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Canadian Adverse Reaction Newsletter
Volume 19 - Issue 2 - April 2009

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Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team

In this Issue:
Atypical antipsychotics and agranulocytosis
Adverse reaction and incident reporting - 2008
Announcement: Cough and cold products
Case presentation: 5-Hour Energy drink and a cardiovascular adverse reaction
Adverse reaction reporting form
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 stimulate adverse reaction reporting, as well as 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: 1-866-234-2345
Fax: 1-866-678-6789

For more information on how to report an adverse reaction, visit the Reporting Adverse Reactions to Drugs and Other Health Products page.

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.

Atypical antipsychotics and agranulocytosis

Atypical antipsychotic medications are indicated for the management of symptoms of schizophrenia and other related psychotic disorders. Clozapine was the first atypical antipsychotic drug and was marketed in Canada in 1991. Since then, 4 others have been marketed: olanzapine, quetiapine, risperidone and ziprasidone.^{1, 2, 3, 4, 5}

Granulocytopenia and agranulocytosis have been shown to occur in association with clozapine; therefore, use of this drug requires regular white blood cell and differential counts.¹ No cases of drug-induced agranulocytosis were reported during the premarketing clinical trials for olanzapine, quetiapine, risperidone and ziprasidone. ^{2, 3, 4, 5} However, recent evidence suggests that these drugs may also be associated with an occurrence of agranulocytosis, but not to the extent of clozapine. ^{6, 7, 8, 9}

Agranulocytosis is a life-threatening condition owing to an increased vulnerability to infection and requires immediate medical attention.¹⁰ According to the Council for International Organizations of Medical Sciences (CIOMS),¹⁰ the term granulocytopenia is used when granulocyte counts are less than 1.5 x 10⁹/L and no distinctions can be made between eosinophilic and basophilic cells from neutrophilic granulocytes. Neutropenia is defined as an absolute neutrophil count of less than 1.5 x 10⁹/L, and severe neutropenia as a count of less than 0.5 x 10⁹/L. Agranulocytosis is defined as a disorder in which severe neutropenia is associated with the sudden onset of signs and symptoms of bacterial infection, such as sore throat, fever, malaise, prostration and typical presentation with oropharyngeal or anorectal lesions.

Agranulocytosis is an idiosyncratic adverse reaction (AR) resulting from the failure of production of neutrophils in the bone marrow, from their peripheral destruction, or both. Even though the pathogenesis of drug-induced agranulocytosis is not completely understood, studies have suggested that it is mediated by immunoallergic or toxic mechanisms.⁸

As of Nov. 30, 2008, Health Canada received 69 reports of granulocytopenia, neutropenia and agranulocytosis suspected of being associated with the use of olanzapine, quetiapine and risperidone (Table 1). No reports were identified about ziprasidone, which was marketed in January 2008. According to the CIOMS definitions, there were 14 cases of agranulocytosis, 6 cases of severe neutropenia, 45 cases of neutropenia and 4 cases of granulocytopenia. Concomitant medical conditions (e.g., cancer, lupus, Tourette syndrome, depression and cardiovascular disease) or concomitant use of other medications (e.g., typical and atypical antipsychotics, antidepressants, anticonvulsants, anti-inflammatory and antineoplastic drugs), or both, was reported in many of these cases.

Health care professionals should be aware of the risk of agranulocytosis suspected of being associated with atypical antipsychotics. Increased awareness leading to early detection and treatment is key to managing this life-threatening AR. Patients should be informed about the importance of symptoms such as fever, sore throat or other infections, and be advised to see their doctor immediately if these symptoms occur.⁸ Health care professionals are encouraged to report any ARs suspected of being associated with the use of atypical antipsychotics to Health Canada.

