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U.S. Department of Health and Human Services

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Questions and Answers: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist)

The U.S. Food and Drug Administration (FDA) is notifying the public of new information about zolpidem, a widely prescribed insomnia drug. FDA recommends that the bedtime dose be lowered because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving. Today’s announcement focuses on zolpidem products approved for bedtime use, which are marketed as generics and under the brand names Ambien, Ambien CR, Edluar, and Zolpimist. 

FDA is also reminding the public that all drugs taken for insomnia can impair driving and activities that require alertness the morning after use. Drowsiness is already listed as a common side effect in the drug labels of all insomnia drugs, along with warnings that patients may still feel drowsy the day after taking these products. Patients who take insomnia drugs can experience impairment of mental alertness the morning after use, even if they feel fully awake.

FDA urges health care professionals to caution all patients (men and women) who use these zolpidem products about the risks of next-morning impairment for activities that require complete mental alertness, including driving. For zolpidem products, data show the risk for next-morning impairment is highest for patients taking the extended-release forms of these drugs (Ambien CR and generics). Women appear to be more susceptible to this risk because they eliminate zolpidem from their bodies more slowly than men.

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. FDA has informed the manufacturers that the recommended 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). FDA also informed the manufacturers that, for men, the labeling should recommend that health care professionals consider prescribing the lower doses―5 mg for immediate-release products and 6.25 mg for extended-release products (see Zolpidem Dosing Recommendations for Adults).

The following questions and answers provide an overview of this safety issue.

Q1.  What is zolpidem?
Q2.  Why is FDA requiring the manufacturers of certain zolpidem-containing products to revise the labeling to lower the recommended dose of zolpidem for women and to recommend consideration of the lower dose in men?
Q3.  What should patients currently taking the 10 mg or 12.5 mg dose of zolpidem-containing insomnia medicines do now?
Q4.  Will a lower dose of zolpidem be effective in treating insomnia?
Q5.  Is FDA requiring the manufacturer of Intermezzo (zolpidem tartrate) sublingual tablets to also change the dosing recommendations?
Q6.  Do any other factors, such as a patient’s age, weight, or ethnicity, have an effect on zolpidem levels?
Q7.  Why is FDA informing the public about this safety risk now, after zolpidem has been on the market for nearly 20 years?
Q8.  Is next-morning impairment the same as complex sleep-related behaviors?
Q9.  Is FDA requiring the manufacturers of other insomnia medicines to revise their dosing recommendations?
Q10.  Do other insomnia medicines have the same gender effect as zolpidem?
Q11.  Do over-the-counter (OTC) insomnia medicines that are available without a prescription have a risk of next-morning impairment?
Q12.  What can patients do to decrease their risk of next-morning impairment with insomnia medicines?
Q13.  How many reports of zolpidem and impaired driving has FDA received? Were these reports used as evidence to support the proposed new dosing recommendations for certain zolpidem-containing products?

Q1.  What is zolpidem?

A.  Zolpidem is a sedative-hypnotic (sleep) medicine that is used in adults for the treatment of insomnia. Zolpidem is available as an oral tablet (Ambien and generics), an extended-release tablet (Ambien CR and generics), a sublingual (under-the-tongue) tablet (Edluar), and an oral spray (Zolpimist).

Zolpidem is also available under the brand name Intermezzo, a lower dose sublingual tablet that is approved for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep.

Q2.  Why is FDA requiring the manufacturers of certain zolpidem-containing products to revise the labeling to lower the recommended dose of zolpidem for women and to recommend consideration of the lower dose in men?

A.  FDA is requiring the manufacturers of certain zolpidem-containing products to revise the labeling to lower the recommended dose of zolpidem-containing medicines for women and to recommend that health care professionals consider prescribing the lower dose for men because next-morning blood levels of zolpidem may be high enough to impair activities that require alertness, including driving. Patients with high levels of zolpidem can be impaired even if they feel fully awake. Zolpidem is eliminated from the body more slowly in women, so the drug can stay in their systems longer than it does in men.

Q3.  What should patients currently taking the 10 mg or 12.5 mg dose of zolpidem-containing insomnia medicines do now?

A.  If you are currently taking the 10 mg or 12.5 mg dose of zolpidem-containing insomnia medicine, continue taking your prescribed dose as directed until you have contacted your health care professional to ask for instructions on how to safely continue to take your medicine. Each patient and situation is unique, and the appropriate dose should be discussed with your health care professional.

Q4.  Will a lower dose of zolpidem be effective in treating insomnia?

A.  FDA has informed the manufacturers that the recommended 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 men, FDA has informed the manufacturers that the labeling should recommend that health care professionals consider prescribing these lower doses. These lower doses of zolpidem (5 mg for immediate-release products and 6.25 mg for extended-release products) will be effective in most women and many men.

Q5.  Is FDA requiring the manufacturer of Intermezzo (zolpidem tartrate) sublingual tablets to also change the dosing recommendations?

