Overview of the Insomnia Drug Zolpidem (AMBIEN, AMBIEN CR, EDLUAR, ZOLPIMIST)

Insomnia is defined as dissatisfaction with sleep quantity or quality and is associated with difficulty initiating or maintaining sleep and early-morning waking with inability to return to sleep.[1] It is a major health and quality-of-life problem that affects up to 10% of adults, and it is more common in women and the elderly.[2] Individuals who have insomnia frequently suffer from fatigue, poor cognitive function or mood disturbance.

The insomnia drug zolpidem, which belongs to a family of drugs known as the non-benzodiazepines or “Z drugs,” is a sedative hypnotic that binds to a specific receptor in the brain to induce sleep.[3] Currently, zolpidem is available in generic versions and as three brand-name immediate-release forms — AMBIEN (tablets that are swallowed), EDLUAR (sublingual tablets) and ZOLPIMIST (oral spray mist) — and a controlled-release tablet form (AMBIEN CR).

Whereas all forms are approved by the Food and Drug Administration (FDA) for the short-term treatment of insomnia characterized by difficulties initiating sleep, AMBIEN CR also is approved for decreasing wake time after sleep onset (sleep maintenance).

According to an analysis of data from a large, nationally representative survey, nearly four million non-hospitalized American adults age 18 to 85 reported using one or more prescriptions for zolpidem in 2015.[4] The survey also showed that 64% of adults age 65 or older taking zolpidem reported using high doses of the drug.

Public Citizen’s Health Research Group for years has designated zolpidem and the rest of the Z drugs as Do Not Use because their risks outweigh their limited benefits.

Limited benefit

Data from clinical trials used to support the approval of Ambien, the first brand-name zolpidem product approved by the FDA in 1992, demonstrated that the drug resulted in minimal improvements in sleep outcomes. Of note, data from 41 clinical trials that assessed the effectiveness of Ambien were submitted to the FDA, but only 27 of these trials had a placebo control group.[5] Moreover, most of the controlled trials either had insufficient data for FDA review or substantial flaws in how they were designed or conducted.

One key trial assessing the effectiveness of Ambien randomly assigned 595 insomnia subjects to receive either zolpidem or placebo. The trial found that zolpidem at doses of 7.5 or 10 milligrams reduced the time it took to fall asleep by an average of only 10 minutes more than a placebo. Additionally, the average amount of time spent asleep as a percentage of total time in bed was 92% in the zolpidem subjects and 88% in the placebo subjects, a difference of only 4%.

Similarly unimpressive improvements in sleep outcomes were seen in the clinical trials used to support the FDA’s approval of Ambien CR in 2005.[6] For example, one of the two placebo-controlled trials that assessed the effectiveness of Ambien CR over two weeks did not find a statistically significant difference between subjects who received zolpidem and those who received a placebo for one of the two primary sleep outcomes of that trial after the first two days of using the drug. As a result, the lead FDA medical reviewer initially opposed approval of Ambien CR.

Risks

When zolpidem was first marketed, it was portrayed as “safer” than benzodiazepines.[7] However, this claim was refuted by new evidence of several risks that appeared over time, requiring changes to the labeling of this drug. In 2013, the FDA reported that, like benzodiazepine users, some zolpidem users who took the drug in the evening had next-morning carryover effects of reduced alertness and impaired activities, including driving.[8] Therefore, the agency required zolpidem manufacturers to cut in half the initial recommended dosages of the drug.

In 2019, the FDA required zolpidem manufacturers to add a black-box warning — the most stringent warning that the agency can require — to the drug labeling regarding complex sleep behavior (including making and eating food, talking on the phone or driving a car while not being fully awake).[9] This behavior can occur in patients who take the lowest recommended dose, even after just a single dose.

Other serious risks of zolpidem are abuse, dependence and withdrawal reactions. In the U.S., zolpidem is classified as a schedule IV controlled substance,[10] the same classification assigned to benzodiazepines.[11]

In fact, a 2019 analysis of more than 33,200 adverse drug reactions reported to the European Medicines Agency showed that zolpidem was more frequently involved in misuse, abuse and withdrawal reactions than other Z drugs.[12]

Zolpidem can cause serious allergic reactions that require emergency medical treatment, including anaphylaxis (a life-threatening allergic reaction that includes a severe drop in blood pressure) and angioedema (swelling of the tongue or throat and trouble breathing), after the first or subsequent doses of the drug.

