Canadian Adverse Reaction Newsletter
Volume 13 · Issue 1 · January 2003
http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/ar-ei_index_e.html
Marketed Health Products Directorate, Health Products and Foods Branch
In This Issue
Suspected hepatobiliary reactions to the newer
antidepressants
Convulsions and newer-generation antihistamines
Drug Safety Information Workshop Report
Case presentation: RespirActin
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
ADR Form
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.
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_e.html
and click on "subscribe".
Suspected hepatobiliary adverse reactions
with the newer antidepressants that affect serotonin neurotransmission
Health Canada continues to monitor suspected hepatobiliary adverse reactions
(ARs) associated with the newer antidepressants that exert an effect on
serotonin neurotransmission. These include citalopram (Celexa), fluoxetine
(Prozac), fluvoxamine (Luvox), mirtazapine (Remeron), nefazodone (Serzone-5HT2),
paroxetine (Paxil), sertraline (Zoloft), trazodone (Desyrel) and venlafaxine
(Effexor). Tables 1 and 2
summarize the reports of suspected hepatobiliary ARs associated with these
antidepressants that were submitted to Health Canada from the time of
marketing to July 24, 2002. Spontaneous reporting systems are suitable
for detecting signals of potential drug safety issues; however, these
data cannot be used to determine the incidence of ARs, because ARs remain
underreported and total patient exposure is unknown. From the data available,
no fatal outcomes were reported for hepatobiliary ARs associated with
these antidepressants. In 2 reports involving nefazodone, liver transplantation
was required. In 3 other reports involving nefazodone liver transplantation
was considered, but the patients' conditions eventually improved after
prolonged hospital care. The time of onset of liver injury ranged from
1 to 4 months. None of these 5 patients had a prior history of liver disease.
Health Canada has been monitoring the safety profile of nefazodone since
it was marketed in Canada in 1994. The following actions have been taken
to inform health care professionals and the public about the safety issues
with nefazodone.
· A summary of reported reactions associated with nefazodone
was profiled in the April 1996 issue of this newsletter.1
· A summary of 9 Canadian case reports of suspected
symptomatic hepatic dysfunction associated with nefazodone was outlined
in the July 1999 issue of this newsletter. 2
· In consultation with Health Canada, 2 Dear Healthcare
Professional Letters were issued by the manufacturers of Serzone-5HT2
and Lin-Nefazodone3 and of Apo-Nefazodone4
recommending that patients be counselled about the risk of hepatotoxic
effects before the initiation of nefazodone therapy and that close monitoring
is required should signs of hepatotoxicity or abnormal liver aminotransferase
or bilirubin levels develop during treatment.
· Health Canada issued a public advisory on the safety
profile of nefazodone on July 9, 2001, related to the risk of severe liver
injury associated with the use of nefazodone.5
The current literature documents several cases of severe hepatic failure
associated with nefazodone.6-8 The US Food
and Drug Administration (FDA) recently included a black-box warning in
Serzone's package insert, stating that the reported rate in the United
States of liver failure resulting in death or liver transplantation is
about 1 case per 250 000–300 000 patient-years of Serzone
treatment. This rate is about 3-4 times the estimated background rate
of liver failure. It is possibly an underestimate of true risk because
of underreporting.9
At present, there is no way to predict in which patient liver failure
is likely to develop.9 Ordinarily, treatment
with nefazodone should not be initiated in patients with active liver
disease or with an elevated baseline serum transaminase level.9
Although it is unclear whether periodic liver function tests can help
prevent serious liver injury, it is generally believed that early detection
of drug-induced hepatic injury along with immediate discontinuation of
the suspected drug enhances the likelihood of recovery.9
Patients should be advised to be alert for signs and symptoms of liver
dysfunction (e.g., dark urine, jaundice [yellow discoloration of the skin
or the eyes], loss of appetite and discoloured stools) and to report them
to their physician immediately.9,10
Mano Murty, MD, CCFP, FCFP; Iza Morawiecka, BScPhm; Suniti Sharma, BSc,
MSc
References
1.Nefazodone: adverse
drug reaction profile. Can Adverse Drug Reaction Newsl 1996;6(2):2.
2.Nefazodone (Serzone)
and hepatotoxicity. Can Adverse Drug Reaction Newsl 1999;9(3):2-3.
3.Important safety information
on nefazodone HCl: severe and serious hepatic events [Dear Healthcare
Professional Letter]. Montreal: Bristol-Myers Squibb Canada Inc and Linson
Pharma Inc; 2001 June 20. Available: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2001/nefazodone_hpc-cps_e.html (accessed
2002 Nov 18).
4.Important safety information
on nefazodone HCl: severe and serious hepatic events [Dear Healthcare
Professional Letter]. Weston (ON): Apotex Inc; 2001 June 28. Available:
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2001/nefazodone_hpc-cps_e.html (accessed
2002 Nov 26).
5.Risk of severe liver
injury associated with the use of the antidepressant nefazodone [public
advisory]. Ottawa: Health Canada; 2001 July 9. Available: www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2001/2001_74_e.html
(accessed 2002 Nov 18).
