Health Product InfoWatch - March 2016

ISSN 2368-8025
Pub. no 150182

Health Products and Food Branch
Marketed Health Products Directorate
Health Product InfoWatch Editorial Team

Contents

• Monthly recap
• New information
  • Review article: Melatonin and neurologic adverse reactions in children and adolescents

Health products mentioned in this issue

Pharmaceuticals and Biologics

• Advil liquid products for infants and children
• Cisplatin
• Piperacillin for Injection
• Piperacillin/Tazobactam for Injection

Natural Health Products

• Durazest for Men
• Forta for Men
• Melatonin
• Pseudoephedrine-containing products

Other

• Unauthorized health products labelled as B17/amygdalin/bitter apricot kernel

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
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.

Monthly recap of health product safety information

The following is a list of health product advisories as well as summaries of completed safety reviews published in February 2016 by Health Canada.

Advil liquid products for infants and children

Pfizer Consumer Healthcare has recalled 126 lots of Advil liquid products for infants and children because of a potential risk of inconsistences in dosing of the product. "Clumps" of ibuprofen may form in the bottle and lead to higher or lower doses that are given to infants and children if it is not shaken well before each use.

Information Update

Cisplatin

This safety review evaluated the potential increased risk of venous thromboembolism with the use of cisplatin. Health Canada's review considers that there is an increased risk of venous thromboembolism with the use of cisplatin in the treatment of advanced bladder, testicular and ovarian cancers. Health Canada has recommended that the prescribing information for cisplatin products be updated by all manufacturers of cisplatin in Canada to include warnings about this increased risk.

Summary Safety Review

Forta for Men

All lots of the product "Forta for Men" (NPN 80045132) were recalled after Health Canada testing confirmed one lot contained an undeclared drug: tadalafil. The same distributor as "Forta for Men" is also recalling all lots of "Durazest for Men" (NPN 80033381) as a precautionary measure.

Advisory

Piperacillin/Tazobactam for Injection and Piperacillin for Injection

This safety review evaluated the potential link between drug reaction/rash with eosinophilia and systemic symptoms (DRESS) and the antibiotic drug combination piperacillin and tazobactam or piperacillin alone. Health Canada's review concluded that there is evidence of a link between the drug combination piperacillin and tazobactam and DRESS. Additionally, a contributing role for piperacillin alone and DRESS could not be ruled out. Health Canada has begun updating the Canadian prescribing information to include this risk. Health Canada has also communicated this information to healthcare professionals.

Summary Safety Review
Health Product InfoWatch

Pseudoephedrine-containing products

This safety review evaluated the potential link between the use of pseudoephedrine and ischemic colitis. Health Canada's review concluded that there is very limited evidence of ischemic colitis linked with the occasional use of pseudoephedrine at recommended dose and duration, in the absence of other risk factors. Health Canada will continue to monitor this issue. Health Canada has also communicated this information to healthcare professionals.

Summary Safety Review
Health Product InfoWatch

Unauthorized health products labelled as B17/amygdalin/bitter apricot kernel

Canadians were advised that a number of potentially dangerous unauthorized health products labelled as B17/ amygdalin/ bitter apricot kernel were available for sale in Canada. No health products containing B17 or amygdalin have been authorized by Health Canada to treat cancer or any other condition.

Advisory (update)
Advisory

New health product safety information

The following topics have been selected to raise awareness and, in some cases, to stimulate reporting of similar adverse reactions.

Review article

Melatonin and neurologic adverse reactions in children and adolescents

Melatonin is a hormone that is secreted by the pineal gland in response to darkness.^{Footnote 1} It helps regulate the sleep/wake cycles, and is used for the management of sleep disorders. In Canada, melatonin is designated as a natural health product (NHP) and is indicated for adult use.^{Footnote 2,Footnote 3} Health Canada has licensed over 500 melatonin-containing NHPs either as single ingredients or multi-ingredient formulations in the form of capsules, sublingual tablets, liquids and gums. In addition, 2 multi-ingredient melatonin cold remedies have been licensed for children 12 years and older since 2011; however they are not currently marketed in Canada. Although little is known about its safety and efficacy in children and adolescents, melatonin has been used in this population, both in Canada and internationally.^{Footnote 4,Footnote 5,Footnote 6}

Recent international reports of neurological adverse reactions (e.g., anxiety, panic reactions, visual hallucinations and seizures) suspected of being associated with the use of melatonin in children and adolescents have been brought to Health Canada's attention by foreign regulators.

