Canadian Adverse Reaction Newsletter
Volume 12 · Issue 4 · October 2002

Marketed Health Products Directorate
Heath Products and Foods Branch

In This Issue
Natural Health Products: adverse reactions
Leflunomide (Arava): hematologic, hepatic and respiratory reactions
Case Presentation: moxifloxacin
Summary of Advisories
Drugs and grapefruit: interactions

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 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
Contact Health Canada
or a Regional AR Centre
free of charge
Phone: 866 234-2345
Fax: 866 678-6789
Email: cadrmp@hc-sc.gc.ca
Form available at:
www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/form/ar-ei_form_e.html

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.

Adverse reactions to natural health products

Over 50% of Canadians now use natural health products in the form of traditional herbal products, vitamin and mineral supplements, traditional Chinese, Ayurvedic and other medicines and homeopathic preparations (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/index_e.html). There seems to be "an overall misconception that these agents are 'naturally' safe because they come from 'natural' plants."^1,2 The use of herbal products, a type of natural health product, can be associated with adverse effects attributable to factors such as inadequate or excessive dosing, low-quality herbs or supplements, misidentified plant species, variability of constituents, contamination with heavy metals, adulteration with prescription drugs, interactions with prescription drugs and allergic reactions.¹ Also, some herbal ingredients are intrinsically toxic.² These factors along with the practice of using health products with multiple ingredients make the evaluation of adverse effects complex.

A number of reported suspected adverse reactions (ARs) to natural health products have been described in this newsletter previously (kava,³ glucosamine^4,5 and ginkgo biloba⁶). Advisories involving natural health products have also been issued by Health Canada (e.g., aristolochia,⁷ ephedra/ephedrine⁸ and St. John's wort⁹ (www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/index_e.html).

With the opportunity for self-selection and the wide availability of natural health products, the public needs to be aware of the possible risks associated with these products as well as their benefits. Many products contain multiple ingredients that may prove challenging for consumers to make informed choices. Furthermore, consumers sometimes receive misleading promotional information about some herbs or ingredients that may either obscure the risks associated with their use or exaggerate their efficacy. Some examples include the presence of ephedra in products used as diet aids or energy boosters, and ginkgo biloba in products promoted as dietary supplements that enhance memory in healthy individuals.

Health care professionals need to know whether their patients are using various health products, including natural health products, certain foods, and prescription and nonprescription drugs, in order to evaluate their overall therapy. Patients may be reluctant to discuss the use of natural health products¹ and may be less likely to report ARs associated with their use than those associated with conventional over-the-counter medicines.¹⁰ Health care professionals should ask their patients if they are using complementary or alternative therapies in order to provide advice and to monitor for possible ARs. As with conventional medicines, specific groups -- pregnant and breastfeeding mothers, children, elderly people, patients with cardiovascular disease, patients undergoing surgery and patients using conventional medicines where there is the potential for interactions -- may be at increased risk of ARs if using complementary and alternative medicines.²

The Marketed Health Products Directorate, in conjunction with the Natural Health Products Directorate and other directorates of Health Canada, continues to monitor the safety of natural health products. All health care professionals and consumers are encouraged to report suspected ARs to these products and to include the exact product name and list of ingredients if possible, so that more can become known about their safety.

Marielle McMorran, BScPharm, Health Canada

References

1. Bielory L. Adverse reactions to complementary and alternative medicine: ragweed's cousin, the coneflower (echinacea), is "a problem more than a sneeze" [editorial]. Ann Allergy Asthma Immunol 2002;88:7-9.

2. Barnes J, Anderson LA, Phillipson JD. Herbal medicines. 2nd ed. London: Pharmaceutical Press; 2002. p. 1,18-21.

3. Case presentation: Kava. Can Adverse React Newsl 2002;12(3):3.

4. Communiqué: Warfarin and glucosamine: interaction. Can Adverse Drug React Newsl 2001;11(2):4.

5. Communiqué: Glucosamine sulfate: hyperglycemia. Can Adverse Drug React Newsl 2000;10(4):4.

6. Communiqué: Gingko biloba: bleeding disorders. Can Adverse Drug React Newsl 2000;10(1):4.

7. Health Canada advising not to use products labelled to contain Aristolochia [Public Advisory]. Ottawa: Health Canada; 2001 Aug. 17. Available: www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2001/2001_91_e.html (accessed 2002 Aug 16).

8. Advisory not to use products containing Ephedra or ephedrine [Public Advisory]. Ottawa: Health Canada; 2001 June 14. Available: www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2001/2001_67_e.html (accessed 2002 Aug 16).

9. Potentially harmful drug interactions with St.John's Wort and prescription drugs [Public Advisory]. Ottawa: Health Canada; 2000 Apr 7. Available: www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2000/2000_36_e.html (accessed 2002 Aug 16).

10. Barnes J, Mills SY, Abbot NC, Willoughby M, Ernst E. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol 1998;45:496-500.

