eszopiclone and zaleplon

To identify and analyze postmarketing cases of complex sleep behaviors (CSBs) resulting in serious injuries, including death, associated with eszopiclone, zaleplon, or zolpidem (Z-drugs).. Retrospective analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 16 December 1992 through 27 February 2018 and medical literature using PubMed and EMBASE. We used random sampling and descriptive statistics.. We identified 66 cases that met inclusion and exclusion criteria, four of which were identified in the medical literature. Twenty cases reported death and 46 cases reported serious injuries in association with CSBs occurring after the use of a Z-drug. Fatal cases described events, such as carbon monoxide poisoning, drowning, falls, hypothermia, motor vehicle collisions, and apparent completed suicide. Nonfatal cases resulting in serious injuries described events, such as accidental overdoses, falls, gunshot wounds, hypothermia, third-degree burns, and self-injuries or suicide attempts. Twenty-two cases reported a previous episode of a CSB while taking a Z-drug prior to the event reported in this case series.. The FAERS and medical literature cases support the need for increased awareness of the consequences that may occur because of CSBs associated with the use of Z-drugs. Therefore, to protect public health, regulatory actions were taken, including adding a Boxed Warning, a Contraindication in patients who have experienced a prior episode of a CSB with a Z-drug, and updating the existing Warnings and Precautions. An FDA Drug Safety Communication was also disseminated to alert healthcare professionals and the public of this potential risk.

Topics: Acetamides; Adult; Adverse Drug Reaction Reporting Systems; Aged; Drug Labeling; Eszopiclone; Female; Humans; Male; Middle Aged; Parasomnias; Pyrimidines; Retrospective Studies; Risk Assessment; Risk Factors; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Somnambulism; Time Factors; Treatment Outcome; Wounds and Injuries; Zolpidem

zolpidem, zopiclone, eszopiclone and zaleplon, also known as 'Z-drugs', are commonly used as alternatives to benzodiazepines (BZDs) to treat insomnia. Z-drugs are often perceived as safer than BZDs. We conducted a systematic review and meta-analysis evaluating the association between Z-drugs and fracutres, falls and injuries.. a systematic review was performed using MEDLINE, EMBASE and ClinicalTials.gov. Pooled effect-sizes were calculated comparing Z-drugs users with non-users, using fixed and random-effect models with corresponding 95% confidence of intervals (CI).. we identified 14 eligible studies reporting on the association between Z-drugs and outcomes of interest. Z-Drugs were associated with a statistically significant increased risk for fractures, with evidence of considerable heterogeneity (OR = 1.63; 95% CI: 1.42-1.87; I2 = 90%; n = 830,877). Likewise, there was a trend suggesting a 2-fold increase in the odds for falls, however, this result was not statistically significant and there was evidence of considerable heterogeneity (OR = 2.40; 95% CI: 0.92-6.27; I2 = 95%; n = 19,505). In an analysis assessing the risk for injuries following exposure to zolpidem we found a statistically significant increased risk of injuries, with no evidence of heterogeneity (OR = 2.05; CI 95%: 1.95-2.15; I2 = 0; n = 160,502). Results were similar in sensitivity analyses, including analyses restricted to studies of high-quality, studies with control groups suffering from insomnia, and with specific Z-drugs.. our results indicate that Z-drugs are associated with an increased risk for fractures, and suggest a possible increased risk for falls and injuries as well. However, studies included were observational and susceptible to confounding. Physicians should consider these potential risks before prescribing these medications in older adults.

Topics: Accidental Falls; Acetamides; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Azabicyclo Compounds; Eszopiclone; Fractures, Bone; Humans; Middle Aged; Piperazines; Pyrimidines; Risk Assessment; Risk Factors; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Zolpidem

Topics: Acetamides; Animals; Eszopiclone; Humans; Hypnotics and Sedatives; Plant Preparations; Pyridines; Pyrimidines; Sleep Initiation and Maintenance Disorders; Somnambulism; Zolpidem

The "z-drugs" zopiclone, zolpidem, eszopiclone, and zaleplon were introduced in the 1980s for the treatment of insomnia, as it was observed that the side effect profile associated with these medications were more benign than those related to the benzodiazepines. This meta-analysis set out to ascertain which domains of cognitive function, if any, were affected by the ingestion of these medications. A total of 20 studies met the study inclusion criteria. Results revealed medium effect sizes for zopiclone and zolpidem on measures of verbal memory. An additional medium effect size was observed for zolpidem on attention. Finally, smaller effect sizes were observed for zolpidem speed of processing and for zopiclone on working memory. It is clear from these data that the use of a single dose of the z-drugs in healthy adults as measured in the morning following the exposure does produce a specific rather than a generalized negative effect on cognitive function. However, there were only enough studies to evaluate the individual cognitive effects of the zolpidem and zopiclone medications; the specific effects of zaleplon and eszopiclone cannot be ascertained because only one study met the inclusion and exclusion criteria for the review.

