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ARCHIVED - Canadian Adverse Reaction Newsletter, Volume 20 - Issue 2 - April 2010

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ISSN 1499-9447
Cat no H42-4/1-20-2E

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Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team

In this Issue

Scope

This quarterly publication alerts health professionals to potential signals detected through the review of case reports submitted to Health Canada. It is a useful mechanism to stimulate adverse reaction reporting, as well as to disseminate information on suspected adverse reactions to health products occurring in humans before comprehensive risk-benefit evaluations and regulatory decisions are undertaken. The continuous evaluation of health product safety profiles depends on the quality of your reports.

Reporting Adverse Reactions
Canada Vigilance Program
Phone: 1-866-234-2345
Fax: 1-866-678-6789

For more information on how to report an adverse reaction, visit the Reporting Adverse Reactions to Drugs and Other Health Products page.

Caveat: Adverse reactions (ARs) to health products are considered to be suspicions, as a definite causal association often cannot be determined. Spontaneous reports of ARs cannot be used to estimate the incidence of ARs because ARs remain underreported and patient exposure is unknown.

Leflunomide and peripheral neuropathy

Key points

  • Neuropathy has been reported in association with several disease-modifying antirheumatic drugs.
  • During the last 7 years, additional data regarding the suspected association between peripheral neuropathy and leflunomide have emerged in the medical literature.
  • In Canada, health care professionals have reported cases of peripheral neuropathy suspected of being associated with leflunomide.

Leflunomide is a disease-modifying antirheumatic drug (DMARD) indicated for use in adults with active rheumatoid arthritis.Footnote 1 It has been marketed in Canada since 2000 under the brand name Arava and is now also available as various generic products.

Peripheral neuropathy is an impairment of the peripheral motor, sensory or autonomic nervous system.Footnote 2 Signs and symptoms include muscular weakness or flaccid paralysis and sensory disturbances, including pain.Footnote 2 Neuropathy has been reported in association with several DMARDs, including sulfasalazine, chloroquine and penicillamine.Footnote 3,Footnote 4

During the last 7 years, several cases of peripheral neuropathy suspected of being associated with leflunomide have been published.Footnote 5,Footnote 6,Footnote 7,Footnote 8,Footnote 9,Footnote 10,Footnote 11,Footnote 12,Footnote 13,Footnote 14,Footnote 15 Patients had paresthesia or weakness, or both, in the upper or lower extremities, or both. In a few cases the symptoms were severe or debilitating.Footnote 12,Footnote 13,Footnote 15 The incidence of peripheral neuropathy has ranged from 1.4% to 10% in open studies to assess leflunomide neurotoxicity. Footnote 5,Footnote 6,Footnote 7,Footnote 8 In these studies, the proportion of patients for whom this adverse reaction (AR) improved after discontinuation of the drug or reduction of the dosage ranged from 37% to 100%.

From the date of marketing to Oct. 31, 2009, Health Canada received 26 AR reports of peripheral neuropathy symptoms suspected of being associated with the use of leflunomide. Peripheral neuropathy was specified in 9 of the reports; the remaining 17 reports described signs and symptoms of peripheral neuropathy such as paresthesia, hypoesthesia or burning sensation of the skin. Of the 26 cases, 23 were reported by health care professionals and 22 were reported as serious. There were 17 women and 7 men (sex not reported in 2 cases). The greater number of women could be explained by the fact that rheumatoid arthritis is 3 times more likely in women than in men.Footnote 16 Some confounding factors reported in the cases included concomitant diseases (e.g., rheumatoid arthritis, diabetes) and concomitant drugs (e.g., methotrexate, hydroxychloroquine).

Electrophysiologic studies had been conducted in 4 of the 9 cases reported as peripheral neuropathy, and the results were positive in 3 cases. The duration of leflunomide therapy in these 9 cases varied from 2 months to 2 years. In 9 of the 26 cases, the reaction abated after stopping the drug.

Additional data regarding the suspected association between peripheral neuropathy and leflunomide has emerged during the past 7 years. Voluntary reporting to Health Canada is an important postmarketing surveillance tool to obtain valuable information about ARs to health products. Health care professionals are encouraged to report to Health Canada any cases of peripheral neuropathy suspected of being associated with leflunomide.

Patrice Tremblay, MD, Health Canada

  • In the Food and Drugs Act and Regulations, a serious AR is defined as "a noxious and unintended response to a drug that occurs at any dose and that requires in-patient hospitalization or prolongation of existing hospitalization, causes congenital malformation, results in persistent or significant disability or incapacity, is life-threatening or results in death."

Footnotes

Footnote 1

Arava (leflunomide) [product monograph]. Laval (QC): sanofi-aventis Canada Inc.;  2006.

