FDA Recommends Lower Bedtime Dose for Zolpidem

Susan Jeffrey

Disclosures

January 10, 2013

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."

Although that still leaves some patients at risk, he said, "Risk mitigation is a tricky business, and for drugs, there are almost always risks. What we try to do is inform the public and mitigate the risk to the extent possible, and we think this is probably our best shot."

"But I want to note, very importantly, that next-morning impairment is not limited to zolpidem," Dr. Unger noted. "All sleep drugs have the potential to cause this, so for all sleep medications, healthcare professionals should prescribe, and patients should take, the lowest doses capable of preventing insomnia. The lower doses will decrease the potential for next-morning impairment and patients who must drive the next morning or performing other activities requiring full alertness should talk to their healthcare professional about whether sleep medicine is appropriate for them."

Dr. Unger confirmed that the FDA is encouraging manufacturers of other drugs to do these kinds of driving simulation studies and will require them in the future as a part of any new drug applications for sleep medications. After the announcement, the American Academy of Sleep Medicine (AASM) issued a statement on the dose changes with zolpidem.

Asked for comment on the changes, Nathaniel F. Watson, MD, a neurologist in Seattle, Washington, and member of the AASM Board of Directors, said sleep physicians have prescribed zolpidem safely for many years, "but the FDA has this concern and physicians certainly need to heed this recommendation. Certainly drowsy driving is a concern regardless of the cause, and any way we can reduce it is going to be helpful for public health."

He made the point, though, that although sleep medications are an important tool for treating insomnia, insomnia can be a symptom of other sleep illness, "and insomnia is a reason to refer a patient to a board-certified sleep specialist, and an AASM-accredited sleep laboratory in order to fully address the insomnia complaint."

Insomnia may, for example, stem from obstructive sleep apnea or restless legs syndrome, said Dr. Watson, "so unless you diagnose and treat the primary disorder, the insomnia is not really going to improve." There are also other nondrug treatments, such as cognitive-behavioral therapy, that can be as effective as or more effective than drugs, he said. As a reference for physicians, the AASM offers a comprehensive Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults.

More information on today's announcement is available on the FDA Web site.

Adverse events related to the use of zolpidem-containing products may be reported to MedWatch, the FDA's safety information and adverse event reporting program, either online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, or with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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