Summary Safety Review - Mefloquine - Assessing the potential risk of rare long-lasting and permanent adverse events related to the brain and nervous system (neurological) and mental health (psychiatric)

Review decision

A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.


Issued: 2017-06-01

Product

Mefloquine

Potential Safety Issue

Rare long-lasting and permanent adverse events related to the brain and nervous system (neurological) and mental health (psychiatric)

Key Messages

  • Mefloquine is a prescription drug authorized for sale in Canada to prevent and treat malaria. Malaria is a serious infectious disease that is spread by mosquitoes in certain parts of the world.
  • Because of ongoing concerns, Health Canada reviewed available evidence on the risk of long-lasting and permanent neurological and psychiatric adverse events with the use of mefloquine.
  • Health Canada's safety review found limited evidence supporting that long-lasting and permanent neurological and psychiatric adverse events are caused by the use of mefloquine. It also concluded that the current product information for mefloquine describes the potential for long-lasting neurological and psychiatric adverse events which aligns with the review findings. However, the risk of rare permanent vestibular damage could be more clearly explained in the Patient Medication Information section.
  • Health Canada will be working with the manufacturer to update the Patient Medication Information section of the product information for mefloquine to better reflect the findings of the safety review. The review also found that some individuals were prescribed mefloquine even though they had past or ongoing neurological or psychiatric conditions, which are reasons not to use mefloquine (contraindications). Therefore, to assist healthcare professionals in deciding whether to prescribe mefloquine to individual patients, a checklist will be developed.

Overview

Health Canada reviewed the potential risk of rare long-lasting and permanent neurological and psychiatric adverse events with the use of mefloquine because it has been an ongoing concern in Canada and internationally. The current Canadian product information for mefloquine warns about neuropsychiatric adverse events including depression, tinnitus (a persistent noise or "ringing" in the ears), dizziness or vertigo (the sensation of motion of self or one's surroundings). These adverse events may last for months or years after stopping the medication. Patients should consult a healthcare professional if these adverse events happen and in order to be prescribed another medication to prevent malaria. Mefloquine should not be prescribed to patients who have or have had serious psychiatric disorders.

The safety review focused on all the evidence available to date to determine whether there was a potential link between the use of mefloquine (for malaria prevention) and rare long-lasting or permanent neurological and psychiatric adverse events, as well as how often these adverse events happen and how serious they are. Another goal of the review was to identify factors that may put certain groups of individuals at increased risk and ways to manage these risks. In this review, a "long-lasting" adverse event was considered to be one that lasted 90 days or more after stopping the use of mefloquine.

Use in Canada

  • Mefloquine is a prescription drug authorized for sale in Canada to prevent and treat malaria. It is one of a small number of medication options to prevent malaria
  • Mefloquine has been marketed in Canada since 1993 under the brand name Lariam but only a generic version is available now. Mefloquine is available in a tablet form.
  • The use of mefloquine has been declining in Canada. The available data estimates that, in 2000, the number of prescriptions filled (new and refills) through retail pharmacies was about 60,000 and, in 2016, about 31,000 prescriptions were filled.

Safety Review Findings

  • From the time mefloquine entered the Canadian market in 1993 to September 30, 2016, Health Canada had received 27 Canadian reportsa of adverse events that met Health Canada's criteria for being categorized as long-lasting or potentially long-lasting. There were 17 reports of long-lasting adverse events related to mefloquine use (lasting for 90 days or more) and 10 of potentially long-lasting (lasting between 30 and 90 days and the patient was reported as having not yet recovered). In addition, 37 international reports (from databases and published literature) of adverse events lasting for 90 days or more, including 5 reports of permanent damage to the vestibular system, were identified for further review.
  • The vast majority of the reports (61 out of 64) were deemed to have a possible link between the use of mefloquine and the long-lasting or permanent adverse events. However, the information provided in the reports was not enough to conclude that mefloquine use was responsible for the adverse event(s) reported.
  • When the prescription information is considered along with the number of reports deemed possible between the years 2000 and 2016, there were about 1.5 reports of long-lasting neurological or psychiatric adverse events for every 100,000 prescriptions filled in Canada.
  • The review also found that some patients were prescribed mefloquine even though they had past or ongoing neurological or psychiatric conditions, which are reasons not to use mefloquine (contraindications).
  • No additional factors that may put certain individuals or groups of individuals at increased risk of experiencing these long-term adverse events were identified.
  • The review of the literature did not identify a clear process (biological mechanism) to explain how mefloquine could cause rare long-lasting or permanent neurological and psychiatric adverse events.
  • Published studies conducted in cells and animals provided little evidence supporting the permanent nature of mefloquine-associated neurological adverse events. A small number of human studies, of which most were based on surveys of patients who had taken mefloquine, suggested that psychiatric adverse events could be long-lasting.
  • The current product information for mefloquine describes the potential for long-lasting neurological and psychiatric adverse events that aligns with the review findings. However, the risk of rare permanent vestibular damage could be more clearly explained in the Patient Medication Information section.

Conclusions and actions

  • Health Canada's safety review found limited evidence supporting that long-lasting and permanent neurological and psychiatric adverse events are caused by the use of mefloquine. The review also found that some individuals were prescribed mefloquine even though they had past or ongoing neurological or psychiatric conditions which are reasons not to use mefloquine.
  • Health Canada will be working with the manufacturer to update the Patient Medication Information section of the product information for mefloquine to better reflect the findings of the safety review. A notice will be issued in the Health Product InfoWatch to inform healthcare professionals and the public once the updates are completed.
  • In addition, a checklist will be developed to assist healthcare professionals in deciding whether to prescribe mefloquine to individual patients.
  • Health Canada will continue to monitor the safety information involving mefloquine, 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 if and when any new health risks are identified.

Additional information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international adverse reaction reports, and what is known about the use of this drug both in Canada and internationally. For additional information, contact the Marketed Health Products Directorate.

Health Canada is aware that the Department of National Defence has completed its own review of mefloquine to help protect the health and safety of members of our Canadian Armed Forces. Health Canada's review focused on the potential long-term neurological and psychiatric adverse events associated with mefloquine in all populations. The Department of National Defence's review focused on treatment options for malaria prevention (including mefloquine) and impact on ability to perform occupational tasks. Although the two reviews were different in scope, Health Canada considered the Department of National Defence's findings before finalizing its review. Please contact the Department of National Defence for information on their findings.

Footnotes

  1. Canadian reports can be accessed through the Canada Vigilance Online Database.

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