Topics: Acetamides; Attention; Azabicyclo Compounds; Eszopiclone; Humans; Hypnotics and Sedatives; Memory; Piperazines; Psychomotor Performance; Pyridines; Pyrimidines; Zolpidem

To investigate the effectiveness of non-benzodiazepine hypnotics (Z drugs) and associated placebo responses in adults and to evaluate potential moderators of effectiveness in a dataset used to approve these drugs.. Systematic review and meta-analysis.. US Food and Drug Administration (FDA).. Randomised double blind parallel placebo controlled trials of currently approved Z drugs (eszopiclone, zaleplon, and zolpidem).. Change score from baseline to post-test for drug and placebo groups; drug efficacy analysed as the difference of both change scores. Weighted raw and standardised mean differences with their confidence intervals under random effects assumptions for polysomnographic and subjective sleep latency, as primary outcomes. Secondary outcomes included waking after sleep onset, number of awakenings, total sleep time, sleep efficiency, and subjective sleep quality. Weighted least square regression analysis was used to explain heterogeneity of drug effects.. 13 studies containing 65 separate drug-placebo comparisons by type of outcome, type of drug, and dose were included. Studies included 4378 participants from different countries and varying drug doses, lengths of treatment, and study years. Z drugs showed significant, albeit small, improvements (reductions) in our primary outcomes: polysomnographic sleep latency (weighted standardised mean difference, 95% confidence interval -0.57 to -0.16) and subjective sleep latency (-0.33, -0.62 to -0.04) compared with placebo. Analyses of weighted mean raw differences showed that Z drugs decreased polysomnographic sleep latency by 22 minutes (-33 to -11 minutes) compared with placebo. Although no significant effects were found in secondary outcomes, there were insufficient studies reporting these outcomes to allow firm conclusions. Moderator analyses indicated that sleep latency was more likely to be reduced in studies published earlier, with larger drug doses, with longer duration of treatment, with a greater proportion of younger and/or female patients, and with zolpidem.. Compared with placebo, Z drugs produce slight improvements in subjective and polysomnographic sleep latency, especially with larger doses and regardless of type of drug. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produced to a reasonably large clinical response.

Topics: Acetamides; Adult; Aged; Azabicyclo Compounds; Confidence Intervals; Eszopiclone; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Piperazines; Polysomnography; Pyridines; Pyrimidines; Sleep Initiation and Maintenance Disorders; Treatment Outcome; United States; United States Food and Drug Administration; Zolpidem

Recent meta-analyses raising concern about risks of hypnotics suggest a need for more clarification of these risks.. Because of preliminary suggestions that eszopiclone causes infections, we studied US Food and Drug Administration files on the 4 most-recently approved hypnotics, combined with published studies, to compile the risk ratios of infections for groups randomly assigned to receive hypnotics versus those assigned to receive placebos in controlled trials. Parallel controlled clinical trials of eszopiclone, ramelteon, zaleplon, and zolpidem were included when data on subjects, duration of exposure, and adverse effects were available. Results of trials were combined by meta-analyses.. Of 8828 participants assigned to the 4 hypnotics and 4383 participants who randomly received placebos, 606 in the hypnotics groups and 200 in the placebo groups were reported to develop some kind of infection (risk ratio = 1.44, 95% confidence interval 1.25-1.64, p < 0.00001). Most infections were apparently mild and did not lead to dropouts. Subanalyses for individual drugs indicated that eszopiclone and zolpidem individually were associated with reported infections. There were insufficient data concerning individual studies of zaleplon and ramelteon for valid secondary meta-analyses of zaleplon or ramelteon by themselves.. Research is needed to objectively determine whether the use of hypnotics increases the risk of infections. Immune compromise or esophageal reflux and aspiration should be studied as possible mechanisms.