6.Aranda-Michel J, Koehler
A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, et al. Nefazodone-induced
liver failure: report of three cases. Ann Intern Med 1999;130:285-8.
7.Schirren CA, Baretton
G. Nefazodone-induced acute liver failure. Am J Gastroenterol 2000;95(6):1596-7.
8.Carvajal A, Garcia
del Pozo J, Sanchez A, Velasco A, Rueda AM, Lucena MI. Hepatotoxicity
associated with the new antidepressants. J Clin Psychiatry 2002;63(2):135-7.
9.Important drug warning
including black box information [Dear Healthcare Practitioner Letter].
New York: Bristol-Myers Squibb; 2002 Jan. Available: www.fda.gov/medwatch/SAFETY/2002/serzone_deardoc.pdf
(accessed 2002 Nov 18).
10.Serzone-5HT2,
nefazodone hydrochloride tablets [product monograph]. Montreal: Bristol-Myers
Squibb Canada Inc.; 2001 Oct 5.
Table 1: Reports submitted
to Health Canada of suspected adverse reactions (ARs) associated with
antidepressants exerting an effect on serotonergic neurotransmission from
date marketed to July 24, 2002*
Table 2: Reports submitted
to Health Canada of suspected hepatobiliary adverse reactions (ARs) associated
with antidepressants exerting an effect on serotonergic neurotransmission
from date marketed to July 24, 2002*
Reports of convulsions with newer-generation
antihistamines
Antagonists of histamine H1 receptors are commonly classified
as first-generation or new-generation antihistamines based on their frequent
sedating effect at therapeutic doses.1 The
"newer-generation" antihistamines, also known as second- or
third-generation antihistamines, include astemizole, cetirizine, desloratadine,
fexofenadine, loratadine and terfenadine, and were developed as nonsedating
alternatives to the first-generation compounds. The sale of terfenadine
and astemizole was stopped in Canada because of associated QT prolongation,
which could lead to torsades de pointes or ventricular fibrillation. Loratadine,
cetirizine, fexofenadine and desloratadine have been marketed in Canada
since 1988, 1991, 1997 and 2002, respectively. Loratadine, fexofenadine
and desloratadine are available as nonprescription drugs. Cetirizine is
available as both a nonprescription (5 and 10 mg) and prescription (20
mg) drug.
Seizures or convulsions have been reported in the literature with some
first-generation antihistamines (chlorpheniramine, diphenhydramine, pheniramine
and pyribenzamine) as well as with some newer-generation antihistamines
(astemizole, cetirizine, fexofenadine, loratadine and terfenadine).1-3
According to the US Food and Drug Administration Adverse Event Reporting
System (July 1999), convulsions associated with cetirizine, fexofenadine
and loratadine accounted for 2.5%, 3.1% and 2.1% respectively of the total
adverse events reported with these drugs.1
From their respective dates of marketing in Canada to Sept. 19, 2002,
Health Canada received 20 reports of suspected convulsive disorders associated
with the use of loratadine (9), cetirizine (7) and fexofenadine (4)
(Table
1). There have been no reports of suspected convulsive disorders associated
with desloratadine at this time. Reports of seizures and convulsions accounted
for 3.6%, 1.4% and 0.9% of the total number of adverse reactions (ARs)
reported with loratadine, cetirizine and fexofenadine respectively. Fifteen
of the 20 cases occurred in patients with a prior history of seizures
or in those who used anticonvulsant drugs concomitantly. However, these
data must be interpreted with caution, as causality has not been confirmed.
It is unclear whether newer-generation antihistamines aggravate the medical
condition of patients with a history of seizures or whether they interact
with anticonvulsants. Further studies and continued monitoring of these
agents regarding their role in causing seizures or convulsions, especially
in patients predisposed to convulsive disorders, are required.
Table 1: Reports submitted
to Health Canada of suspected convulsive adverse reactions (ARs) associated
with newer-generation antihistamines from date marketed in Canada to Sept.
