Canadian Adverse Reaction Newsletter, Volume 21 - Issue 3 - July 2011

ISSN 1499-9447
Cat no H42-4/1-21-3E

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

In this Issue:

• Proton pump inhibitors: hypomagnesemia accompanied by hypocalcemia and hypokalemia
• Adverse reaction and incident reporting - 2010
• Case presentation: Floseal hemostatic matrix and suspected association with misinterpretation as recurrent malignant disease
• Risk communication information
• 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.

Proton pump inhibitors: hypomagnesemia accompanied by hypocalcemia and hypokalemia

Proton pump inhibitors (PPIs) are widely used for the treatment of conditions related to gastric acid secretion (e.g., duodenal and gastric ulcers, reflux esophagitis and gastroesophageal reflux disease). In Canada, 6 marketed PPIs are available as prescription medications: omeprazole (first marketed in 1989), lansoprazole (1995), pantoprazole (1997), esomeprazole (2001), rabeprazole (2002) and dexlansoprazole (2010).

The potential association between PPI treatment and hypomagnesemia has been suggested in the literature and communicated by other regulatory authorities.^{Footnote a1,Footnote a2,Footnote a3,Footnote a4,Footnote a5,Footnote a6,Footnote a7,Footnote a8} Recent studies have suggested that hypomagnesemia can be induced by several if not all PPIs.^{Footnote a1,Footnote a2,Footnote a4,Footnote a6}

The mechanism by which PPIs induce hypomagnesemia is unclear. It may involve defects in magnesium absorption in the small intestine by affecting the function of the transient receptor potential melastin 6 (TRPM6) channel.^{Footnote a1,Footnote a2,Footnote a6} Effects on magnesium absorption have not been reported with short-term use of PPIs. Published case reports suggest that PPI-induced hypomagnesemia occurs after prolonged use (≥ 1 year).^{Footnote a1,Footnote a2,Footnote a3,Footnote a4,Footnote a5,Footnote a6} Magnesium is involved in bone metabolism. Its deficiency may induce parathyroid dysfunction and hypoparathyroidism, thereby affecting the regulation of calcium levels.^{Footnote a9,Footnote a10,Footnote a11} Hypomagnesemia may also trigger hypokalemia via activation of the potassium channel of the thick ascending limb of the loop of Henle, resulting in urinary potassium wasting.^{Footnote a4,Footnote a12}

The effects of PPIs on serum magnesium levels seem to be reversible.^{Footnote a1,Footnote a2,Footnote a3,Footnote a4,Footnote a5,Footnote a6} In all published cases, electrolyte levels returned to normal following cessation of PPI treatment (positive dechallenge). Recurrence of hypomagnesemia following reintroduction of the PPI (positive rechallenge) was documented in 3 cases.^{Footnote a1,Footnote a3,Footnote a6} In most cases, secondary hypokalemia or hypocalcemia, or both, accompanied the hypomagnesemia, with some patients presenting with symptoms of potentially life-threatening cardiac arrhythmias and neurologic manifestations (e.g., seizures, loss of consciousness and tetany).

As of Jan. 31, 2011, Health Canada received 5 reports of hypomagnesemia suspected of being associated with the following PPIs: omeprazole (n = 2), lansoprazole (n = 1), pantoprazole (n = 1) and esomeprazole (n = 1). One case was life threatening, and 4 patients required hospital care. Secondary hypokalemia was reported in 3 of the cases. One report described a positive dechallenge and a positive rechallenge.

Health professionals are reminded that, in some patients, hypomagnesemia may occur after prolonged treatment with PPIs, and it may be accompanied by hypocalcemia and hypokalemia. This adverse reaction may be underdiagnosed and underreported because of the low frequency of magnesium measurement in routine clinical practice.^{Footnote a1,Footnote a6} Health care professionals are encouraged to report any cases of hypomagnesemia suspected of being associated with the use of PPIs.

Rania Mouchantaf, PhD, Health Canada

Adverse reaction and incident reporting - 2010

Canada Vigilance Program

The Canada Vigilance Program collects reports of suspected adverse reactions (ARs) to health products (pharmaceuticals, biotechnology products, blood products and biologics, natural health products, radiopharmaceuticals, and cells, tissues and organs). Further information about the program and its database can be found on the MedEffect™ Canada Web site.

Domestic and foreign AR reports

In 2010, Health Canada received 32 921 domestic AR reports, of which 77% were considered to be serious. Domestic AR reports received by product type are provided in Table 1. The 32 921 reports represent 22 241 AR cases. A case consists of all information describing the AR(s) experienced by one patient at one time and suspected of being related to the use of one or more health products; thus, an AR case will include an initial AR report as well as any subsequent additional information received as follow-up report(s).

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 2010, MAHs submitted 78.9% of all the domestic reports received. The remaining reports were received directly from the community and hospitals (Table 2).

The number of domestic AR reports was 19.7% higher in 2010 than in 2009 (Figure 1). Most of the domestic reports received by both MAHs and Health Canada originated from health care professionals (Table 3).