Topics: Acetamides; Azabicyclo Compounds; Eszopiclone; Humans; Hypnotics and Sedatives; Indenes; Infections; Piperazines; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Risk; Zolpidem

Given the well-established problems with sleep at high altitude, it is not uncommon for people planning trips to the mountains to seek advice from clinicians regarding pharmacologic options for improving sleep during their trip. This review article considers the various medications that have been studied for this purpose at high altitude with an emphasis on both their efficacy and safety. The available data support the use of either acetazolamide, temazepam, zolpidem or zaleplon in this environment. Other agents commonly used at sea-level such as eszopiclone and diphenhydramine have not been studied at high altitude but are likely safe to use given their mechanism of action and known side effects. Limited evidence suggests diazepam may cause hypoventilation at high altitude and its use in this environment should be discouraged. Insufficient data exist to determine which agent is most effective at altitude nor do we know whether combination therapy with acetazolamide and a hypnotic agent offers any benefits over monotherapy.

Topics: Acetamides; Acetazolamide; Altitude Sickness; Anti-Anxiety Agents; Azabicyclo Compounds; Benzodiazepines; Diphenhydramine; Eszopiclone; GABA Agonists; Humans; Hypnotics and Sedatives; Mountaineering; Piperazines; Pyridines; Pyrimidines; Sleep Initiation and Maintenance Disorders; Sleep Stages; Temazepam; Wakefulness; Zolpidem

Topics: Acetamides; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Eszopiclone; Humans; Pyrimidines; Safety Management; Sleep Initiation and Maintenance Disorders; United States; United States Food and Drug Administration; Zolpidem

The objective of this study was to test the hypothesis that use of zolpidem, eszopiclone, and zaleplon would be associated with increased risk of traumatic brain injury (TBI) and hip fracture.. We conducted a case-crossover study on a 5% random sample of Medicare beneficiaries age 65 y or older hospitalized with either TBI (n = 15,031) or hip fracture (n = 37,833) during 2007-2009. Use of zolpidem, eszopiclone, or zaleplon during the 30-day period prior to injury hospitalization was compared to use during four control periods at 3, 6, 9, and 12 mo prior to injury. The primary outcome was hospitalization for TBI or hip fracture.. Zolpidem use during the month prior to injury was associated with increased risk of TBI (odds ratio [OR] 1.87; 95% confidence interval [CI] 1.56, 2.25); however, eszopiclone use during the same period was not associated with increased risk (OR 0.67; 95% CI 0.40, 1.13). Zolpidem use during the month prior to injury was associated with increased risk of hip fracture (OR 1.59; 95% CI 1.41, 1.79); however, eszopiclone use during the same period was not associated with increased risk (OR 1.12; 95% CI 0.83, 1.50). Analysis of zaleplon use in the month prior to injury was limited by low drug utilization but was not associated with increased risk of TBI (OR 0.85; 95% CI 0.21, 3.34) or hip fracture (OR 0.92; 95% CI 0.40, 2.13) in this study.. For the treatment of insomnia in older adults, eszopiclone may present a safer alternative to zolpidem, in terms of fall-related injuries.

Topics: Accidental Falls; Acetamides; Aged; Aged, 80 and over; Brain Injuries, Traumatic; Cross-Over Studies; Eszopiclone; Female; Hip Fractures; Hospitalization; Humans; Hypnotics and Sedatives; Male; Odds Ratio; Pyridines; Pyrimidines; Risk Assessment; Sleep Initiation and Maintenance Disorders; Zolpidem

Topics: Acetamides; Azabicyclo Compounds; Controlled Clinical Trials as Topic; Double-Blind Method; Eszopiclone; Humans; Hypnotics and Sedatives; Piperazines; Pyridines; Pyrimidines; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Zolpidem

Eszopiclone is the active S-enantiomer of R,S-zopiclone, and is a cyclopyrrolone hypnotic acting via the GABA-benzodiazepine receptor system. Nearly 6 million prescriptions for eszopiclone are written yearly in the United States.. This paper addresses the pharmacokinetic properties of eszopiclone and the extent to which the longer half-life of eszopiclone compared to other commonly used hypnotics (immediate-release zolpidem, modified-release zolpidem, triazolam, zaleplon) may translate into either improved efficacy in enhancing sleep maintenance, or increased probability of residual sedative or performance-impairing effects.. Eszopiclone is metabolized mainly by Cytochrome P450-3A (CYP3A) isoforms. The mean half-life in healthy nonelderly individuals (6.1 h) is prolonged in the elderly, in patients with hepatic insufficiency, and by coadministration of CYP3A inhibitors. In clinical trials, eszopiclone consistently improves sleep maintenance relative to placebo, based on measures of shortened wake time after sleep onset, and prolonged total sleep time. However eszopiclone may also produce residual sedation and impairment of driving performance in the initial morning waking hours. A bitter or metallic taste is a common though non-serious adverse effect of eszopiclone. Overall, eszopiclone provides a therapeutic option for patients with sleep maintenance problems, though with accompanying potential for residual morning sedation, as well as a relatively high dollar cost of treatment.

