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Canadian Adverse Reaction Newsletter
Volume 18 • Issue 2 • April 2008
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Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team
In this Issue:
Varenicline and serious psychiatric reactions
Serious adverse reaction and medication incident
Adverse reaction reporting - 2007
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
Canada Vigilance Program
Phone: 866-234-2345
Fax: 866-678-6789
Click here for the Adverse Reaction Reporting Form
Caveat: 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.
Varenicline (Champix) and serious psychiatric reactions
Varenicline tartrate (Champix) has been marketed in Canada since April 2007 and is indicated for smoking-cessation treatment in adults in conjunction with smoking-cessation counselling.1 The efficacy of varenicline in smoking cessation is believed to be a result of the drug's partial agonist activity at the a4ß2 nicotinic acetylcholine receptor. By binding to these receptors, varenicline induces 2 results.2 First, it signals the release of dopamine and creates similar reinforcing effects, but not to the full extent that nicotine does because of its partial binding of the receptor.2 Second, it acts as a physical antagonist by binding to the nicotine receptor and by blocking the effects of nicotine or a nicotine-replacement agent.2
Smoking cessation with or without treatment is associated with various symptoms such as depressed mood, insomnia, irritability, frustration or anger, and anxiety.1 From Apr. 1 to Nov. 23, 2007, Health Canada received 107 reports of adverse reactions (ARs) suspected of being associated with varenicline. Of these reports, 46 described psychiatric ARs of which 14 reported cases of aggression, depression or suicidal ideation (Table 1). The remaining cases of psychiatric disorders included ARs such as amnesia, abnormal dreams, anxiety, insomnia, abnormal thinking and somnolence.
The impact of a smoking-cessation product with partial nicotinic-receptor agonist properties in patients with underlying psychiatric illness is unknown, and care should be taken with these patients.1 Two case reports recently described the exacerbation of schizophrenia in one patient3 and a manic episode in a patient with bipolar disorder taking varenicline.4
The Canadian Product Monograph for varenicline was recently revised to indicate that there have been postmarket reports of depressed mood, agitation, changes in behaviour, suicidal ideation and suicide.1 The product monograph states that not all patients had known pre-existing psychiatric illness and not all had completely discontinued smoking.1 In November 2007 and February 2008, the US Food and Drug Administration communicated safety notices concerning psychiatric ARs occurring in patients taking varenicline.5,6 Health Canada is continuing to monitor ARs suspected of being associated with varenicline. Any new safety information on results of analysis will be communicated via the MedEffect e-Notice.
Maria Longo, BScPharm; Tanja Kalajdzic, MSc; Marielle McMorran, BSc, BSc(Pharm), Health Canada
| Table 1: Summary of reports of aggression, depression and suicidal tendency suspected of being associated with varenicline submitted to Health Canada from Apr. 1, 2007, to Nov. 23, 2007* | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Note: NA = not available. * These data cannot be used to determine the incidence of adverse reactions (ARs) because ARs are underreported and neither patient exposure nor the amount of time the drug was on the market has been taken into consideration. † Terms are listed according to the World Health Organization Adverse Reaction Terminology (WHOART). ‡ Estimated from the beginning of the treatment. § At the time of reporting, the patient was still taking varenicline and had not yet recovered. ¶ The onset of depression was after the discontinuation of the drug. ** Family history of depression was reported. |
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References
- Champix (varenicline tartrate tablets) [product monograph]. Kirkland (QC): Pfizer Canada Inc; 2007.
- Stack NM. Smoking cessation: an overview of treatment options with a focus on varenicline. Pharmacotherapy 2007;27(11):1550-7.
PubMed - Freedman R. Exacerbation of schizophrenia by varenicline. Am J Psychiatry 2007;164(8):1269. PubMed
- Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar disorders. Am J Psychiatry 2007; 164(8):1269-70. PubMed
- Early Communication About an Ongoing Safety Review - Varenicline (marketed as Chantix). Rockville (MD): US Food and Drug Administration; 2007 Nov 20. (accessed 2008 Feb 18).
- Information for Healthcare Professions - Varenicline (marketed as Chantix). Rockville (MD): US Food and Drug Administration; 2008 Feb 1. (accessed 2008 Feb 18).
Serious adverse reaction and medication incident
A 67-year-old woman with a history of metastatic breast cancer that was controlled had cardiomyopathy caused by the chemotherapy, which resulted in ongoing atrial fibrillation and symptoms of congestive heart failure. The patient was taking losartan, metoprolol, warfarin and clodronate. The metoprolol dose was increased and a diuretic added to therapy. The patient's cardiologist later gave her a sample package of long-acting diltiazem (Tiazac) and asked her to come back for follow-up.
The patient took her first dose of diltiazem the following morning and became dizzy and nauseous in the afternoon; she was transported to hospital by ambulance. The emergency physician was unaware that the patient had received a dose of diltiazem because the medication was dispensed as a sample pack and the report from the ambulance attendants was not part of the patient's chart in the treating area. Attempts to gather further information from electronic health records did not indicate that the patient's cancer was controlled. The electronic records did not include information on the diltiazem sample, since they are not designed to capture this type of information. Investigations did not reveal the cause of the rapid onset of the slow heart rate, and therefore the patient was diagnosed with cardiogenic shock due to a poor functioning heart. Given the patient's overall health status, and with no known cause of the rapid deterioration of heart function, a decision to withdraw medical treatment followed, and the patient died.
