Canadian Adverse Drug Reaction Newsletter
Volume 7 · Number 3 · July 1997
In This Issue
ACE inhibitors and bronchospasm
Interferon beta-1b
Radiopharmaceuticals
New Expert Advisory Committee on Pharmacovigilance
New name
The Drugs Programme and the Medical Devices Programme were
merged late in 1996. As of May 1, 1997, we became the Therapeutic Products Programme.
We are still the same people, doing the same jobs, at the same locations, and
we look forward to continuing to work with you!
ACE inhibitors and bronchospasm
Angiotensin-converting-enzyme (ACE) inhibitors approved in
Canada are indicated for the treatment of mild to moderate essential hypertension.
Some ACE inhibitors are also indicated for congestive heart failure or diabetic
nephropathy or for use after myocardial infarction. Those available in Canada
are benazepril hydrochloride, captopril, cilazapril, enalapril maleate, enalaprilat,
fosinopril sodium, lisinopril, perindopril erbumine, quinapril hydrochloride
and ramipril.
A dry, tickly, persistent and often bothersome cough is one of the most common
adverse effects of ACE inhibitors that has emerged as a class effect and seems
to be independent of the dose. This symptom may occur shortly after therapy
is started but also months or even a year later. The cough will usually resolve
within a few days after withdrawal of the ACE inhibitor.1
The relationship between ACE inhibitors and bronchial hyperresponsiveness, however,
has not been as clearly established.2 It has been
proposed that ACE inhibitor-induced bronchospasm may be caused by potent bronchoconstrictors
such as bradykinin and substance P, which are degraded by ACE and may accumulate
in the lungs of patients receiving ACE inhibitors.2
It has also been postulated that an ACE inhibitor-induced cough may be due to
an irritant inflammatory state in the airways of susceptible patients and that
this symptom may have pathophysiological features in common with the cough seen
as an early symptom of asthma.3 However, other mechanisms
of ACE inhibitor-induced cough and bronchospasm have been proposed, and the
exact mechanism involved still remains unknown.1,4
Although ACE inhibitors are safe for use in most patients with obstructive airway
disease, there have been occasional reports of asthmatic symptoms, exacerbation
of asthma or a rise in bronchial reactivity; however, these findings have not
been universal.1,2 Two large retrospective studies
have evaluated reported adverse respiratory reactions associated with ACE inhibitors.
One, a controlled cohort study in New Zealand, found a significantly higher
occurrence of new-onset bronchospasm and a relapse of previous bronchospasm
in the cohort treated with an ACE inhibitor than in the control group given
lipid-lowering drugs.1,2,5 In the other study,6
based on data from the Swedish Drug Information System, a number of patients
were identified in whom ACE inhibitors apparently had caused or worsened asthmatic
symptoms or dyspnea. Some patients developed respiratory symptoms with different
ACE inhibitors, which suggested a class effect rather than an allergic reaction
to a specific substance.
A review of the Canadian Adverse Drug Reaction Monitoring Program (CADRMP) database,
over 15 years, revealed 126 reports involving ACE inhibitor-associated respiratory
disorders. Of these, 82 included coughing reactions and 11 included various
combinations of reactions reported as dyspnea, bronchospasm or asthma with or
without cough. (Cases of bronchospasm reported as being part of a wider allergic
process, such as anaphylaxis or angioedema, were excluded from this review.)
The 11 reports of interest involved 10 patients (7 women and 3 men, age range
43-73 years) and are summarized in Table 1. Five patients
were receiving an ACE inhibitor for hypertension and 1 for congestive heart
failure; no indication was specified for the remaining 4 patients.
There were 7 instances (in 6 patients) in which symptoms resolved after the
therapy was stopped. One patient (cases 9 and 10) experienced the same symptoms
after being exposed to 2 different ACE inhibitors at different times. In both
instances the symptoms disappeared after the therapy was stopped. In another
patient the ACE inhibitor was stopped and Ventolin® was given as treatment,
but the patient's outcome was not specified. Two patients who experienced shortness
of breath died; however, both had confounding disease states, which precludes
any definitive association with the ACE inhibitors. Finally, one patient received
significant treatment for acute shortness of breath and asthma, but further
to a rechallenge the physician reported that the adverse event was not related
to the ACE inhibitor. It is unclear how this assessment was made.
The onset of symptoms ranged from a few hours to 6 months after the start of
the ACE inhibitor therapy; 3 cases occurred within a few hours, 5 within
less than 1 month and 2 after 3 to 6 months; the time of onset was not
specified in 1 case.
Controversy still exists regarding the role of ACE inhibitors in inducing bronchospasm
and the precipitation of asthmatic symptoms. These reactions appear to be rare,
but health care professionals should be aware that they can occur.7
Any suspected bronchospasm or aggravated asthma should be carefully monitored.
Discontinuation of the ACE inhibitor is usually required.6
This article is under the direction of: Ann Sztuke-Fournier,
BPharm
Références
1.Overlack A. ACE inhibitor-induced cough and bronchospasm.
Incidence, mechanisms and management. Drug Safety 1996;15(1):72-8.