Marc Poitras, MSc, PhD, MBA, Health Canada

References

1. Clozaril (clozapine) [product monograph]. Dorval (QC): Novartis Pharmaceuticals Canada Inc.; 2007.
2. Zyprexa (olanzapine) [product monograph]. Toronto (ON): Eli Lilly Canada Inc.; 2008.
3. Seroquel (quetiapine fumarate) [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2008
4. Risperdal (risperidone) [product monograph]. Toronto (ON): Janssen-Ortho Inc.; 2008
5. Zeldox (ziprasidone) [product monograph]. Kirkland (QC): Pfizer Canada Inc.; 2008
6. Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23 Suppl 1:27-41. [ PubMed]
7. Andrès E, Maloisel F. Idiosyncratic drug-induced agranulocytosis or acute neutropenia. Curr Opin Hematol 2008;15(1):15-21. [ PubMed]
8. Garbe E. Non-chemotherapy drug-induced agranulocytosis. Expert Opin Drug Saf 2007;6(3):323-35.[ PubMed]
9. Duggal HS, Singh I. Psychotropic drug-induced neutropenia. Drugs Today (Barc) 2005;41(8):517-26.[ PubMed]
10. Council for International Organizations of Medical Sciences. Reporting adverse drug reactions: definitions of terms and criteria for their use. Geneva: The Council; 1999.

Adverse reaction and incident reporting - 2008

Canada Vigilance Program
The Canada Vigilance Program collects reports of suspected adverse reactions (ARs) to health products (pharmaceuticals, biologics, natural health products, radiopharmaceuticals and biotechnology products). This new AR monitoring program and database was implemented within Health Canada in March 2008 and allows for more sophisticated breakdown of data and reports. Further information about the program and its database can be found on the Health Canada web site.

In 2008, Health Canada received 20 360 domestic AR reports (Table 1), of which 69.2% were considered to be serious.* Domestic AR cases received by product type are provided in Table 2.

In Canada, Market Authorization Holders (MAHs) are required to submit AR reports received in accordance with the requirements of the Food and Drugs Act and Regulations. MAHs are required to send, within 15 days, all reports of serious ARs that have occurred in Canada (domestic) and all reports of serious unexpected ARs that have occurred outside Canada (foreign) to the Canada Vigilance Program. In 2008, MAHs submitted 71.8% of all the domestic reports received. The remaining reports were received directly from the community and hospitals (Table 1).

*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."

The number of domestic AR reports was 15.6% higher in 2008 than in 2007 (Fig. 1). The majority of domestic cases reported to both MAHs and Health Canada originated from health care professionals (Table 3).

The number of foreign AR reports received from MAHs was 241 417 (Fig. 2). At this time, foreign reports are not included in the Canada Vigilance 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. Any suspected ARs associated with the use of health products can be reported to the Canada Vigilance Program by one of the following methods:

• Call toll free at 1-866-234-2345
• Report online
• Complete a Canada Vigilance Reporting Form and:
  • fax it toll free (866 678-6789) or
  • mail it to:
    Canada Vigilance Program
    Health Canada
    Address Locator 0701C
    Ottawa ON  K1A 0K9

Postage-paid labels, the Canada Vigilance Reporting Form and the AR reporting guidelines ("Guidelines -- Voluntary Reporting of Suspected Adverse Reactions to Health Products by Health Professionals and Consumers") are available on the MedEffect™ Canada web site. The reporting form is also located in the back of the Compendium of Pharmaceuticals and Specialties (CPS).

Fig. 1: Number of domestic reports of adverse reactions received by Health Canada from 2001 to 2008

Fig. 2: Number of foreign reports of adverse reactions received by Health Canada from 2001 to 2008

Medical device incidents
Medical device incidents are collected by the Health Product and Food Branch Inspectorate and are entered into the medical device system. The Inspectorate is responsible for compliance monitoring activities for a broad spectrum of regulated health products, including medical devices which range from adhesive bandages to pacemakers. It is also responsible for the delivery of a national compliance and enforcement program in an effort to minimize health risks to Canadians while maximizing the safety of health products. A major component of this program involves the collection, review and follow-up of incidents related to medical devices, which are reported to the Inspectorate via the submission of mandatory and voluntary problem reports. Manufacturers and importers are required to submit mandatory reports as per section 59-61 in the Medical Device Regulations. Voluntary reports are submitted mostly by health care professionals and patients/users. In 2008, a total of 4491 incidents were entered into the medical device system. Of these reports, 4091 (91.0%) were mandatory and 400 (9.0%) voluntary.

