Drug Profile

Zolpidem (AMBIEN, AMBIEN CR, EDLUAR) is approved by the Food and Drug Administration (FDA) for short-term relief of insomnia. We designated this drug as Do Not Use because its risks far outweigh its benefits.

Zolpidem belongs to the family of drugs known as nonbenzodiazepine sleeping pills, which also includes the other two of the three so-called “Z drugs”: zaleplon (SONATA) and eszopiclone (LUNESTA). These three drugs all work in a way that is similar to the sleeping pills and tranquilizers called benzodiazepines (an older family of drugs that includes diazepam [VALIUM]), but they have a different chemical structure. Although zolpidem is not a benzodiazepine, it shares many similarities with that family of drugs.[1] Like the benzodiazepine drug family, zolpidem can cause drowsiness. Also, it can be habit-forming, so zolpidem is a controlled substance.

Patients should keep in mind that nondrug treatment is the best option for the management of insomnia.

Adverse effects

In a 2004 review of zolpidem, zaleplon and zopiclone (an old drug that contains eszopiclone), the National Institute for Health and Clinical Excellence in Britain concluded the following:

There have been multiple reports of sleepwalking (inappropriate or strange automatic behavior while asleep, including binge eating and house painting) recorded in patients using zolpidem during the first year the drug was on the market.[2]

In 2019, the FDA required that a black-box warning be added to the product labeling for zolpidem about complex sleep behaviors, including sleepwalking, sleep driving and engaging in other activities while not fully awake, that are associated with use of the drug. The warning notes that these events may result in serious injury or death and that the drug should be discontinued immediately if a patient experiences such sleep behaviors.[3]

Zolpidem also has been linked to an increased risk of suicide and attempted suicide.[4],[5]

A February 2007 Australian Adverse Drug Reactions Bulletin also found 16 reports of sleepwalking in patients using zolpidem during the first year the drug was on the market.

The effects of zolpidem on balance and cognition after awaking from sleep were evaluated in a randomized, placebo-controlled trial where patients were administered either zolpidem or a placebo prior to sleep. The study found that patients who received zolpidem were at a higher risk of balance and cognition impairment, including instability when walking, which is especially concerning for elderly patients at risk of falls and fractures.[6] In fact, the drug has been shown to increase the risk of hip fractures in elderly patients.[7]

The FDA also wants the professional product labels of certain sleeping pills to warn users about anaphylaxis, a severe and life-threatening allergic reaction, and angioedema, severe facial swelling that can occur the first time a sleeping pill is taken.[8]

In June 2012, Australia’s Medicine Safety Update reported that it continues to receive reports of sleep-related adverse effects and amnesia associated with zolpidem use. The agency urges prescribers and patients to be cautious when using this drug.[9]

The Drug Abuse Warning Network reported that in 2010, 19,487 emergency room visits involved the use of zolpidem. This was three times more emergency visits than were associated with zolpidem in 2005. About two-thirds of the patients were women, and almost three-quarters were 45 or older (with those 65 or older accounting for one-third of all visits).[10] Another study, published in JAMA Psychiatry in September 2014, found that from 2009 through 2011, zolpidem was the drug most frequently linked to emergency department visits for psychiatric-drug—induced adverse drug reactions.[11] Nearly a quarter of these visits resulted in hospitalization.

Studies show...

One meta-analysis compared the effectiveness of drug treatment with that of behavioral therapy in the management of persistent insomnia. The authors of the study concluded the following: “Overall, behavior therapy and pharmacotherapy produce similar short-term treatment outcomes in primary insomnia.”[12]

A March 2014 study in the United Kingdom found an increase in the risk of death in people using tranquilizers or sleeping pills. The results were similar to those from a 2012 study. Concerns about the effect of these drugs on premature mortality have been fueled by studies documenting increased risk of dementia, daytime fatigue, lack of coordination, falls, road traffic incidents, and pneumonia and other infections.[13]

Regulatory actions surrounding zolpidem

2006: In December, the FDA requested that sleeping pill manufacturers include information about risks such as anaphylaxis, angioedema and complex sleep-related behaviors (e.g., driving, making phone calls and preparing and eating food while asleep) on their product labels.[14]

2007: The FDA warned that hallucinations were reported in 7.4% of pediatric patients taking zolpidem. None of the pediatric patients receiving a placebo reported hallucinations.[15]

In March, the FDA asked manufacturers of sedative hypnotic drugs, such as zolpidem, to update the drug product labels concerning potential risks associated with use of these medications, including “severe allergic reactions and complex sleep-related behaviors.” Allergic reactions included anaphylaxis and angioedema. Complex sleep-related behaviors included sleep-driving, making phone calls and preparing and eating food while asleep.

The following medications were specifically mentioned in the FDA advisory:

• zolpidem (AMBIEN/AMBIEN CR — Sanofi Aventis)
• butabarbital (BUTISOL SODIUM — Medpointe Pharmaceuticals HLC)
• pentobarbital and carbromal (CARBRITAL — Parke-Davis)
• flurazepam (DALMANE — Valeant Pharmaceuticals)
• quazepam (DORAL — Questcor Pharmaceuticals)
• triazolam (HALCION — Pharmacia & Upjohn)
• eszopiclone (LUNESTA — Sepracor)
• ethchlorvynol (PLACIDYL — Abbott)
• estazolam (PROSOM — Abbott)
• temazepam (RESTORIL — Tyco Healthcare)
• ramelteon (ROZEREM — Takeda Pharmaceutical)
• secobarbital (SECONAL — Eli Lilly)
• zaleplon (SONATA — King Pharmaceuticals)[16]

The FDA also requested that Medication Guides be developed for consumers. Click here to see the Medication Guide for zolpidem.

2010: In April, the FDA updated the product label of zolpidem to state that there have been reported cases of severe neonatal respiratory depression when zolpidem was used at the end of pregnancy. These cases were more common when zolpidem was taken with other central nervous system depressants.[17]

2013: In January, the FDA issued an advisory concerning the dosage of zolpidem related to impairment of activities requiring alertness the next day. The FDA recommended a decreased bedtime dose of zolpidem based on new data showing that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving.

According to the advisory, the data showed the risk of next-morning impairment to be the highest for women and anyone taking an extended-release formulation. Women appear to be more susceptible to the risk of next-morning impairment because they eliminate zolpidem from their bodies more slowly than men do.

Because lower doses of zolpidem will result in lower levels of the drug in the blood the next morning, the FDA is requiring manufacturers to lower the recommended dose.[18]

2016: In December, the FDA updated the product label of zolpidem to warn that patients with liver disease who use the drug have an increased risk of hepatic encephalopathy, a condition in which the liver is not able to remove poisonous substances from the body. Those substances can build up and interfere with brain function, leading to confusion and even coma.[19]