A.  No. When Intermezzo was FDA-approved in November 2011, the label already recommended a lower dosage in women compared to men. The recommended and maximum dose of Intermezzo is 1.75 mg for women and 3.5 mg for men, taken only once per night as needed if a middle-of-the-night awakening is followed by difficulty returning to sleep.

Q6.  Do any other factors, such as a patient’s age, weight or ethnicity, have an effect on zolpidem levels?

A.  Based on data from pharmacokinetic trials, no relationship was evident between the zolpidem blood level and patients’ body weight or ethnicity. In elderly patients, zolpidem blood levels can be higher, and the lower doses are already recommended. In contrast to younger patients, zolpidem blood levels in elderly patients are not affected by gender.

Q7.  Why is FDA informing the public about this safety risk now, after zolpidem has been on the market for nearly 20 years?

A.  Since the approval of zolpidem, FDA has been continually monitoring the drug’s safety profile. As more data became available, FDA continued to assess the benefits and risks of zolpidem treatment. Over the years, FDA has received reports of possible driving impairment and motor vehicle accidents associated with zolpidem; however, in most cases it was difficult to determine if the driving impairment was related to zolpidem or to specific zolpidem blood levels because information about time of dosing and time of the impairment was often not reported. Recently, data from clinical trials and driving simulation studies have become available that allowed FDA to better characterize the risk of driving impairment caused by specific blood levels of zolpidem and to recognize the increased risk of driving-impairing blood levels of zolpidem in women. This led FDA to require the manufacturers of certain zolpidem-containing products to revise the dosing recommendations.

Q8.  Is next-morning impairment the same as complex sleep-related behaviors?

A.  No, they are different. Next-morning impairment occurs when patients are awake the next morning, but levels of the insomnia medicine in their blood remain high enough to impair activities that require alertness, including driving.

Complex sleep-related behaviors occur when patients get out of bed while not fully awake, and sleep walk or do an activity such as drive a car, prepare and eat food, make phone calls, or have sex.

Both problems are made worse by high levels of zolpidem. The changes that FDA is requiring to the dosing recommendations in the drug labeling are expected to decrease the risk of both next-morning impairment and complex sleep-related behaviors.

Q9.  Is FDA requiring the manufacturers of other insomnia medicines to revise their dosing recommendations?

A.  No. At this time, FDA is only requiring the manufacturers of certain zolpidem-containing products to revise their dosing recommendations.

FDA is continuing to evaluate ways to lower the risk of next-morning impairment with other insomnia medicines.

Q10.  Do other insomnia medicines have the same gender effect as zolpidem?

A.  FDA is currently evaluating other insomnia medicines to determine if they affect men and women differently.

Q11.  Do over-the-counter (OTC) insomnia medicines that are available without a prescription have a risk of next-morning impairment?

A.  Yes. OTC insomnia medicines also have a risk for next-morning impairment. FDA is not recommending that patients who are currently taking prescription insomnia medicines switch to OTC insomnia medicines.

Patients who drive or perform activities that require full alertness the next morning should discuss with their health care professional if the insomnia medicine they are using is right for them.

Q12.  What can patients do to decrease their risk of next-morning impairment with insomnia medicines?

A.  Patients can decrease their risk of next-morning impairment by taking the lowest dose of their insomnia medicine that treats their symptoms. It is important for patients to take their insomnia medicine exactly as prescribed. Taking a higher dose than prescribed or using more than one insomnia medicine is dangerous if patients drive or perform activities that require full alertness the next morning, even if the drugs are taken at the beginning of the night. In addition, patients should not take insomnia medicine intended for bedtime use if less than a full night’s sleep (7-8 hours) remains. Likewise, patients should not take Intermezzo, a zolpidem product that is approved for use in the middle of the night, if less than 4 hours of sleep remain.

Q13.  How many reports of zolpidem and impaired driving has FDA received? Were these reports used as evidence to support the proposed new dosing recommendations for certain zolpidem-containing products?

A.  FDA has received about 700 reports of zolpidem and “impaired driving ability and/or road traffic accident.” Following a zolpidem label change in 2007, which added information to the Warnings and Precautions section of the label about complex sleep-related behaviors, including sleep-driving (patients getting out of bed while not fully awake and driving), there was a great deal of media attention. Since such publicity tends to “stimulate” reporting, this led to the considerable number of reports of zolpidem and impaired driving that were submitted to FDA’s Adverse Event Reporting System (AERS) database.

However, while AERS reports generally can be helpful in evaluating safety concerns, these AERS reports for zolpidem lacked the information necessary to understand whether high morning blood levels of zolpidem were the cause of the reported impaired driving. Specifically, these reports often did not include the dose or time zolpidem was taken, the time of the accident, whether alcohol or other drugs were also taken, and whether and when blood levels of the drug were measured. It wasn’t until FDA received the new data on next-day blood levels and driving simulation studies that the apparent frequency of next-morning mental impairment was better identified.