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Canadian Adverse Reaction Newsletter
Volume 12 · Issue 4 · October 2002
Date: 2002-10-01
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MHPD-DPSC
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/ar-ei_form-eng.php
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-eng.php). 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 glucosamine4,5 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-eng.php).
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-eng.php (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-eng.php (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-eng.php (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
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-eng.php (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.
Newsletter and Advisories by email
To receive the Newsletter and Advisories free by email, join Health Canada's MedEffect e-Notice mailing list. Go to http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/index-eng.php and click "subscribe".
Summary of health professional and consumer
advisories
issued since May 24, 2002
| Date | Product | Subject and Web address |
|---|---|---|
| Aug. 21 | Kava | Health Canada issues a stop-sale order for all products
containing Kava |
| Aug. 13 | Aspirin | Health Canada is advising Canadians of incorrect information
on new approved uses for Aspirin |
| Aug. 8 | Aspirin | Important update regarding indications for Aspirin |
| July 30 | IV tubing and monitor leads | Notice to Hospitals - Risk of Strangulation of Infants by IV Tubing
and Monitor Leads |
| July 29 | Cochlear implants | Notice to Hospitals - Cochlear Implant Recipients may
be at Greater Risk for Meningitis |
| July | Lioresal | Important Safety Information - Lioresal intrathecal
(baclofen) - Novartis |
| July 18 | Matulane (formerly Natulan) | Important drug safety update for patients using MATULANE®
(procarbazine hydrochloride) capsules (formerly marketed under the
name NATULAN®) - Sigma-Tau Pharmaceuticals, Inc. |
| July 10 | Propofol | Notice to Hospitals - Propofol contraindicated for sedation
in pediatric patients receiving intensive care |
| July 4 | Eprex (epoetin alfa) |
Safety update: updated information about EPREX* (epoetin
alfa) provided to Canadian healthcare professionals - Janssen-Ortho
Inc. and Ortho Biotech - Consumer Information |
| June 25 | Eprex (epoetin alfa) |
EPREX (epoetin alfa) - Pure Red Cell Aplasia (PRCA,
Erythroblastopenia) Janssen-Ortho Inc. and Ortho Biotech |
| June 21 | Drugs with grapefruit juice | Health Canada is advising Canadians not to take certain
drugs with grapefruit juice - Consumer Information |
| June 19 | Seven herbal supplements | Health Canada is warning Canadians not to use seven
herbal supplements: Arthrin, Osporo, Poena, Neutralis, Oa Plus, Ra
Spes and Hepastat - Consumer Information |
| June 14 | Bejai Bowyantan | Health Canada is warning Canadians not to use Bejai
Bowyantan, a traditional chinese medicine for infants - Consumer Information |
| June 4 | Gentamicin sulfate | Important safety reminder for patients using gentamicin
sulfate-containing ear drops - Consumer information |
| May 30 | Garasone/ Garamycin | Important Drug Warning - Garasone / Garamycin - Schering
Canada Inc. |
To receive the Newsletter and health product Advisories
free by email,
join Health Canada's MedEffect e-Notice mailing list.
Go to http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/index-eng.php and click on "subscribe".
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
USPS periodical postage paid at Champlain, NY, and additional locations.
Aussi disponible en français.
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.
