Canadian Adverse Reaction Newsletter
Volume 11 · Number 1 · January 2001
In This Issue
Thioridazine (Mellaril) and
mesoridazine (Serentil): prolongation of the QTc interval
Clopidogrel (Plavix): hematological reactions
Gentamicin ear drops and ototoxicity: update
Drugs of Current Interest
Thioridazine
(Mellaril) and mesoridazine (Serentil): prolongation of the QTc interval
Thioridazine and mesoridazine are phenothiazines used as tranquilizers
or antipsychotic drugs. On July 31 and Sept. 22, 2000, Novartis Pharmaceuticals
Canada Inc. issued a notice to health care professionals advising them
that Mellaril and Serentil has been shown to prolong the QTc interval
in a dose related manner,1, 2
and that drugs with this potential, including Mellaril and Serentil, have
been associated with torsade de pointes-type arrhythmias and sudden death.1,
2
Novartis Pharmaceuticals Canada Inc., in consultation with Health Canada,
therefore recommends Mellaril and Serentil only for schizophrenic
patients who fail to show an acceptable response to adequate treatment
with other antipsychotic drugs, either because of insufficient effectiveness
or the inability to achieve an effective dose because of intolerable adverse
effects.1, 2 The use of
thioridazine is now contraindicated in association with certain drugs
such as fluvoxamine, propranolol, pindolol and any drug that inhibits
the cytochrome P450 2D6 isozyme (e.g., fluoxetine and paroxetine).1
Thioridazine and mesoridazine are also contraindicated in association
with drugs known to prolong the QTc interval (e.g., quinidine).1,2
Patients with congenital long QT syndrome or a history of cardiac arrhythmias
should not receive thioridazine or mesoridazine. 1,2
Also, patients with reduced levels of the cytochrome P450 2D6
isozyme1 should not receive thioridazine.
An ECG and measurement of serum potassium levels are recommended before
starting treatment with thioridazine or mesoridazine, and it may be useful
to repeat these tests periodically during treatment. 1,2
Patients with a QTc interval greater than 450 msec should not receive
these drugs, and if the QTc interval is greater than 500 msec, treatment
with thioridazine or mesoridazine should be discontinued.1,
2
Similar measures have been taken in the United States.3,
4 Further information about the effect of thioridazine
on the QTc interval, in the context of a study on ziprasidone (Zeldox)
and other antipsychotic drugs, has been published by the Psychopharmacological
Drugs Advisory Committee of the US Food and Drug Administration in the
Briefing Information document of July 19, 2000
( http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1.htm ).
The Therapeutic Products Programme also posts public health advisories
on its Web site at the addresses shown in references 1 and 2 below.
Written by: Susie Dallaire, BPharm, Program coordinator, Québec
ADR Regional Centre.
References
1.Important drug warning:
Mellaril. Dorval (QC): Novartis Pharmaceuticals Canada Inc., 2000
July 31. Available:
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/mellaril_hpc-cps_e.pdf
2.Important drug warning:
Serentil. Dorval (QC): Novartis Pharmaceuticals Canada Inc., 2000
Sept 22. Available:
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/serentil_hpc-cps_e.pdf
3.Food and Drug
Administration, US Department of Health and Human Services. Important
drug warning [Mellaril]. [Retyped text of a letter from Novartis Pharmaceuticals
Corporation, East Hanover, NJ, 2000 July 7.] Available: www.fda.gov/medwatch/safety/2000/mellar.htm
4.Food and Drug
Administration, US Department of Health and Human Services. Important
drug warning [Serentil]. [Retyped text of a letter from Novartis Pharmaceuticals
Corporation, East Hanover, NJ, 2000 Sept 22.] Available: www.fda.gov/medwatch/safety/2000/serent.htm
Newsletter's 10th anniversary!
This edition marks the 10th anniversary of the Canadian Adverse Drug
Reaction Newsletter. The first issue was produced by Dr. W. Curt Appel
and Lori J. Anderson of the Bureau of Pharmaceutical Surveillance in January
1991. The newsletter's main objectives are to provide regular feedback
on adverse drug reactions (ADRs) reported in Canada and to communicate
important drug safety information to health professionals and individuals
interested in the area of post-approval surveillance of drugs. We thank
all those who have contributed to this newsletter and welcome suggestions
to improve future issues of this newsletter. Your comments may be directed
to the Editors, at the national address indicated on the last page.
