Insomnia, characterized by difficulty falling asleep or staying asleep, is a highly prevalent condition. On the basis of duration and frequency, insomnia can be classified ranging from mild to severe. Adverse consequences of insomnia may include excessive daytime sleepiness; lack of energy; anxiety; depression; irritability; and difficulty focusing on tasks, paying attention, learning, and remembering.
Zolpidem tartrate was first approved in the United States in 1992 as the drug Ambien. The newly approved formulation (Intermezzo) is a lower dose than Ambien, but it is still a federally controlled substance because of its potential for abuse or dependence. The drug is first approved drug for people who wake in the middle of the night and can't fall back asleep. The FDA advises that the individual should have at least 4 hours of sleep time remaining before they have to get up.
This new drug preparation is discussed in a recent Medscape issue for physicians.
Study Synopsis and Perspective
The US Food and Drug Administration (FDA) announced approval for zolpidem tartrate sublingual tablets (Intermezzo, Transcept Pharmaceuticals Inc.) for use as needed for insomnia characterized by middle-of-the-night wakening followed by difficulty returning to sleep.
This is the first time the FDA has approved a drug for this indication, the agency notes in a statement. It cautions that the drug should only be used when there are at least 4 hours of bedtime remaining.
Zolpidem tartrate was first approved in the United States in 1992 as Ambien (sanofi-aventis), the statement notes; Intermezzo is a lower-dose formulation of zolpidem. The recommended and maximal doses of this new formulation are 1.75 mg for women and 3.5 mg for men, taken once per night.
The recommended dose for women is lower because women clear zolpidem from the body at a lower rate than men, the statement notes. It should not be taken if alcohol has been consumed or with any other sleep aid, the agency adds.
"For people whose insomnia causes them to wake in middle of the night with difficulty returning to sleep, this new medication offers a safer choice than taking a higher dose of zolpidem upon waking," said Robert Temple, MD, deputy center director for clinical science in the FDA's Center for Drug Evaluation and Research. "With this lower dose there is less risk of a person having too much drug in the body upon waking, which can cause dangerous drowsiness and impair driving."
This formulation was studied in 2 clinical trials involving more than 370 patients. In the studies, patients taking the drug had a shorter time to fall back asleep after waking compared with those receiving placebo. The most commonly reported adverse reactions were headache, nausea, and fatigue.
As with other sleep medications, this formulation may cause serious adverse effects, including getting out of bed while not fully awake and doing an activity that patients do not know they are doing or do not remember having done, the FDA statement notes. Reported activities while under the influence of sleep medications include driving a car, making and eating food, having sex, talking on the phone, and sleep walking — without knowing at the time or remembering later. Chances of such activity increase if a person has consumed alcohol or has taken other medications that cause drowsiness. Zolpidem is a federally controlled substance because it can be abused or lead to dependence, the statement notes.
In 2009, Transcept Pharmaceuticals received a complete response letter from the FDA for the zolpidem formulation in Intermezzo because of concerns about a safe dosing strategy that would prevent users from taking the drug with less than 4 hours of bedtime remaining, or inadvertently taking a double dose in 1 night.
At that time, the FDA requested additional data demonstrating that zolpidem does not present an unacceptable risk for next-day residual effects when used according to its proposed label. Regulators put special emphasis on driving safety.
The company resubmitted in January 2011, and this summer, the agency rejected zolpidem again because of similar concerns. In September, after meeting with the FDA, the company announced it would resubmit the new formulation without conducting additional studies.
More information on newly formulated zolpidem is available on the FDA Web site.
Clinical Implications
- The FDA has approved a new formulation of zolpidem tartrate sublingual tablets for use as needed for insomnia in which awakening in the middle of the night is followed by difficulty returning to sleep. This drug is the first to be approved by the FDA for this specific indication.
- Zolpidem tartrate should be given once per night, as needed. The recommended and maximal doses are 1.75 mg for women and 3.5 mg for men, which are lower than provided in Ambien. This new dosage is thought to be safer than taking a higher dose of zolpidem on waking, with less risk for dangerous drowsiness and/or impaired driving caused by excessive blood levels of the drug on waking.
- Zolpidem tartrate should be taken only if there are 4 or more hours of bedtime remaining. It should not be taken if alcohol or any other sleep aid has been ingested that evening or during the night. Headache, nausea, and fatigue were the adverse reactions most commonly reported in clinical trials. As with other sleep medications, zolpidem tartrate has the potential for abuse and/or dependence and may result in serious adverse effects.
