Regulatory Focus™ > News Articles > Top CDER Regulators Explain Logic Behind Sleep-Aid Restrictions, New Requirements

Top CDER Regulators Explain Logic Behind Sleep-Aid Restrictions, New Requirements

Posted 08 August 2013 | By Alexander Gaffney, RAC

Months after requiring labeling changes for sleep-aid drugs containing the active ingredient zolpidem in light of their potential to cause dangerous effects, particularly in women, several prominent regulators with the US Food and Drug Administration (FDA) are casting more light on that decision, writing in the New England Journal of Medicine (NEJM) that the specific attributes of the drug and its effects prompted its unusual actions.


Zolpidem is the primary active ingredient in the sleep-aid drugs Ambien, Ambien CR, Edluar and Zolpimist.

In January 2013, FDA announced it would require all manufacturers of products containing the ingredient to submit labeling changes to the agency that would have the effect of reducing the recommended daily intake for the drug.

Perhaps most interesting of all was the announcement's recommendation with respect to dosing differences between genders. Prior to the announcement, men and women were prescribed the medicine at the same doses: Either 10 mg or 12.5 mg.

The problem, regulators said, was that the drug seemed to remain effective-particularly in women-for hours after its effects should have worn off, causing impaired driving and reaction times, putting their lives and the lives at others at risk.

"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, wrote 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."

As a result, FDA said it would require new labeling and dosing information to be submitted from sponsors, with the new dosing recommendations being cut in half for women from their current recommended levels. Men, however, could continue to take the old recommended doses of the drug, but were also recommended to take the "lowest dose capable of treating the patient's insomnia."



Old Recommended Dose

10 mg / 12.5 mg

10 mg / 12.5 mg

New Recommended Dose

Optional: 10 mg / 12.5 mg /

Recommended: 5 mg OR 6.25 mg

5 mg / 6.25 mg

Changes Made to Labels and Expectations

As Focus reported in May 2013, those labeling changes have already been approved by FDA and gone into effect, affecting Sanofi's Ambien and Ambien CR, Meda Pharmaceuticals' Edluar and Novadel's Zolpimist, a spray version of the drug. 

A press call in January 2013 on the changes indicated that FDA would require similar sleep drugs to submit driving study data to the agency in order to support approval. One such driving simulation study would be sufficient to support approval so long as "it is conducted well," Unger said on the call. 

Those requirements have already been felt by sponsors of new sleep-aid drugs, such as Merck's and its new experimental insomnia drug suvorexant. A highly unusual FDA Advisory Committee meeting in May 2013 saw the drug approved, but only after FDA recommended it be approved at a lower dose than Merck had requested. The meeting would eventually see FDA recommending approval at the 10 mg dose, while Merck was arguing the drug would not be effective at that dose-an odd reversal of the traditional roles at an advisory committee.

The drug is still expected to obtain approval in the coming months, according to some reports.

New Insights

But writing in the NEJM on 7 August 2013, regulators Ronald Farkas, Ellis Unger and Robert Temple-three of the top officials within FDA's Center for Drug Evaluation and Research (CDER)-note that the zolpidem decision was one of the more unusual ones they've made in recent years.

Key among their concerns, they wrote, was the length of time for which the drug stayed active in patients. While the drugs were indeed effective as getting patients to sleep, they were a little too effective at prolonging its effects, causing potentially deleterious effects thereafter.

They noted that their lower-dose approach was in many ways influenced by the agency's review of Intermezzo, a sleep-aid drug intended to help people fall back asleep after waking in the middle of the night. The drug also contained zolpidem, but at a 3.5mg dose for men and 1.75 mg for women, reportedly "since new data revealed a difference between men and women in morning blood drug levels."

"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," the 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.

But even that was relatively unusual, the regulators wrote. After all, most adverse effects prompt FDA to require a manufacturer to update the drug's labeling to include a new warning, up to and including package inserts or black box warning intended to emphasize the risk to a patient. Why not do the same here?

The regulators wrote that this was considered, but ultimately discounted because of data that showed people affected by zolpidem impairment frequently didn't recognize the extent of their own impairment.

"Patient self-perception is not an adequate gauge for impairment," they said. In other words, even if patients heeded the warnings, it might not be sufficient to promote caution.

"Among patients whose sleep needs are satisfied with the use of the lower doses, unnecessary risk can be avoided, and as the labels point out, patients whose symptoms do not respond to the lower doses can be given the higher doses," Farkas, Ellis and Temple concluded." The sex-specific labeling revisions reflect an evidence-based approach to risk management and dose individualization."

NEJM Piece on Zolpidem Changes

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