Clopidogrel (Plavix): hematological
reactions
Clopidogrel (Plavix), a thienopyridine derivative structurally similar
to ticlopidine, is a specific inhibitor of adenosine diphosphate (ADP)-induced
platelet aggregation. Clopidogrel is indicated for the secondary prevention
of vascular ischemic events (myocardial infarction, stroke, vascular death)
in patients with a history of symptomatic atherosclerotic disease.1
Recent revisions to the Plavix product monograph warn of the possibility
of thrombotic thrombocytopenic purpura (TTP) occurring rarely following
the use of clopidogrel.1 TTP is a serious
condition requiring prompt treatment with plasmapheresis. 1
In a study examining 11 cases of TTP associated with clopidogrel,2
TTP was shown to appear earlier with clopidogrel (as early as 3 days in
2 cases) than with ticlopidine; all except 1 of the 11 cases occurred
within the first 2 weeks of initiation of treatment. The authors have
suggested that the mechanism causing TTP may be different for the 2 drugs.
Another author has estimated that the observed rate of TTP among clopidogrel
recipients is no higher than that expected in the general population (about
3.7 cases per million population).3
The concern over TTP and clopidogrel prompted the Canadian Adverse Drug
Reaction Monitoring Programme (CADRMP) to review the Canadian reports.
Between Oct. 31, 1998, when clopidogrel was first marketed in Canada,
and Aug. 31, 2000, the CADRMP received 61 domestic reports of suspected
ADRs associated with clopidogrel; 51 were classified as serious.4
The average age of patients was 70 years; 46% were women and 46% men (sex
unknown in 8%).
Three of the 61 patients died. One death was associated with intracranial
hemorrhage. The other 2 causes of death (myocardial infarction, cancer)
were reported to be unrelated to clopidogrel.
A closer look at the suspected hematological reactions revealed 17 reports
with disorders of blood components, particularly white blood cell and
platelet disorders (Table 1). Although
there were 11 reports of thrombocytopenia and 1 of pancytopenia, there
was none of TTP in Canada.
The use of cholesterol-lowering agents, particularly the statins such
as simvastatin and atorvastatin, has also been suggested to play a role
in the occurence of TTP, and the possibility of adverse pharmacologic
interactions with clopidogrel deserves further study.2,5
Three reports of thrombocytopenia indicated concomitant use of cholesterol-lowering
statins (Table 1, cases
13, 15 and 16).
Most of the reports of hematological reactions described elderly patients
with underlying cardiovascular disease taking concomitant medications.
Twelve of the 17 patients were taking multiple anticoagulant or antiplatelet
medications, including ASA (Table 1). Confounding factors of age, disease
and concomitant medications make interpretation of the adverse reaction
data difficult. Additional studies and continual ADR reporting are required
to elucidate a clearer pattern of potential risks of TTP associated with
clopidogrel.
Written by: Heather Dunlop, BNSc, MLIS, Bureau of Licensed Product
Assessment.
References
1.PlavixTM,
clopidogrel bisulfate [product monograph]. Markham (ON): Bristol-Myers
Squibb/Sanofi Canada; 2000 Sept 7.
2.Bennett CL, Connors
JM, Carwile JM, Moake JL, Bell WR, Tarantolo SR, et al. Thrombotic thrombocytopenic
purpura associated with clopidogrel. N Engl J Med 2000;342:1773-7.
3.Hankey GJ. Clopidogrel
and thrombotic thrombocytopenic purpura. Lancet 2000;356:269-70.
4.Canadian Adverse
Drug Reaction Monitoring Programme guidelines for the voluntary reporting
of adverse drug reactions by health professionals. Ottawa: Therapeutic
Products Programme, Health Canada. Available:
http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/guide/ar-ei_guide-ldir_e.html
5.McCarthy LJ, Porcu P,
Pausel CA, Sweeney CJ, Danielson CFM. Thrombotic thrombocytopenic purpura
and simvastatin. Lancet 1999;352:1284.
