Health Product InfoWatch – March 2022

Contents

• Health products mentioned in this issue
• Coronavirus disease (COVID-19)
• Drug and vaccine authorizations and communications for COVID-19
  • Covifenz (COVID-19 Vaccine)
  • Nuvaxovid (COVID-19 Vaccine)
  • Omicron Variant and COVID-19 Treatments: Sotrovimab update
  • Spikevax (COVID-19 Vaccine Moderna)
• Monthly recap of health product safety information
• New health product safety information
• Review articles:
  • Oral, over-the-counter diphenhydramine-containing products and the risk of serious adverse events in children and adolescents
  • Ketamine: Off-label use
• Product monograph update:
  • Lokelma (sodium zirconium cyclosilicate)
• Scope
• Reporting Adverse Reactions
• Helpful links
• Suggestions?
• Copyright

Health products mentioned in this issue

Pharmaceuticals and biologics

• Beovu (brolucizumab)
• Covifenz (COVID-19 Vaccine)
• Ketamine
• Lokelma (sodium zirconium cyclosilicate)
• Methadone
• Nuvaxovid (COVID-19 Vaccine)
• Sotrovimab
• Spikevax (COVID-19 Vaccine Moderna)

Medical devices

• Baxter Corporation's MiniCap Extended Life Peritoneal Dialysis Transfer Sets
• Rapid antigen test kits

Natural and non-prescription health products

• Diphenhydramine-containing products
• Hand sanitizers that may pose health risks

Other

• Unauthorized health products

Coronavirus disease (COVID-19)

For the most up-to-date information on COVID-19, please visit the Government of Canada Coronavirus disease (COVID-19) website Canada.ca/coronavirus, which includes a dedicated section for healthcare professionals, and for the health product industry.

The COVID-19 vaccines and treatments portal provides information for consumers, healthcare professionals and researchers on vaccines and treatments authorized for COVID-19.

For information about adverse events following immunization that individuals have reported after receiving a COVID-19 vaccine in Canada, new safety signals or other safety updates, please visit the COVID-19 vaccine safety in Canada webpage, which is updated weekly.

Drug and vaccine authorizations and communications for COVID-19

New information and recent communications related to authorized COVID-19 vaccines and treatments are highlighted in this section.

Covifenz (COVID-19 Vaccine)

Covifenz was authorized by Health Canada on February 24, 2022 for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 18 to 64 years of age. Covifenz, which is manufactured by Medicago, is authorized as a two-dose regimen to be administered 21 days apart.

Authorization with terms and conditions: Covifenz COVID-19 Vaccine

Nuvaxovid (COVID-19 Vaccine)

Nuvaxovid was authorized by Health Canada on February 17, 2022 for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 18 years of age and older. In order to provide rapid access to Nuvaxovid in the context of the global pandemic, Novavax, Inc. will distribute product vials, cartons and package inserts that are in English-only for a period of time. The English-only vial and carton labels are missing some important Canadian-specific information normally found on Health Canada approved labels.

Health Professional Risk Communication: Nuvaxovid (COVID-19 Vaccine)

Omicron Variant and COVID-19 Treatments: Sotrovimab update

On March 25, 2022, the U.S. Food & Drug Administration announced that, based on available evidence, the authorized dose of sotrovimab, 500 mg, is unlikely to be effective against the SARS-CoV-2 Omicron BA.2 variant. In vitro pseudovirus neutralization assays indicate that sotrovimab retains neutralization potency against the Omicron BA.1 variant. Health Canada is working with the manufacturer to review available data, in a timely manner, and take appropriate action(s) as deemed necessary.

Spikevax (COVID-19 Vaccine Moderna)

Spikevax was authorized by Health Canada on March 17, 2022 for the extension of the indication to include active immunization to prevent coronavirus disease 2019 (COVID-19) in individuals 6 years to 11 years of age.

Authorization with terms and conditions: Spikevax (COVID-19 Vaccine Moderna)

Monthly recap of health product safety information

The following is a list of health product advisories, type I recalls and summaries of completed safety reviews published in February 2022 by Health Canada.

For health product advisories related to COVID-19 vaccines and treatments, please see the Drug and vaccine authorizations and communications for COVID-19 section.

Baxter Corporation's MiniCap Extended Life Peritoneal Dialysis Transfer Sets

Health Canada advised patients who use MiniCap Extended Life Peritoneal Dialysis Transfer Sets, manufactured by Baxter Corporation, that direct contact between the sets and certain cleaning products, including hand sanitizers and solvents, may damage the sets. Damaged sets could leak or crack, which may cause microbial contamination leading to the development of peritonitis in some cases.