• Information on mandatory and voluntary reporting of medical device incidents can be found on the Health Canada web site.
• Completed Medical Devices Problem Report forms can be submitted by email as attachments to: mdpr@hc-sc.gc.ca
• Please include the acronym MDPR in the subject line of the email in order to generate an automated confirmation of receipt by the Inspectorate.

Jennifer Lo, BSc, BA; Fannie St-Gelais, PhD; Shawn Hopewell, MSc, Health Canada

Case Presentation

Recent Canadian cases are selected based on their seriousness, frequency of occurrence or the fact that the reactions are unexpected. Case presentations are considered suspicions and are presented to stimulate reporting of similar suspected adverse reactions.

5-Hour Energy drink: suspected association with a cardiovascular adverse reaction

Energy drinks are popular and are widely available on the Canadian market. They are classified as natural health products and are promoted to provide energy and contribute to mental alertness and physical performance. 5-Hour Energy drink is not authorized for sale in Canada. However, it is available in a 2-ounce (59-mL) bottle and contains among its ingredients niacinamide 30 mg, vitamin B₆ 40 mg, folic acid 400 µg, vitamin B₁₂ 500 µg, sodium 10mg, and "Energy Blend" (citicoline, glucuronolactone, N-acetyl L-tyrosine, L-phenylalanine, taurine, malic acid, caffeine). Labelling on the bottle states "For maximum energy, drink entire bottle at one time. For moderate energy, drink a half bottle or less" and "Caution: contains about as much caffeine as a cup of coffee." However, caffeine amounts in coffee vary according to brewing methods and coffee type. A plain brewed 250-mL cup of coffee contains 95 mg of caffeine.¹

Health Canada received a report of a 55-year-old man who drank a 5-Hour Energy drink for lethargy. About 30 minutes to an hour later, he felt his heart beating rapidly and had chest pain. At the emergency department, his systolic blood pressure was 200 mm Hg. The patient was known to have a heart condition and was taking rosuvastatin, hydrochlorothiazide, acetylsalicylic acid, quinapril and long-acting diltiazem. He was released from hospital the same day after treatment with lorazepam.

Health Canada encourages the reporting of similar suspected adverse reactions to the Canada Vigilance Program.

References

1. How much caffeine is in your daily habit? Mayo Foundation for Medical Education and Research; 2007. Available: www.mayoclinic.com/health/caffeine/AN01211 (accessed 2008 Dec. 23).

Canadian Adverse Reaction Newsletter

Health Canada
Marketed Health Products Directorate
Address Locator 0701C
Ottawa ON K1A 0K9
Telephone: 613-954-6522
Fax: 613-952-7738

Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Ilhemme Djelouah, BScPharm, RPh, DIS, AFSA, Medical Biology (University of Paris V)
Gilbert Roy, BPharm
Jared Cousins, BSP
Alanna Maloney, BHSc
Mary Joy, BScPharm, RPh
Candace Fisher, BSc, MSc

Acknowledgments
We thank the following members of the Expert Advisory Committee on the Vigilance of Health Products for their review of material for this issue: Colleen J. Metge, BSc(Pharm), PhD; Dugald Seely, ND, MSc; and Sylvia Hyland, RPh, BScPhm, MHSc.

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Reporting Adverse Reactions
Canada Vigilance Program
Telephone: 866-234-2345
Fax: 866-678-6789

Copyright
© 2009 Her Majesty the Queen in Right of Canada. 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.

Due to time constraints relating to the production of this publication, information published may not reflect the most current information.
ISSN 1499-9447; Cat no H42-4/1-19-2E

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.