Summary Safety Review - Prescription Oral Ibuprofen (Non-Steroidal Anti-inflammatory Drug) - Risk of Serious Heart and Stroke Adverse Events at High Doses

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: 2015-04-23

Product

Oral Ibuprofen (Non-steroidal Anti-inflammatory Drug; NSAID)

Potential Safety Issue

Risk of serious heart and stroke adverse events at high doses

Key Messages

  • Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used to treat pain, reduce fever, and relieve inflammation.
  • A safety review was initiated by Health Canada following the publication of a study, suggesting that ibuprofen at a daily dose of 2400 mg or higher increased the risk of serious heart and stroke related adverse events.
  • Health Canada's safety review determined that the overall benefits of ibuprofen continue to outweigh the risk when used as recommended. No evidence of an increased cardiovascular risk has been found for over-the-counter oral ibuprofen at a maximum daily dose of 1200 mg or less when taken for a short duration of time (7 days or less).
  • Prescription oral ibuprofen at high doses (a daily dose of 2400 mg or more) has been found to be associated with an increased risk of heart attack and stroke, especially in patients having a history of, or risk factors for heart disease or stroke. This risk increases with dose and duration of use. The maximum recommended daily dose for prescription ibuprofen in Canada is 2400 mg

Overview

A safety review was initiated by Health Canada to evaluate the possible link between heart and stroke related adverse events and the use of ibuprofen especially at high doses compared to other NSAIDs, including cyclo-oxygenase-2 (COX-2) selective inhibitors like celecoxib (Celebrex). This issue was identified by a published study, which found that ibuprofen at a daily dose of 2400 mg or more increased the risk of serious heart and stroke related adverse events. These findings were comparable to those associated with COX-2 inhibitors.

Use in Canada

  • Most ibuprofen-containing products are sold as over-the-counter drugs for use by adults and children to treat pain, reduce fever, and relieve inflammation. These products contain 400 mg or less of ibuprofen, and the maximum recommended daily dose of ibuprofen for these products is 1200 mg.
  • Products containing 600 mg of ibuprofen are available by prescription only for use by adults and children above 12 years to relieve the symptoms of arthritis (osteoarthritis and rheumatoid arthritis). The maximum recommended daily dose of ibuprofen for these prescription products is 2400 mg.
  • Approximately 780 000 prescriptions for 600 mg strength oral ibuprofen have been issued each year in Canada over the last 5 years (2010-2014).

Safety Review Findings

  • At the time of the review, Health Canada had received a total of 26 Canadian case reportsa of serious heart and stroke related adverse events suspected of being associated with ibuprofen use. In the majority of these reports, the daily doses were unknown. Of these reports, 15 cases were further evaluated to determine whether the use of ibuprofen was the cause of the heart and stroke related adverse events. Ibuprofen was found to be a possible cause of these adverse events in 11 of these cases.
  • Epidemiological data analyzed in the safety review suggested that there may be a slight increased risk of heart attack and stroke associated with ibuprofen at a daily dosage range between 1800 and 2400 mg, however additional studies would be needed to further assess this potential risk.
  • The safety review found that patients who take oral ibuprofen at a prescription daily dose of 2400 mg or more have an increased risk of heart attack and stroke when compared to patients who do not use ibuprofen. The risk is comparable to patients who take COX-2 inhibitors, a subgroup of NSAIDS that includes celecoxib. The risk increases when ibuprofen is taken for a long duration and among patients having a history of, or risk factors for heart disease, stroke, or uncontrolled blood pressure.

Conclusions and actions

  • Health Canada concluded that there was evidence of an association between oral ibuprofen at a daily dose of 2400 mg or more and an increased risk of heart attack and stroke related adverse events. This is comparable to those associated with COX-2 inhibitors. The overall benefits of ibuprofen continue to outweigh the risks when used as recommended.
  • Oral ibuprofen at a daily dose of 2400 mg should be avoided in patients with ischemic heart disease, cerebrovascular disease, congestive heart failure or with risk factors for cardiovascular disease.
  • The Canadian prescribing information for ibuprofen-containing products will be updated to reflect this new information.
  • The safety review did not find any evidence to show that ibuprofen presented an increased cardiovascular risk for over-the-counter use at the maximum daily dose of 1200 mg or less.
  • Health Canada continues to monitor the risk of heart attack and stroke associated with oral ibuprofen at a daily dose range between 1800 mg and 2400 mg. As new studies become available, these will be assessed and regulatory actions taken as appropriate.
  • Health Canada will continue to monitor adverse reaction information involving ibuprofen, 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 information on this risk is 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.

References

  1. Bhala N, Emberson J, Merhi A, et al. Coxib and traditional NSAID trialist CNT Collaboration group: Vascular and upper gastrointestinal effects on non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.Lancet 2013;382:769-79.

Footnotes

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

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