In 2010, the number of foreign AR reports received from MAHs was 363 961 (Figure 2). At this time, foreign reports are not included in the Canada Vigilance database.

Sex and age

The distribution for the 22 241 cases by sex was 57% female, 38% male and 5% sex unknown. The distribution by age group is 7% pediatric (< 19 years), 47% adult (19-64 years), 25% elderly (≥ 65 years) and 21% age unknown.

Suspect products

The top 10 groups of suspect products most commonly identified in AR reports are listed in Table 4. Anatomical Therapeutic Chemical (ATC) groups are classified according to the  World Health Organization's ATC classification system. Several factors may influence the number of ARs reported for a specific health product or product type, such as length of time a product is on the market, volume of use, publicity of an AR, regulatory actions, method of data collection (reports submitted voluntarily v. organized data-collection systems). For example, ARs may be reported more frequently in organized data-collection systems (e.g., patient registries, surveys, patient support and disease management programs) and may affect the pattern of reporting. It is not possible to compare the risk of health products based solely on numbers of AR reports. In addition, rare and serious reactions may not necessarily represent a large number of reported ARs.

Adverse reactions

Table 5 displays the top 10 ARs reported to the Canada Vigilance Program, based on System Organ Class. The most commonly reported ARs were general disorders and administration site conditions, which include disorders that affect several body systems or sites (e.g., drug ineffective, fatigue, fever, edema, pain, reactions at the administration site). The next most common ARs were gastrointestinal disorders.

Conclusion

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. The purpose of postmarket spontaneous reporting systems is the identification and analysis of new safety information for health products. Any ARs suspected of being associated with the use of health products can be reported to the Canada Vigilance Program.

Medical device incidents

Medical device incidents are collected by the Health Products and Food Branch Inspectorate and are entered into the Medical Device System database. 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 sections 59 to 61 in the Medical Devices Regulations. Voluntary reports are submitted mostly by health care professionals and patients/users.

In 2010, a total of 7588 reports were entered into the Medical Device System database. Of these reports, 5828 (76.8%) were domestic mandatory reports, 1354 (17.8%) were foreign mandatory reports, and 406 (5.4%) were domestic voluntary reports.

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-dimm@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.

Marielle McMorran, BSc, BSc(Pharm); Melanie Adams, PhD, 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.

Floseal hemostatic matrix: suspected association with misinterpretation as recurrent malignant disease

Floseal is a granular hemostatic agent that consists of a bovine-derived gelatin matrix component and a human-derived thrombin component. Before application, these two components are combined to allow the mixing and reconstitution of the thrombin into the gelatin matrix. Floseal is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional methods is ineffective or impractical. Floseal is expected to resorb in the tissues within 6 to 8 weeks.^{Footnote 1} In Canada, the product is regulated as a class IV medical device (highest risk class).

In 2010, Health Canada received 2 reports of adverse incidents in which Floseal was suspected of persisting at surgical sites following partial nephrectomy for cancer. In both cases, follow-up radiographic imaging several months after surgery (6 and 9 months, respectively) revealed an asymptomatic mass (1 cm x 1.5 cm, and 3 cm x 4 cm, respectively) that was initially interpreted as recurrent malignant disease. The physician later reinterpreted the mass as a possible persistence of Floseal. In both cases, the report suggested that the mass could have been related to excess use of Floseal without adequate irrigation. Other cases have been reported in the medical literature in which Floseal persisted in the tissues after tumour resection and was misinterpreted as recurrent malignant disease during follow-up.^{Footnote 2,Footnote 3}

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

Risk communication information

Health Canada considers many factors in the evaluation of an emerging health product safety concern (e.g., availability and reliability of data, seriousness of the event) and the urgency of the communication.

The chart below outlines the urgency level of each type of communication disseminated by Health Canada and industry for public and professional audiences.

To provide health product risk information to Canadians as quickly as possible, Health Canada posts risk communications on the MedEffect™ Canada Web site. This central hub of health product safety information offers the most comprehensive coverage and access to risk communications issued by both Health Canada and industry.

More information can be found in Health Canada's Fact Sheet: Risk Communication: Protecting Canadians through Information. This document is available under Reports and Publications on the MedEffect™ Canada Web site.

Quarterly Summary of

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Canadian Adverse Reaction Newsletter

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

Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Jared Cousins, BSP
Hoa Ly, BSc
Patricia Carruthers-Czyzewski, BScPhm, MSc
Gilbert Roy, BPharm
Christianne Scott, BPharm, MBA
Sophie Bourbonnais, BScPht

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 Benjamin Pearson and Aleksandar Brezar, students in Health Sciences and Biopharmaceutical Sciences, respectively, and Aline Labaki, BSc, LLL, LLB, for their participation in the production of the newsletter.

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Reporting Adverse Reactions
Canada Vigilance Program
Telephone: 1-866-234-2345
Fax: 1-866-678-6789

Copyright
© 2011 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.