FDA Approves Vioxx and Avandia

By William T. Elliott, MD, FACP

Merck's entry into the cox-2 market, the highly anticipated rofecoxib (Vioxx) was approved by the FDA on May 21. The drug was approved for the treatment of osteoarthritis pain, menstrual pain and acute pain in adults. Rofecoxib joins Searle’s celecoxib (Celebrex) as the only drugs in this class of "safer" NSAIDs. Celecoxib was approved in December for the treatment of osteoarthritis and rheumatoid arthritis, and Merck is hoping that the pain indication for rofecoxib will be a marketing edge in what promises to be a very competitive drug class. Merck provided studies to the FDA that demonstrated equivalency of refocoxib to existing NSAIDs for the treatment of pain, the standard the FDA required for the indication. COX-2 inhibitors have a lower tendency to induce gastroduodenal ulcers than standard NSAIDs, and have no affect on platelet function. Their effect on renal blood flow is the same as existing NSAIDs. Rofecoxib is available in 12.5 and 25 mg tablets, and is taken once a day. The recommended dose is 12.5-25 mg/d for arthritis, and up to 50 mg/d for pain. The drug will cost about $2.50 per tablet for both strengths.

The FDA has also approved SmithKline Beecham's rosiglitazone (Avandia) for the treatment of type 2 diabetes as monotherapy, or, in combination with metformin. The drug is a thiazolidinedione similar to Warner Lambert's troglitazone (Rezulin), a drug that was recently the subject of new FDA restrictions because of the risk of liver toxicity. Although no liver toxicity was found in trials with rosiglitazone, the FDA is recommending liver enzyme monitoring every two months for the first two years of therapy. SmithKline is quick to point out however that they feel the risk for liver toxicity is low since it metabolized differently than troglitazone, and is less likely to cause drug - drug interactions. Lilly/Takeda's pioglitazone (Actos), the third drug is this class is also nearing approval.

One of the most important prevention trials is recent years is enrolling patients. The Study of Tamoxifen and Raloxifene (STAR) trial will enroll over 20,000 women who are at risk for breast cancer to compare effectiveness of the two drugs in preventing breast cancer. The study is being run by the National Cancer Institute at 400 centers in the US, Canada, and Puerto Rico. Women will be randomized to either tamoxifen 20 mg/day or raloxifene 60 mg/day for five years. Tamoxifen was shown to effectively reduce the rate of breast cancer in high-risk women in the Breast Cancer Prevention Trial published in 1998. Raloxifene is currently approved for the treatment of osteoporosis, but early studies suggest that it may be effective in preventing breast cancer. The STAR study is a head to head study, with no placebo group.

Should low molecular weight heparin become the standard for the treatment of inpatient deep venous thrombosis? While physicians and patients love the ease and the safety of low molecular weight heparin, hospital administrators have been concerned about the costs. A new study looked at the cost effectiveness of low molecular weight heparin vs standard unfractionated heparin, and found that the overall costs of care were similar with the two drugs. Cost savings favored low molecular weight heparin therapy if any of the following were true: there were fewer late complications, as few as 8% of the patients were treated as outpatients, 13% or more of patients were eligible for early discharge, or pharmacy costs were reduced by at least 31% (Ann Int Med 1999;130:789-799). These are all likely scenarios, especially when many hospitals are discharging the majority of patients early to self-administer the drug.The authors analysis suggests that low molecular weight heparin is cost-effective for this indication.

The FDA has issued a warning regarding Immunex’s recently approved rheumatoid arthritis drug etanercept (Enbrel). Postmarketing reports point to a higher than expected incidence of sepsis and other serious infections in treated patients, some of them fatal. The company has issued a "Dear Doctor" letter urging caution when using the drug in patients with infections or patients that are at risk of developing infections. Etanercept is a tissue necrosis factor (TNF) inhibitor that is given by subcutaneous injection twice weekly. The drug was initially studied as a potential therapy for sepsis, but the studies were halted when it was found that the mortality rate was higher in etanercept treated patients. According to the FDA, approximately 25,000 RA patients have been treated with etanercept, with reports of 30 serious infections including sepsis. Immunex plans to perform large, prospective studies to assess the risk of infection in patients treated with etanercept. In related news, the FDA recently granted etanercept an indication for juvenile arthritis. Immunex is also reporting early results from Phase III studies demonstrating effectiveness in slowing progression and reducing signs of early RA.

Is low-dose hormone replacement therapy (HRT) effective in preventing osteoporosis? A recent study looked at the lowest available dose of conjugated estrogen (0.3 mg/d) and medroxyprogesterone (2.5 mg/d) as a daily HRT regimen in preventing osteoporosis in women over the age of 65 (Ann Intern Med. 1999;130:897-904). When used with at least 1000 mg/ day of calcium and vitamin D, bone density increased by 3.5% over 3.5 years in an intention-to-treat analysis, and by 5.2% among patients with greater than 90% adherence to therapy. This compares favorably with reports of studies of higher dose regimens in elderly women. Adverse reactions to HRT tend to be dose-related, and many women desire lower dose regimens, hence the importance of this study.

Preven, Barr and Gynetic’s new emergency contraceptive kit has hit an unusual road block in marketing its product, many drug stores refuse to carry it. The kit, which is for use within 72 hours of unprotected sex, is mistakenly being called an "abortion drug," even though the primary effect of this combination kit of high-dose oral contraceptives is to prevent pregnancy. Recently Wal-Mart, one of the largest retail pharmacy chains in the country, announced that they would not stock Preven, and many local pharmacies have followed suit. The American College of Obstetricians and Gynecologists has roundly criticized this trend, arguing that the drug is no different in concept from other forms of contraception, and its ready availability will likely reduce the number of abortions in this country each year.