Canadian Adverse Reaction Newsletter
Volume 9 · Number 3 · July 1999
In This Issue
Alteplase (Activase® rt-PA) for acute ischemic stroke
Abciximab (ReoProTM): risk of acute thrombocytopenia
Nefazodone (Serzone®) and hepatotoxicity
Communiqué
Alteplase (Activase® rt-PA)
for acute ischemic stroke:
special precautions for new indication
Alteplase is a serine protease that binds to fibrin
in a thrombus or blood clot resulting in conversion of plasminogen to
plasmin and initiation of local fibrinolysis. Alteplase has been approved
in Canada since 1987 for the management of acute myocardial infarction.
On Feb. 16, 1999, the Therapeutic Products Programme
(TPP) approved the drug Activase® rt-PA (alteplase) in
accordance with the Notice of Compliance with Conditions policy, which
was issued on May 28, 1998, for the management of acute ischemic stroke
in adults to improve neurological recovery and reduce the incidence of
disability. The purpose of the Notice of Compliance with Conditions Policy
is to provide earlier access to promising new drugs to patients suffering
from serious, life-threatening or severely debilitating diseases or conditions
and to create a mechanism to ensure that the manufacturer conducts confirmatory
studies to establish the link between anticipated and real benefit.
Under the conditions specifically associated with the
approval of Activase® rt-PA, the Canadian sponsor Hoffmann-La
Roche Limited has committed to the following:
· To develop and implement a physician education plan concerning proper
use of the drug in the treatment of stroke.
· To conduct a general mailing to all Canadian Board-certified neurologists
and heads of emergency medicine departments reinforcing the key conditions
for drug administration in the management of stroke.
· To report the results of safety monitoring and post-marketing studies
at specified times to the TPP.
· To support a study to try to identify stroke patients who would benefit
most from treatment with alteplase.
The use of alteplase in acute ischemic stroke increases
the risk of intracranial hemorrhage.1 Data
from the most favourable clinical study showed that the incidence of intracranial
hemorrhage in patients with acute ischemic stroke was higher in the alteplase
group than in the placebo group (6.4% v. 0.6% within 36 hours of administration).
1,2
There was, however, no difference in the overall rate of death at day
90 between the 2 groups, although there was a trend toward a higher death
rate among patients with severe stroke in the alteplase group than among
those in the placebo group.1 Doses greater
than 0.9 mg/kg may be associated with an increased risk of intracranial
hemorrhage. Therefore, a dose of 0.9 mg/kg (maximum 90 mg) should not
be exceeded when used in stroke treatment.1
The use of alteplase in the treatment of stroke is limited
to the following situations:
Physicians must be experienced in acute stroke management, and be
treating patients in a hospital setting equipped with appropriate laboratory
facilities to follow the neurological and hematological status of the
patient.1
Treatment should be started only within the first 3 hours after the
onset of stroke symptoms, and only after exclusion of intracranial hemorrhage
by a cranial CT scan or other diagnostic imaging method sensitive for
the presence of hemorrhage.1 Treatment
started more than 3 hours after the onset of symptoms is not recommended.
Few patients (< 10%) present to hospital emergency departments
within 3 hours after onset of stroke symptoms.3
Treatment is contraindicated in situations where the risk of bleeding
is increased, including recent surgery, head trauma or previous stroke,
active internal bleeding, anticoagulant use, low platelet count (less
than 100 × 109/L) or uncontrolled hypertension (e.g., systolic
pressure greater than 185 mm Hg or diastolic pressure greater than 110
mm Hg).1,2
A separate, comprehensive product monograph pertaining
only to the use of alteplase in the treatment of stroke has been prepared.
1
This Notice of Compliance with Conditions is subject
to revocation if the above-mentioned conditions are not met, or result
in data indicating that the risks of treatment outweigh the benefits in
stroke patients.
Written by: Catherine Parker, BSc, and Harold Rode, PhD,
Bureau of Biologics and Radiopharmaceuticals.
References
1. Activase rt-PA®, alteplase: lyophilized
powder for injection [product monograph for acute ischemic stroke
indication]. Mississauga (ON): Hoffmann-La Roche Limited; Feb 1999.
2. National Institute of Neurological Disorders and
Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute
ischemic stroke. N Engl J Med 1995;333:1581-7.
