Regulatory Focus™ > News Articles > Second Major Sleep Drug Associated With Impaired Driving as FDA Dials Back Recommended Dosing

Second Major Sleep Drug Associated With Impaired Driving as FDA Dials Back Recommended Dosing

Posted 15 May 2014 | By Alexander Gaffney, RAC

Second Major Sleep Drug Associated With Impaired Driving as FDA Dials Back Recommended Dosing

The US Food and Drug Administration (FDA) has again issued a warning about a sleep drug, this time requiring a labeling change for the popular sleep drug Lunesta after data indicated that some patients experienced long-lasting effects that could impair their ability to function, even after a full night's sleep.


Sleep drugs have long been on FDA's radar, primarily due to their association with impaired driving. The concern has been that some patients respond atypically to the sleep drugs, resulting in elevated levels of the drug which last until the next morning and impact activities that "require alertness, including driving."

In January 2013, FDA announced that it would require manufacturers of sleep drugs containing zolpidem to submit labeling changes to the agency. The requirement was seen as highly unusual in that the changes disproportionately affected women, whose recommended dose was cut in half.

 Old Recommended Dose New Recommended Dose
Ambien, Edluar, ZolpimistMen and Women: 10 mg once dailyWomen: 5 mg once daily

Men: 5 or 10 mg once daily

Ambien CRMen and Women: 12.5 mg once dailyWomen: 6.25 mg once daily

Men: 6.25 or 12.5 mg once daily

“Over the years, FDA has received spontaneous adverse event reports of driving impairment and motor vehicle accidents associated with zolpidem, but these reports lacked the information necessary to fully understand whether and how zolpidem affected people’s mental alertness and ability to drive,” Ellis Unger, director of the Office of Drug Evaluation, said at the time. “Recently, data from clinical trials and other types of studies have become available, which allowed FDA to better characterize the risk of next-morning impairment.”

“To decrease the potential risk of impairment with all insomnia drugs, health care professionals should prescribe, and patients should take, the lowest dose capable of treating the patient’s insomnia,” added Unger. “Patients who must drive in the morning or perform some other activity requiring full alertness should talk to their health care professional about whether their sleep medicine is appropriate.”

Prior to Zolpidem…

FDA regulators later took to the pages of the New England Journal of Medicine to defend their decision to require labeling changes, saying that their decision was informed in large part by their review of another sleeping drug, Intermezzo, a drug used to help people fall back asleep after waking in the middle of the night.

"The review and approval of Intermezzo was particularly informative, because a study was conducted to assess the relationship between blood zolpidem levels and driving impairment," FDA regulators wrote. "The study assessed patients three hours after taking the drug (the label instructs patients to take the product at least four hours before morning awakening) and revealed significant impairment in driving ability in patients whose blood concentration of zolpidem was above 50 ng per milliliter. Such impairment is thought to increase the risk of a motor vehicle accident."

This data would ultimately reveal the sex differences between zolpidem's effects, prompting FDA to require changes to the recommended dosing on the drugs' labeling.

The review also made clear that FDA could not rely on patient self-perception to gauge impairment. Data indicated that people affected by zolpidem impairment frequently didn't recognize the extent of their own impairment, the agency said.

FDA said in January 2013 that it would be requiring manufacturers of other sleep drugs to submit driving study data to the agency in order to support approval. In a press call in January 2013, FDA said it envisioned at least one well-conducted driving simulation study being used as the basis of a safety evaluation.

New Actions

Now FDA is requiring a labeling change for all drugs containing the active ingredient eszopiclone, better known by its brand name, Lunesta.

The drug, used to treat insomnia, is currently taken by about 920,000 patients in the US, and was prescribed three million times in 2013 according to FDA data.

"Data show that eszopiclone levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving, even if they feel fully awake," FDA said in a statement.

Similar to zolpidem-containing drugs, FDA said it would be reducing by half the recommended dose for both men and women, and recommend that patients take the lowest-recommended dose capable of treating their insomnia.

FDA said it was basing its decision on a 91-person study that indicated a 3 mg dose of Lunesta was associated with "severe next-morning psychomotor and memory impairment in both men and women 7.5 hours after taking the drug," and caused further impairments up to 11 hours after taking the drug.

Critically, FDA said the study indicated that the patients were unaware of the extent of their impairment.

FDA said it has already approved labeling changes to the Lunesta prescribing information and its patient Medication Guide (MedGuide) to account for the reduced recommended dosing. In the future, patients should be started on the 1 mg dose of the drug, and only increase to 2 mg or 3 mg "if needed" and in consultation with their healthcare provider.

FDA Statement

FDA Warning


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