Canadian Adverse Reaction Newsletter, Volume 15 • Issue 2 • April 2005
Health Products and Food Branch, Marketed Health Products Directorate
In this Issue
Hylan G-F 20: joint inflammation and pain
Adverse reaction reporting - 2004
Products derived from bees: serious adverse reactions
Case presentation: rhabdomyolysis with clopidogrel, atorvastatin and cyclosporine
Summary of advisories
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
Click here for the Adverse Reaction Reporting
Form.
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.
Hylan G-F 20 (Synvisc): reported incidents of joint inflammation and pain
Hylan G-F 20 (Synvisc) is an elastoviscous fluid containing hylan polymers, which are
derivatives of hyaluronan (sodium hyaluronate). It is indicated for the treatment of pain
caused by osteoarthritis of the knee in patients who have failed to respond adequately to
conservative nonpharmacologic therapy and simple analgesics. A treatment course involves
intra-articular injection once a week for 3 weeks. Aspiration of synovial fluid or effusion
should be performed before each injection. The most commonly reported adverse incidents have
been pain, swelling and effusion in the injected knee.1
From Mar. 22, 1996, to Jan. 15, 2005, Health Canada received 31 reports of suspected incidents
associated with Synvisc; 23 were received in 2003-2004. In 9 cases the synovial fluid was not
removed before each injection, and in 5 the course of injection was continued after the occurrence
of adverse symptoms. Six of the 23 recent reports described patients who had pain, walking
disability and knee swelling with or without effusion after the third injection of the first
course. Two of these 23 patients were admitted to hospital.
The occurrence of post-injection effusion may be associated with the number of injections.
1 There have been reports in the literature of pseudosepsis
(severe inflammation of the joint occurring 24 to 72 hours after intra-articular injection of hylan)
.2 In affected patients, pseudosepsis typically occurs after more
than 1 injection. Sepsis or pseudogout should be ruled out. Mononuclear cells are present in the
synovial fluid.2 Although the cause of pseudosepsis is not fully
understood, there is increasing evidence to suggest an immunologic mechanism.2
Health care professionals should be aware of these possible adverse incidents and encouraged
to follow the labelled procedure, including aspiration of synovial fluid before each injection.
1 Patients should be alerted of the occurrence of such events,
and those who have severe inflammation of the joint after an injection should be fully evaluated.
3
Health Canada will continue to monitor incident reports associated with hylan G-F 20. Any
serious or unexpected adverse incidents associated with medical devices should be reported to
Health Canada at the following address:
Health Products and Food Branch Inspectorate
Health Canada
AL 3002C
Ottawa ON K1A 0K9
Inspectorate Hotline: 800 267-9675
Momir Nesic, MD, PhD; Barbara Harrison, RN; Philippe Haziza, MD, MBA, Health Canada
References
1. Synvisc Hylan G-F 20 [prescribing information] Ridgefield
(NJ): Genzyme Biosurgery. Revised 2004
Nov 15.
2. Goldberg VM, Coutts RD. Pseudoseptic reactions to hylan
viscosupplementation: diagnosis and treatment. Clin Orthop 2004;(419):130-7.
3. Bernardeau C, Bucki B, Liote F. Acute arthritis after
intra-articular hyaluronate injection: onset of effusions without crystal. Ann Rheum Dis
2001;60(5):518-20.
Adverse reaction reporting -- 2004
Health Canada received 10 238 new domestic reports of suspected adverse reactions (ARs) in 2004.
The ARs were reported for the most part by health professionals (pharmacists, physicians, nurses,
dentists, coroners and others), either directly to Health Canada or indirectly through another source
(Table 1). A further analysis of the total number of reports by reporter type (originator) is outlined
in Table 2.
Of the AR reports received, 7000 (68.4%) were classified as serious. A serious AR is defined in the
Food and Drugs Act and Regulations as "a noxious and unintended response to a drug which occurs
at any dose and requires inpatient hospitalization or prolongation of existing hospitalization, causes
congenital malformation, results in persistent or significant disability or incapacity, is life-threatening
or results in death."
There has been a steady increase in the reporting of ARs in Canada over the past 6 years, with 11.2%
more reports in 2004 than in 2003 (Fig. 1).
