Canadian Adverse Reaction Newsletter, Volume 20 • Issue 1 • January 2010

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

In this Issue:
Black cohosh products and liver toxicity: update
Canada Vigilance Online Database
Case presentation: Denture adhesive creams and neuropathy
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.

Black cohosh products and liver toxicity: update

Black cohosh (Actaea racemosa, formerly Cimicifuga racemosa) is a herbal medicine used mainly to alleviate menopausal symptoms. In recent years, several international regulatory agencies have monitored a possible relationship between black cohosh and liver toxicity.^{Footnote 1,Footnote 2,Footnote 3,Footnote 4} In 2005, an article in the Canadian Adverse Reaction Newsletter^{Footnote 5} was published to inform health care professionals of international reports of liver reactions suspected of being associated with the use of this natural health product. At the time of publication, Health Canada had not received domestic reports of such reactions. To alert the public about this risk, Health Canada issued a public advisory^{Footnote 6} and a fact sheet^{Footnote 7} and required cautionary labelling on authorized black cohosh products.

From January 2005 to March 2009, Health Canada received 6 domestic reports of liver adverse reactions suspected of being associated with black cohosh. All 6 cases were reported as being serious (Table 1).

Analysis by Health Canada laboratories of 3 products (one patient was taking 2 Swiss Herbal products) suspected in 2 adverse reactions identified in the reports revealed that these products did not contain authentic black cohosh. Their phytochemical profiles were consistent with the presence of other related herbal species. Although research has shown problems with the herbal identity of some products marketed in the United States as black cohosh,^{Footnote 8} these domestic cases demonstrate that products not containing authentic black cohosh may be associated with liver adverse reactions.^{Footnote 9,Footnote 10}

A recent review of the herbal authenticity of all licensed products containing black cohosh in Canada was conducted; updated methods required for unequivocal identity testing were used.^{Footnote 11} This review resulted in the voluntary withdrawal of several products that did not contain authentic black cohosh from the market, including products reported in 4 of the cases in Table 1.

Health Canada continues to monitor the situation, and further recalls by other manufacturers are possible. Health care professionals are encouraged to report any adverse reactions suspected of being associated with the use of products containing black cohosh to Health Canada.

Danika Painter, PhD; Shahid Perwaiz, PhD; Mano Murty, MD, CCFP, FCFP, Health Canada

Acknowledgment: The authors acknowledge the important contributions of members of the Natural Health Products Program Directorates to this article.

Table 1: Summary of reports of liver toxicity suspected of being associated with black cohosh that were received by Health Canada from Jan. 1, 2005 to Mar. 31, 2009

Case	Age/sex	Product (strength)	Reactions	Outcome	Product analysis	Product status
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 health product was on the market has been taken into consideration. Reaction terms are listed according to the Medical Dictionary for Regulatory Activities (MedDRA). At the time of reporting. Voluntarily recalled means that an analysis was conducted and the sponsor voluntarily recalled the product because it did not contain authentic black cohosh. Not authorized means that the suspected product was not authorized for sale by Health Canada, and data on herbal authenticity are not available. Natural health products authorized for sale in Canada have an 8-digit Natural Product Number (NPN) or a Homeopathic Medicine Number (DIN-HM) on the label. These numbers indicate that the products have been assessed by Health Canada's Natural Health Products Directorate for safety, effectiveness and quality. Authorized natural health products are listed in Health Canada's searchable Licensed Natural Health Products Database.
1	Unknown/F	Swiss Herbal Natural HRT Extra Strength (not specified)	Ocular icterus	Unknown	Not authentic (sponsor analysis)	Voluntarily recalled
2	47/F	Swiss Herbal Menopause Natural HRT and Natural HRT Nightime (not specified)	Autoimmune hepatitis, abnormal liver biopsy, elevated bilirubin, fatigue, jaundice	Not yet recovered	Not authentic (Health Canada analysis)	Voluntarily recalled
3	56/F	Her Balance (not specified)	Upper abdominal pain, fatigue, increased hepatic enzymes	Not yet recovered	Unknown	Not authorized
4	64/F	Swiss Herbal Natural HRT Extra Strength (not specified)	Jaundice, upper abdominal pain	Recovered	Not authentic (sponsor analysis)	Voluntarily recalled
5	51/F	Swiss Herbal Remedies Black Cohosh (100 mg)	Abdominal pain, increased liver enzymes, elevated bilirubin, jaundice	Recovered	Not authentic (Health Canada analysis)	Voluntarily recalled
6	55/F	Black cohosh Health Balance (80 mg)	Lower abdominal pain, increased liver enzymes, increased bilirubin, fatigue, hepatic cirrhosis, chronic active hepatitis, jaundice	Recovered with sequelae	Unknown	Not authorized

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.