Table 1: Reports of hematolgical
reactions associated with clopidogrel submitted to the CADRMP between
Oct. 31, 1998, and Aug. 31, 2000
Gentamicin ear drops and ototoxicity:
update
Aminoglycoside ear drops have a potential for ototoxicity (both cochlear
and vestibular) when administered in the presence of a tympanic membrane
perforation.1,2 This
ototoxicity appears to develop in only a small number of patients despite
widespread product use; however, the actual incidence is unknown. 1,2
Some investigators have suggested that vestibulotoxicity may be unrecognized
and underreported.2 In 1997 we summarized
7 cases of ototoxicity associated with the use of Garasone Ophthalmic/Otic
Solution (gentamicin sulfate with betamethasone sodium phosphate), an
aminoglycoside otic preparation.3 Individual
reports of vestibulotoxicity in patients given Garasone ear drops in the
presence of tympanic membrane defects have also been published. 1,2,4,
5 Because topical aminoglycoside ototoxicity
may be more common than once thought, in June 2000 the Ontario Medical
Association's Section of Otolaryngology sent an alert to Ontario physicians.
6
Between 1981 and Oct. 6, 2000, the CADRMP received 18 domestic suspected
reports of ototoxicity (including published cases) associated with the
use of Garasone ear drops in the presence of tympanic membrane perforation
or tympanoplasty tubes. Sixteen were of vestibular disorders and 2 of
hearing loss. Tympanic membrane defects were either unilateral or bilateral.
In most cases the conditions being treated were middle ear disorders with
otorrhea. Duration of treatment ranged from 5 days to "long term."
In 6 cases patients used the product for no longer than 5 to 7 days. At
the time of reporting, 15 patients had not recovered from their symptoms.
In addition to these 18 cases, 2 reports were associated with the use
of gentamicin ear drops (brand not specified): one of persistent dizziness
and imbalance and another of temporary hearing loss in a patient being
treated for Ménière's disease. In the latter case, gentamicin
ear drops were used as an adjunct to high-dose gentamicin infusion (26
mg 3 times daily) in the middle ear.
Labelling changes were made by the sponsor to both Garasone Ophthalmic/Otic
Solution and Garamycin Ophthalmic/Otic Solution (gentamicin sulfate) in
March 1996 and April 1996 respectively. 7
The changes are as follows:
· limit the indications and clinical uses of
these products to topical treatment of lesions in the external ear canal
(acute otitis externa, eczematoid-dermatitis, seborrheic dermatitis and
contact dermatitis) secondarily infected with susceptible organisms;
· expand the contraindications to patients with absent or perforated
tympanic membranes; and
· recommend patient monitoring.
Written by: Margaret Stockwell, MD, FRCPC, Bureau of Licensed
Product Assessment.
References
1.Marais J, Rutka JA.
Ototoxicity and topical ear drops. Clin Otolaryngol 1998;23(4):360-7.
2.Bath AP, Walsh RM,
Bance ML, Rutka JA. Ototoxicity of topical gentamicin preparations. Laryngoscope
1999;109:1088-93.
3.Hélal A. Aminoglycoside
ear drops and ototoxicity. Can Adverse Drug React Newsl 1997;7(2):3.
[Also in CMAJ 1997;156(7):1056-8.]
4.Wong D, Rutka J. Do
aminoglycoside otic preparations cause ototoxicity in the presence of
tympanic membrane perforations? Otolaryngol Head Neck Surg 1997;116(3):404-10.
5.Longridge NS. Topical
gentamicin vestibular toxicity. J Otolaryngol 1994;21(6):444-6.
6.Ontario Medical Association,
Section of Otolaryngology. Ototoxicity alert. Ototoxicity of topical
gentamicin containing preparations. 2000 June 22. (Reprint requests:
Ototoxicity Information, 20 Torbay Rd., Markham ON L3R 1G6; fax 1 800
420-3616).
7.Welbanks L, editor-in-chief.
Compendium of Pharmaceuticals and Specialties. 35th ed. Ottawa:
Canadian Pharmacists Association; 2000. p. 636-9.
