Serious Drug Interactions Prevention

by Food and Drug Administration (FDA)

A single report of a drug reaction in a 39-year-old woman ultimately contributed to the removal of the allergy drug Seldane (terfenadine) from the market in 1998.

Doctors at the National Naval Medical Center in Bethesda, Md., admitted the woman to the hospital because of fainting episodes. She had been prescribed Seldane 10 days before. She also started using the prescription drug Nizoral (ketoconazole) for a vaginal yeast infection. That combination caused potentially fatal changes in her heart rhythm.

The case, published in 1990 in the Journal of the American Medical Association, prompted further investigation of abnormal heart rhythms related to Seldane. The Food and Drug Administration issued warnings indicating that ketoconazole interfered with Seldane's metabolism, which resulted in increased levels of Seldane in the blood and slowed its elimination from the body. The FDA also warned that a similar effect could occur if Seldane was taken with the antibiotic erythromycin. People with liver disease, another barrier to properly metabolizing the drug, were also at increased risk.

Approved by the FDA in 1985, Seldane was the first prescription antihistamine that didn't cause drowsiness. This was considered a big benefit because it lowered the risk of falls and other accidents. Though warnings and labeling changes about Seldane's newly found risks worked to some extent, the FDA determined that the potential for heart rhythm problems due to dangerous interactions was too risky. The drug was taken off the market when Allegra (fexofenadine), a safer alternative, was approved.

According to FDA experts, discovering Seldane's interactions with other drugs marked a significant advance. Other drugs with interaction problems similar to Seldane's were also identified around the same time. The discoveries improved the ability of the FDA and drug manufacturers to test for drug interactions and to investigate risks of heart rhythm abnormalities before drugs could be marketed. This, in turn, helped the FDA in its mission to protect the public against dangerous medicines and ensure safety.

Predicting Potential Problems

Early in a drug's development, companies conduct research to detect or predict potential interactions between drugs. FDA experts evaluate the drug-interaction studies as part of assessing a drug's safety. "We look at the issues that go into getting the best study design to identify drug interactions," says Larry Lesko, Ph.D., director of the FDA's Office of Clinical Pharmacology and Biopharmaceutics. "Once we have data in hand, we analyze the information and make decisions about whether a drug can be approved and how to communicate any risks of drug interactions to health professionals and consumers."

Mixing two drugs together could make one of the drugs ineffective. The combination also could increase a drug's effect, and be harmful. The result might be mild symptoms such as nausea, stomach upset, or headache, or more serious symptoms such as a dramatic drop in blood pressure, irregular heart beat, or damage to the liver-the primary way that drugs pass through the human body.

When a drug is taken orally, it usually travels from the stomach to the liver, where it can be metabolized-the process of breaking down and removing chemicals from the body. Enzymes are complex proteins that act as catalysts in starting or speeding up chemical reactions. They cause a specific chemical change in other substances without being changed themselves.

The most important enzymes in the liver that metabolize drugs are called the cytochrome P450 family of enzymes. These enzymes break down drugs when they pass through the liver or small intestine. Paul Watkins, M.D., professor of pharmacology at the University of North Carolina at Chapel Hill, says, "Just in the last 15 years, we've seen big advances in our ability to predict drug interactions because of the discovery of cytochromes P450 and what we've learned about the five major players in the family-CYP1A, CYP3A, CYP2C9, CYP2C19, and CYP2D6."

A drug may affect these enzymes by inhibiting them, which causes reduced activity of the enzyme and a buildup of the drug in the body. Or drugs may "induce" the enzymes, which causes increased activity of the enzyme and a reduction of the drug in the body. It turned out that ketoconazole inhibited the metabolism of Seldane through the CYP3A enzyme, causing a buildup of the drug in the blood. Found in the liver and the gastrointestinal tract, the CYP3A pathway metabolizes a majority of drugs on the market.

It used to be that the only way to test for drug interactions was in people, Watkins says. "Now drug companies can take five test tubes with the five major pathways for metabolism and put their drugs in to see whether it's metabolized by CYP450," he says. "This allows them to generate a list of possible interactions based on their findings."

This phase of research in test tubes, known as in vitro studies, allows researchers to perform drug-interaction studies in labs by testing a drug with other drugs that have the same route. "This has made the research faster and more accurate," says David Flockhart, M.D., Ph.D., chief of the division of clinical pharmacology at Indiana University's School of Medicine. "If two drugs go through the same enzyme, the presence of one drug can prevent the metabolism of the other. So this allows you to look at the worst-case scenarios and ask: 'What if we put this drug with that one, knowing that they have the same route?'"

Not everything that happens in a test tube will become meaningful in humans, though. "Results from these test-tube studies tell us whether we need to do further testing in people to find out if an interaction is clinically significant," says Steven Wrighton, Ph.D., a research fellow at Eli Lilly and Company in Indianapolis. "In vitro studies help us prioritize."

About the Author

www.fda.gov
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.