2.Dicpinigaitis PV, Dobkin JB. Effect of angiotensin-converting
enzyme inhibition on bronchial responsiveness. J Clin Pharmacol 1996;36(4):361-4.
3.Andersson RG, Persson K. ACE inhibitors and their influence
on inflammation, bronchial reactivity and cough. Eur Heart J 1994;15(suppl
C):52-6.
4.Semple PF. Putative mechanisms of cough after treatment
with angiotensin converting enzyme inhibitors. J Hypertension 1995;13(suppl
3):S17-21.
5.Wood R. Bronchospasm and cough as adverse reactions to the
ACE inhibitors captopril, enalapril and lisinopril. A controlled retrospective
cohort study. Br J Clin Pharmacol 1995;39(3):265-70.
6.Lunde H, Hedner T, Samuelsson O. Dyspnoea, asthma, and bronchospasm
in relation to treatment with angiotensin converting enzyme inhibitors. BMJ
1994;308:18-21.
7.Craig TJ. Drugs to be used with caution in patients with
asthma. Am Fam Physician 1996;54(3):947-53.
Table 1: Details of 11 reports of dyspnea,
bronchospasm and asthma associated with the use of angiotensin-converting-enzyme
(ACE) inhibitors
Help wanted!
Because ADR reports are a critical source of drug safety information,
the CADRMP is seeking your help in detecting and reporting ADRs. Reports on
the use of drugs in different patient populations, concomitant drug use, duration
of therapy and patient compliance are helpful. Your continued support is crucial
in building a more complete drug safety profile. The CADRMP is grateful to all
who are so diligently reporting suspected ADRs.
Interferon beta-1b
Betaseron®, an interferon beta-1b approved in July 1995, is indicated
for use in ambulatory patients with relapsing-remitting multiple sclerosis to
reduce the frequency of clinical exacerbations. Because Canada is one of the
first countries to approve interferon beta-1b, data on ADRs associated with
its use are limited.
Radiopharmaceuticals
Although approved radiopharmaceuticals, kits and generators have been used for
diagnosis and therapy in Canadian nuclear medicine facilities for years, the
rate of reporting ADRs resulting from these products is low.
The CADRMP strongly encourages voluntary reporting by health
care professionals of ADRs associated with the administration of all marketed
drugs. ADRs should be reported to the Adverse Drug Reaction Reporting Unit,
Continuing Assessment Division, Bureau of Drug Surveillance, AL 4103B1, Ottawa
ON K1A 1B9, fax 613 957-0335; or to a participating regional
centre (check the CPS Clin-Info section on ADR reporting for complete
addresses).
New Expert Advisory Committee on Pharmacovigilance
The Therapeutic Products Directorate (newly merged from the
Drugs and Medical Devices Directorates) of Health Canada has established a new
Expert Advisory Committee on Pharmacovigilance. This committee replaces the
Canadian Adverse Drug Reaction Advisory Committee (CADRAC). It has a broader
scope than that of CADRAC and will provide the directorate with on-going and
timely advice on issues related to post-approval safety, quality and effectiveness
of drug products. Decisions on regulatory issues will continue to be made by
the Therapeutic Products Directorate.
The new advisory committee comprises 8 members selected on the basis of their
knowledge and expertise in different disciplines related to post-approval drug
surveillance: family and clinical medicine, pharmacy, pharmacology, pharmacoepidemiology,
geriatrics, pediatrics, and poison information and control. It will identify
specific issues and concerns, provide advice on matters of science and policy,
assess adverse drug reaction (ADR) reports and drug product complaints, and
evaluate drug safety issues related to misuse, abuse or off-label use. In the
interest of enhancing professional and consumer awareness of post-approval drug
surveillance issues, the committee will be invited to suggest topics for this
newsletter and to recommend educational programs or other interventions, as
deemed appropriate.
The terms of reference for the committee are posted on the Therapeutic Products
Programme external electronic bulletin board and at http://www.hc-sc.gc.ca/dhp-mps/index_e.html,
where minutes of future meetings will also be posted. For information on the
Expert Advisory Committee on Pharmacovigilance, contact the coordinator: Malle
Jurima-Romet, PhD, tel 613 957-9026, fax 613 941-8933.
Expert Advisory Committee on Pharmacovigilance
Dr. Anne Holbrook
Centre for Evaluation of Medicines
St. Joseph's Hospital
Hamilton
Dr. Debra A. Kent
BC Drug and Poison Information Centre
Vancouver
Dr. Sheldon Koven
Occupational Medicine/Family Practice
Winnipeg
Dr. Jacques LeLorier
Centre de Recherche
Hôtel-Dieu de Montréal
Montreal
Dr. Louise Mallet
Department of Pharmacy
Royal Victoria Hospital
Montreal
Dr. Robert G. Peterson
Department of Paediatrics
Children's Hospital of Eastern Ontario
Ottawa
Dr. Kenneth W. Renton
Department of Pharmacology
Dalhousie University
Halifax
Dr. Neil Shear
Clinical Pharmacology
Sunnybrook Health Science Centre
Toronto
Canada
The Canadian Adverse Drug Reaction Monitoring Newsletter is prepared and
funded by the Therapeutic Products Directorate, Health Canada and published
in the CMAJ regularly.
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