FDA Approves Intermezzo, First Drug for Early Wakening

Susan Jeffrey

Posted: 11/23/2011

November 23, 2011 — The US Food and Drug Administration announced today 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. They caution 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 maximum 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 side 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 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.