Canadian Adverse Reaction Newsletter
Volume 13, Number 2, April 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
Withdrawal reactions with paroxetine and other SSRIs
Adverse reaction reporting - 2002
Case presentation: divalproex
Safe use of products containing acetaminophen
Hormone replacement therapy
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
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Withdrawal reactions with paroxetine and
other SSRIs
Selective serotonin reuptake inhibitors (SSRIs) are widely used and represent
the largest market share of all prescribed antidepressants in Canada.1
Withdrawal reactions or discontinuation symptoms have been documented
with all SSRIs.2,3 These reactions are
clinically relevant because they are common, can cause significant morbidity,
may be misdiagnosed, leading to inappropriate treatment, and can adversely
affect compliance with future antidepressant treatment.2
Although defining the true incidence of withdrawal reactions associated
with SSRIs is problematic, Canadian adverse reaction (AR) data along with
spontaneous AR data from Australia, France, the United Kingdom and the
United States reveal that withdrawal reactions are reported more frequently
with paroxetine than with other SSRIs.4-7
Although the mechanism of the SSRI withdrawal syndrome is not completely
understood, the onset, frequency and intensity of the symptoms seem to
vary according to the pharmacologic and pharmacokinetic properties of
the drug, such as the half-life (major risk factor), the presence of active
metabolites and the anticholinergic effects of the agent.3,8
Compared with other SSRIs, paroxetine has a short half-life, no active
metabolite, a greater anticholinergic effect and greater potency in blocking
serotonin reuptake, which could be seen as contributing factors.3,5
The withdrawal symptoms may occur after the treatment is stopped, the
dose is reduced, the treatment is switched to another antidepressant,
or doses are missed.2,3,9
With paroxetine, symptoms occurred and became statistically significant
as early as the second dose of placebo in a study evaluating the interruption
of SSRI treatment.8 The symptoms observed
following SSRI discontinuation can either be physical or psychological
and are often grouped into the following categories: disequilibrium (e.g.,
dizziness, vertigo, ataxia), gastrointestinal disturbances (e.g., nausea,
vomiting), influenza-like symptoms (e.g., fatigue, lethargy,myalgia),
sensory disturbance (e.g., paresthesia), sleep disorder (e.g., insomnia,
vivid dreams) and psychiatric disturbance (e.g., anxiety, agitation, confusion).9,10
Withdrawal symptoms can easily be misdiagnosed as recurrence of depression,
evidence of ineffectiveness of the antidepressant in a noncompliant patient,
or adverse reactions of the new antidepressant following a switch of medication.2
Most withdrawal reactions are mild and transient, usually occurring within
1-3 days (up to 1 week) after stopping the medication and lasting 7-14
days, but occasionally the symptoms last for several weeks.2,9
However, some reactions can be severe and may require acute treatment.9
The October 1998 issue of this newsletter outlined a summary of 26 Canadian
reports of suspected withdrawal reactions associated with SSRIs.10
Health Canada continues to receive spontaneous reports of such reactions
for each SSRI, and Table 1 outlines these reports from
the time each SSRI was marketed in Canada to Oct. 31, 2002. There were
102 reports of suspected withdrawal reactions (citalopram [5], fluoxetine
[6], fluvoxamine [2], paroxetine [79] and sertraline [10]), and 49% were
identified as serious. Table 2 outlines the symptoms
described in these reports.
General strategies to prevent and manage symptoms associated with the
discontinuation of SSRIs have been outlined previously in this newsletter
and include a gradual tapering of the dose when discontinuing treatment
with any SSRI except for fluoxetine.10
If withdrawal reactions occur while tapering or at the end of treatment,
it may be necessary to increase the dose and initiate a slower rate of
taper.2,3 Some authors suggest switching
to fluoxetine if symptoms are severe and the patient is unable to discontinue
the SSRI despite tapering.2,10,11
For paroxetine, some suggest reducing the dose by 5 mg/d at weekly intervals
to below the initial minimum therapeutic dose.9
Clinicians should be aware that the use of an antidepressant with a short
half-life may be an important risk factor for withdrawal reactions.9
Patients should be informed of the risks of withdrawal reactions on initiation
of therapy to prevent unguided cessation of treatment. Proper diagnosis
of withdrawal reactions may prevent unnecessary reinstatement of long-term
antidepressant treatment, unnecessary tests to elucidate an underlying
problem or an undesirable escalation of dose.
Table
1: Reports submitted to Health Canada of suspected withdrawal syndrome
associated with SSRIs from date marketed to Oct. 31, 2002*
Table
2: Symptoms described in the 102 reports submitted to Health Canada of
suspected withdrawal syndrome associated with SSRIs from date marketed
to Oct. 31, 2002*
References
1.Hemels MEH, Koren G,
Einarson TR. Increased use of antidepressants in Canada:1981-2000. Ann
Pharmacother 2002;36:1375-9.
2.Haddad PM. Antidepressant
discontinuation syndromes. Drug Safety 2001;24(3):183-97.
3.Zajecka J, Tracy KA,
Mitchell S. Discontinuation symptoms after treatment with serotonin reuptake
inhibitors: a literature review. J Clin Psychiatry 1997;58(7):291-7.
4.Committee on Safety
of Medicines and the Medicines Control Agency. Selective serotonin reuptake
inhibitors (SSRIs). Curr Probl Pharmacovigilance 2000;26:11-2.
Available:
 http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/urgent.htm#ssri (accessed 2003 Feb 14).
5.Stahl MMS, Lindquist
M, Pettersson M, Edwards IR, Sanderson JH, Taylor NFA, et al. Withdrawal
reactions with selective serotonin re-uptake inhibitors as reported to
the WHO system. Eur J Clin Pharmacol 1997;53:163-9.