DRUGS OF CURRENT INTEREST
The purpose of the Drugs of Current Interest (DOCI) list is to stimulate
reporting for a selected group of marketed drugs in order to identify
drug safety signals. The maintenance of this list by the CADRMP facilitates
regular monitoring and constitutes one element of post-approval assessment
activities.
abacavir (Ziagen)
alteplase (Activase rt-PA)
celecoxib (Celebrex)
clopidogrel (Plavix)
delavirdine (Rescriptor)
Factor VII-recombinant,
activated (NiaStase)
Hypericum perforatum (St. John's wort)
indinavir (Crixivan)
naratriptan (Amerge)
nevirapine (Viramune)
oseltamivir (Tamiflu)
pioglitazone (ACTOS)
ritonavir (Norvir)
rituximab (Rituxan)
rofecoxib (Vioxx)
rosiglitazone (Avandia)
saquinavir (Invirase)
trastuzumab (Herceptin)
zaleplon (Starnoc)
zanamivir (Relenza)
zolmitriptan (Zomig)
If you have observed any suspected ADRs with the drugs in the Communiqué
or the DOCI list, please report them to the :
Canadian Adverse Reaction Monitoring Program (CADRMP)
Bureau of Licensed Product Assessment
AL: 0201C2, Ottawa, ON K1A 1B9
Tel: (613) 957-0337 Fax: 613 957-0335
cadrmp@hc-sc.gc.ca
or to a participating regional ADR centre.
The ADR form is available from the Compendium
of Pharmaceuticals and Specialties and the National and Regional ADR
Centres.
ADR Guideline
British Columbia
BC Regional ADR 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
Ontario
Ontario Regional ADR 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
New Brunswick, Nova Scotia, Prince
Edward Island and Newfoundland
Atlantic Regional ADR Centre
Queen Elizabeth II Health
Sciences Centre
Drug Information Centre
Rm. 2421, 1796 Summer St.
Halifax NS B3H 3A7
tel 902 473-7171- fax 902 473-8612
rxkls1@qe2-hsc.ns.ca
Saskatchewan
Sask ADR Regional Centre
Dial Access 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 306 966-6377
vogt@duke.usask.ca
Québec
Québec Regional ADR Centre
Drug Information Centre
Hôpital du Sacré-Coeur de Montréal
5400, boul. Gouin ouest
Montréal QC H4J 1C5
tel 514 338-2961, ext. 2961 or 888 265-7692
fax 514 338-3670
cip.hscm@sympatico.ca
Other provinces and territories
National ADR Unit
Adverse Reaction Review and Information Unit
Bureau of Licensed Product Assessment
Finance Building, Tunney's Pasture
AL 0201C2
Ottawa ON K1A 1B9
tel 613 957-0337
fax 613 957-0335
cadrmp@hc-sc.gc.ca
The Canadian Adverse Drug Reaction Newsletter is prepared and funded
by the Therapeutic Products Programme, Health Canada, and is published
quarterly in CMAJ. It is also online
Please Note: A voluntary reporting system thrives
on intuition, lateral thinking and open mindedness. Most adverse drug
reactions (ADRs) can only be considered to be suspicions, for which a
proven causal association has not been established. Because ADRs are under
reported and because a definite causal association cannot be determined,
spontaneous ADR reports cannot be used to estimate the incidence of adverse
reactions. ADRs are nevertheless valuable as a source of potential new
and undocumented signals. Health Canada does not assume liability for
the accuracy or authenticity of the ADR information contained in the newsletter
articles. Furthermore, the Therapeutic Products Programme monitors and
assesses suspected ADRs as a means of continuously evaluating drug safety
profiles. Regulatory decisions are not made within the context of this
newsletter.
Newsletter Editors: Ann Sztuke-Fournier, BPharm,
and Heather Dunlop, BNSc, MLIS, Bureau of Licensed Product Assessment.
We thank the Expert Advisory Committee on Pharmacovigilance,
the ADR Regional Centres and the Therapeutic Products Programme for their
contributions to these articles.
© Her Majesty the Queen in Right of Canada,
2000. This publication may be reproduced without permission provided the
source is fully acknowledged.
ISSN 1492-8167, Cat. No. H42-4/1-11-2E-IN
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