19, 2002*
Also of note are 2 reports of patients who apparently took more than
the recommended daily dose of the drug. One report involved a 27-year-old
woman receiving phenytoin therapy who had been seizure free for over 2
years. She took 3 doses of cetirizine (20 mg each) in 24 hours and experienced
a seizure 1½ hours after the third dose. The maximum recommended
daily dose of cetirizine is 20 mg.4 The
other report was of a healthy 37-year-old man with no history of seizures
who experienced 2 grand mal seizures, 3 hours apart, after 3 days of taking
25 mg of loratadine daily (in the form of 2 tablets of Claritin [each
containing 10 mg loratadine] and 1 tablet of Claritin Extra [containing
5 mg loratadine and 120 mg pseudoephedrine]). The patient had also
ingested alcohol (½ beer) the night before the seizure. The recommended
daily adult dose of loratadine is 10 mg.5,6
Convulsive disorders are serious ARs. Health care professionals are requested
to report any suspected cases of seizures or convulsions associated with
the use of newer-generation antihistamines to Health Canada. Patients
should be reminded to read package labels carefully and not to exceed
the recommended or maximum daily dose of any therapeutic health product,
including nonprescription drugs. Patients should also be made aware that
multiple products may contain the same active ingredients and to consult
their health care professional for further information.
Pascale Springuel, BPharm; Duc Vu, MSc, PhD, Health Canada
References
1.Ten Eick AP, Blumer
JL, Reed MD. Safety of antihistamines in children. Drug Safety
2001;24(2):119-47.
2.Blain PG, Lane RJM.
Neurological disorders. In: Davies DM, Ferner RE, De Glanville H, editors.
Davies's textbook of adverse drug reactions. 5th ed. London: Chapman
and Hall Medical; 1998. p. 591-3.
3.Murphy K, Delanty N.
Drug-induced seizures: general principles in assessment, management and
prevention. CNS Drugs 2000;14(2):135-46.
4.Reactine, cetirizine
hydrochloride tablets, syrup [product monograph]. Kirkland (QC): Pfizer
Canada Inc; 2000 Sept 29.
5.Claritin, loratadine
tablets, rapid dissolve tongue tablets, syrup [product monograph].
Pointe-Claire (QC): Schering Canada Inc; 2001 Jun 15.
6.Claritin Extra, loratadine
and pseudoephedrine repetabs tablets [product monograph]. Pointe-Claire
(QC): Schering Canada Inc; 1998 Mar 13.
Communicating Drug Safety Information
Workshop · summary report
Health Canada hosted the Communicating Drug Safety Information
workshop on Nov. 29–30, 2001, with representatives from the pharmaceutical
industry, health professional associations, consumer interest groups and
regulatory authorities to discuss how to enhance the reporting and distribution
of information about adverse drug events. Participants identified partnership
opportunities to assist them in the sharing and communication of drug
safety information. A second meeting is being planned for 2003. The summary
report from the workshop is available at www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/cdsi-dicim_sum_rep_e.pdf.
Case Presentation
Recent cases are selected based on their seriousness, frequency of occurrence
or the fact that the reactions are unexpected. Please report similar reactions.
RespirActin
An 18-year-old man used RespirActin (exact dose not indicated) 1 to
3 times per week for 1½ years for the treatment of allergies. RespirActin
lists the following ingredients: water, rosemary (leaf), honey, witch
hazel (leaf), fenugreek (seed), black cumin (seed), Ho Shou Wu (seed),
Chinese ginseng (root), damiana (leaf), marshmallow (leaf), sage (leaf),
juniper (fruit), chamomile (flower), clove (fruit), cinnamon (bark), spearmint
(leaf) and thyme (leaf). Following 1 week of fatigue the patient
presented to hospital and was noted to have jaundice. During the next
week the jaundice progressed, with increasing liver failure. Liver biopsy
showed extensive fibrosis. The patient's condition progressed to hepatic
encephalopathy, which necessitated an orthotopic liver transplant. The
AR report indicated that there were no concomitant medications or other
medical history and that alcohol use was not a contributing factor. Another
potential causal factor identified in the follow-up information for this
case was the patient's previous work environment, which was a poorly ventilated
area where paint or solvent fumes were present.
Comments: A number of factors must be considered when a natural
health product with multiple ingredients is suspected to be associated
with an adverse effect. An adulterant or misidentified ingredients could
be present in the product that may be responsible for any adverse effects.1,2
Possible toxicity due to excessive dosing or prolonged intake should also
be considered.1,2 Some
herbs may contain hepatotoxins, and others may contribute to idiosyncratic
hepatotoxic reactions and may involve an immunological response.2
There are published cases of hepatic adverse effects associated with Ho
Shou Wu (Polygonum multiflorum).3,4
Internal consumption of witch hazel is not recommended because it contains
appreciable amounts of hydrolysable tannins.5
The toxicity of tannins is complex and not well known. Although the tannins
in witch hazel are poorly absorbed following oral administration, hepatic
damage may occur if they are absorbed to an appreciable extent.5
References
1.McMorran M. Adverse reactions
to natural health products. Can Adverse Reaction Newsl 2002;12(4):1-2.
2.Shivakumar C, Farrell
GC. Herbal hepatoxicity: an expanding but poorly defined problem. J
Gastroenterol Hepatol 2000;15(10):1093-9.