6.Adverse Drug Reactions
Advisory Committee (ADRAC). SSRIs and withdrawal syndrome. Aust Adverse
Drug React Bull 1996;15(1):3. Available: www.health.gov.au/tga/docs/html/aadrbltn/aadr9602.htm
(accessed 2003 Feb 14).
7.Trenque T, Piednoir
D, Frances C, Millart H, Germain ML. et al. Reports of withdrawal syndrome
with the use of SSRIs: a case/non-case study in French Pharmacovigilance
database. Pharmacoepidemiol Drug Saf 2002;11:281-3.
8.Michelson D, Fava M,
Amsterdam J, Apter J, Londborg P, Tamura R, et al. Interruption of selective
serotonin reuptake inhibitor treatment. Br J Psychiatry 2000;176:363-8.
9.Schatzberg AF, Haddad
P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Young AH, et al. Serotonin reuptake
inhibitor discontinuation syndrome: a hypothetical definition. J Clin
Psychiatry 1997;58(Suppl 7):5-10.
10.Macdonald L. Discontinuation
reactions associated with SSRIs. Can Adverse Drug Reaction Newsl
1998;8(4):2-3. Also in CMAJ 1998;159(7):846-7.
11.Taman
L, Ozpoyraz N. Selective serotonin reuptake inhibitor discontinuation
syndrome: a review. Adv Ther 2002;19(1):17-26.
Adverse reaction reporting - 2002
Health Canada received 8566 domestic reports of suspected ARs to health
products in 2002. 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. The proportion
of reports submitted by patients and consumers has increased steadily
in recent years.
Of the AR reports received, 5889 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 15.9% more reports in 2002 than in 2001 (Fig.
1).
Health Canada would like to thank all who have contributed to the program
and encourages the continued support of postmarketing surveillance through
AR reporting. Since 2001, health professionals and consumers may report
ARs by using the toll-free telephone (866 234-2345) and fax (866 678-6789)
lines.Your call will be directed to the appropriate Regional AR Centre.Manufacturers
must continue to report ARs using the established fax line 613 957-0335.
Table
1: Source of reports of adverse reactions (ARs) received by Health Canada
in 2001 and 2002
Table
2: Number of AR reports by type of reporter (originator) in 2001 and 2002
Fig. 1: Number of reports of
adverse reactions received annually by Health Canada from 1998 to 2002
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.
Divalproex
A 14-year-old girl (weight 59 kg) with a history of absence seizures
was prescribed divalproex sodium therapy in anticipation of obtaining
her driver's licence.When the patient started taking the anticonvulsant,
she began to withdraw socially.With 3 subsequent dosing increments to
control the seizures, she became increasingly depressed, suicidal and
then psychotic. The dosages and ARs were reported as follows:
-
Aug 2000: dose: 375 mg orally twice daily to initiate therapy; ARs:
social withdrawal, described as "not as sharp"
-
Oct 2000: dose: 500 mg orally twice daily; ARs: increasing signs
of depression
-
Feb 2001: dose: 625 mg orally twice daily; ARs: suicidal ideation,
suicide attempt (Apr 2001), emotional volatility, confrontational
behaviour
-
Aug 2001: dose: 625 mg orally in the morning, 750 mg in the evening;
ARs: delusional reaction, paranoid reaction, hostile and threatening
behaviour, self-mutilation, cognitive difficulties
The patient was admitted to hospital twice in May 2001 and again in October
2001. She was treated with citalopram (Celexa) 20 mg/d from May to September
2001 and then 40 mg/d to October 2001. In addition, the patient attended
weekly psychotherapy sessions and in October 2001 received a few doses
of quetiapine (Seroquel). During the third admission to hospital, the
divalproex treatment was stopped at the request of her parents. The divalproex
was tapered over 5 weeks, and the other drugs were also stopped. The problems
gradually resolved after the divalproex was discontinued; the drug was
not reintroduced.The patient had not been treated for depression or other
psychiatric disorders before starting the anticonvulsant therapy.
The safe use of products containing acetaminophen
In an effort to inform consumers about the risks of taking multiple acetaminophen-containing
preparations simultaneously, Health Canada has issued a Public Advisory
(www.hc-sc.gc.ca/english/protection /warnings/2003/2003_06.htm). In addition,
Health Canada has posted an "It's Your Health" document that outlines
the safe use of all medications
(
www.hc-sc.gc.ca/english/iyh/medical/safe_medicine.html
). These documents advise consumers
on ways to minimize the risk of adverse effects associated with medications, which include
carefully reading the labels of all medications and consulting with their health
care professional.We encourage health care professionals to share the
above information with their patients.
"It's Your Health": hormone replacement
therapy
Recent studies have raised questions about the long-term safety of combined
estrogen and progestin hormone replacement therapy (HRT).Health Canada
has posted an "It's Your Health" document on its Web site
( www.hc-sc.gc.ca/english/iyh/medical/estrogen.html )
that summarizes the health risks and benefits of HRT that were reported
from studies included in the Women's Health Initiative of the United States
National Institutes of Health. The decision to use HRT should be based
on the individual patient's needs and health, following a medical evaluation
and a discussion of the benefits and risks with a physician.
Summary
of advisories
Summary of health professional and consumer advisories posted since Nov.
27, 2002 (advisories are available at
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_advisories_e.html and
www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2003/index_e.html)
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
Email: cadrmp@hc-sc.gc.ca
Editors
Ann Sztuke-Fournier, BPharm
Marielle McMorran, BScPharm
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 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 H42-4/1-13-2E
USPS periodical postage paid at Champlain, NY, and
additional locations.
Canadian Adverse
Reaction Newsletter
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