3. Grotta J. T-PA -- the best current option for most
patients.
N Engl J Med 1997;337:1310-2.
Acute thrombocytopenia after abciximab (ReoProTM)
therapy
Platelet- and thrombin-mediated thromboses contribute
to the abrupt artery closure and acute ischemic complications that may
follow percutaneous coronary intervention. Abciximab (ReoProTM), approved
in Canada since 1996, is a potent antiplatelet agent that is increasingly
being used to prevent ischemic complications of percutaneous coronary
revascularization. Abciximab binds to the platelet glycoprotein IIb/IIIa
receptor and inhibits platelet aggregation.
Thrombocytopenia (platelet count less than 100 x 109/L),
including acute profound thrombocytopenia (platelet count variously defined
as below 20-40 x 109/L), has been reported to occur with this
agent.1-4 The mechanism of profound thrombocytopenia following
abciximab therapy is not clearly understood.2,
4
The risk of acute profound thrombocytopenia is estimated to be about 0.5%
(95% confidence interval 0.01%-1.1%).2
Review of the literature documenting abciximab-induced
acute thrombocytopenia provides limited information as to the timeframe
over which this adverse reaction can occur, and indicates that it generally
occurs within the first 24 hours of infusion.1-3
More recently, Berkowitz and associates4 reported 2
cases in which baseline platelet counts were normal and acute profound
thrombocytopenia was documented within 2 hours of infusion of abciximab.
Between July 29, 1997, and Mar. 18, 1999, the Canadian
Adverse Drug Reaction Monitoring Program (CADRMP) received 21 case reports
of individuals experiencing adverse reactions associated with the use
of abciximab. In 15 the adverse reaction was described as thrombocytopenia.
One of the 15 patients died, with the cause of death attributed to intracranial
bleeding; the report indicated that the baseline platelet count was normal
4 days before the start of abciximab therapy, and within 3 hours of the
initial infusion of the drug, the platelet counts were reported as not
countable.
The remaining 14 cases were reviewed to assess the rapidity
of onset and the severity of thrombocytopenia. In 3 cases acute profound
thrombocytopenia (platelet counts 6-40 × 109/L) was documented
as occurring between 2 and 4 hours after the initiation of abciximab therapy.
In 9 cases thrombocytopenia (platelet counts 5-65 × 109/L)
was documented, but the onset after the start of abciximab therapy was
less rapid (11 hours to 5 days). The baseline platelet counts, which were
generally obtained within 72 hours before infusion of abciximab, were
within normal limits in all 12 cases. Two reports did not provide sufficient
detail regarding platelet monitoring to allow for assessment.
The dosage regimens used in the majority of the 15 cases
generally appear to be in keeping with that recommended in the product
monograph. 5
In conclusion, abciximab therapy is well documented
in the literature to be associated with the occurrence of acute and occasionally
profound thrombocytopenia within 24 hours after the start of therapy.
The product monograph currently labels thrombocytopenia as a risk of therapy
and recommends that platelet counts be monitored 2-4 hours after the bolus
dose of abciximab.5 The objective of this
report is to heighten physicians' awareness of the potential for acute
profound thrombocytopenia to occur very rapidly after the start of abciximab
therapy and to confirm the importance of monitoring the platelet count
early in the course of treatment. Institution of platelet monitoring as
early as 2 hours after the bolus dose may provide the greatest opportunity
to diagnose, monitor and, if necessary, introduce therapy for rapidly
evolving episodes of thrombocytopenia.
Written by: Mary Jean Beddall, MD, Bureau of Drug Surveillance.
References
1. Berkowitz SD, Harrington RA, Rund MM, Tcheng JE.
Acute profound thrombocytopenia after c7E3Fab (abciximab) therapy. Circulation
1997;95(4):809-13.
2. Ferrari E, Thiry M, Touati C, Gibelin P, Baudouy
M. Acute profound thrombocytopenia after c7E3 Fab therapy.
Circulation 1997;96(10):3809-10.
3. Kereiakes DJ, Essell JH, Abbottsmith CW, Boderick
TM, Runyon JP. Abciximab-associated profound thrombocytopenia: therapy
with immunoglobulin and platelet transfusion. Am J Cardiol 1996;78(10):1161-3.