Chronic, excessive use of denture adhesive creams: suspected association with neuropathy

Denture adhesives are used as a means to enhance denture retention, stability and function.^{Footnote 1} In Canada, denture adhesives are regulated as medical devices. Active ingredients in current formulations can include combined polymethyl vinyl ether-maleic anhydride (PVM-MA) zinc and calcium salts with carboxymethylcellulose.^{Footnote 1} Chronic, excessive ingestion of zinc can result in copper deficiency, which is an established and increasingly recognized cause of neurologic disease.^{Footnote 2} This may manifest as weakness and numbness of the extremities. Some marketed denture adhesive creams, including certain Fixodent and Poli-Grip formulations, contain zinc at levels of about 17 to 34 mg/g.^{Footnote 2}

In November 2006, Health Canada received a report of a 52-year-old woman who had used Ultra Poli-Grip Denture Adhesive Cream over a period of years and was reported to have ingested large amounts of the product. The patient experienced numbness in both of her legs (date not reported).

In September 2009, Health Canada received a report of a 56-year-old woman who had used Fixodent Original Denture Adhesive for 7 to 8 years. She recently experienced unexplained pain, numbness and loss of sensitivity in her limbs.

Similar cases have been published of neurologic disease suspected of being associated with the overly liberal use (more than one 68-g tube per week) and chronic, excessive ingestion of denture adhesive creams containing zinc.^{Footnote 2,Footnote 3}

Health Canada encourages the reporting of similar suspected adverse incidents involving denture adhesives to the Health Products and Food Branch Inspectorate through the toll-free hotline (1-800-267-9675).

Quarterly Summary of health professional and consumer advisories (posted on Health Canada's Web site: Aug. 22, 2009 - Nov. 10, 2009)

Date	Product	Subject
Nov 5	Chaotic beverages	Recall due to health risks to children
Nov 4	H1N1 flu products	Update - fraudulent products online
Nov 3	Relenza (zanamivir) inhalation powder	Association with fatal outcome when administered by nebulization
Oct 30	Medical device clocks	Update - switch to Standard Time
Oct 27	Propofol Injection	Type I product recall
Oct 26	Apo-Lithium Carbonate	Type II product recall - SR 300-mg strength tablets
Oct 23	Tamiflu (oseltamivir)	Update - important information
Oct 21	Rituxan (rituximab)	Association with progressive multifocal leukoencephalopathy
Oct 20 & 21	Cesamet (nabilone) and Trazorel (trazodone)	Type I product recall - mislabelling; potential risk of serious adverse effects
Oct 20	Hospital beds	Risk of entrapment of patients
Oct 15	Ceftriaxone	Updated prescribing information
Oct 15 & 19	Intelence (etravirine)	Severe skin and hypersensitivity reactions
Oct 14	Foreign products	Alerts - Syntrax Fyre, Texiao Fengshi Gutong Ling, Kam Yuen Brand Wan Ying Yang Gan Wan; STEAM lot # 80214 and 90260; Dynasty Worldwide Jinglida So Young Formula; Bao Ling
Oct 13	Tamiflu (oseltamivir) powder for oral suspension	Risk of dosing error
Oct 7	Sleep aid drugs	Risk of complex sleep-related behaviours
Sept 25	Liquid Tamiflu	Potential medication errors
Sept 25	Hospira devices	Medical device recall - defective AC power cords
Sept 17	Apotex health products	Information update - voluntary recall
Sept 15	Portex uncuffed pediatric-sized tracheal tubes	Medical device recall
Sept 11	PediCap Pediatric End-Tidal carbon dioxide detectors	Urgent medical device recall
Sept 10	Cesium chloride	Association with cardiac risks
Sept 4	Foreign products	Alerts - Reduce Weihgt; Dr. Health Series SB Factor and Dr. Health Series GQ Factor
Sept 3	Foreign products	Alerts - Hardcore Energize Bullet; Jin Yuan Pai Xue Guan Qing Dao Fu Jiao Nang and Kam Yuen Brand Xue Guan Qing Dao Fu tablet; Libipower Plus; LibieXtreme, Y-4ever, Powermania, Libimax X and Herbal Disiac; Slim House: Green algae fat-melting agent; One Weight Loss Pill, SlimDemand and Botanical Weight Loss

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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)
Jared Cousins, BSP
Alanna Maloney, BHSc
Mary Joy, RPh, BScPhm
Hoa Ly, BSc
Patricia Carruthers-Czyzewski, BScPhm, MSc

Acknowledgement
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. We also thank Kaitlyn Proulx and Darija Muharemagic, students in Biopharmaceutical Science, for their participation in the production of the newsletter.

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

Copyright
© 2010 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 H42-4/1-20-1E

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.