Canadian Adverse Reaction Newsletter
Volume 14, Issue 2, April 2004
Health Products and Food Branch
Marketed Health Products Directorate
In this Issue:
Sterol and sterolin-containing products: hematologic adverse
reactions
Adverse reaction reporting — 2003
Feasibility study of active surveillance of adverse reactions
in children
Public opinion survey on post-market surveillance
Case presentation: clopidogrel
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.
Sterol and sterolin-containing products: hematologic
adverse reactions
Although not approved by Health Canada, sterol and sterolin-containing
products are used by some primarily for their presumed immune-enhancing
properties. Plant sterols (phytosterols) are structurally related to cholesterol
and perform the same functions in plant membranes as does cholesterol
in animal membranes. The main phytosterols derived from the diet include
ß-sitosterol, campesterol and stigmasterol, all of which are unsaturated.1
Sterolins are glucosides of sterols.2 In
humans, the absorption of phytosterols is low (5% or less of ingested
sitosterol); however, people who have the rare inherited lipid storage
condition known as phytosterolemia or sitosterolemia can absorb up to
63% of an ingested dose of sitosterol.1
Cholestasis and blood dyscrasias, including thrombocytopenia and hemolytic
anemia, have been noted in adults and children receiving phytosterol-containing
lipid emulsions with parenteral nutrition.1,3,4
The thrombocytopenia associated with parenteral nutrition is similar to
that observed in cases of phytosterolemia with increased peripheral destruction
of platelets.1,3
Reduced intake of such emulsions leads to decreased plasma phytosterol
levels and subsequent alleviation of hepatic and platelet effects in some
patients.1,3
A search of the Health Canada adverse reaction database revealed 4 reports
in which sterol and sterolin-containing products were suspected of being
associated with hematologic adverse reactions.
Case 1: After 2–3 weeks of taking “Moducare Sterinol”
(1 capsule per day) a 22-year-old man experienced a life-threatening hemolytic
anemia requiring admission to hospital and treatment with steroids, intravenous
immune globulin therapy and a blood transfusion. At the time of the adverse
reaction, the patient was not taking any concomitant medications; however,
he had a history of severe idiopathic thrombocytopenic purpura (ITP) and
splenectomy. Upon discontinuation of the product, the reaction slowly
resolved.
Case 2: A 76-year-old man with a history of atrial fibrillation was taking
Coumadin and had a stable international normalized ratio (INR) of 2.3–2.5.
After an unknown interval of taking “Sterinol” (1 capsule
per day), his INR fell to 1.6. Two weeks after discontinuing the “Sterinol”,
his INR increased to 3.4. The patient began taking the Sterinol again,
on a less frequent interval (1 capsule every 2 days), and his INR decreased
to 2.0.
Case 3: A 75-year-old woman had been taking “Moducare” (1
capsule 3 times daily) for about 2 months when she experienced abdominal
cramping and spotting. The first episode of spotting lasted 3 days, and
the second episode lasted 7 days. The patient was taking concomitant drugs,
including multiple antibacterial agents, an antihypertensive drug, a bone
metabolism regulator (bisphosphonate), an H2 -receptor antagonist,
a topical antineoplastic agent and inhalation aerosols.
Case 4: A 6-year-old girl was given “New Roots Herbal Sterols and
Sterolins” once a day for about 2 years. The child presented with
bruising, vaginal bleeding and thrombocytopenia. Her platelet count was
1 (normally 150–400) x109/L. Other abnormal hematological
values were hemoglobin 101 (normally 110–157) g/L, hematocrit 0.29
(normally 0.34–0.46), erythrocyte count 3.7 (normally 3.8–5.6)
x 1012/L, neutrophil count 8.6 (normally 0.8–7.2) x 109/L
and lymphocyte count 0.9 (normally 1.3–8.0) x 109/L.