Return to footnote 1 referrer

Footnote 2

Council for International Organizations of Medical Sciences. Next link will take you to another Web site Reporting adverse drug reactions: definitions of terms, and criteria for their use (PDF version - 1853 K). Geneva: The Council; 1999. (accessed 2009 Dec. 4).

Return to footnote 2 referrer

Footnote 3

Parker D Jr. Peripheral neuropathy. In: Tisdale JE, Miller DA, editors. Drug-induced diseases: prevention, detection, and management. Bethesda (MD): American Society of Health-System Pharmacists; 2005.

Return to footnote 3 referrer

Footnote 4

Argov Z, Mastaglia FL. Next link will take you to another Web site Drug-induced peripheral neuropathies. BMJ 1979;1:663-6. [PubMed]

Return to footnote 4 referrer

Footnote 5

Bharadwaj A, Haroon N. Next link will take you to another Web site Peripheral neuropathy in patients on leflunomide. Rheumatology (Oxford) 2004;43: 934. [PubMed]

Return to footnote 5 referrer

Footnote 6

Richards BL, Spies J, McGill N, et al. Next link will take you to another Web site Effect of leflunomide on the peripheral nerves in rheumatoid arthritis. Intern Med J 2007; 37:101-7. [PubMed]

Return to footnote 6 referrer

Footnote 7

Metzler C, Arlt AC, Gross WL, et al. Next link will take you to another Web site Peripheral neuropathy in patients with systemic rheumatic diseases treated with leflunomide. Ann Rheum Dis 2005;64:1798-800. [PubMed]

Return to footnote 7 referrer

Footnote 8

Martin K, Bentaberry F, Dumoulin C, et al. Next link will take you to another Web site Peripheral neuropathy associated with leflunomide: Is there a risk patient profile? Pharmacoepidemiol Drug Saf  2007;16:74-8. [PubMed]

Return to footnote 8 referrer

Footnote 9

Bonnel RA, Graham DJ. Next link will take you to another Web site Peripheral neuropathy in patients treated with leflunomide. Clin Pharmacol Ther 2004;75:580-5. [PubMed]

Return to footnote 9 referrer

Footnote 10

Adverse Drug Reactions Advisory Committee. Next link will take you to another Web site Leflunomide and peripheral neuropathy. Aust Adv Drug Reactions Bull 2006;25:18-9.

Return to footnote 10 referrer

Footnote 11

Martin K, Bentaberry F, Dumoulin C, et al. Next link will take you to another Web site Neuropathy associated with leflunomide: a case series. Ann Rheum Dis 2005;64:649-50. [PubMed]

Return to footnote 11 referrer

Footnote 12

Gabelle A, Antoine JC, Hillaire-Buys D, et al. Next link will take you to another Web site[Leflunomide-related severe axonal neuropathy]. Rev Neurol (Paris) 2005;161:1106-9. [PubMed]

Return to footnote 12 referrer

Footnote 13

Carulli MT, Davies UM. Next link will take you to another Web site Peripheral neuropathy: An unwanted effect of leflunomide? Rheumatology (Oxford) 2002;41:952-3. [PubMed]

Return to footnote 13 referrer

Footnote 14

Hill CL. Next link will take you to another Web site Leflunomide-induced peripheral neuropathy: rapid resolution with cholestyramine wash-out. Rheumatology 2004;43:809.

Return to footnote 14 referrer

Footnote 15

Lormeau C, Vandecandelaere M, Gasseu N, et al. Neuropathies périphériques au cours d'un traitement par léflunomide: deux nouvelles observations. Revue Rhu 2003;70:1001.

Return to footnote 15 referrer

Footnote 16

Lipsky PE. Rheumatoid arthritis. In: Fauci AS, Braunwald E, Hauser SL, et al, editors. Harrison's principles of internal medicine. 17th ed. New York (NY): McGraw-Hill; 2008. p. e2083-e2091.

Return to footnote 16 referrer

Adverse reaction and incident reporting - 2009

Canada Vigilance Program

The Canada Vigilance Program collects reports of suspected adverse reactions (ARs) to health products (pharmaceuticals, biologics, natural health products, radiopharmaceuticals, biotechnology products and cells, tissues and organs). Further information about the program and its database can be found on the MedEffect™ Canada Web site.

In 2009, Health Canada received 27 496 domestic AR reports. Of the domestic reports received, 74.9% were considered to be serious. Domestic AR reports received by product type are provided in Table 1.

In Canada, Market Authorization Holders (MAHs) are required to submit AR reports received in accordance with the requirements of the Food and Drugs Act and Regulations. MAHs are required to send, within 15 days, all reports of serious ARs that have occurred in Canada (domestic) and all reports of serious unexpected ARs that have occurred outside Canada (foreign) to the Canada Vigilance Program. In 2009, MAHs submitted 69.4% of all the domestic reports received. The remaining reports were received directly from the community and hospitals (Table 2).

