Summary Safety Review - Cholinesterase Inhibitors (donepezil-, rivastigmine- and galantamine-containing products) - Assessing the Potential Risk of QT Interval Prolongation and Torsade de Pointes

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: 2022-07-19

Product

Cholinesterase inhibitors (donepezil-, rivastigmine- and galantamine-containing products)

Potential Safety Issue

Serious abnormal heart rhythm caused by abnormal electrical activity in the lower chambers of the heart (QT interval prolongation and torsade de pointes).

Key Messages

  • Cholinesterase inhibitors (donepezil-, rivastigmine- and galantamine-containing products) are authorized for sale in Canada to treat dementia (memory loss and mental changes) associated with Alzheimer's disease and/or Parkinson’s disease.
  • Health Canada reviewed the risk of QT interval prolongation and torsade de pointes associated with the use of cholinesterase inhibitors. This safety review was triggered by updates made to the product safety information for 2 cholinesterase inhibitors (donepezil and galantamine) by the European Medicines Agency (EMA).
  • At the time of the review, the Canadian product safety information (Canadian product monograph [CPM]) for cholinesterase inhibitors included differing information about QT interval prolongation and/or torsade de pointes. The purpose of this review was to assess whether any actions were required in Canada.
  • Health Canada’s review of available information supported a link between the use of all 3 cholinesterase inhibitors and the risk of QT interval prolongation and torsade de pointes. This risk is increased in patients with a history of certain heart conditions; a history or family history of QT interval prolongation; low levels of certain electrolytes, such as magnesium, potassium or calcium in the blood; or taking certain medications that can affect heart rhythm at the same time as the cholinesterase inhibitors.
  • Health Canada will work with the manufacturers of all cholinesterase inhibitors to strengthen the information in the CPM about the risk of QT interval prolongation and torsade de pointes. Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch communication.

Overview

Health Canada reviewed the risk of QT interval prolongation and torsade de pointes with the use of cholinesterase inhibitors. This safety review was initiated when Health Canada learned that the EMA had updated the product safety information related to this risk for 2 cholinesterase inhibitors (donepezil and galantamine).

At the time of review, the CPM for cholinesterase inhibitors included differing information about QT interval prolongation and/or torsade de pointes. The purpose of this review was to assess whether additional warnings or other actions for QT interval prolongation and torsade de pointes were required in Canada.

Use in Canada

  • Cholinesterase inhibitors are prescription drugs authorized for sale in Canada to treat dementia (memory loss and mental changes) associated with Alzheimer's disease and/or Parkinson’s disease.
  • Cholinesterase inhibitors have been marketed in Canada since 1997 under different brand names. Generic versions of all 3 cholinesterase inhibitors are also available. Cholinesterase inhibitors are currently available in various dosage forms, including patches, tablets (including rapidly disintegrating), capsules (including extended-release), and oral solution.
  • Cholinesterase inhibitors are widely used in Canada. About 3 million prescriptions were dispensed annually by Canadian retail pharmacies between 2016 and 2020, with donepezil being the most frequently dispensed, followed by galantamine and then rivastigmine.

Safety Review Findings

  • Health Canada reviewed the available information from searches of the Canada Vigilance databasea, international databases and published literature.
  • Health Canada reviewed 53 case reports (1 Canadian, 52 international) of QT interval prolongation and torsade de pointes in patients taking cholinesterase inhibitors. Of the 53 reports, 35 were for donepezil, 10 (1 Canadian) for galantamine, and 8 for rivastigmine.
    • For donepezil, 2 cases were found to be probably linked, 30 cases were possibly linked, 2 cases were unlikely to be linked and 1 case could not be assessed. Four deaths were reported (2 of which were determined to have a possible link and 2 unlikely to be linked).
    • For galantamine, 3 cases were found to be probably linked, 5 cases were possibly linked, 1 case was unlikely to be linked and 1 case (Canadian) could not be assessed. One death was reported and was unlikely to be linked.
    • For rivastigmine, 7 cases were found to be possibly linked and 1 case was unlikely to be linked.
  • Health Canada also reviewed 20 articles published in the scientific literature. There was limited evidence to support a link between the use of cholinesterase inhibitors and the risk of QT interval prolongation and torsade de pointes in these articles.

Conclusions and actions

  • Health Canada’s review supported a link between the use of all 3 cholinesterase inhibitors and the risk of QT interval prolongation and torsade de pointes, and determined that product information updates were warranted.

  • Health Canada will work with the manufacturers of all cholinesterase inhibitors to strengthen the information in the CPMs about the risk of QT interval prolongation and torsade de pointes. This update will also advise that the risk is increased in patients with a history of certain heart conditions; a history or family history of QT interval prolongation; low levels of certain electrolytes, such as magnesium, potassium or calcium in the blood; or taking certain medications that can affect heart rhythm at the same time as the cholinesterase inhibitors. Health Canada will inform healthcare professionals about these updates through a Health Product InfoWatch communication.
  • Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of cholinesterase inhibitors and other health products to the Canada Vigilance Program.
  • Health Canada will continue to monitor safety information involving cholinesterase inhibitors, 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 any new health risks be identified.

Additional information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of cholinesterase inhibitors both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

Footnotes

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