Leflunomide (Arava): hematologic, hepatic and respiratory reactions

Treatment of rheumatoid arthritis has shifted toward earlier and more aggressive therapy with disease-modifying antirheumatic drugs (DMARDs).^1,2 Leflunomide (Arava), a newer immunomodulatory DMARD, is indicated for the treatment of active rheumatoid arthritis in adults.³

Because leflunomide has an active metabolite with a long elimination half-life of about 2 weeks, serious ARs (e.g., hepatotoxic, hematotoxic or allergic) may occur even after leflunomide treatment has been stopped.³ As well, recovery from ARs may be prolonged.⁴

The European Medicines Evaluation Agency raised concerns about the safety profile of this drug, especially with regard to hepatotoxicity, pancytopenia and serious skin reactions.^5,6 As well, in Canada the manufacturer has issued a safety alert regarding severe and serious hepatic reactions.⁷

From Mar. 29, 2000 (when leflunomide was marketed in Canada) to May 31, 2002, Health Canada received 99 reports of suspected ARs involving the drug, 79 considered to be serious and 4 with a fatal outcome. Three fatal cases were due to respiratory system disorders, with 1 case reporting concomitant use of methotrexate. The fourth fatal case was due to a cardiac system disorder. Suspected hematologic, hepatic and respiratory ARs associated with leflunomide reported to Health Canada are summarized in Table 1. Combined use of leflunomide and methotrexate is associated with an increased risk of toxicity³ and is not approved in Canada.⁷ Nevertheless, a number of the AR reports received described concomitant use.

Concomitant use of leflunomide with DMARDs toxic to liver and bone marrow is not advisable, as such therapy can lead to additive or even synergistic toxicity.³ Strict vigilance in monitoring liver and bone marrow function is recommended for all patients prescribed leflunomide, particularly if used with other medications associated with increased risk of hepatic or hematologic reactions.³

Table 1: Summary of reports submitted to Health Canada of suspected hematologic, hepatic and respiratory adverse reactions (ARs) associated with leflunomide from Mar. 29, 2000, to May 31, 2002*

Recommended monitoring parameters are as follows:³

• Alanine aminotransferase and aspartate aminotransferase levels before treatment with leflunomide and at monthly or more frequent intervals during the first 6 months, and every 8 weeks thereafter.
• A complete blood count, including differential white blood cell count and platelet count, before treatment with leflunomide and every 2 weeks for the first 6 months, and every 8 weeks thereafter.

It is important to note that, if a severe undesirable effect occurs during treatment with leflunomide, the washout procedures outlined in the product monograph should be followed in order to clear the active metabolite from the body. These washout procedures should also be followed when changing therapy from leflunomide to another DMARD, since the possibility of additive risks of ARs exists for a long time after switching.³

Health care professionals are reminded that treatment with leflunomide may have serious hepatic, hematologic and respiratory effects⁴ and that these risks may be increased with concomitant methotrexate use.

Lili Loorand-Stiver, BScPhm; Mano Murty, MD, CCFP, FCFP, Health Canada

References

1. Kremer J. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med 2001;134(8):695-706.

2. Schuna A, Megeff C. New drugs for the treatment of rheumatoid arthritis. Am J Health Syst Pharm 2000;57:225-37.

3.Arava, leflunomide tablets [product monograph]. Laval (QC): Aventis Pharma Inc.; 2001 Dec 18.

4. Adverse Drug Reactions Advisory Committee (ADRAC). Leflunomide: serious hepatic, blood, skin and respiratory reactions. Aust Adverse Drug Reactions Bull 2001;20(2):7. Available: http://www.tga.gov.au/problem/index.htm (accessed 2002 Aug 19).

5.EMEA public statement on leflunomide (Arava): pancytopenia and serious skin reactions [doc ref EMEA/31637/99]. London (UK): European Agency for the Evaluation of Medicinal Products; 1999 Oct 25. Available: www.emea.eu.int/htms/human/drugalert/drugalert.htm (accessed 2002 Aug 19).

6. European Agency for the Evaluation of Medicinal Products. EMEA public statement on leflunomide (Arava): severe and serious hepatic reactions [doc ref EMEA/5611/01/en]. London (UK): European Agency for the Evaluation of Medicinal Products; 2001 Mar 12. Available: www.emea.eu.int/htms/human/drugalert/drugalert.htm (accessed 2002 Aug 19).

7.Important safety information on Arava: severe and serious hepatic reactions. Laval (QC): Aventis Pharma Inc; 2001 May 4. Available: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2001/arava_hpc-cps_e.html (accessed 2002 Aug 19).

Case Presentation - moxifloxacin (Avelox)

Optic neuritis developed in a 22-year-old woman with sinusitis while she was receiving moxifloxacin (Avelox) therapy. After 1 dose she experienced fainting and somnolence, which resolved 2 days after initiation of therapy. After 4 days of treatment she lost vision in her left eye. She consulted an ophthalmologist and continued therapy for 6 days. An MRI scan ruled out multiple sclerosis. The patient was taking birth control pills concomitantly. It was reported that her vision would not likely return.

"Its Your Health": The Effects of Grapefruit and Its Juice on Certain Drugs

In an effort to inform consumers of potential interactions between grapefruit juice and certain drugs, Health Canada has issued an "Its Your Health" document on its Web site

(www.hc-sc.gc.ca/english/iyh/food/grapefruit.html). The document provides precautions to minimize the risk of adverse effects when consuming grapefruit or its juice, recommendations to consult their health care professional, and additional sources of information. We encourage health care professionals to share this information with their patients.

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Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
AL 0201C2
Ottawa ON K1A 1B9
Tel 613 957-0337
Fax 613 957-0335

Health professionals/consumers report toll free
Tel 866 234-2345
Fax 866 678-6789
E-mail: cadrmp@hc-sc.gc.ca

Editors
Ann Sztuke-Fournier, BPharm and Marielle McMorran, BScPharm

Acknowledgements
Expert Advisory Committee on Pharmacovigilance and AR Regional Centres, Health Canada staff

Suggestions?
Your comments are important to us. Let us know what you think by reaching us at cadrmp@hc-sc.gc.ca

Copyright
Her Majesty the Queen in Right of Canada, 2002. 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.

ISSN 1492-8167, Cat no H42-4/1-12-4E-IN

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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.