Additional adverse effects of zolpidem include anxiety, hallucinations, depression, daytime somnolence (sleepiness), memory impairment, increased risk of fractures, major head injury or fracture requiring hospitalization, and new-onset cancer.[13]

Zolpidem can interact with other drugs or substances. For example, postmarketing evidence shows that overdose (resulting in impairment of consciousness that ranges from somnolence to coma, compromised breathing or blood circulation, and death) can occur with zolpidem when it is taken alone or in combination with other central nervous system depressants, including alcohol, opioids and tranquilizers.

Moreover, zolpidem interacts with several drugs that are broken down by liver enzymes, which can either decrease or increase the effects of these drugs.

What You Can Do

Do not take zolpidem or any other drug for sleep problems. If you are currently taking zolpidem and develop complex sleep behaviors, discontinue the drug immediately and seek medical help.[14] Otherwise, if you have been taking zolpidem for awhile, work with your doctor to create a schedule to stop it gradually to avoid withdrawal reactions (including stomach cramps, vomiting, nervousness and panic attacks).[15]

To manage sleep problems, rely on cognitive behavioral therapy for insomnia — including cognitive therapy for sleep, behavioral interventions (such as sleep restriction and stimulus control) and good sleep hygiene.[16] Examples of good sleep hygiene practices are avoiding caffeine-containing products, nicotine or alcohol (especially later in the day); avoiding heavy meals within at least two hours of bedtime; and creating an atmosphere conducive to sleep, such as using earplugs to block out noise and sleeping in a dark room.

It is important to consult a health care professional about any medical condition that may be contributing to your insomnia.
 

References

[1] Qaseem A, Kansagara D, Forciea MA, et al. Management of chronic insomnia disorder in adults: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-133.

[2] Ibid.

[3] Sanofi-aventis U.S. LLC. Label: zolpidem (AMBIEN). August 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019908s046lbl.pdf. Accessed April 1, 2020.

[4] Moore TJ, Mattison DR. Assessment of patterns of potentially unsafe use of zolpidem. JAMA Intern Med. 2018. 178(9):1275-1277.

[5] Food and Drug Administration. Clinical reviews for NDA 19-908 for Ambien. https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019908_S000_MOR.pdf. Accessed April 1, 2020.

[6] Food and Drug Administration. Medical reviews for NDA 21-774, Ambien CR. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021774s000_MedR.pdf. Accessed April 1, 2020.

[7] Zolpidem: next-morning residual effects. Prescrire Int. 2014;23(145):18.

[8] Food and Drug Administration. FDA Drug safety communication: 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). January 10, 2013. https://www.fda.gov/media/84992/download. Accessed April 1, 2020.

[9] Food and Drug Administration. FDA drug safety communication: FDA adds boxed warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. April 30, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia. Accessed April 1, 2020.

[10] Sanofi-aventis U.S. LLC. Label: zolpidem (AMBIEN). August 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019908s046lbl.pdf. Accessed April 1, 2020.

[11] Drug Enforcement Administration. Controlled substance schedules. https://www.deadiversion.usdoj.gov/schedules/. Accessed April 1, 2020.

[12] Schifano F, Chiappini S, Corkery JM, Guirguis A. An insight into z-drug abuse and dependence: An examination of reports to the European Medicines Agency database of suspected adverse drug reactions. Int J Neuropsychopharmacol. 2019;22(4):270-277.

[13] Wilt TJ, MacDonald R, Brasure M, et al. Pharmacologic treatment of insomnia disorder: An evidence report for a clinical practice guideline by the American college of physicians. Ann Intern Med. 2016;165(2):103-112.

[14] Sanofi-aventis U.S. LLC. Label: zolpidem (AMBIEN). August 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019908s046lbl.pdf. Accessed April 1, 2020.

[15] Drug profile: zolpidem. July 31, 2019. /monographs/view/89. Accessed April 1, 2020.

[16] Qaseem A, Kansagara D, Forciea MA, et al. Management of chronic insomnia disorder in adults: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-133.