Trovan Scrutinized by FDA
By William T. Elliott, MD, FACP
Pfizer’s trovafloxacin (trovan) has been the subject of intense scrutiny by the FDA in this country and the European Union’s Committee of Proprietary Medicinal Products. At issue is the risk of liver toxicity associated with the use of the antibiotic. Since trovafloxacin’s approval nearly 18 months ago, 140 cases of hepatic injury, 14 cases of acute liver failure, and at least five deaths have been linked to the drug. The European Union recommended that the drug be subject to a 12-month suspension, while the FDA took a more lenient stance, recommending that the drug only be started on patients who are hospitalized or in long-term nursing facilities, and that the drug only be used for limited indications. Trovan is available in both oral and intravenous forms (alatrofloxcin) and was initially approved for an unprecedented fourteen indications. Public Citizen, a consumer advocacy group, has been lobbying the FDA to withdraw the drug from the market in this country, a step the FDA is so far unwilling to take.
There is a battle brewing between three of the largest drug manufacturers over their new COX-2 inhibitors. Searle and Pfizer, who co-market celecoxib (Celebrex) have accused Merck, the manufacturer of rofecoxib (Vioxx), of stretching the truth regarding the merits of their drug. Celecoxib, which was approved in December 1998 and represented the only member of this new drug class of "safer NSAIDs," has recently been challenged in the marketplace by the approval of Merck’s drug. Rofecoxib, unlike celecoxib, was approved for the treatment of pain, in addition to the treatment of osteoarthritis. Now, Merck is claiming that a head-to-head study of the two drugs shows that rofecoxib had a faster onset of action, had better peak efficacy, and lasted longer. Searle and Pfizer say that the study, which was reported at a conference in Scotland and is yet to be published, used doses of the two drugs that were not equivalent. At stake is a market estimated to be more than $1 billion per year.
Is low-dose aspirin more effective than high-dose aspirin in preventing vascular events? It seems to be, at least for preventing perioperative complications in patients undergoing carotid endarterectomy. In a study from Canada (Lancet 1999;353:2179-2184), more than 2800 patients who were to undergo carotid surgery were randomized to daily doses of 81 mg, 325 mg, 650 mg, or 1300 mg starting the day prior to surgery. They continued the same dose for three months after surgery when they were evaluated for the outcomes of stroke, myocardial infarction (MI), or death. The stroke rate in the two low-dose groups was one half that in the higher dose groups (3.2% vs 6.9%). The result for MI was even more dramatic (0.9% low-dose vs 3.3% high-dose). The mortality rate was also lower in the low-dose group (1.6% vs 2.2%). These data help dispel the notion that higher doses of aspirin are needed to prevent stroke and heart attacks in high-risk patients.
There is increasing evidence that women treated with raloxifene (Evista-Lilly) have a lower incidence of breast cancer. The latest data come from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a multicenter study of more than 7700 postmenopausal women (JAMA 1999;281:2189-2197). Three groups of women were treated with either 120 mg of raloxifene per day, 60 mg of raloxifene per day, or placebo for a mean of 40 months. Women who had a history of breast cancer or were taking estrogen were excluded. There was a 76% reduction in the incidence of newly diagnosed invasive breast cancer in the raloxifene treated groups, almost all of it due to a reduction in estrogen receptor-positive breast cancer. During the MORE trial, lead author Cummings and his colleagues noted a higher risk of thromboembolic disease in the treatment group. Raloxifene is approved only for the treatment of osteoporosis and has also been shown to have minimal effect on endometrial tissue.
Several pharmaceutical houses are working on antivirals to treat common viral infections, especially influenza. Roche Pharmaceuticals may be the closest to actually bringing a product to market with oseltamivir, an oral neuraminidase inhibitor. The company has completed two Phase III studies and is analyzing data from several other studies performed in the most recent flu season. Glaxo Wellcome is also developing an anti-influenza neuraminidase inhibitor called zanamivir. Unlike oseltamivir, zanamivir is delivered by an inhalation system, but the delivery system has raised some concerns at the FDA because of the difficulty learning the appropriate inhalation technique.
Most of us have been taught since residency that treating hyponatremia with saline solution may be hazardous, even fatal, and that fluid restriction is the treatment of choice. Now, a study from Baylor and The University of California at San Francisco on 53 postmenopausal women with chronic symptomatic hyponatremia suggests that the opposite is true (JAMA 1999;281:2299-2304). Their study showed that fluid restriction was ineffective and was associated with severe adverse outcomes (including death in all the women who were treated in such a fashion). Conversely, all women treated with hypertonic saline showed no evidence of brain damage at one year. The study was a nonrandomized prospective study. An accompanying editorial suggests that fluid restriction should be abandoned as therapy for hyponatremia (JAMA 1999;281:2342-2343).
Celecoxib (Celebrex-Searle) may be considered as the anti-inflammatory of choice in patients on warfarin, since the drug has no effect on platelet aggregation. But several reports on increases in prothrombin times in patients taking warfarin and celecoxib concurrently have prompted Searle to issue a "Dear Doctor" letter regarding a potential drug interaction. They are recommending that anticoagulant activity should be monitored closely when initiating celecoxib in patients on warfarin. There have been no reports of bleeding due to the drug combination. There is no indication if Merck’s reofecoxib (Vioxx), the other COX-2 inhibitor currently available, has also been reported to increase INR by 8-11%, and requires monitoring when used concurrently with with warfarin.
Janssen’s astemizole (Hismanal) was one of the first nonsedating antihistamines available in this country. Soon after its release, however, reports started coming in to the FDA of arrhythmias and other severe reactions associated with use of the drug, especially when it was taken in combination with certain other drugs. Now, astemizole has met the same fate as terfenadine (Seldane) with Janssen’s announcement last month that it is voluntarily withdrawing astemizole from the U.S. market. The company said that the reason for the withdrawal is competition from other allergy medications—not safety concerns.
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