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ARCHIVED - Canadian Adverse Reaction Newsletter
Volume 18 • Issue 2 • April 2008

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Canadian Adverse Reaction Newsletter, Volume 18, Issue 2, April 2008 (PDF will open in a new window) (228 KB)


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 a4▀2 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*
Case Patient age/sex History of psychiatric condition Adverse reaction(s) Time to onset of reaction, d Outcome after discontinuation of varenicline
1 51/F No Aggressiveness 4 Unknown
2 65/M Yes Aggressiveness 36 Recovered
3 46/M Yes Depression 1 Recovered
4 55/F Unknown Depression <2 Recovered
5 64/M No Depression 2 Recovered
6 NA/F Yes Depression <42 NA§
7 64/F Unknown Depression Unknown NA
8 33/F No Suicidal tendency 11 Unknown
9 55/F Unknown Suicidal tendency <14 Unknown
10 53/F No** Suicidal tendency/ depression <29 Recovered
11 30/F Unknown Suicidal tendency/ depression <31 Unknown
12 46/M No Suicidal tendency/ depression <32 Recovered
13 54/M No Suicidal tendency/ depression <72 Recovered
14 58/F Yes Suicidal tendency/depression/anger <13 Recovered
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.

References

  1. Champix (varenicline tartrate tablets) [product monograph]. Kirkland (QC): Pfizer Canada Inc; 2007.
  2. Stack NM. Smoking cessation: an overview of treatment options with a focus on varenicline. Pharmacotherapy 2007;27(11):1550-7. Next link will take you to another Web site PubMed
  3. Freedman R. Exacerbation of schizophrenia by varenicline. Am J Psychiatry 2007;164(8):1269. Next link will take you to another Web site PubMed
  4. Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar disorders. Am J Psychiatry 2007; 164(8):1269-70. Next link will take you to another Web site PubMed
  5. Next link will take you to another Web site 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).
  6. Next link will take you to another Web site 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 ▀-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 ▀-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

  1. Tiazac (Diltiazem HCl Extended-Release Capsules) [product monograph]. Mississauga (ON): Crystaal Corporation; 1997.
  2. 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:

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

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

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)
Date Product Subject and type
Feb 14 Fentanyl Fentanyl Transdermal Pain Patches recalled due to health risk
- consumer information
Feb 12 Hip Implants Important Safety Information on Stryker Trident Hip Implants
- notice to hospitals
Feb 6 Foreign products Foreign Product Alert: Liang Gel San Concentrated Powder and Qing Xin Lian Zi Yin Concentrated Powder
- consumer information
Feb 6 Foreign product Foreign Product Alert: Conforer Global Yang Tonic-2
- consumer information
Feb 6 Foreign products Foreign Product Alert: Yogaraja Gulgulu Pills and Pilsol Capsule
- consumer information
Feb 6 Foreign products Foreign Product Alert: Ding Lu Brand Guipi Wan; Ding Lu Brand Bushen Yijing Wan; Ding Lu Brand Shiquan Dabu Wan; Ding Lu Brand Xiangsha Liujun Wan; Ding Lu Brand Xiaoyao Wan; Medco Brand Vitality Essence Extract Of Deer Fetus; Plasmin
- consumer information
Feb 6 Foreign products Foreign Product Alert: VPX 'No Shotgun' and BSN 'Cell Mass' Body Building Powders
- consumer information
Feb 6 Foreign product Foreign Product Alert: Wannianqing Pai Danggui Niantong Tang
- consumer information
Feb 6 Foreign products Foreign Product Alert: Xiao Qin Long Wan; Chuan Xiong Cha Tiao Wan Tablets; Bai Tou Weng Wan
- consumer information
Feb 6 Foreign product Foreign Product Alert: Xiao Qin Long Capsules
- consumer information
Feb 6 Foreign products Foreign Product Alert: Jingzhi Kesou Tanchuan; Guanxin Suhe capsules; Qing Re An Cang Wan; and Guan Xin Su He
- consumer information
Jan 28 Foreign product Foreign Product Alert: RGC-RMC Rheumax Capsule
- consumer information
Jan 28 Foreign product Foreign Product Alert: Physio Care Lida Dai Dai Hua Jiao Nang Slimming Capsules
- consumer information
Jan 28 Foreign products Foreign Product Alert: ZhenZhu HouFengSan Penji; Vyling Cornu Saigae Tataricae Cooling Tea; Natorny Kwek's Herb 106; Chinese Herbal Heritage Herbal Slimming Tea; Vyling Urticaria Itch-Killer A; Vyling Water-Melon Pearls Powder; Phoenix Brand Tea For Sore Throat And Fever; Qing Yin Bai Hua Tea; Yinqiao Flu & Fever Tea
- consumer information
Jan 23 Yeniujyn Warning: Unauthorized health product contains heavy metals
- consumer information
Jan 7 Foreign product Foreign Product Alert: Santi Bovine Penis Erecting Capsule
- consumer information
Jan 7 Foreign product Foreign Product Alert: Galactogil
- consumer information
Jan 2 Foreign product Foreign Product Alert: Baby's Bliss Gripe Water (apple flavour)
- consumer information
Jan 2 Foreign product Foreign Product Alert: Zhong Ti Xiao Er Jian Pi San
- consumer information
Dec 28 Wild Vineyard products Advisory: Unauthorized health products manufactured by Wild Vineyard may pose health risks
- consumer information
Dec 28 Magnetic Inductor Advisory: Use of Unlicensed Pap-Ion Magnetic Inductor May Pose Health Risk
- consumer information
Dec 21 Ultiva Recall of ULTIVA (remifentanil hydrochloride) 1 mg vials due to potential for overdose
- health professional communication
- Abbott Laboratories, Limited.
Dec 21 & 18 Alertec New warnings regarding ALERTEC (modafinil) and serious rash, allergic reactions, and mental problems
- consumer information and health professional communication
- Shire Canada Inc.
Dec 11 Vaccine Warning: Three Lots of Measles, Mumps and Rubella Vaccine Suspended from Use
- consumer information
Dec 6 Breast Implants It's Your Health: Breast Implants
- consumer information
Dec 4 Cold & Flu Information Update: Health Canada reminds Canadians of precautions during cold and flu season
- consumer information
Nov 28 Foreign products Foreign Product Alert: Axcil and Desirin
- consumer information
Nov 23 Trasylol Important Safety Information and availability of Trasylol (aprotinin)
- notice to hospitals
- Bayer Inc.
Nov 14 Foreign product Foreign Product Alert: Steripaste Medicated Paste Bandages
- consumer information
Nov 14 Foreign product Foreign Product Alert: Royal Medic No.1 Chinese Caterpillar Fungus
- consumer information
To receive the Newsletter and health product Advisories free by email, join Health Canada's MedEffect e-Notice.

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

Suggestions?
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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 franšais.

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.