Vioxx approved for Tx of rheumatoid arthritis

OB/GYN News, June 15, 2002 by Elizabeth Mechcatie

Changes to the precautions section and text have been added to the label for Vioxx, to reflect the findings of a trial that unexpectedly found a significantly higher rate of serious cardiovascular events in rheumatoid arthritis patients treated with the cyclooxygenase-2 inhibitor, compared with those on naproxen.

The changes also include the addition of gastrointestinal safety data from the same study, which found that GI side effects were significantly lower among subjects on Vioxx.

In April, the Food and Drug Administration approved those changes and a new indication for Vioxx: rheumatoid arthritis (RA). Vioxx, a nonsteroidal anti-inflammatory drug with selective cyclooxygenase-2 (COX-2) inhibitory properties, was approved in 1999 for primary dysmenorrhea, management of acute pain, and for the relief of the signs and symptoms of osteoarthritis. The generic name of Vioxx, marketed by Merck, is rofecoxib.

In a press release, the FDA said it approved the modifications based on the results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, a yearlong, prospective, randomized, double-blind study comparing about 4,000 patients with RA on 50 mg of Vioxx a day, twice the standard chronic dose, with about 4,000 patients on the standard 1,000 mg a day dose of naproxen.

The cumulative incidence of serious upper GI adverse events was significantly lower in the Vioxx-treated subjects. The rate was 0.52% for those on Vioxx vs. 1.22% among those on naproxen, more than a 50% reduction in risk.

However, results of the study revealed that the cumulative rate of cardiovascular (CV) thromboembolic events, such as myocardial infarctions, angina, and peripheral vascular events, was significantly higher among those treated with Vioxx than among those on naproxen (1.8% vs. 0.6%). In two smaller studies where a 25-mg dose of Vioxx was used, no differences in the serious CV event rates were seen.

At a meeting of the FDA's Arthritis Panel in February 2001, Merck representatives speculated that the difference in CV event rates was due to naproxen's cardioprotective effects, while an FDA official said that other explanations were a prothrombotic effect of rofecoxib or other factors.

But in the statement, the FDA said the "relationship of the cardiovascular findings in the VIGOR study to use of Vioxx is not known." After a careful review of the VIGOR results, the statement said, the agency had agreed with the expert panel's recommendations that information on the lower rate of GI side effects and the higher rate of serious cardiovascular events in Vioxx-treated subjects, compared with those on naproxen, be added to the labeling, The standard NSAID warning about the GI effects remains but adds that the results of VIGOR showed that the risk of GI toxicity with 50 mg of Vioxx a day is significantly less than with naproxen 500 mg a day.

The revised label also recommends that physicians "use caution" in prescribing Vioxx for patients with ischemic heart disease and that 50 mg a day is not recommended for chronic use.