Why Drugs Get Pulled Off the Market : More Toxic than Expected, Safer Options

by Food and Drug Administration (FDA)

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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. "In its first few years, Baycol had a small market share," says Sandra Kweder, M.D., acting director of the FDA's office of review management. "But when FDA approved a higher dose of the drug after initial marketing, use of the drug grew and we could see clearly that Baycol caused the problem more frequently than the other drugs in its class." Problems with Baycol were reported most frequently when it was used at higher doses, when used in elderly patients, and particularly, when used with another lipid-lowering drug called Lopid (gemfibrozil). Baycol was voluntarily withdrawn in the summer of 2001.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 in such patients were partly successful, but fatal rhythm abnormalities continued to be reported. According to Temple, removal of the drug was considered, but that would have left only one non-sedating antihistamine, so Seldane remained available.

"But the equation shifted when Allegra came on the market in 1997," Temple says. "Allegra provided exactly the same benefits of terfenadine but without the risk of the potentially fatal heart condition." So the new availability of Allegra (fexofenadine) weighed heavily in the 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 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 it interacted with. In the absence of any special benefit of Posicor compared to other members of its class, such as effectiveness in people who don't respond to other treatments, the FDA concluded that the drug should be removed from the market.

When taken at a higher than recommended dose and when taken with other drugs, Hismanal (astemizole), another non-sedating antihistamine approved in 1988, posed risks similar to Seldane. The drug was withdrawn in 1999, as safer alternatives became available.

Beginning about 1990, many potentially harmful interactions between drugs and even between drugs and foods (such as grapefruit juice) were noted with Seldane and other drugs. The discovery led to greater attention by the FDA and drug manufacturers to such interactions before drugs are marketed, Temple says. This represents a significant enhancement of safety assessment.

Improper Use

The term "safe" also depends on whether a drug is used according to the labeling. This is why the FDA makes sure labeling and advertising for prescription drugs are accurate and balanced — presenting both the benefits and the risks.

The major problem with Duract (bromfenac), a nonsteroidal anti-inflammatory drug, was that the directions were not followed. The pain drug was withdrawn in 1998 after liver failure occurred in patients who took the short-term treatment for pain for more than the 10 days recommended in the labeling. Clinical trials indicated that a higher incidence of elevated liver enzymes was associated with longer use. Duract's manufacturer, Wyeth-Ayerst Laboratories, Philadephia, added a new warning (Continued from page 14) to the labeling and sent letters out to doctors, but reports of long-term use of the drug continued.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.