When potentially serious side effects of a prescription medication are well documented and become unreasonably dangerous, the drug may eventually be removed from the marketplace by the U.S. Food and Drug Administration. Usually, when the FDA believes it is clear that a drug no longer has a place in treatment, it will ask the manufacturer to withdraw the drug voluntarily. If a company does not agree, the FDA can bring formal proceedings to require withdrawal.

Many complex factors go into deciding whether a drug should be taken off the market. Here are some major issues, often overlapping, that weigh into the decision-making process.

Rare, Unpredictable Problems

Most drugs on the market are well-tolerated, and their adverse effects are known. Known side effects cause more injuries and deaths than unrecognized side effects. But some problems happen so infrequently that they can't be seen or predicted before a drug gets on the market. Drugs are typically tested in several thousand subjects, allowing for the detection of relatively common, serious adverse events, such as those affecting 1 in 1,000 people. The practical size of clinical trials means we can't know everything about a drug when it gets on the market. Rare events will only surface when the drug is used in larger numbers of people. Sometimes less severe events that are seen in trials can be used to predict the occurrence of rare, more serious events, but that is not always the case, and such predictions have considerable uncertainty.

More Toxic than Expected

There are also times when a drug's toxicity is known, but the drug turns out to be more toxic than the clinical trials suggested, which again may only be seen when the drug is used in larger numbers or in different ways.

Initially approved in 1997, Baycol (cerivastatin) was a member of a class of cholesterol lowering drugs known as "statins." Baycol and the other five drugs in its class--Lipitor (atorvastatin), Lescol (fluvastatin), Mevacor (lovastatin), Pravachol (pravastatin), and Zocor (simvastatin) -- have all been associated with rare reports of rhabdomyolysis, a condition that causes marked breakdown of muscle cells and can sometimes lead to fatal kidney failure and other problems.

Knowing this about the statin drugs, the FDA made sure to look for the problem when deciding to approve Baycol. But the agency didn't find unusual risk associated with the drug at that time.  When the FDA approved a higher dose of the drug after initial marketing, however, use of the drug grew, and the FDA saw clearly that Baycol caused rhabdomyolysis more frequently than the other drugs in its class. Problems with Baycol were reported most frequently when it was used at higher doses, used in elderly patients, and particularly, when used with another lipid-lowering drug called Lopid (gemfibrozil). Baycol was voluntarily withdrawn from the U.S. market in the summer of 2001.

When Safer Options Are Available

When the FDA approved Seldane (terfenadine) in 1985, the drug became the first prescription antihistamine to relieve allergies without causing drowsiness -- a side effect that can cause accidents and injuries. A few years after approval, it was discovered that Seldane could cause fatal heart rhythm irregularities when it was used together with drugs that slowed its elimination from the body, or in patients with liver disease.

Major efforts to warn against use by such patients were partly successful, but fatal rhythm abnormalities continued to be reported. Removal of the drug was considered, but that would have left only one non-sedating antihistamine on the market, so Seldane remained available.

When the drug Allegra came on the market in 1997, and was shown to provide exactly the same benefits of terfenadine but without the risk of the potentially fatal heart condition, the new availability of Allegra (fexofenadine) weighed heavily toward the ultimate decision to withdraw Seldane.

Dangerous Combinations

Like Seldane, a heart drug called Posicor (mibefradil) posed problems mainly when used with other drugs. Although Posicor itself did not have unusual toxicity, it was taken off the market in 1998 because of its interactions with at least 25 other drugs. It markedly increased the blood levels of those drugs, leading to potentially fatal side effects of the other medications.

When Posicor was first marketed in 1997, its labeling warned of possible interactions with three drugs. Two more drugs were later added, but reports of interactions and resulting adverse reactions with even more drugs kept coming. There was concern over whether it was realistic to expect physicians to be able to use Posicor safely, given the many drugs with which it interacted. In the absence of any special benefit of Posicor compared to other members of its class, such as effectiveness in people who didn't respond to other treatments, the FDA concluded that the drug should be removed from the market.