The Vioxx labeling change will allow Merck to discuss the COX-2 inhibitor's cardiovascular safety profile in the context of a rheumatoid arthritis indication and a gastrointestinal safety benefit.

FDA approved the addition of data from the Vioxx Gastrointestinal Outcomes Research study to product labeling April 11. Vioxx (rofecoxib) received approval for treatment of the signs and symptoms of rheumatoid arthritis the same day.

Merck appears to have concluded its labeling discussions with FDA with the best possible outcome: the only change to the Vioxx warnings section is a positive statement on GI safety, and new information on increased risk of cardiovascular thrombotic events, included in the precautions section, is balanced by caveats and additional data.

The cardiovascular risk information leads off with the statement: "The information presented below should be taken into consideration and caution should be exercised when Vioxx is used in patients with a medical history of ischemic heart disease." Merck estimates that 10% of arthritis patients have existing ischemic heart disease.

Labeling cites CV data from VIGOR: "The risk of developing a serious cardiovascular thrombotic event was significantly higher in patients treated with Vioxx 50 mg once daily (n=45) as compared to patients treated with naproxen 500 mg twice daily (n=19)." Mortality due to thrombotic events was similar between the treatment groups, with seven deaths in Vioxx patients versus six for naproxen.

CV data from VIGOR is also balanced in labeling by placebo-controlled studies that lend support to Merck's argument that naproxen has a cardioprotective benefit. In two trials on 2,142 elderly patients, the number of serious thrombotic events was 21 for Vioxx 25 mg, versus 35 for placebo. Mortality due to thrombotic events was eight for Vioxx versus three for placebo.

Vioxx' precautions section also notes VIGOR was not prospectively designed to look at CV effects.

The significance of CV findings from VIGOR and the two placebo-controlled studies is "unknown," labeling says. "Prospective studies specifically designed to compare the incidence of serious CV events in patients taking Vioxx versus NSAID comparators or placebo have not been performed."

Merck is conducting a CV safety study with Vioxx and its COX-2 follow-on Arcoxia (etoricoxib); earlier plans called for enrollment of 30,000 patients (¹ Also see "Merck COX-2 Cardiovascular Safety Studies Will Enroll 30,000 Subjects" - Pink Sheet, 17 December, 2001., p. 12). Merck said it is in the process of finalizing its plans for the study.

The Vioxx labeling change follows FDA advisory committee recommendations to include both GI safety benefits and CV risk factors from the VIGOR study (² [A#00630070000], p. 3).

Also consistent with the committee's recommendations on GI toxicity, the revised Vioxx label does not remove the NSAID class warning, but immediately follows it with a new safety statement. "Although the risk of GI toxicity is not completely eliminated with Vioxx," labeling says, VIGOR results "demonstrate that in patients treated with Vioxx, the risk of GI toxicity with 50 mg once daily is significantly less than with naproxen 500 mg twice daily."

Noting that the GI risk reduction was maintained in patients with or without risk factors, Merck expects to see "additional demand for Vioxx among lower GI risk patients," U.S. Human Health President David Anstice told investors April 11. The modified warning will also encourage managed care organizations that do not have Vioxx on formulary to include it, he added.

The marketing challenge for Merck will be to reverse the damage done last year by an article published in the Journal of the American Medical Association suggesting an adverse CV effect with COX-2 inhibitors (³ Also see "FDA Anti-Inflammatory Division Director Will Be Celebrex Investigator Simon" - Pink Sheet, 3 September, 2001., p. 3).

Pharmacia's discussions with FDA over Celebrex GI label changes are ongoing. The FDA committee voted against any changes to the celecoxib label, but later agreed that Pharmacia could add its GI data. Celebrex showed a GI advantage over ibuprofen as a secondary endpoint only (⁴ Also see "COX-2 Class Labeling From Vioxx/Celebrex Data Proposed By FDA Consultant" - Pink Sheet, 19 February, 2001., p. 11).

Vioxx' approval for RA was based on two 12-week trials in 2,000 patients. The indication puts it on par with Celebrex in arthritis and analgesic indications.

Vioxx Label Balances CV Risk With GI Safety: Can Merck Reverse Damage?

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