Denmark wants EU to take another look at NSAID safety
This article was originally published in SRA
Denmark’s drug regulator is seeking a further European Union review of the cardiovascular risks associated with non-steroidal anti-inflammatory drugs after a pharmaco-epidemiological study in an apparently healthy Danish population found an increased risk of heart attack or death not only in users of selective COX-2 inhibitors but in people taking over-the-counter painkillers such as diclofenac1.
The Danish Medicines Agency has taken the matter to the Pharmacovigilance Working Party (PhVWP) of the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). According to the EMEA, however, either the European Commission or a member state would have to raise the issue directly with the CHMP for a Europe-wide review of NSAID safety to be taken up2.
The Danish agency’s concerns stem from a study based partly on information from the Danish Register of Medical Product Statistics and published in the journal Clinical Pharmacology & Therapeutics3.
Researchers from the University Hospital of Copenhagen, the National Institute of Public Health in Copenhagen and Gentofte University Hospital in Hellerup used a historical cohort design to assess the risk of death and myocardial infarction associated with NSAID use in 1,028,437 individuals defined as healthy, in that they had no prior hospital admissions and were not taking specified drugs for heart disease. The average age of the participants was 40 years and the average duration of use for the NSAIDs was two to three weeks.
The results showed that, compared with not taking any NSAIDs, the hazard ratios (95% confidence limits) for death/myocardial infarction were 1.01 for ibuprofen, 1.63 for diclofenac, 0.97 for naproxen, 2.13 for rofecoxib and 2.01 for celecoxib. A dose-dependent increase in cardiovascular risk was seen with the selective COX-2 inhibitors (ie rofecoxib and celecoxib) and with diclofenac.
“It came as no surprise that the study found a statistically significant increased risk of heart attack or death from the use of the two COX-2 inhibitors,” the DMA commented. “What was more surprising was that the study also found an increased risk of death or heart attack from the use of especially diclofenac and to a lesser extent ibuprofen.”
With all the NSAIDS reviewed, the agency noted, there was an increased risk from the use of large doses compared with small doses, “but the statistically significant risk of death/heart attack was also present from the use of small doses of rofecoxib, celecoxib and diclofenac”. It described the findings as “disturbing”, particularly given that both diclofenac and ibuprofen at lower doses can be bought over the counter in Denmark and many other European countries.
The Danish regulator presented the study’s findings to the PhVWP during the week beginning 17 November, “with the aim of initiating a common European review of the safety of NSAID products relative to cardiovascular adverse reactions”. The DMA also asked its licensing committee, which advises the agency on cases concerning applications for – and annulment of – marketing authorisations for medicinal products and clinical testing of medicinal products, to look into the issue, with particular attention to whether medicines containing ibuprofen and diclofenac should retain their OTC status in Denmark.
“Until the results of these assessments are available, the DMA continues to recommend that NSAID products are used with caution, ie, in the smallest dose possible and for the shortest period of time possible,” it stated. NSAIDs should be prescribed only after careful consideration of the alternatives and only after weighing up the benefits and risks for the individual patient, including cardiovascular disease risks. Pharmacies should also advise consumers to use NSAIDs “with due consideration, and preferably in the smallest dose possible and for the shortest period of time possible”, the agency said.
CHMP recommendations
The recommendations were generally in line with those issued by the CHMP in October 2006 after, responding to a request from the French medicines agency, Afssaps, it reviewed the cardiovascular safety of non-selective NSAIDs4. That assessment found that diclofenac might be associated with an increased risk of arterial thrombotic events, particularly at high doses, while high doses of ibuprofen might be linked to a higher risk of thrombotic events – although epidemiological studies did not suggest low-dose ibuprofen was associated with an increased risk of myocardial infarction5.
In June 2007, the CHMP recommended restrictions on the use of medicines containing the NSAID piroxicam, due to the associated risk of gastrointestinal side effects and severe skin reactions6. Then in October the committee recommended restricting the use of painkillers containing nimesulide (also a non-selective NSAID) to limit the risk of liver injury7.
An EMEA spokesperson confirmed that the CHMP “has not started a European-wide review” of the cardiovascular risks of NSAIDs. To date, concerns over the Danish study had not been brought to the CHMP level. At this stage, the Danish findings were the responsibility of the national competent authorities, the spokesperson added, without ruling out the possibility that the issue might be taken further. This was because the NSAIDs had been approved at national level, not through the EMEA’s centralised procedure.While the PhVWP did meet at the EMEA, it had a “dual remit” whereby it examined issues relating to centrally authorised medicines but also those raised by individual member state representatives over nationally approved products, the spokesperson pointed out.
References
1. DMA announcement, 19 November 2008, www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=14412&newsletter=true
2. Personal communication, EMEA, 4 December 2008
3. Fosbøl EL, Gislason S, Jacobsen F 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, Clinical Pharmacology & Therapeutics, 2008, advance online publication 5 November 2008, doi:10.1038/clpt.2008.204, www.nature.com/clpt/journal/vaop/ncurrent/abs/clpt2008204a.html
4. The Regulatory Affairs Journal – Pharma, 2006, 17(11), 752-753
5. CHMP opinion, 18 October 2006, www.emea.europa.eu/pdfs/human/opiniongen/nsaids.pdf
6. The Regulatory Affairs Journal – Pharma, 2007, 18(8), 558
7. The Regulatory Affairs Journal – Pharma, 2007, 18(10), 696