The patient was given prednisone and after discontinuation of the product
she had fully recovered. She had no pre-existing medical conditions, nor
was she receiving any concomitant medications. With respect to family
history, it was noted that the patient’s father had ITP at 4 years
of age.
Health professionals are reminded to ask their patients to list the natural
health products they are taking and to be vigilant of potential interactions.5
Patients should be advised not to self-treat with products that claim
to treat serious medical conditions.6 Health
Canada continues to monitor the safety profile of natural health products.
Scott Jordan, PhD; Jenna Griffiths, MSc, PhD; Karen Pilon, RN, Health
Canada
References
1. Ratnayake WMN, Vavasour E.
Potential health effects associated with large intakes of plant sterols.
In: Dutta P, editor. Plant sterols: analytical, nutritional and safety
aspects as functional food components. New York: Marcel Dekker; 2004.
p. 365-95.
2. Pegel KH. The importance of sitosterol and sitosterolin
in human and animal nutrition. S Afr J Sci 1997;93:263-9.
3. Clayton PT, Bowron A, Mills KA, Massoud A, Casteels
M, Milla PJ. Phytosterolemia in children with parenteral nutrition-associated
cholestatic liver disease. Gastroenterology 1993;105(6):1806-13.
4. Goulet O, Girot R, Maier-Redelsperger M, Bougle
D, Virelizier JL, Ricour C. Hematologic disorders following prolonged
use of intravenous fat emulsions in children. J Parenter Enteral Nutr
1986; 10(3):284-8.
5. Awang DV, Fugh-Berman A. Herbal interactions with
cardiovascular drugs. J Cardiovasc Nurs 2002;16(4):64-70.
6. Safe use of natural health products. It’s
Your Health January 2004. Available:
 http://www.hc-sc.gc.ca/iyh-vsv/med/nat-prod_e.html
Adverse reaction reporting — 2003
Health Canada received 9209 new domestic reports of suspected adverse
reactions (ARs) in 2003. For the most part, ARs were reported 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, 6 414 (69,6%) 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.”
A steady increase in the reporting of ARs in Canada over the past 5 years
has been noted, with 7.5% more reports in 2003 than in 2002 (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.
Lynn Macdonald, BSP, Health Canada
Table 1: Source of reports of adverse reactions (ARs)
received by Health Canada in 2002 and 2003
| |
No. (and %) of reports
received |
| Source |
2002 |
2003 |
| Manufacturer |
5794 |
(67.6) |
6125 |
(66.5) |
| Regional AR Center |
2529 |
(29.5) |
2671 |
(29.0) |
| Other* |
243 |
(2.8) |
413 |
(4.5) |
| Total |
8566 |
(100.0) |
9209 |
(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 |
2002 |
2003 |
| Pharmacist |
2141 |
(25.0) |
2369 |
(25.7) |
| Physician |
2093 |
(24.4) |
2176 |
(23.6) |
| Health professional* |
1780 |
(20.8) |
1974 |
(21.4) |
| Consumer/patient |
1581 |
(18.5) |
1628 |
(17.7) |
| Nurse |
421 |
(4.9) |
689 |
(7.5) |
| Other |
550 |
(6.4) |
373 |
(4.1) |
| Total |
8566 |
(100.0) |
9209 |
(100.0) |
*Type not specified in report.
Fig. 1: Number of adverse reaction reports received annually
by Health Canada from 1999 to 2003.
Feasibility study of active surveillance of adverse
reactions in children
In January 2004, the Marketed Health Products Directorate (MHPD) of Health
Canada, in collaboration with the Canadian Paediatric Society and the
Pharmaceutical Outcomes Programme of the Children’s and Women’s
Health Centre of British Columbia, initiated a 3-year study to investigate
the feasibility of using active surveillance methods to generate additional
data on serious and life-threatening adverse reactions (ARs) in Canadian
children under 18 years of age.
Data will be collected through the Canadian Paediatric Surveillance Program
(CPSP), an established active surveillance network that reaches over 2300
pediatricians and pediatric subspecialists monthly. These physicians provide
health care to a geographically diverse pediatric population of over 6
million.