Health Canada would like to thank all who have contributed to the program and encourages the continued
support of post-marketing surveillance through AR reporting. ARs may be reported by using the toll-free
telephone (866 234-2345) and fax (866 678-6789) lines.
Bill Wilson, BSc, BA, Health Canada
Table 1: Source of reports of adverse reactions (ARs) received by Health
Canada in 2003 and 2004
| |
No. (and %) of reports received |
| Source |
2003 |
2004 |
| Manufacturer |
6 125 |
(66.5) |
6 114 |
(59.7) |
| Regional AR centre |
2 671 |
(29.0) |
3 617 |
(35.3) |
| Other* |
413 |
(4.5) |
507 |
(5.0) |
| Total |
9 209 |
(100.0) |
10 238 |
(100.0) |
* Includes, but not limited to, professional associations, nursing homes,
hospitals, physicians, pharmacists, Health Canada regional inspectors, coroners, dentists and patients.
Table 2: Number of AR reports by type of reporter (originator)
| |
No. (and %) of reports |
| Reporter |
2003 |
2004 |
| Pharmacist |
2 369 |
(25.7) |
3 011 |
(29.4) |
| Physician |
2 176 |
(23.6) |
2 667 |
(26.2) |
| Health professional* |
1 974 |
(21.4) |
1 499 |
(14.6) |
| Consumer/patient |
1 628 |
(17.7) |
1 928 |
(18.8) |
| Nurse |
689 |
(7.5) |
873 |
(8.5) |
| Other |
373 |
(4.1) |
260 |
(2.5) |
| Total |
9 209 |
(100.0) |
10 238 |
(100.0) |
* Type not specified in report.
Fig. 1: Number of AR reports received annually by Health Canada from 1999 to 2004.
Products derived from bees: serious adverse reactions
Substances derived from bees include bee pollen, royal jelly and propolis. Bee pollen can come from
a variety of plants and may include pollen to which people are commonly allergic (e.g., ragweed pollen).
Royal jelly consists of the secretions of the hypopharyngeal and mandibular glands of worker bees.
Propolis substrates are collected from poplar resin and conifer buds and are mixed with wax by bees.
These substances are marketed alone or in combination products under various trade names and are
indicated for multiple uses, from general health tonics to allergy and asthma treatment.
1
From Jan. 1, 1998, to Oct. 30, 2004, Health Canada received 14 reports of suspected adverse reactions
(ARs) involving bee products; 10 were considered serious. Four of the ARs were suspected allergic reactions:
acute oral and laryngotracheal edema with respiratory distress; suspected autoimmune hepatitis; edema,
rash and hives; and a questioned allergic reaction with chest pain. Other serious reactions were bleeding,
hepatitis and seizures. Causality could not be assigned specifically to the bee product in many of
the cases because of confounding factors such as pre-existing medical conditions, concomitant drug
use or other suspect components of the product in question.
Allergic reactions involving products derived from bees have been documented in the literature.
2-5 The literature also suggests that there is no direct correlation
between sensitivity to bee venom (stings) and sensitivity to bee products.4
Products containing bee pollen, royal jelly or propolis are readily available to the public; however,
they often do not have a label warning of possible adverse reactions. The public and health care
practitioners should be aware of the risk of allergic reactions to products derived from bees. It
has been reported that atopic and asthmatic individuals may be at an increased risk of allergic
reactions, possibly anaphylaxis, after ingestion of products containing royal jelly.
1,4 Individuals with seasonal allergic rhinitis (e.g., pollen allergies)
may also be at an increased risk for similar serious allergic reactions to bee pollen.
1,3 With the implementation of the new Natural Health Products
Regulations in January 2004, all natural health products approved for sale in Canada will eventually
carry a Natural Product Number (NPN) or Drug Identification Number - Homeopathic Medicine (DIN-HM).
The number will let consumers know that the product has undergone and passed a review of its
quality, formulation, labelling and instructions for use. Products derived from bees are covered
under the new regulations.
Chad Sheehy, BSc, ND; Trudy Hall, MSc, MD, CCFP; Karen Pilon, RN, Health Canada
References
1. Jellin JM, Gregory PJ, Batz F, Hitchens K, et al.
Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database.