Advisory: Baxter Corporation's MiniCap Extended Life Peritoneal Dialysis Transfer Sets

Beovu (brolucizumab)

An increased incidence of intraocular inflammation, including retinal vasculitis and retinal vascular occlusion, was observed in patients who received Beovu 6 mg with every 4 weeks dosing beyond the first 3 doses, compared to aflibercept 2 mg every 4 weeks, in neovascular (wet) age-related macular degeneration in the MERLIN study. More intraocular inflammation events were seen among patients who developed anti-brolucizumab antibodies during treatment. Retinal vasculitis and retinal vascular occlusion are immune-mediated events (BASICHR0049 study).

Health Professional Risk Communication: Beovu (brolucizumab)

Certain hand sanitizers that may pose health risks

Health Canada advised Canadians that certain hand sanitizers were recalled due to various safety-related issues, including the presence of ingredients that were not permitted by Health Canada, improper labelling, unauthorized products, and missing safety information.

Advisory: Certain hand sanitizers that may pose health risks

Methadone

This safety review evaluated the risk of hypoglycemia associated with the use of methadone. Health Canada's review of the available information found a possible link. Health Canada will be working with the manufacturers of methadone to update the Canadian product monographs to include the risk of hypoglycemia.

Summary Safety Review: Methadone

Rapid antigen test kits

Following an increase in reports to poison control centres, Health Canada advised Canadians about potential risks associated with the misuse, accidental ingestion, or spillage of COVID-19 rapid antigen test kit solutions on the skin.

Advisory: Rapid antigen test kits

Unauthorized health products

Health Canada advised Canadians about various unauthorized health products being sold at retail locations across Canada or online that may pose serious health risks.

Advisory: Ayurvedic medicinal products sold by Kerela Ayurvedic & Natural Herbal Consultation in Toronto, ON

New health product safety information

The following topics have been selected to raise awareness and encourage reporting of similar adverse reactions.

Review articles

Oral, over-the-counter diphenhydramine-containing products and the risk of serious adverse events in children and adolescents

Diphenhydramine is a first-generation antihistamine.^{Footnote 1} Oral, over-the-counter diphenhydramine is authorized for sale in Canada as single ingredient or multi-ingredient products, and is commonly used for the symptomatic relief of seasonal and year-round allergies, the temporary relief of dry cough due to the common cold, and as sleep aids.^{Footnote 2}

Pediatric indications vary depending on patient age and product strength. In 2008, Health Canada announced that cough and cold products, including those containing diphenhydramine, should not be used in children under the age of 6 due to safety concerns. Diphenhydramine-containing products are still authorized for allergy indications in children less than 6 years old.^{Footnote 2} As well, sleep aid products containing diphenhydramine are authorized for children 12 and above.

In recent years, additional concerns have been raised regarding the safety of diphenhydramine. In 2019, the Canadian Society of Allergy and Clinical Immunology published a position statement, recommending the use of newer-generation over first-generation antihistamines for the treatment of allergic rhinitis and urticaria because of the unfavourable risk-benefit profile of first-generation antihistamines.^{Footnote 3}

In September 2020, the U.S. Food & Drug Administration warned that taking higher than recommended doses of diphenhydramine could lead to serious heart problems, seizures, coma, or even death. This Drug Safety Communication followed social media videos posted on the TikTok platform that encouraged the ingestion of large amounts of diphenhydramine to cause hallucinations.^{Footnote 4}

As a precaution, Health Canada carried out a safety review to determine if there was a change in the type and/or frequency of adverse events associated with the use of diphenhydramine-containing products in children and adolescents. The review focused on known and potential serious adverse events in children less than 2 years of age (all use) and in children less than 18 years of age (abuse, misuse or overdose).

Health Canada reviewed the available information from domestic case reports in the Canada Vigilance database, published literature, and information received from industry.

A small number of Canadian case reports contained sufficient information to allow for an assessment. These reports were found to be possibly or probably associated with the use of diphenhydramine, and described adverse reactions such as dyskinesia, delusions, hallucinations, disorientation, dizziness, hyperactivity, dilated pupils, tachycardia, vomiting and seizure. None of the Canadian cases reported a fatal outcome.

Health Canada also reviewed the scientific literature. Many of the serious adverse events reported in children and adolescents involved accidental unsupervised ingestions, caregiver error, and intentional misuse/overdose.^{Footnote 5}, ^{Footnote 6}, ^{Footnote 7}, ^{Footnote 8}, ^{Footnote 9}, ^{Footnote 10}, ^{Footnote 11} These events involved single ingredient diphenhydramine and cough and cold remedies containing diphenhydramine. Doses as low as 2 to 3 times the maximum daily dose were reported to cause severe toxicity resulting in an anticholinergic toxidrome, seizures, rhabdomyolysis, and death from cardiac arrhythmias in children.^{Footnote 12}

The adverse events reported in the Canadian cases and in the literature were consistent with the known safety profile for diphenhydramine.