The number of domestic AR reports was 35.0% higher in 2009 than in 2008 (Figure 1). The majority of domestic cases reported to both MAHs and Health Canada originated from health care professionals (Table 3).

The number of foreign AR reports received from MAHs was 305 847 (Figure 2). At this time, foreign reports are not included in the Canada Vigilance database.

Health Canada would like to thank all who have contributed to the Canada Vigilance Program and encourages the continued support of postmarketing surveillance through AR reporting. Any ARs suspected of being associated with the use of health products can be reported to the Canada Vigilance Program by one of the following methods:

  • Call toll free at 1-866-234-2345
  • Report online
  • Complete a Canada Vigilance Reporting Form and:
    • fax it toll free (1-866-678-6789) or
    • mail it to:
      Canada Vigilance Program
      Health Canada
      Address Locator 0701D
      Ottawa ON  K1A 0K9

Postage-paid labels, the Canada Vigilance Reporting Form and the AR reporting guidelines ("Guidelines -- Voluntary Reporting of Suspected Adverse Reactions to Health Products by Health Professionals and Consumers") are available on the MedEffect™ Canada Web site. The reporting form is also located in the back of the Compendium of Pharmaceuticals and Specialties (CPS).

Table 1: Number of domestic reports of adverse reactions by product type in 2009
Product type No. (%) of reports
  • Canada Vigilance receives reports for both initial and follow-up information concerning suspected ARs to health products. Reports of ARs redirected to other programs are not included.
Pharmaceuticals 18 301 (70.2)
Biotechnology products 5 998 (23.0)
Biologics 833 (3.2)
Natural health products 516 (2.0)
Radiopharmaceuticals 379 (1.5)
Cells, tissues and organs 34 (0.1)
Total 26 061 (100.0)
 
Table 2: Number of domestic reports of adverse reactions by source in 2009
Source No. (%) of reports
MAH = Market Authorization Holder
  • Canada Vigilance receives reports for both initial and follow-up information concerning suspected ARs to health products. Reports of ARs redirected to other programs are not included.
  • Consumer, patient and non-hospital-based health care professionals.
MAH 20 054 (77.0)
Community 4 794 (18.4)
Hospital 1 120 (4.3)
Other 93 (0.3)
Total 26 061 (100.0)
 
Table 3: Number of domestic reports of adverse reactions by type of originating reporter in 2009
Reporter type No. (%) of reports
  • Canada Vigilance receives reports for both initial and follow-up information concerning suspected ARs to health products. Reports of ARs redirected to other programs are not included.
  • Type not specified in report.
Consumer/patient 8 428 (32.3)
Physician 6 064 (23.3)
Health professional 4 364 (16.7)
Pharmacist 3 853 (14.8)
Nurse 2 906 (11.2)
Dentist 6 (0.02)
Naturopath 3 (0.01)
Other 437 (1.7)
Total 26 061 (100.0)

Figure 1: Number of domestic reports of adverse reactions received by Health Canada from 2001 to 2009.

Figure 1: Number of domestic reports of adverse reactions received by Health Canada from 2001 to 2009

Figure 2: Number of foreign reports of adverse reactions received by Health Canada from Market Authorization Holders from 2001 to 2009.

Figure 2: Number of foreign reports of adverse reactions received by Health Canada from Market Authorization Holders from 2001 to 2009

Medical device incidents

Medical device incidents are collected by the Health Products and Food Branch Inspectorate and are entered into the medical device system. The Inspectorate is responsible for compliance monitoring activities for a broad spectrum of regulated health products, including medical devices which range from adhesive bandages to pacemakers. It is also responsible for the delivery of a national compliance and enforcement program in an effort to minimize health risks to Canadians while maximizing the safety of health products. A major component of this program involves the collection, review and follow-up of incidents related to medical devices, which are reported to the Inspectorate via the submission of mandatory and voluntary problem reports. Manufacturers and importers are required to submit mandatory reports as per section 59-61 in the Medical Device Regulations. Voluntary reports are submitted mostly by health care professionals and patients/users. In 2009, a total of 5 269 incidents were entered into the medical device system. Of these reports, 4 839 (91.8%) were mandatory and 430 (8.2%) voluntary.

Information on mandatory and voluntary reporting of medical device incidents can be found on the Medical Devices.

Completed Medical Devices Problem Report forms can be submitted by email as attachments to: mdpr-dimm@hc-sc.gc.ca. Please include the acronym MDPR in the subject line of the email in order to generate an automated confirmation of receipt by the Inspectorate.