The concomitant administration of diltiazem with ß-adrenergic blocking drugs warrants caution and careful monitoring.1 Such an association may have an additive effect on heart rate, atrioventricular conduction or blood pressure.1 In this case, the attending health professionals did not have all the relevant information on the patient's current medications to diagnose a known adverse drug reaction following an interaction between the calcium-channel blocker diltiazem1 and the ß-blocker metoprolol. A recent article on patient safety published by the World Health Organization2 highlights 2 critical areas relevant to this case where the potential for medication errors exists: communication gaps during patient handovers and incomplete medication lists at transition in care. Health care professionals are encouraged to report to Health Canada any adverse reactions suspected of being associated with medication incidents.
Marielle McMorran, BSc, BSc(Pharm), Health Canada
References
- Tiazac (Diltiazem HCl Extended-Release Capsules) [product monograph]. Mississauga (ON): Crystaal Corporation; 1997.
- WHO Collaborating Centre for Patient Safety Releases: nine life-saving patient safety solutions. Int J Risk Safety Med 2007;19:171-3.
Adverse reaction reporting - 2007
In 2007, Health Canada received reports of 12 294 new domestic cases of suspected adverse reactions (ARs) to health products (pharmaceuticals, biologics [e.g., fractionated blood products, and therapeutic and diagnostic vaccines], natural health products and radiopharmaceuticals), which were derived from 17 608 reports. The initial report and all subsequent information received as follow-up reports are combined and considered to be one case. The majority of domestic cases were reported by health professionals, either directly to Health Canada or indirectly through another source (Table 1). A further analysis of the total number of cases by reporter type (originator) is outlined in Table 2. In Canada, Market Authorization Holders (MAHs) of health products are required to submit to Health Canada all reports of serious domestic ARs within 15 days of receipt. In addition, MAHs are required to send within 15 days all reports of serious unexpected ARs that have occurred outside Canada (foreign ARs) for the products they sell in other countries as well as in Canada. Of the domestic cases received, 8133 (66.2 %) were classified as serious.*
The reporting of domestic ARs in Canada has increased steadily over the last several years, with 1776 (16.9%) more cases in 2007 than in 2006 (Figure 1).
Health Canada also received 258 892 reports of foreign ARs in 2007, a 2.5% increase since 2006 (Figure 2). At this time, foreign reports are not included in the domestic AR database.
Health Canada would like to thank all who have contributed to the Canada Vigilance Program and encourages the continued support of postmarketing surveillance through AR reporting. To report an AR:
- complete and submit a report online at Health Canada's MedEffect website, or
- download and print a paper copy of the reporting form and submit it by toll-free fax (866 678-6789) or by mail to one of the Canada Vigilance Regional Offices (addresses are on page 2 of the form).
You can also report an AR by toll-free phone (866 234-2345); calls will automatically be directed to the appropriate Canada Vigilance Regional Office. Incidents involving medical devices are not collected by the Canada Vigilance Program and should be reported toll free through the Inspectorate Hot Line (800 267-9675).
Jennifer Lo, BSc, BA, Health Canada
* In the Food and Drugs Act and Regulations, a serious AR is defined as "a noxious and unintended response to a drug that occurs at any dose and that requires in-patient 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 serious unexpected AR is defined as "a serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out on the label of the drug."
| Table 1: Source of domestic cases* of adverse reactions (ARs) received by Health Canada in 2006 and 2007 | ||||
| Source | No. (%) of cases received | |||
| 2006 | 2007 | |||
| Manufacturer | 6 937 | (66.0) | 7 573 | (61.6) |
| Canada Vigilance Regional Office | 3 370 | (32.0) | 4 507 | (36.7) |
| Other† | 211 | (2.0) | 214 | (1.7) |
| Total | 10 518 | (100.0) | 12 294 | (100.0) |
* Cases result from the merge of initial, follow-up and duplicate reports.
† Includes, but not limited to, professional associations, nursing homes, hospitals, physicians, pharmacists, Health Canada regional inspectors, coroners, dentists and patients.
| Table 2: Number of domestic AR cases* by type of reporter (originator) in 2006 and 2007 | ||||
| Reporter | No. (%) of cases received | |||
| 2006 | 2007 | |||
| Physician | 3 077 | (29.2) | 3 903 | (31.8) |
| Pharmacist | 2 396 | (22.8) | 2 201 | (17.9) |
| Nurse | 806 | (7.7) | 872 | (7.1) |
| Health professional† | 1 281 | (12.2) | 1 488 | (12.1) |
| Consumer/patient | 2 544 | (24.2) | 3 592 | (29.2) |
| Other | 414 | (3.9) | 238 | (1.9) |
| Total | 10 518 | (100.0) | 12 294 | (100.0) |
* Cases result from the merge of initial, follow-up and duplicate reports.
† Type not specified in report.
Figure 1: Number of domestic reports and cases of adverse reactions (ARs) received by Health Canada from 2001 to 2007. (Reports include follow-up, duplicate and unenterable reports. Cases result from the merge of initial, follow-up and duplicate reports.)
Figure 2: Number of foreign AR reports received by Health Canada from 2001 to 2007. (Reports include follow-up, duplicate and unenterable reports.)
| Quarterly Summary of health professional and consumer advisories (posted on Health Canada's Web site : Nov. 11, 2007 - Feb. 14, 2008) |
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Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
AL 0701C
Ottawa ON K1A 0K9
Tel 613 954-6522
Fax 613 952-7738
Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Ilhemme Djelouah, BScPhm, DIS, AFSA, Medical Biology (University of Paris V)
Gilbert Roy, BPharm
Jared Cousins, BSP
Michel Trottier, BScPhm, RPEBC, RPh
Christianne Scott, BPharm, MBA
Reporting Adverse Reactions
Canada Vigilance Program
Phone: 866-234-2345
Fax: 866-678-6789
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Copyright
Her Majesty the Queen in Right of Canada, 2008. 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 H42-4/1-18-2E
USPS periodical postage paid at Champlain, NY, and additional locations.
Aussi disponible en français.
Caveat: 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.
