Summary Safety Review - Levetiracetam and Methotrexate - Assessing the Potential Risk of Drug-Drug Interaction

October 24, 2016

Product

Levetiracetam and methotrexate

Potential Safety Issue

Drug-drug interaction

Key Messages

• Levetiracetam is used to help epilepsy treatment be more effective. Methotrexate is used to treat cancer or to treat arthritis.
• A safety review was carried out after a scientific article^{Footnote 1} was published regarding the potential interaction between levetiracetam and methotrexate, as well as the issue being reviewed by the European Medicines Agency.
• Health Canada's review concluded that there are risks of serious side effects when these drugs are taken together and recommended that the product information for levetiracetam and methotrexate products be updated to inform about this drug interaction. Product labelling now recommends that the amounts of levetiracetam and methotrexate be carefully monitored in the blood when patients are treated with the two drugs at the same time.

Overview

Health Canada carried out a safety review after learning that the European Medicines Agency was looking into a potential interaction between levetiracetam and methotrexate. The interaction between the two drugs may lead to higher amount of methotrexate in the blood, which may cause serious side effects. The side effects, which can be fatal, include sudden (acute) kidney failure.

Use in Canada

• Levetiracetam is a drug used to help epilepsy treatment be more effective. Levetiracetam is available in Canada as oral tablets. It has been marketed under the brand name Keppra since 2003. Generic versions are also available.
• Methotrexate is a drug used to treat cancer and also arthritis at a lower dose. Methotrexate is available in Canada as oral tablets and as an injectable liquid. It has been marketed since 1955 under various brand names and generic versions are also available.
• Given its potential serious side effects, methotrexate is used to treat life-threatening stages of cancers, and in patients with disease in the joints (arthritis) severe enough to cause disability, and when standard treatments have failed.

Safety Review Findings

• At the time of the review, there were no reported cases, in the Canada Vigilance Database, of patients who had received levetiracetam and methotrexate at the same time.
• The manufacturer of levetiracetam provided 13 international reports of a potential interaction between levetiracetam and methotrexate. The review of these reports was limited by many factors such as pre-existing diseases, other medications taken, and lack of laboratory data (e.g. blood levels of methotrexate).
• Of these 13 reports, 5 reports noted that patients who were taking both levetiracetam and methotrexate at the same time had greater amounts of methotrexate in their blood.
• Some of these 13 reports noted side effects to the kidneys when levetiracetam and methotrexate were taken together. Kidney damage and a sudden failure of the kidneys is a known potential side effect when taking methotrexate; this risk is mentioned in the product safety information.

Conclusions and Actions

• Health Canada's safety review found that there is a potentially greater risk of side effects when levetiracetam and methotrexate are taken together.
• The assessment recommended that the product information for levetiracetam and methotrexate products be updated to inform about this drug interaction. Product labelling now recommends that blood methotrexate and levetiracetam levels should be carefully monitored in patients treated with the two drugs at the same time.
• Health Canada will continue to monitor side effect information involving levetiracetam and methotrexate, 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.

Reference