Health Canada
Symbol of the Government of Canada

Common menu bar links

Drugs and Health Products

Summary Safety Review - ARICEPT (donepezil) - Risk of Rhabdomyolysis and Neuroleptic Malignant Syndrome

January 21, 2015

Issue

A safety review was conducted to evaluate the available information on the potential risk of rhabdomyolysis (muscle breakdown) and/or Neuroleptic Malignant Syndrome (NMS), a life-threatening neurological disorder associated with donepezil. The review was prompted by a case of rhabdomyolysis reported to Health Canada.

Background

Approved use of donepezil in Canada

Donepezil is used to treat the symptoms of Alzheimer's disease. Donepezil has been marketed in Canada under the brand names ARICEPT® since 1997 and ARICEPT® Rapidly Disintegrating Tablet (RDT) since 2006. As of November 2014, 16 companies have also received authorizations to sell generic donepezil in Canada.

Risk of Rhabdomyolysis

Rhabdomyolysis is a condition that results in the breakdown of muscle tissue. Typical clinical symptoms can include muscle pain, fever, weakness, nausea, and dark urine. Rhabdomyolysis can lead to life-threatening abnormal heart rhythms and kidney failure. Rhabdomyolysis can be drug-induced, but can also happen due to chemicals causing muscular damage, physical overexertion or other causes.

Risk of Neuroleptic Malignant Syndrome (NMS)

NMS is a rare life-threatening condition with changes in the nervous, muscular and cardiovascular systems. Symptoms of NMS include fever, mental changes, agitation, delirium, and muscle rigidity that can potentially lead to rhabdomyolysis. NMS is most often associated with the use of antipsychotics and dopamine enhancing drugs. It is believed that NMS is caused by an imbalance in brain cell chemicals.

Objective

To assess the available evidence concerning the risk of developing rhabdomyolysis and/or NMS with the use of donepezil. The evidence considered included Canadian adverse reaction reports, scientific and medical literature, as well as what is known about the use of this medicine in Canada and internationally. The review evaluated the risks and suggested ways to minimize it. Since there is overlap in clinical symptoms of rhabdomyolysis and NMS relating to muscle pain/rigidity, and in several of the cases, both medical conditions were reported, the risks of rhabdomyolysis and NMS were reviewed together.

Key Findings

Use of donepezil in CanadaFootnote 1

The number of donepezil prescriptions filled in community pharmacies in Canada has been increasing at a rate of approximately 10% annually since 2008. It is estimated that 2,041,755 prescriptions of donepezil, both brand name and generic were dispensed in Canada in 2013.

Canadian reports of rhabdomyolysis and/or NMS associated with the use of donepezil

As of June 30th 2014, Health Canada received one Canadian report of rhabdomyolysis with donepezil. The report described an incident in a patient taking donepezil among other medications. The patient recovered. The event of rhabdomyolysis was found to be possibly related to donepezil. As of 30-Jun-2014, there have been no Canadian cases of NMS reported with donepezil.

Scientific reports and international data

Health Canada asked the brand name manufacturer of donepezil products to submit their case reports of rhabdomyolysis and NMS. A total of 88 international cases of rhabdomyolysis and 67 international cases of NMS with donepezil were received and reviewed. Most cases of rhabdomyolysis or NMS occurred alone but some cases presented both conditions. There were 3 fatal cases associated with rhabdomyolysis, and 9 fatal cases with NMS. The majority of fatalities occurred in Japan. The prescribing information for health care professionals in other countries (i.e. Europe, Australia, and Japan) includes the risk of rhabdomyolysis resulting from NMS.

Conclusions and Actions

The available evidence suggests that rhabdomyolysis and/or NMS may occur with donepezil use. The prescribing information for ARICEPT® and ARICEPT® RDT has been updated to include the possible risks of rhabdomyolysis and NMS. Manufacturers of generic products will also update their product information. It is important for healthcare professionals and patients to be aware of the possibility of these rare serious reactions, and for steps to be taken for early detection of rhabdomyolysis and/or NMS. Health Canada has issued an Next link will take you to another Web site Information Update to inform health care professionals and Canadians of the risks of rhabdomyolysis and/or NMS for donepezil. Health Canada will keep Canadians informed and take action, as appropriate, if any new safety information is identified.

Additional Information

For additional information, contact the Marketed Health Products Directorate.

ReferencesFootnote 2

Grace JB, Thompson P. Neuroleptic malignant like syndrome in two patients on cholinesterase inhibitors. Int J Geriatr Psychiatry 2006; 21(2):193-4.

Sahin OZ, Ayaz T, Yuce S, et al. A Rare Case of Acute Renal Failure Secondary to Rhabdomyolysis Probably Induced by Donepezil. Case Rep Nephrol 2014;2014:214359.

Warwick TC, Moningi V, Jami P, et al. Neuroleptic malignant syndrome variant in a patient receiving donepezil and olanzapine Nat Clin Pract Neurol 2008; 4(3):170-4.

Footnotes

Footnote 1

IMS utilization data provided by: IMS Health Canada Inc, An external party cannot refer to nor use IMS data, which have been generated by Health Canada, without a Third Party Agreement in place.

Return to footnote 1 referrer

Footnote 2

This list of references is not intended to be exhaustive. References have been selected as suggestions for further reading and reflect the most current information at the time of the safety review.

Return to footnote 2 referrer