Jennifer Lo, BSc, BA; Fannie St-Gelais, PhD, Health Canada

  • This includes AR reports received for product types that do not fall under the review of the Canada Vigilance Program. These reports were redirected to the appropriate AR reporting program.
  • In the Food and Drugs Act and Regulations, a serious AR is defined as "a noxious and unintended response to a drug that occurs at any dose and that requires in-patient hospitalization or prolongation of existing hospitalization, causes congenital malformation, results in persistent or significant disability or incapacity, is life-threatening or results in death." A serious unexpected AR is defined as "a serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out on the label of the drug."
Quarterly Summary of health professional and consumer advisories (posted on Health Canada's Web site: November 11, 2009 - February 19, 2010)
Date Product Subject
  • Date of issuance. This date may differ from the posting date on Health Canada's Web site.
Feb 11 & 16 Accutane Severe skin reactions
Feb 9 Complete 7-Day Cleanse Recall - possible serious health risks
Feb 4 Surgical mesh Complications associated with transvaginal implantation
Feb 2 NeXus I, II and III Rollators Association with falls and serious injury
Jan 29 Nipro GlucoPro insulin
syringes
Recall - needles may detach during use
Jan 29 Products containing glucomannan Risk of choking if used with insufficient fluid
Jan 29 Natural Choice products Unauthorized health products
Jan 27 Medication for Parkinson disease Update - availability of some medication
Jan 16 Rolaids tablets Recall - possible health risks
Jan 14 The Slimming Coffee Unauthorized weight loss product
Jan 8 & 12 Optimark Association with nephrogenic systemic
fibrosis
Jan 8 Stiff Nights Unauthorized health product
Jan 6 Foreign products Alerts - Ku Xiu Ba Xiang Jian Fei Wan, Super Slim (Yani), SHoufsy, MIGAC (sic) FAT BURMING (sic) FACTOR, RockHard Weekend, Pai You Guo, M-Action and Full Contact Max Potency
Dec 31 Foreign product Alert - Tylenol Arthritis Pain Caplet: recall in the United States
Dec 29 BiCNU Type I product recall - risk of infection
Dec 24 RevolutionDS Weight Loss Unauthorized weight loss product
Dec 22 Foreign products Alerts - Power-Plus P, Show Party and Zeng Da Yan Shi Wan
Dec 21 & 23 Myfortic Reports of pure red cell aplasia
Dec 21 Cerezyme Supply and recommendations for restarting Cerezyme
Dec 10 Foreign products Alerts - S-DROL and Bodybuilding
products
Dec 8 Acai Berry products Update - adulterated products
Dec 8 Opioid pain medications It's Your Health: Opioid pain medications
Dec 4 Zaditen tablets Recall of lot #440494 - decreased effectiveness
Nov 30 & Dec 3 Exjade Proposed changes to the Canadian product monograph
Nov 26 Rapamune Blood level measurement changes
Nov 26 Vaccines It's Your Health: Misconceptions about vaccine safety
Nov 25 & 26 Heparin Information on changes to potency
Nov 25 Once More Unauthorized health product
Nov 24 Drugs on the Internet It's Your Health: Buying drugs over the Internet
Nov 19-25 Thyrogen and certain
Genzyme products
Foreign particles detected in certain products
Nov 12 Arepanrix H1N1 Vaccine Authorization for sale and postmarketing activities

To receive the Newsletter and health product advisories free by e-mail, subscribe to MedEffect e-Notice.

Canadian Adverse Reaction Newsletter

Health Canada
Marketed Health Products Directorate
Address Locator 0701C
Ottawa ON K1A 0K9
Telephone: 613-954-6522
Fax: 613-952-7738

Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Jared Cousins, BSP
Mary Joy, RPh, BScPhm
Hoa Ly, BSc
Patricia Carruthers-Czyzewski, BScPhm, MSc
Gilbert Roy, BPharm
Christianne Scott, BPharm, MBA

Acknowledgement
We thank the following members of the Expert Advisory Committee on the Vigilance of Health Products for their review of material for this issue: Colleen J. Metge, BSc(Pharm), PhD; Dugald Seely, ND, MSc; and Sylvia Hyland, RPh, BScPhm, MHSc. We also thank Kaitlyn Proulx and Darija Muharemagic, students in Biopharmaceutical Science, for their participation in the production of the newsletter.

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Reporting Adverse Reactions
Canada Vigilance Program
Telephone: 1-866-234-2345
Fax: 1-866-678-6789

Copyright
© 2010 Her Majesty the Queen in Right of Canada. This publication may be reproduced without permission provided the source is fully acknowledged. The use of this publication for advertising purposes is prohibited. Health Canada does not assume liability for the accuracy or authenticity of the information submitted in case reports.

Due to time constraints relating to the production of this publication, information published may not reflect the most current information.