3.But PP, Tomlinson B,
Lee KL. Hepatitis related to the Chinese medicine Shou-wu-pian manufactured
from Polygonum multiflorum. Vet Human Toxicol 1996;38(4):280-2.
4.Park GJH, Mann SP, NGU
MC. Acute hepatitis induced by Shou-Wu-Pian, a herbal product derived
from Polygonum multiflorum. J Gastroenterol Hepatol 2001;16(1):115-7.
5.Witch hazel. In: DerMarderosian
A.. editor. The review of natural products. St. Louis (MO): Facts and
Comparisons Inc.; 1997.
Summary of health professional and consumer advisories
issued since Aug. 22, 2002
(advisories are available at
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/index_e.html and
http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2002/index_e.html)
| Date |
Product |
Subject and type |
|
Nov 26
|
Tamoxifen
|
Tamoxifen associated with increased risk of stroke, pulmonary embolism
and uterine cancer
- consumer information
|
|
Nov 7
|
Tamoxifen
|
Important safety information regarding tamoxifen
- health professional advisory
|
|
Oct 31
|
Serzone-5HT2/
Seroquel
|
Important safety information regarding medication errors resulting
from confusion between Seroquel and Serzone-5HT2 - AstraZeneca
and Bristol-Myers Squibb
- health professional advisory and consumer information
|
|
Oct 30
|
Refludan
|
Important safety information regarding Refludan — Berlex
Canada Inc.
- health professional advisory
|
|
Oct 22
|
Menomune
|
Urgent vaccine recall - voluntary recall of single-dose Menomune
- A/C/Y/W-135 (meningococcal polysaccharide vaccine groups
A, C, Y and W-135 combined) - Aventis Pasteur
- health professional advisory
|
|
Oct 17
|
Risperdal (risperidone)
|
Updated safety information for Risperdal (risperidone) in elderly
dementia patients, announced in Canada by Janssen–Ortho Inc.
- consumer information
|
|
Oct 11
|
Risperdal (risperidone)
|
Important drug safety information: Risperdal (risperidone) and
cerebrovascular adverse events in placebo-controlled dementia trials
by Janssen–Ortho Inc.
- health professional advisory
|
|
Sept 20
|
Infant formulas
|
Enterobacter sakazakii infection and powdered infant formulas
- health professional advisory
|
|
Aug 27
|
Cryolife tissues
|
Risks associated with soft tissues from Cryolife Inc. used for
transplantation
- notice to hospitals
|
|
To receive the Newsletter and health product Advisories
by email,
join Health Canada's MedEffect e-Notice mailing list.
Go to http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/index_e.html
and click on "subscribe".
|
How to report adverse reactions
To report a suspected adverse reaction (AR) to therapeutic products marketed
in Canada, health professionals should complete a copy of the AR Reporting
Form. Copies of this form are also available from your Regional AR Centre
or the National AR Centre (see addresses below), the Canadian Compendium
of Pharmaceuticals and Specialties (CPS) and the Health Canada Web site.
British Columbia
BC Regional AR Centre
c/o BC Drug and Poison Information Centre
1081 Burrard St.
Vancouver BC V6Z 1Y6
Tel: 604 806-8625; Fax: 604 806-8262
adr@dpic.bc.ca
Saskatchewan
Sask AR Regional Centre
Saskatchewan Drug Information Service
College of Pharmacy and Nutrition
University of Saskatchewan
110 Science Place
Saskatoon SK S7N 5C9
Tel: 306 966-6340 or 800 667-3425
Fax: 306 966-2286
vogt@duke.usask.ca
Ontario
Ontario Regional AR Centre
LonDIS Drug Information Centre
London Health Sciences Centre
339 Windermere Rd.
London ON N6A 5A5
Tel: 519 663-8801; Fax: 519 663-2968
adr@lhsc.on.ca
Québec
Québec Regional AR Centre
Drug Information Centre
Hôpital du Sacré-Coeur de Montréal
5400, boul. Gouin ouest
Montréal QC H4J 1C5
Tel: 514 338-2961; Fax: 514 338-3670
cip.hscm@sympatico.ca
New Brunswick, Nova Scotia, Prince Edward Island and Newfoundland
Atlantic Regional AR Centre
c/o Queen Elizabeth II Health Sciences Centre
Drug Information Centre
2421–1796 Summer St.
Halifax NS B3H 3A7
Tel: 902 473-7171; Fax: 902 473-8612
adr@cdha.nshealth.ca
All other provinces and territories
National AR Centre
Marketed Health Products Safety and Effectiveness
Information Division
Marketed Health Products Directorate
Finance Building, Tunney's Pasture
AL 0201C2
Ottawa ON K1A 1B9
Tel: 613 957-0337; Fax 613 957-0335
Toll free: Tel 866 234-2345; Fax 866 678-6789
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, 2003. 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 H42-4/1-13-1E
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.
|