Health Canada continues to monitor and collect AR and medication incident
reports, including those generated through the CPSP. All these data are
also maintained in the national computerized database. This database is
a major tool in the continuing assessment of marketed health products.
The information from suspected AR and medication incident reports is analyzed
to detect potential health product safety signals. A signal is considered
to be the preliminary indication of a product-related issue. The identification
of a signal is not by itself proof of an association between an AR and
a health product; rather, it triggers the need to investigate a potential
association further.
CPSP’s study investigators are responsible for the review and analysis
of data derived from the active surveillance study, both during and upon
completion of data collection, which may result in the development of
practice guidelines, published articles and presentations. MHPD of Health
Canada is responsible for the coordination of consistency of post-marketing
surveillance and the assessment of signals and safety trends concerning
all marketed health products.
For more information on this study, visit the Canadian Paediatric Society’s
Web site
( http://www.cps.ca/english/CPSP/Studies/drugreactions.htm ).
Public opinion survey on key issues pertaining to post-market
surveillance of marketed health products in Canada
In 2003, Health Canada commissioned Decima Research to conduct a national
survey of Canadians, including health care professionals, on their opinions
on post-marketing surveillance of marketed health products (prescription
drugs, nonprescription drugs and natural health products) available in
Canada. Respondents provided important information on the effectiveness
of Health Canada’s methods used to communicate health product safety
information. This feedback included perceptions of health product safety
and health risks posed by adverse reactions (ARs); awareness, use of,
familiarity and satisfaction with available sources of new health product
safety information; views on mandatory AR reporting by health care professionals;
and views on patient informed consent before AR reporting. These survey
results will be used to evaluate the effectiveness of Health Canada sources
of new drug safety information (e.g., Dear Health Care Professionals Letters,
Public Advisories and the Canadian Adverse Reaction Newsletter)
and will provide direction for improvements and baseline data for future
evaluations. This report is available at:
http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/index_e.html
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 association with hepatitis
Health Canada has received 2 case reports of hepatitis suspected to be
associated with clopidogrel. An 84-year-old woman was prescribed clopidogrel
(75 mg/d, orally) as adjunctive therapy to Aspirin to prevent further
transient ischemic attacks. No other medications were reported. Eight
weeks after starting the clopidogrel therapy, she presented with clinical
and laboratory signs of acute mixed hepatocellular-cholestatic hepatitis.
Serologic testing ruled out infectious causes, and results for autoantibodies
were negative. There was no history of alcohol abuse and no history of
toxic exposure. Further workup showed no evidence of biliary tract disease,
hemochromatosis or other metabolic liver disease. Liver biopsy confirmed
the finding of hepatotoxicity, and clopidogrel was discontinued. Complete
resolution of symptoms and biochemical profile occurred over several weeks.1
The other case report described a flare-up of hepatitis with elevated
liver enzyme levels in a 76-year-old woman who had been receiving clopidogrel
for about 11 months. However, insufficient information was reported regarding
the patient’s concomitant medications or medical conditions, which
limits our analysis of the report.
Reference
1. Batwa F, Lamoureux E, Friedman
G. Clopidrogel-induced liver injury. Can J Gastroenterol 2003;17(Suppl
A):137.
Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
AL 0701C
Ottawa ON K1A 0K9
Tel 613 957-0337
Fax 613 948-7996
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, BScPharm, DIS Medical Biology (University of Paris V)
Karen Kouassi, BScBiochimie
Gilbert Roy, BPharm
Acknowledgements
Expert Advisory Committee on Pharmacovigilance,
AR Regional Centres and Health Canada staff.
Suggestions?
Your comments are important to us. Let us know what you think by reaching
us at
E-mail: cadrmp@hc-sc.gc.ca
Copyright
Her Majesty the Queen in Right of Canada, 2004. 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 H42-4/1-14-2E
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.
|