Conclusion

Health Canada's review of the available information found no change in the type or frequency of serious adverse events associated with the use of diphenhydramine-containing products in children and adolescents. There are no new safety concerns to warrant regulatory action at this time.

Caregiver error, accidental unsupervised ingestion, and intentional misuse/overdose of diphenhydramine may lead to serious adverse events in children and adolescents. Caregivers may not be aware of the known risks of diphenhydramine use. Therefore, healthcare professionals are encouraged to discuss with parents and caregivers on safe storage and proper supervision as they are important in preventing accidental unsupervised ingestion and misuse.^{Footnote 8} Parents and caregivers should also be reminded to select child-resistant packaging and to make sure that the cap is properly closed after each use. Medicines should be locked up to prevent accidental poisonings by children and misuse by teens.

Healthcare professionals are encouraged to report to Health Canada any serious adverse reactions suspected of being associated with the use of oral, over-the-counter diphenhydramine-containing products in children and adolescents to support the ongoing monitoring of this safety issue. Information such as dosage, duration of exposure to diphenhydramine, concomitant medications, medical history, and time to onset of adverse reactions are important to be included in the reports, to help Health Canada better assess the safety issue.

References

Ketamine: Off-label use

Ketamine is authorized in Canada under the brand name Ketalar, as an injection for anesthetic-related purposes during diagnostic or surgical procedures.^{Footnote 13} It is also available as a generic product. Ketamine, a controlled substance, is a racemic mixture of two molecules, S-ketamine (esketamine) and R-ketamine (arketamine).^{Footnote 14}, ^{Footnote 15}

Esketamine is authorized in Canada under the brand name Spravato, as a nasal spray, for the treatment of moderate to severe major depressive disorder where patients have not responded to other antidepressants, or where urgent psychiatric care is required.^{Footnote 13} Due to the well-established risks associated with its use, esketamine is only available through a controlled distribution program. The product has specific instructions for distribution in addition to requirements for medication administration and post-administration monitoring by a healthcare professional.

The Canadian product monographs, which are available on Health Canada's Drug Product Database, should be used for complete product reference.

Health Canada has become aware of an increased interest in the off-label use of ketamine for the treatment of different conditions, such as mental illnesses, utilizing various formulations, including compounded products. The risks and benefits of ketamine used for off-label conditions have not been assessed by Health Canada. There are currently clinical trials underway to further characterize the safety and efficacy of ketamine for various therapeutic uses.^{Footnote *}

Health Canada would like to provide healthcare professionals with the following safety information for ketamine:

Health Canada will continue to monitor safety information involving ketamine, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

References

Product monograph update

The following safety labelling update, which was recently made to the Canadian product monograph, has been selected for your awareness. A complete list of safety labelling updates for pharmaceuticals is available on Health Canada's Product monograph brand safety updates page. Canadian product monographs can be accessed through Health Canada's Drug Product Database.

Lokelma (sodium zirconium cyclosilicate)

The Warnings and Precautions and Patient Medication Information sections of the Canadian product monograph for Lokelma have been updated with the risk of x-ray imaging interference.

Reference

Scope

This monthly publication is intended primarily for healthcare professionals and includes information on pharmaceuticals, biologics, medical devices and natural health products. It provides a summary of key health product safety information published in the previous month by Health Canada, as well as a selection of new health product safety information meant to raise awareness. New information contained in this issue is not comprehensive but rather represents a selection of clinically relevant items warranting enhanced dissemination.

Reporting Adverse Reactions

Canada Vigilance Program
Telephone: 1-866-234-2345
Fax or mail: Form available on MedEffect Canada

For more information on how to report an adverse reaction, visit the Adverse Reaction and Medical Device Problem Reporting page.

Helpful links

• MedEffect^TM Canada
• Recalls and Safety Alerts Database
• New Safety and Effectiveness Reviews
• Canada Vigilance Adverse Reaction Online Database
• Drug Product Database
• Medical Devices Active Licence Listing
• Licensed Natural Health Products Database
• The Drug and Health Product Register
• Drug Shortages Canada
• Stop Illegal Marketing of Drugs and Devices
• List of drugs for exceptional importation and sale
• Drug and vaccine authorizations for COVID-19: List of authorized drugs, vaccines and expanded indications
• Reported side effects following COVID-19 vaccination in Canada

Suggestions?

Your comments are important to us. Let us know what you think by reaching us at infowatch-infovigilance@hc-sc.gc.ca

Health Canada
Marketed Health Products Directorate
Address Locator 1906C
Ottawa ON K1A 0K9
Telephone: 613-954-6522
Fax: 613-952-7738

Copyright

^©2022 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.

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.

Due to time constraints relating to the production of this publication, information published may not reflect the most current information.