The FDA and Merck Fielding Concerns About Vioxx
Pharmacology Watch

Merck announced on September 30th that it is voluntarily withdrawing rofecoxib (Vioxx) from the worldwide market. The decision was based on data from the APPROVe (Addenomatous Polyp Prevention on Vioxx) trial, a company sponsored perspective randomized, placebo-controlled trial designed to assess whether the drug reduces the risk of colorectal polyps in patients with a history of colorectal adenomas. However, after 18 months of the study, patients on 25 mg of rofecoxib were noted to have an increased risk of cardiovascular events such as myocardial infarction and stroke, compared to those patients taking placebo. The FDA supported Merck’s action and acknowledged that, while the risk to any individual on rofecoxib is small, the risk increases with continued use. The APPROVe trial showed that the risk of cardiovascular events with rofecoxib was twice that of placebo, according to information published on the FDA News website ( Previous studies, including a recently reported Kaiser Permanente/FDA retrospective trial, showed the risk to be 3 times that of placebo. The FDA is investigating whether cardiovascular risk may be a class effect of COX-2 inhibitors (coxibs), and is reviewing data from similar trials with celecoxib (Celebrex) and valdecoxib (Bextra). Meanwhile, Merck is initiating a buy-back program for unused Vioxx prescriptions, reimbursing patients for their unused prescriptions. The withdrawal has enormous implications for the company and its shareholders, not only from the loss of nearly $2 billion in revenues from drug, but lost share value for the company stock and the risk of future legal action. It is estimated that 2 million patients in the United States were taking Vioxx at the time of the withdrawal, and over 84 million people worldwide have taken drug at some point since its approval in May 1999. The October issue of the New England Journal of Medicine has 2 scathing reviews of Merck and the FDA with regard to the approval and marketing of rofecoxib. Dr. Eric Topol of The Cleveland Clinic, who was one of the first to raise concerned about rofecoxib, calls for a full Congressional review of this case. The senior executives at Merck, and the leadership of the FDA, share responsibility for not having taken appropriate action and not recognizing that they are accountable for the public health (N Engl J Med. 2004;351:1707-1709). Dr. Garrett FitzGerald of the University of Pennsylvania suggests evidence has been there all along that coxibs, including celecoxib and valdecoxib, may promote cardiovascular disease by blocking prostaglandin I2, which inhibits platelet aggregation, promotes vasodilation, and prevents the proliferation of vascular smooth muscle cells in vitro. At the same time, coxibs have little effect on thromboxane A2, which is responsible for platelet aggregation. Traditional NSAIDs and aspirin block thromboxane production, accounting for their cardioprotective effects. Dr. FitzGerald states, "It is essential to determine whether cardiovascular risk is or is not a class effect." The burden of proof now rests with those who claim that this is a problem for rofecoxib alone, and does not extend to other coxibs." (N Engl J Med. 2004;351:1709-1711).

Erythromycin and the Risk of Sudden Death

Erythromycin may be associated with an increased risk of sudden death, according to new study in the New England Journal of Medicine. Oral erythromycin, which is extensively metabolized by cytochrome P-450 3A (CYP3A), prolongs cardiac repolarization, and has been associated with reports of torsades de pointes. Commonly used medications that inhibit CYP3A may increase plasma erythromycin levels, increasing the risk of ventricular arrhythmias and sudden death. Researchers from Vanderbilt reviewed data from a Tennessee Medicaid cohort that included more than 1.2 million person-years of follow-up and 1476 confirmed cases of sudden death from cardiac causes. The patients in the study were relatively young, with a mean age of 45. Seventy percent were female, and 58% were white. The multivariate adjusted rate of sudden death from cardiac causes among patients using erythromycin was twice as high as that among those who had not used any of the study antibiotic medications (incident-rate ratio 2.01; 95% CI, 1.08-3.75; P = 0.03). There was no increase in sudden death among patients using amoxicillin, or former users of erythromycin. For patients who were taking erythromycin with concurrent use of a CYP3A inhibitor (nitroimadazole antifungal agent, diltiazem, verapamil, or troleandomycin), the adjusted rate of sudden death was 5 times as high (incident rate ratio 5.35; 95% CI, 1.72-16.64; P = 0.004). The authors conclude that erythromycin should be avoided in patients who are taking CYP3A inhibitors (N Engl J Med. 2004;351:1089-1096).

Vaccine Shortage Putting Americans At Risk

Just as healthcare providers are about to start their annual flu vaccination program, British regulators have shut down Chiron Corporation’s Liverpool flu vaccine manufacturing plant due to sterility problems. Chiron was expected to supply nearly 50 million doses of vaccine this year, half of the hundred million doses health officials expected to be administered to Americans this fall. Aventis, the other major supplier of vaccine, has told health officials that he could produce an additional million doses this year, but no more. Compounding the shortage, is the addition of 2 groups of patients recommended to receive the vaccine this year—children between the ages of 6 and 23 months (who require 2 doses 1 month apart) and pregnant women (or women who anticipate being pregnant during the flu season). Other high-risk patients include people over age 65, people in nursing homes, people with chronic illnesses, and those caring for people in these groups. Healthcare workers are also considered the highest priority for vaccination. The nasal flu vaccine, FluMist, does little to alleviate the shortage since it is only indicated for healthy children and adults between the ages of 5 and 49 years.

FDA Actions

The FDA will move ahead with warnings for many antidepressants stating that the drugs sometimes raise the risk of suicidal behavior in youth. The recommendation comes after an agency advisory panel, on a split vote, recommended a Black box warning. The agency may not go that far, however, since some advisors were concerned that warnings may discourage treatment of depressed children and teens who can benefit from antidepressants medications. The drugs subject to the warning are those with the brand names Prozac, Paxil, Wellbutrin, Zoloft, Celexa, Effexor, Luvox, and Remeron.

The recently approved antidepressant duloxetine (Cymbalta) has received FDA approval for treatment of pain associated with diabetic neuropathy. This is the first drug approved for this indication in this country. In 2 studies submitted to the FDA, the drug reduced 24-hour average pain levels, compared with placebo, in patients who had diabetes for an average of 11 years, and had neuropathic pain for average of 4 years.

The FDA has approved a new extended release formulation of hydromorphone for the management of persistent moderate-to-severe pain in patients requiring continuous, round-the-clock opioid pain relief for extended periods of time. The product is an extended release formulation that can be dosed once a day, and will be available in 12, 16, 24, and 32 mg capsules. The drug is only recommended for patients already receiving opioid therapy who have demonstrated opioid tolerance, and who require a minimum total daily opioid dose equivalent to 12 mg of oral hydromorphone. It will be marketed by Purdue pharmaceuticals with the trade name Palladone.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: