European authorities announce regulatory action on COX-2 inhibitors

Temporary measures in place to limit use of the drugs until a final review completes in April.

The European Medicines Agency is instituting several new safety restrictions on the use of cyclooxygenase-2 inhibitors. The changes follow a meeting by the Committee for Medicinal Products for Human Use (CHMP), held Feb. 15 to 17, which concluded that the available data on cyclooxygenase-2 (COX-2) inhibitors show an increased risk of cardiovascular adverse events. It also noted an association between duration of treatment, drug dose and the probability of suffering a cardiovascular event, according to a press release.

For all COX-2 inhibitors available in the European Union, the European Medicines Agency (EMEA) will now require the following: (1) a contraindication for use of all COX-2 inhibitors in patients with ischemic heart disease or stroke; (2) a contraindication for etoricoxib (Arcoxia, Merck & Co.) in patients with uncontrolled hypertension; and (3) a warning for physicians to use caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidemia, diabetes and smoking, and for patients with peripheral arterial disease.

The EMEA also now advises physicians to prescribe only the lowest effective dose for the shortest possible duration of treatment. The agency implemented these temporary measures while the CHMP completes its review of the COX-2 drug class, which is expected in April. The CHMP also concluded that more research is needed to evaluate the cardiovascular safety of COX-2 inhibitors and that ongoing cardiovascular trials should continue as planned.

Product recalls

The EMEA began its review of COX-2 inhibitors in October 2004 at the request of the European Commission after Merck & Co. Inc., manufacturers of Vioxx (rofecoxib), pulled its arthritis drug off the worldwide market in September.

Merck decided to recall the drug based on three-year data from its APPROVe (Adenomatous Polyp Prevention on Vioxx) trial. The trial, which enrolled 2600 patients randomized to receive either 25 mg of rofecoxib or placebo, sought to evaluate the drug for prevention of recurrent colorectal polyps in patients with a history of colorectal adenomas, according to an earlier report by Orthopaedics Today International ("Regulators and industry react to withdrawal of Vioxx," November/December 2004, page 23).

After 18 months of treatment, researchers noted an increased risk of confirmed myocardial infarction and stroke compared to patients receiving placebo. However, Merck said the increase was not noted during the first 18 months.

The EMEA held an informal meeting with Merck shortly after the recall and reviewed safety aspects of the drugs. Based on data available at that time, the scientific committee said the overall benefits of COX-2 inhibitors outweighed the risk of possible side effects for the target patient population.

However, it noted physicians and patients need to know about possible side effects involving the stomach, intestine, heart and skin.

For more information:

The European Medicines Agency (EMEA) public statement on its regulatory actions on COX-2 inhibitors can be found at the EMEA Web site.