr Marie-Pierre Dumas, Laval University Dr Marc Cotran, McGill University Dr Isabelle Hébert, University of Montreal Dr Myriam Champagne, University of Sherbrooke Dr Amy Brennan, Dalhousie University Dr Sheldon Butt, Memorial University of Newfoundland These awards recognize the leadership abilities of outstanding senior family medicine residents from each of Canada’s family medicine residency programs. They are supported by donations from Scotiabank.

Drs Susan Nouch and Jill Cunes, University of British Columbia Dr Brett Poulin, University of Calgary Dr Helene O’Connor, University of Alberta Drs Katherine Bisby, Conrad Veikle, and Diana Hammond, University of Saskatchewan Dr Rehana Alarakhia, University of Manitoba Dr Tyler Christie, Northern Ontario School of Medicine Dr Emily Kelly, University of Western Ontario

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Early Career Development Awards

Dr Jonathan Kerr, Belleville, Ont Dr Michael Lee-Poy, Kitchener, Ont These awards recognize outstanding family physicians in their first 5 years of practice for their early career leadership abilities. They are supported by donations from TD Meloche Monnex.

CANADIAN FAMILY PHYSICIAN AWARD Canadian Family Physician Best Original Research Article

CFPC Family Medicine Resident Leadership Awards

CFPC Family Medicine Resident Awards for Scholarship

Drs Amy Bourns, Anusha Kathiravelu, and Jeanne Yip, University of Toronto Dr Norma M. Charrière, Queen’s University Dr Amanda Flanagan, University of Ottawa Drs Geneviève Desbiens, Marie-Eve Bergeron, Juan Carlos Ochoa, and Marie-Eve Larivière, Laval University Dr André Jakubow, McGill University Dr Myriam Mazza, University of Montreal Drs Kevin Girard, Alexandre Dufour, Mélodie Pedneault, Marie-Anne Gagnon, and Catherine Girard-Martel, University of Sherbrooke Drs Philip Bock and Brian Milligan, Dalhousie University Dr Keith Short, Memorial University of Newfoundland These awards recognize the best scholarly work of senior family medicine residents from each university department of family medicine in Canada.

Dr Karen Tu, Toronto, Ont with Ms Karen Cauch-Dudek and Dr Zhongliang Chen Comparison of primary care physician payment models in the management of hypertension. Can Fam Physician 2009;55:719-27. Recipients are recognized for original research judged to be the best of its genre published in Canadian Family Physician during the preceding year.

CONTINUING EDUCATION AND PROFESSIONAL DEVELOPMENT AWARDS C. Robert Kemp Palliative Care Scholarships

Dr Barbara Fischer, Whitecourt, Alta Dr Eileen Nicolle, Toronto, Ont These awards, presented in memory of the late Dr C. Robert Kemp, a Past President of the Ontario College of Family Physicians (1967 to 1968), support family physicians’ participation in palliative care continuing education programs. These awards are supported by donations from the Kemp Family Stoney Creek Fund of the Hamilton Community Foundation.

Hollister King Rural Family Practice Scholarship

Dr Richard Claveau, Hearst, Ont Awarded in memory of the late Dr Hollister King, CFPC President from 1977 to 1978 and former Chief of Family Practice at Women’s College Hospital in Toronto, Ont, this scholarship provides an opportunity for a practising family physician to attain or enhance special skills in delivery of rural medical care. This award is supported by member donations to the REF Hollister King Fund.

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Honouring the best of the best in family medicine | Vital Signs Janus Continuing Professional Development and Continuing Medical Education Scholarships

Dr Marie-Hélène Boudreau, Quebec, Que Dr Vimal Kapoor, Toronto, Ont Dr Rahul Khosla, Nelson, BC Dr Nadia Knarr, Belleville, Ont Dr Allan Kopyto, Hamilton, Ont Dr Robert Lam, Toronto, Ont Dr Sophie Low-Beer, Vancouver, BC Dr Patricia Marchand, Trois-Rivières, Que Dr Patrick Merrett, Montreal, Que Dr Lili Mileva, Kingston, Ont Dr Christie Newton, Port Moody, BC Dr Danielle O’Keefe, St John’s, Nfld Dr Rick Penciner, Toronto, Ont Dr April Sanders, Vernon, BC Dr David Singleton, Rainy River, Ont Dr Trina Stewart, Summerside, PEI Through these scholarships, the CFPC’s Janus Project supports family doctors carrying out continuing professional development activities related to meeting the changing needs of their patients and communities. These scholarships are supported by donations from Associated Medical Services Inc and Scotiabank.