Topics: Acetamides; Adult; Aged; Azabicyclo Compounds; Clinical Trials as Topic; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Eszopiclone; Half-Life; Hepatic Insufficiency; Humans; Hypnotics and Sedatives; Piperazines; Pyridines; Pyrimidines; Receptors, GABA-A; Sleep; Sleep Initiation and Maintenance Disorders; Triazolam; United States; Zolpidem

Insomnia in patients with bipolar disorder (BD) can cause distress, daytime dysfunction, cognitive impairment, worsening of hypomanic/manic symptoms and increased suicide risk. Physicians often prescribe hypnotics for BD patients with insomnia although no hypnotic has a specific FDA indication for this use. In this study, the patterns of use, efficacy and safety of five nonbenzodiazepine hypnotics (NBZHs) were assessed in a large group of outpatients with BD.. A chart review was performed for all older adolescents and adult BD outpatients in a private outpatient clinic. Clinical data was collected for any patient who had ever been prescribed a NBZH for insomnia and included successful current use, past unsuccessful treatments, side effects, duration of use, concurrent psychiatric medications, and absence or presence of untoward events often associated with chronic use of hypnotics.. A significant number of BD patients take NBZHs as needed or on a daily basis. Four NBZHs had adequate success rates; ramelteon was limited in efficacy. Some patients experienced satisfactory results from a NBZH after unsuccessful trials with one or more other NBZHs. About half of the current NBZH users are taking them on a daily long-term basis, and none of these patients have experienced unacceptable untoward events. About three quarters of the chronic NBZH users are taking antimanic medications concurrently, and less than half of the chronic users are taking antidepressants.. The results may not be generalizable to other BD populations. A control group was not included in the design. Chronic users of NBZHs were not asked to discontinue their NBZH in order to confirm indication for long-term use.. Most NBZHs can be effective and safe agents for selected BD outpatients with episodic or chronic insomnia. Failure to respond to one or more NBZH does not preclude a satisfactory response to a different NBZH. Some BD patients who take maintenance antimanic agents also require NBZH treatment. Overactivation from antidepressant treatment does not contribute to chronic NBZH use in most BD patients.

Topics: Acetamides; Adolescent; Adult; Azabicyclo Compounds; Bipolar Disorder; Eszopiclone; Female; Humans; Hypnotics and Sedatives; Indenes; Male; Piperazines; Pyridines; Pyrimidines; Retrospective Studies; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Zolpidem

To summarize the signalment, clinical signs observed, time to onset of clinical signs, duration of clinical signs, and the outcome in a large case series of nonbenzodiazepine sleep aid ingestions in dogs, including 2 sleep aids that have not been previously described in the veterinary literature.. Retrospective study conducted between 2004 and 2010.. An animal poison control center based out of Bloomington, MN.. During this time frame, 453 cases were identified involving 467 dogs. Of these cases, 150 cases were excluded due to incomplete medical records, multipet households, or the inability to calculate a dose exposure. A total of 317 dogs with presumed sleep aid medication toxicosis were included.. None.. Records of dogs with sleep aid medication toxicosis identified by a review of an animal poison control center electronic database were evaluated. The most common sleep aid medications ingested were zolpidem (240/317 [75.7%]), eszopiclone (62/317 [19.5%]), and zaleplon (15/317 [4.7%]). Overall, clinical signs developed in 36% of patients (115/317), while 64% (202/317) remained asymptomatic. The most common organ systems affected and clinical signs seen involved the central nervous system (eg, agitation, sedation) and gastrointestinal tract (eg, anorexia, hypersalivation, vomiting).. Overall, the prognosis for dogs with sleep aid medication toxicosis was excellent, and no fatalities were reported in this clinical population. As significant clinical signs can still be seen with ingestion, appropriate decontamination is warranted in asymptomatic patients via emesis or gastric lavage, followed by activated charcoal administration. Symptomatic patients should be hospitalized for monitoring and supportive care for a minimum of 12 hours or until clinical signs resolve.

