Pharmacology Update

The Latest Information on New Drugs and New Indications

Wyeth-ayerst laboratories announced a voluntary withdrawal of its NSAID pain reliever Duract (bromfenac) from the market on June 22. This follows reports of severe liver toxicity associated with the use of the drug, some resulting in liver failure, transplantation, and even death. Duract was approved for short-term management of pain-less than 10 days-an indication that was strengthened by a black box warning from the FDA in February. Despite this, cases of liver toxicity continued to be reported, primarily in patients taking the drug for longer than 10 days, prompting the company's dramatic move. Patients are advised to discontinue the drug immediately. Wyeth-Ayerst will be issuing a "Dear Doctor" letter to physicians and other health professionals with information about the withdrawal.

Viagra is generally safe and effective, but there is one absolute contraindication to the drug-its concomitant use with nitrates. Irreversible hypotension due to vasodilation from the combination of Viagra and nitrates may have contributed to several deaths across the country. Pfizer is now warning physicians about using the drug in patients who may have coronary disease. Inadvertent administration of nitroglycerin to a man having chest pain, commonly done by ambulance crews or by emergency department physicians, may become life-threatening if the man has recently taken Viagra. Patients on long-acting nitrates, or patients who take an occasional nitrate for angina should never be prescribed the drug, regardless of how long they say they have been off the nitrate.

"Natural progesterone" has finally been formulated in a way that ensures absorption into the gut. Progesterone that is identical to the hormone produced by the ovaries has been manufactured from wild Mexican yams for years. However, the drug has been so poorly absorbed that attempts at creating a commercial product have failed. Recently, the FDA has approved Prometrium (Solvay Pharmaceuticals), a micronized formulation that presents more drug to the surface of the gut, allowing better absorption. There is evidence from the PEPI trial that natural progesterone may have little effect on HDL cholesterol when used in a hormone replacement role as opposed to other progestins that tend to lower HDL (JAMA 1995;273:199-208).

Roche continues to have difficulty bringing its weight management drug, orlistat (Xenical), to the market. The company had hoped to have the drug approved and ready for marketing by mid-1997, but it now looks more likely that it will not be available until next year. Orlistat inhibits pancreatic lipase in the gut, blocking fat absorption. Although little of the drug is absorbed, there has been a trend toward higher rates of breast cancer in treatment groups in clinical trials. A large European trial is now in progress to evaluate the safety and efficacy of the drug.

In other bad news for Roche, the company announced June 8, 1998, that is was voluntarily withdrawing Posicor (mibefradil) from the market as a result of new information about potentially harmful interactions with other drugs. The list of drugs that were incompatible with Posicor had grown from three, at the time of the drug's release, to more than 25, including several statins. Roche has sent out a "Dear Doctor" letter to health providers apprising them of this action.

New delivery systems are becoming as cutting edge as new drugs. Aradigm Corporation has developed a pulmonary drug delivery system (AERxv) for insulin. Presented at the American Diabetes Association's 58th Annual Scientific Meeting, inhaled insulin is reported to work faster than subcutaneously injected insulin. The same company has a pain medication delivery system in phase II trials. Meanwhile, Aviron, Inc. is seeking FDA approval for a nasal-spray influenza vaccine for children. Biovector Therapeutics is also teaming with BioChem to develop an influenza vaccine nasal spray. These preparations are not only generally more acceptable to children, they also trigger mucosal IgA antibodies. Finally, genetically engineered plants are being developed with antigens that trigger immunity to certain diseases in humans. The early work is being done with potatoes grown with cholera antigen, but work is also being done with other diarrheal diseases and hepatitis B.

A court battle is ensuing between the FDA and Pharmanex, Inc. of California. The company is the manufacturer of the over-the-counter product Cholestin, a food additive marketed to lower cholesterol, that the FDA withdrew from the market in May. The FDA determined that Cholestin is an unapproved drug because it contains lovastatin and other naturally HMG-CoA reductase inhibitors derived from ground red yeast rice. The withdrawal was done under the terms of the Federal Food, Drug and Cosmetic Act, as amended by the Dietary Supplement Health and Education law enacted in 1994 to regulate the growing dietary supplement industry.

The FDA is in the final steps of approving the first Lyme disease vaccine. The monovalent vaccine, developed by SmithKline Beecham, is given in three shots at zero, one, and 12 months. The vaccine is most effective in those younger than 65 years. Long-term efficacy or side effects have not been studied. At least one other company, Pasteur Merieux Connaught, is also close to seeking approval for their own Lyme vaccine.

RU-486, the so-called abortion drug also known as mifpristone, has been shown to be effective in terminating early-term pregnancies in a multicenter study conducted for the first time in the United States (N Engl J Med 1998;338:1241-1247). The drug, when coupled with the prostaglandin misoprostol, was 75% effective in terminating pregnancy at 24 hours, with the highest success rate in women in the earliest stages of pregnancy. The Population Council has applied for FDA approval for the drug, but, so far, the group cannot find a pharmaceutical manufacturer willing to take on the political and social aspects of producing the drug.