Janus Scholarship for International Health Projects

Dr Jane Philpott, Stouffville, Ont This scholarship supports a CFPC member engaging in global health care projects either in Canada or abroad and promoting family medicine abroad. Clinical activities, teaching, research, or conference attendance are considered. This scholarship is supported by donations from the CFPC, Associated Medical Services Inc, and Scotiabank.

CFPC Scholarships in Women’s Health Dr Lopita Banerjee, Brampton, Ont Dr Liny Laroche, Saint-Augustin-de-Desmaures, Que Dr Naomi Lear, Toronto, Ont Dr Shehnaz Pabani, Sudbury, Ont Dr Aleksandar Radan, Goderich, Ont Dr Sarah Rice, Ottawa, Ont Dr Lucie Rochefort, Quebec, Que Dr Fay Sliwin, Toronto, Ont These scholarships are awarded to family physicians to support continuing professional development activities related to women’s health. They are supported by donations from the Society of Obstetricians and Gynaecologists of Canada’s Foundation for Sexual and Reproductive Health.

Geeta Gupta Equity and Diversity Award

Dr Peter Granger, Vancouver, BC This award is presented in honour of Dr Geeta Gupta, a family physician devoted to working with minority and ethnic communities, and recognizes an outstanding family physician who has shown leadership in caring for diverse patients or populations. This award is supported by donations to the REF from the Ben Topor Family Foundation through the Jewish Community Foundation of Montreal.

CFPC RESEARCH AWARDS AND GRANTS Janus Research Grants, Senior Dr Lisa Graves, Sudbury, Ont

Dr Maureen Mayhew, Vancouver, BC Dr Leah Steele, Toronto, Ont

Janus Research Grants, Novice-Intermediate Dr Dr Dr Dr

Chantal Guimont, Quebec, Que Namta Gupta, Montreal, Que Jason Hosain, Saskatoon, Sask Shayna Watson, Kingston, Ont

Janus Research Proposal Development Grants Dr François Couturier, St Lambert, Que Dr Réjean Duplain, Trois-Rivières, Que

D.M. Robb Research Grant

Dr Christine Bourbonnière, Ottawa, Ont This award honours the late Dr Douglas Robb, a Past President of the New Brunswick Chapter of the College (1979 to 1980), and supports the research activities of a community-based family physician.

CFPC Outstanding Family Medicine Research Article Dr Marshall Godwin, St John’s, Nfld with Miu Lam, Richard Birtwhistle, Dianne Delva, Rachelle Seguin, Ian Casson, and Susan MacDonald A primary care pragmatic cluster randomized trial of the use of home blood pressure monitoring on blood pressure levels in hypertensive patients with above target blood pressure. Fam Pract 2010;27(2):135-42. Epub 2009 Dec 23. This award recognizes the best research article published in a national or international journal during the preceding year that was based on family medicine research carried out by a CFPC member.

British Columbia College of Family Physicians (BCCFP) Research Awards Dr Lisa Mu, Vancouver, BC Dr Chris A. Whittington, Abbotsford, BC These awards support original research carried out by practising family physician members of the BCCFP, postgraduate family medicine residents, or medical students enrolled at the University of British Columbia. These awards are supported by the BCCFP Research Awards Fund.

FELLOWSHIP

Fellowship in the College of Family Physicians of Canada (FCFP) is an honour the CFPC confers upon Certificant members in good standing who have maintained their Certification for a minimum of 10 consecutive years, demonstrating their ongoing commitment to continuing professional development and lifelong learning. The names of CFPC Fellows for 2010 can be found at www.cfpc.ca/awards.

LIFE MEMBERS

Life membership is awarded to those 70 years of age or older who have been CFPC members in good standing for at least 10 consecutive years immediately before the date of nomination. The names of Life Members for 2010 can be found at www.cfpc.ca/awards.