A review was conducted on the use of melatonin in the pediatric population.^{Footnote 7} At the time of the review, Health Canada had received 18 Canadian reports of adverse reactions suspected of being associated with the use of melatonin-containing NHPs in children and adolescents. The most frequently reported adverse reaction was daytime sleepiness. Of the 18 cases, 5 were considered serious. Two cases occurred in children with an established diagnosis of epilepsy: one child had a seizure, and the other had an increase in seizure frequency while taking melatonin and carbamazepine. Another child who was known to have attention deficit hyperactivity disorder (ADHD) as well as complex psychological problems developed anxiety, a panic reaction and visual hallucinations while taking melatonin and an ADHD medication. The other 2 serious cases described dyspnea and an increase in liver enzymes. In all cases received by Health Canada, information was limited; therefore, a causal association between the use of melatonin and these adverse reactions could not be established.

A review of international data from the World Health Organization's Global Individual Case Safety Reports Database System (VigiBase) identified 163 reports of adverse reactions, including 8 from Canada, suspected of being associated with the use of melatonin in the pediatric population.^{Footnote a} The most commonly reported adverse reactions were general fatigue, aggression, abnormal dreams, and headache. Seventy-one of the non-Canadian cases were considered serious, but they could not be assessed further due to limited information available.

Evidence from the scientific literature on the safety and efficacy of melatonin is limited, and suggests that melatonin is only modestly effective in improving sleep quality in adults.^{Footnote 8,Footnote 9,Footnote 10} Some systematic reviews have supported the hypothesis that melatonin decreases sleep onset latency and increases total sleep time in certain patients when used for less than 4 months, though improvements are modest.^{Footnote 9,Footnote 10} Some studies have also shown potential benefits for certain sleep problems in children.^{Footnote 4,Footnote 6,Footnote 11,Footnote 12,Footnote 13} Studies in special populations (e.g., ADHD, autism spectrum disorders) provide the best evidence for the usefulness of melatonin in children.^{Footnote 4,Footnote 6,Footnote 11,Footnote 13} However, child behaviour and family functioning outcomes did not improve consistently.^{Footnote 4,Footnote 5,Footnote 12} Adverse reactions reported in these studies, including neurological reactions, appear to be mild or limited with short term use.^{Footnote 4,Footnote 5,Footnote 6,Footnote 11,Footnote 13,Footnote 14} Based on current evidence, a relationship between the pediatric use of melatonin and the occurrence of neurological adverse reactions, such as seizures, could not be established.^{Footnote 5,Footnote 6,Footnote 13,Footnote 14} In addition, the short term impact on psychological development and the long term effect on growth in the pediatric population remain uncertain, and more studies are needed in the future to better characterize these issues.^{Footnote 4,Footnote 5,Footnote 11,Footnote 12,Footnote 14,Footnote 15}

Parents and caregivers should be encouraged to speak to a healthcare professional about the risks and benefits of using melatonin products as sleep aids in children. In addition, the use of pharmacological therapy for sleep problems in children and adolescents should only be considered after behavioral interventions.^{Footnote 5,Footnote 11,Footnote 14} Sleep hygiene interventions for pediatric sleep problems have been shown to produce clinically significant improvements. Healthcare professionals are encouraged to report to Health Canada any adverse reaction suspected of being associated with the use of melatonin. Information such as the dosage, duration of exposure to melatonin, concomitant medications and time to onset of adverse events are important to include when reporting adverse reactions.

Article citation: Health Canada. Melatonin and neurologic adverse reactions in children and adolescents. Health Product InfoWatch March 2016.

References

Helpful links

• MedEffect™ Canada
• Recalls and Safety Alerts Database
• Summary Safety Reviews
• New Safety Reviews
• Canada Vigilance Adverse Reaction Online Database
• Drug Product Database
• Medical Devices Active License Listing
• Licensed Natural Health Products Database
• The Drug and Health Product Register
• Canadian Drug Shortage Database

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 0701D
Ottawa ON K1A 0K9
Telephone: 613-954-6522
Fax: 613-952-7738

Copyright

© 2016 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.