6th ed. Stockton (CA): Therapeutic Research Faculty; 2004. p. 107-8, 1053-54, 1110-11.
2. Chivato T, Juan F, Montoro A, Laguna R. Anaphylaxis induced
by the ingestion of a pollen compound. J Investig Allergol Clin Immunol 1996;6(3):208-9
3. Greenberger P, Flais M. Bee pollen-induced anaphylactic
reaction in an unknowingly sensitized subject. Ann Allergy Asthma Immunol 2001;86:239-42.
4. Thien FCK, Leung R, Baldo BA, Weiner JA, Plomley R, Czarny
D. Asthma and anaphylaxis induced by royal jelly. Clin Exp Allergy 1996;26(2):216-22.
5. Hausen BM, Wollenweber E, Senff H, Post B. Propolis allergy.
(I). Origin, properties, usage and literature review. Contact Dermatitis 1987;17(3):163-70.
Case Presentation
Recent Canadian cases are selected based on their seriousness, frequency of occurrence or the fact
that the reactions are unexpected. Case presentations are considered suspicions and are presented to
stimulate reporting of similar suspected adverse reactions.
Clopidogrel (Plavix): suspected drug interaction with atorvastatin (Lipitor) and cyclosporine
resulting in rhabdomyolysis
A 57-year-old woman who had a heart transplant more than 10 years ago, and a myocardial infarction
in 2003, was receiving cyclosporine (65 mg orally twice daily), Lipitor (80 mg orally daily), Imuran,
prednisone, lisinopril, Apo-Allopurinol and furosemide. Plavix (75 mg orally daily) was added when a
cardiac stent was inserted. Three weeks after starting the Plavix, the patient was admitted to hospital
with muscle pain and weakness. Her creatine kinase level was 94 000 (normally ≤190) U/L, and
rhabdomyolysis was diagnosed. The cyclosporine, Lipitor, Plavix and Apo-Allopurinol therapies were
stopped. Cyclosporine was reintroduced at a lower dose 3 days later, and Lipitor was restarted
following the adverse reaction without consequence. The muscle pain and weakness resolved, and the
patient was discharged from hospital 11 days later.
The risk of myopathy and rhabdomyolysis during treatment with HMG-CoA reductase inhibitors is
increased with concurrent administration of cyclosporine.1,2 Because
the patient had been taking cyclosporine since the heart transplant and Lipitor for years before
this reaction, the reporter suspected that the rhabdomyolysis occurred when Plavix was added. Two
similar cases are described in the literature where the authors believed that clopidogrel precipitated
the development of rhabdomyolysis when added to a stable regimen of cyclosporine and an HMG-CoA
reductase inhibitor.2
References
1. Lipitor (atorvastatin) [product monograph].
Kirkland (QC): Pfizer Canada Inc; 2004.
2. Uber PA, Mehra MR, Park MH, Scott RL. Clopidogrel and
rhabdomyolysis after heart transplantation [letter]. J Heart Lung Transplant 2003;22(1):107-8.
Update
In the January 2005 issue of this newsletter (Vol. 15, Issue 1; also in CMAJ 2005;172[1]:127-32)
an article was published on a suspected interaction between telithromycin (Ketek) and warfarin.
In consultation with Health Canada, Aventis Pharma Inc. updated the product monograph on Dec.
17, 2004, to reflect the potential interaction between Ketek and warfarin.
Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
AL 0701B
Ottawa ON K1A 0K9
Tel 613 954-6522
Fax 613 952-7738
Health professionals/consumers report toll free
Tel 866 234-2345
Fax 866 678-6789
E-mail: cadrmp@hc-sc.gc.ca
Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Ilhemme Djelouah, BScPhm, DIS, AFSA, Medical Biology (University of Paris V)
Gilbert Roy, BPharm
Acknowledgements
Expert Advisory Committee on Pharmacovigilance,
Regional AR Centres and 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, 2005. 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 1499-9447; Cat no H42-4/1-15-2E
USPS periodical postage paid at Champlain, NY, and additional locations.
Aussi disponible en français.
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.
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