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Vital Signs | College

Collège

Honouring the best of the best in family medicine Cal Gutkin

MD CCFP(EM) FCFP, EXECUTIVE DIRECTOR AND CHIEF EXECUTIVE OFFICER

amily Medicine Forum 2010 in Vancouver, BC, provided a beautiful backdrop for the College of Family Physicians of Canada (CFPC) and its Research and Education Foundation (REF) to recognize the recipients of our annual honours and awards. The following family physicians, medical students, family medicine residents, and colleagues were acknowledged as outstanding contributors to clinical care, teaching, research, College activities, and health system initiatives. They should be celebrated for their personal achievements and for representing thousands of others working with them every day in communities throughout Canada. The CFPC’s honours and awards are supported through member and corporate donations to the REF. We thank our generous donors and congratulate all the recipients.

Executive Director from 1965 to 1985, recognizes an outstanding CFPC family physician member for contributions to teaching and leadership in our discipline, and supports the award recipient for a 2-year period to present his or her experiences and perspectives at Chapter scientific assemblies and department of family medicine conferences. This award is supported by member donations to the D.I. Rice Fund of the REF.

Jean-Pierre Despins Award

Dr Cheryl Levitt, Hamilton, Ont This award, named in memory of the late Dr Jean-Pierre Despins, CFPC President from 1995 to 1996 and Chair of the Board of the REF from 1999 to 2000, honours a CFPC family physician member identified as an outstanding advocate and public spokesperson for family medicine, family physicians, and patients. This award is supported by member donations to the J-P Despins Fund of the REF.

W. Victor Johnston Award

Dr Rob Wedel, Taber, Alta This award is named in honour of the late Dr W. Victor Johnston, the CFPC’s first Executive Director, from 1954 to 1964. It recognizes outstanding national or international family medicine leaders for their continuous and enduring contributions to our specialty, with the recipient presenting the W. Victor Johnston Oration at Convocation.

Ian McWhinney Family Medicine Education Award

Dr Paul Grand’Maison, Sherbrooke, Que This award, named in honour of Dr Ian McWhinney, the first Professor and Chair of a Canadian University Department of Family Medicine (University of Western Ontario, 1968 to 1987), is presented to a family medicine teacher recognized by peers and students for his or her outstanding contribution to family medicine education. This award is supported by member donations to the Ian McWhinney Fund of the REF.

CFPC-Scotiabank Family Medicine Lectureship

Dr Robert Thirsk, Seabrook, Tex This award recognizes an outstanding Canadian or international figure who has contributed substantially in thought or deed to issues related to the health and well-being of people in Canada or around the world. This award is supported by donations from Scotiabank.

Family Medicine Researcher of the Year

Dr Rick Birtwhistle, Kingston, Ont This award honours a family medicine researcher who has been a pivotal force in, and has made an original contribution to, family medicine research.

Canada’s Family Physicians of the Year: Reg L. Perkin Awards

Dr Ronald A. Wilson, Vancouver, BC Dr Karen Lundgard, Peace River, Atla Dr Carla Eisenhauer, Saskatoon, Sask Dr Anne Durcan, Winnipeg, Man Dr Catherine Faulds, London, Ont Dr Ruth Vander Stelt, Gatineau, Que Dr Jennifer Hall, Saint John, NB Dr Charles Dewar, O’Leary, PEI Dr David MacNeil, Bedford, NS Dr Catherine Penney, St Anthony, Nfld These awards, named in honour of Dr Reg L. Perkin, CFPC Executive Director from 1985 to 1996, recognize outstanding CFPC family physician members who exemplify the 4 principles of family medicine through contributions to patient care, teaching, research, and community services. These awards are supported by Health Canada and donations from Merck Frosst Canada Ltd.

Lifetime Achievement Awards in Family Medicine Research

Dr Brian Dixon-Warren, Saturna Island, BC Dr William Andre Falk, Sidney, BC Dr John Hilditch, Victoria, BC Dr Michael Klein, Roberts Creek, BC These awards honour individuals who were trailblazers and leaders in, and who have made a considerable career contribution to, family medicine research.

Honorary Membership

Dr Dana Hanson, Fredericton, NB Dr Nick Kates, Hamilton, Ont Mr Sam Sullivan, Vancouver, BC This honour recognizes individuals who are not CFPC members who have made outstanding contributions to the CFPC, family medicine, the health system, or the health and well-being of the population in Canada or abroad.

Donald I. Rice Award

Dr Garey Mazowita, Vancouver, BC This award, named in honour of Dr Donald I. Rice, CFPC

continued on page 133

Cet article se trouve aussi en français à la page 128.

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