WASHINGTON -- Makers of sleep drugs containing zolpidem, including Ambien and Ambien CR, must cut the recommended dosages for women by half -- to 5 mg for immediate-release products and 6.25 mg for extended-release formulations -- to reduce morning drowsiness, the FDA announced Thursday.
Drug labeling should also recommend that healthcare professionals consider a lower dose for men, the agency said.
New data suggest that the drugs can leave levels of zolpidem high enough the morning after use to impair activities such as driving, the agency said.
The issue is especially acute in women, according to Ellis Unger, MD, director of the FDA's Office of Drug Evaluation I.
"We've learned here, rather recently, that women appear to be more susceptible to the risk of next-morning impairment because they eliminate zolpidem from their bodies more slowly than men," Unger told reporters in a telephone briefing.
The reason for the difference remains unclear, he said, adding it's "unusual" to have dosing recommendations that differ by sex.
Besides the Ambien products, the dosage change applies to the Edluar and Zolpimist branded products, as well as generic formulations.
"Over the years," Unger said, "we have received reports of possible driving impairment and motor vehicle accidents related to zolpidem."
But, he added, in most cases data was so sketchy -- lacking, for instance, information on blood levels of the drug or concomitant use of alcohol -- that it was "very difficult to point your finger at zolpidem."
For that reason, he said, the labeling changes are "not tied to any specific case or any specific reports of adverse events."
Instead, the changes are based on new evidence that, in some people, zolpidem levels the morning after use remain above 50 ng/mg of blood. Indeed, 8 hours after taking the extended release version of the drug, a quarter of men and a third of women had levels higher than that, Unger said.
And recent driving simulations, undertaken during the approval process for another zolpidem-containing drug, Intermezzo, suggested the 50 ng/mg level is high enough to cause impaired alertness.
"By cutting the dose in half, we really significantly reduce the numbers of people who have that kind of level," he said.
New drugs under development will be required to carry out similar driving simulations as part of the approval process, Unger said, and makers of approved drugs will be asked to do so as well.
Unger also said that next-morning impairment is a common side effect of all insomnia drugs, and alertness can be impaired even when people don't feel sleepy. The FDA is continuing to evaluate other sleep medications, he said.
Patients with a prescription for any of the drugs should continue to take them as prescribed, he said, until they can discuss the issue with their doctors.