Wrong dose, bad news

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I often use sleeping pills containing zolpidem (Ambien is the predominant brand-name version) to help reset my biological clock when I travel across time zones, or if I just have trouble getting to sleep. And I'm not alone. Doctors wrote about 40 million prescriptions for it in 2012.

Although this drug has been used extensively for two decades, it was not until January that the U.S. Food and Drug Administration got around to recommending that women should receive a lower dose of zolpidem than men -- 5 milligrams instead of the standard 10. The reason is that as long as eight hours after taking it, women may have unacceptably high blood levels of zolpidem that can impair driving and other activities that require alertness.

Doctors have known for a long time that although zolpidem is quite safe and effective, it can have side effects, including drowsiness while driving and elaborate sleepwalking episodes that patients can't recall.

Gender-specific differences in the recommended dose of zolpidem should not come as a surprise to the medical community. There are, after all, other population subgroups for whom dosage adjustments of various medicines are needed: Aging, for example, causes important variations in responses.

For several reasons, older patients are far more likely to experience adverse drug reactions. For one thing, on average they take a larger number of drugs than younger people, which increases the likelihood that two or more will interact in a harmful way. Also, elimination of the drugs by the kidneys and liver is reduced.

Another interesting age-related anomaly concerns a decrease in total body water and a relative increase in body fat. (And women have a higher percentage of body fat than men.) Because of these changes, water-soluble drugs become more concentrated in the blood, and fat-soluble drugs have longer half-lives.

Similarly, there is wide variation in the ability of various ethnic groups and individuals to clear medications from the bloodstream. Drug safety and efficacy are affected by differences in the genes that code for enzymes that metabolize drugs. One genetic locus, for example, is responsible for the enzymes that degrade as much as 20 percent of commonly prescribed drugs. There are a large number of variants of this family of genes, some of which produce enzymes that perform poorly.

This phenomenon is important because (with the exception of drugs that must be converted in the body from an inactive to an active form) individuals with low-metabolizing enzymes clear certain drugs slowly and have more medication in their blood for longer periods than those with high-metabolizing ones.

To ensure that the cure isn't worse than the disease, regulators, medical professionals and patients need to be aware of the spectrum of individuals' responses to drugs, especially for those medicines that have a narrow therapeutic range or that can cause serious side effects when the levels are too high. To minimize adverse reactions, it is often prudent to start a new drug at a very low dose and to increase it until the desired effect is achieved.


Henry I. Miller is a physician and was founding director of the Office of Biotechnology at the FDA. He wrote this for the Los Angeles Times.


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