4. Berkowitz SD, Sane DC, Sigmon KN, Shavender J, Harrington
RA, Tcheng JE, et al. Occurrence and clinical significance of thrombocytopenia
in a population undergoing high-risk percutaneous coronary revascularization.
J Am Coll Cardiol 1998;32(2):311-9.
5. ReoProTM (abcimixab); solution for intravenous injection;
chimeric monoclonal antiplatelet antibody [product monograph]. Leiden
[Netherlands]: Centocor; 1998. [Distributed in Canada by Eli Lilly Canada
Inc.]
Hepatotoxicity associated with nefazodone (Serzone®)
Nefazodone hydrochloride (Serzone®) is
an antidepressant agent that has been approved for use in Canada since
Apr. 27, 1994. During postmarketing surveillance, hepatic adverse reactions
such as jaundice, hepatitis, hepatic necrosis and hepatic failure have
been reported in patients receiving therapeutic doses of nefazodone.
1,2
On occasion, these events resulted in liver transplantation and/or death.
Clinical manifestations of hepatic injury in patients
receiving nefazodone have included the following: anorexia, fatigue, asthenia,
abdominal pain, nausea, vomiting, discoloured stools, dark urine, coagulopathy,
weight loss, myalgia, rash, pruritus, jaundice, ascites, confusion, asterixis,
encephalopathy and hepatic coma.1,2
Laboratory evidence of hepatotoxicity has included elevated levels of
alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase,
gamma-glutamyl-transferase and bilirubin, as well as increased prothrombin
times.1,2
The majority of these events occurred within the first 9 months of treatment.
As of Mar. 18, 1999, the CADRMP has received 9 reports
of symptomatic hepatic dysfunction associated with the use of nefazodone
(Table 1).
In addition to these 9 cases, 4 events of asymptomatic
liver enzyme elevations have been reported in temporal association with
nefazodone use.
Health Canada continues to analyse these adverse reactions
and requests that health care professionals continue to report any suspect
adverse drug reactions in association with the use of nefazodone.
References
1. 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.
2. Nefazodone -- looks like an SSRI, but ... hepatic
dysfunction ... visual disorders. Aust Adverse Drug React Bull
1998;14(4):14.
Table 1: Details of 9 reports
of symptomatic hepatic dysfunction associated with nefazodone
COMMUNIQUÉ
The purpose of this section is to increase awareness
of ADRs recently reported to the CADRMP. The following cases have been
selected on the basis of their seriousness, or the fact that the reactions
do not appear in the product monograph. They are intended to prompt reporting.
(The terminology used for expressing reactions is based on the World
Health Organization's Adverse Reaction Dictionary using the "preferred
term.")
Amlodipine (NorvascTM): hearing loss
Sudden hearing loss with residual effects was reported
during amlodipine therapy.
If you have observed comparable cases or any
other serious events, please report them to the Adverse Drug Reaction
Reporting Unit, Continuing Assessment Division, Bureau of Drug Surveillance,
AL 0201C2, Ottawa ON K1A 1B9; fax 613 957-0335; or to a participating
regional ADR centre.
The ADR form is available.
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 published
in the CMAJ regularly. It can be found on line, under Publications, at
http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/ar-ei_index_e.html
Please Note: A voluntary reporting system thrives
on intuition, lateral thinking and openmindedness. For these reasons,
most adverse drug reactions (ADRs) can be considered only to be suspicions,
for which a proven causal association has not been established. Because
there is gross underreporting of ADRs and because a definite causal association
cannot be determined, this information cannot be used to estimate the
incidence of adverse reactions. ADRs are nevertheless invaluable as a
source of potential new and undocumented signals. For this reason, Health
Canada does not assume liability for the accuracy or authenticity of the
ADR information contained in the newsletter articles.
Newsletter Editors: Ann Sztuke-Fournier, BPharm,
and Marielle McMorran, Bsc(Pharm),
Bureau of Drug Surveillance.
We thank the Expert Advisory Committee on Pharmacovigilance,
and the staff of the Adverse Drug Reaction Regional Centres and the Therapeutic
Products Programme for their valuable comments.
© Her Majesty the Queen in Right of Canada, 1999.
This publication may be reproduced without permission provided the source
is fully acknowledged.
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