Summary Safety Review - Diclofenac - Risk of Major Heart and Stroke Related Adverse Events
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: 2014-10-06
issue
A safety review was conducted to evaluate the currently available information regarding the potential heart and stroke related risks with diclofenac-containing products in tablet and suppository forms (VOLTAREN and VOLTAREN SR, VOLTAREN RAPIDE, or ARTHROTEC and generic equivalents). The review was prompted by the results of a study published in the scientific journal, The Lancet (Bhala et al, 2013). This study indicated that diclofenac increases heart and stroke related adverse events more than other non-steroidal anti-inflammatory drugs (NSAIDs) and comparably to cyclooxygenase 2 (COX-2) inhibitors, a subgroup of NSAIDs which includes celecoxib.
Background
Approved use of diclofenac in Canada
Diclofenac is used for relieving pain and inflammation in conditions such as arthritis. Diclofenac is also used for the short-term treatment of pain and inflammation related to muscle, bone or soft tissue trauma, including sprains and pain following dental extractions. It belongs to a group of drugs called NSAIDs. Diclofenac was first marketed in Canada on December 31, 1989.
Heart and stroke related side effects
Serious heart and stroke related adverse events are rare, but are known potential side effects associated with the use of diclofenac and other NSAIDs. The risk of heart attack or stroke is higher in patients with a history of heart attack or stroke, or other risk factors for heart disease or stroke, including, angina, congestive heart failure, high blood pressure, high levels of fats in the blood, diabetes, and smoking. The risk of serious heart and stroke related adverse events is outlined in the product information available to the public.
Objective
To assess the available evidence concerning the association of diclofenac with an increased risk of serious heart and stroke related adverse events, especially in patients with a history of, or risk factors for heart disease or stroke. This review considered scientific and medical literature, Canadian patient reports and what is known about the use of this drug both in Canada and internationally.
Key findings
Use of diclofenac in Canada1
From 2008 to 2012, over 2 million prescriptions for oral diclofenac-containing products and around 30,000 prescriptions for rectal diclofenac-containing products were dispensed annually by pharmacies in Canada.
Canadian reports of serious heart and stroke related adverse events in Canada
From January 1, 2008 to December 31, 2012, Health Canada received 39 reports of serious heart and stroke related adverse events potentially associated with diclofenac use. One of these cases had a fatal outcome. Although some of the reports did not provide sufficient information for thorough analysis, a number of cases did suggest a possible role for diclofenac in causing the serious heart and stroke related adverse event.
Scientific reports
In 2008, Health Canada completed a safety review for diclofenac and found that diclofenac, especially at high doses (150 mg per day or more), is associated with an increased risk of serious heart and stroke adverse events. Information on the increased risk associated with the higher doses was included in the prescribing information for diclofenac-containing products. The current review investigated the more recent evidence published since 2008. The evidence confirmed the risk of serious heart and stroke adverse events in patients taking diclofenac for all indications, particularly at high doses (150 mg per day). Several large scale studies confirmed that users of diclofenac were at higher risk of heart and stroke related side effects than non-users as well as users of other NSAIDs.
Additionally, evidence suggests that diclofenac, particularly at higher doses (150 mg per day or more), is associated with an increased risk of heart and stroke related adverse events that is comparable to COX-2 inhibitors. The risk may increase with the dose and duration of use. Patients with a history of, or risk factors for heart disease, stroke or uncontrolled high blood pressure may be at greater risk.
International data2
At the time of this review, the World Health Organization (WHO) Global Individual Case Safety Reports Database System (VigiBase) contained 1740 heart and stroke related adverse events associated with diclofenac use. These heart and stroke related reports come from over 50 different countries.
The European Medicines Agency (EMA) also commissioned a review of the current evidence and issued a safety communication regarding the increased risk of serious heart and stroke related adverse events with diclofenac use which is comparable to the use of COX-2 inhibitors.
Conclusions and actions
Health Canada's review of the safety of diclofenac has found that diclofenac is associated with an increased risk of heart and stroke related adverse events that is comparable to COX-2 inhibitors, and that this risk should be considered when prescribing or taking diclofenac.
In order to further reduce the risks associated with diclofenac, additional information is being added to the prescribing information for diclofenac-containing products, which includes:
- Specifying that diclofenac at a higher dose (150 mg per day) is associated with an increased risk of heart and stroke related adverse events that is comparable to COX-2 inhibitors;
- Reducing the maximum daily dose for diclofenac from 150 mg to 100 mg for all indications, excluding VOLTAREN RAPIDE which allows for a 200 mg dose only on the first day of treatment for dysmenorrhea.
- Recommending that for patients with a high risk of developing a heart and stroke related adverse events, other treatment options that do not include NSAIDs, particularly COX-2 inhibitors and diclofenac, should be considered first.
The update to the prescribing information does not refer to topical formulations of diclofenac, such as gel or eye drops.
Health Canada has also issued a communication to inform healthcare professionals and patients about this risk and the changes to the Canadian prescribing information.
Health Canada has determined that the overall benefits of diclofenac continue to outweigh the risks, when used as recommended. Health Canada will keep Canadians informed and take action, as appropriate, if any new safety information is identified.
References
- Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects on non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382(9894):769-79.
- PRAC recommends the same cardiovascular precautions for diclofenac as for selective COX-2 inhibitors. London (UK): European Medicines Agency; 2013 June 14. (accessed 2014 Aug 28).
- Fosbøl EL, Gislason GH, Jacobsen S, et al. Risk of myocardial infarction and death associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009;85(2):190-7.
- McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med 2011; 8(9):e1001098.
- Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342:c7086.
Footnotes
- 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.
- World Health Organization (WHO) adverse reaction information provided by: The WHO Collaborating Centre for International Drug Monitoring. This information is not homogeneous with respect to the sources of the information or the likelihood that the health product caused the suspected adverse reaction. Also, this information does not represent the opinion of the WHO.
- 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.