FDA Recommends Lower Bedtime Dose for Zolpidem

The US Food and Drug Administration (FDA) announced today a new recommendation that bedtime doses of the sedative-hypnotic zolpidem be reduced, on the basis of data showing morning blood levels in some patients may be high enough to impair activities requiring alertness, such as driving.

The recommendation applies to zolpidem products approved for bedtime use, marketed as generics and under the brand names Ambien, Ambien CR, Edluar, and Zolpimist. Data show the risk for morning impairment is highest with extended-release forms of these drugs, and women appear to be more susceptible to this effect because they eliminate zolpidem more slowly than men, a statement from the FDA notes.

"Because use of lower doses of zolpidem will result in lower blood levels in the morning, FDA is requiring the manufacturers of Ambien, Ambien CR, Edluar, and Zolpimist to lower the recommended dose," the FDA statement notes.

"FDA is continuing to evaluate the risk of impaired mental alertness with other insomnia drugs, including over-the-counter (OTC) drugs available without a prescription."

Specific recommendations are:

The dose of zolpidem for women should be lowered from 10 mg to 5 mg for immediate-release products (Ambien, Edluar, and Zolpimist) and from 12.5 mg to 6.25 mg for extended-release products (Ambien CR).

For zolpidem and other insomnia drugs, physicians should prescribe the lowest dose that treats the patient's symptoms.

Inform patients that impairment from sleep drugs can be present even if they feel fully awake.

The recommended doses of Intermezzo, a lower-dose zolpidem product approved for middle-of-the-night awakenings, are not changing. At the time of Intermezzo's approval in November 2011, the label already recommended a lower dosage for women than for men.

The FDA has prepared a list of questions and answers to provide an additional overview of this safety issue.

Ellis Unger, MD, director, Office of Drug Evaluation I in the Office of New Drugs, Center for Drug Evaluation and Research, at the FDA, addressed reporters during a conference call on this topic.

He said this change was not driven by any event in particular. Instead, it hinged on having data from driving simulation studies that were submitted to support approval of Intermezzo, along with pharmacokinetic data on residual blood levels the morning after a 12.5-mg dose. "As you read the Drug Safety Communication, you'll see that after taking that 12.5-mg dose, 8 hours later about a quarter of men and a third of women had a level in their bloodstream that exceeded 50 ng/mL," Dr. Unger said. "But by cutting that dose in half, you really significantly reduce the numbers of patients who have those kinds of levels."