Topics: Acetamides; Animals; Azabicyclo Compounds; Benzodiazepines; Comorbidity; Dog Diseases; Dogs; Eszopiclone; Female; Hypnotics and Sedatives; Male; Piperazines; Poison Control Centers; Prognosis; Pyridines; Pyrimidines; Retrospective Studies; Sleep Initiation and Maintenance Disorders; Zolpidem

Topics: Acetamides; Animals; Azabicyclo Compounds; Carcinoma, Basal Cell; Eszopiclone; Humans; Indenes; Piperazines; Pyrimidines; Randomized Controlled Trials as Topic; Skin Neoplasms; Sleep Initiation and Maintenance Disorders; United States; United States Food and Drug Administration

Fifteen epidemiologic studies have associated hypnotic drugs with excess mortality, especially excess cancer deaths. Until recently, insufficient controlled trials were available to demonstrate whether hypnotics actually cause any cancers. The US Food and Drug Administration (FDA) Approval History and Documents were accessed for zaleplon, eszopiclone and ramelteon. Since zolpidem was used as a comparison drug in zaleplon trials, some zolpidem data were also available. Incident cancers occurring during randomized hypnotics administration or placebo administration were tabulated. Combining controlled trials for the four drugs, there were 6190 participants given hypnotics and 2535 given placebo in parallel. There were eight mentions of incident non-melanoma skin cancers among participants receiving hypnotics but no comparable mentions of cancers among those receiving placebo (P = 0.064, one-tailed). There were also four mentions of incident tumors of uncertain malignancy among those receiving hypnotics but none among those receiving placebo, so combining uncertain and definite malignancies yielded a more significant contrast (P = 0.016). FDA files revealed that all four of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. Together with the epidemiologic data and laboratory studies, the available evidence signals that new hypnotics may increase cancer risk. Due to limitations in available data, confirmatory research is needed.

Topics: Acetamides; Animals; Azabicyclo Compounds; Carcinoma, Basal Cell; Causality; Cross-Sectional Studies; Eszopiclone; Follow-Up Studies; Humans; Hypnotics and Sedatives; Incidence; Indenes; Melanoma; Piperazines; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Skin Neoplasms; Sleep Initiation and Maintenance Disorders; United States; United States Food and Drug Administration; Zolpidem

Although it has been claimed that insomnia causes an increased risk for depression, adequate controlled trials testing this hypothesis have not been available. This study contrasted the incidence of depression among subjects receiving hypnotics in randomized controlled trials versus those receiving placebo.. The incidence of depression among patients randomized to hypnotic drugs or placebo was compiled from prescribing information approved by the United States Food and Drug Administration (FDA) and from FDA New Drug Application documents. Available data for zolpidem, zaleplon, eszopiclone, and ramelteon were accessed.. Data for 5535 patients randomized to a hypnotic and for 2318 randomized to placebo were compiled. The incidence of depression was 2.0% among participants randomized to hypnotics as compared to 0.9% among those randomized in parallel to placebo (p < 0.002).. Modern hypnotics were associated with an increased incidence of depression in data released by the FDA. This suggests that when there is a risk of depression, hypnotics may be contra-indicated. Preventive treatments such as antidepressant drugs, cognitive-behavioral therapy, or bright light might be preferred. Limitations in the FDA data prevented a formal meta-analysis, and there was a lack of information about drop-out rates and definitions of depression. Trials specifically designed to detect incident depression when treating insomnia with hypnotic drugs and better summarization of adverse events in trials submitted to the FDA are both necessary.

Topics: Acetamides; Azabicyclo Compounds; Cross-Sectional Studies; Depressive Disorder, Major; Drug Prescriptions; Eszopiclone; Follow-Up Studies; Humans; Hypnotics and Sedatives; Incidence; Indenes; Long-Term Care; Odds Ratio; Piperazines; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; United States; United States Food and Drug Administration; Zolpidem

According to the National Institutes of Health, approximately 30 percent of all Americans complain of sleep disruption, while 10 percent display symptoms congruent with chronic insomnia. One of the most common treatments for insomnia is prescription sleep medications that help people fall asleep and remain asleep. Historically barbiturates were initially popular for treating insomnia, but their long "hangover" effect made them easily replaced with the introduction of the benzodiazepines. Triazolam (Halcion), diazepam (Valium), and oxazepam (Serax) rapidly became the treatment of choice for insomnia. Recently a new class of nonbenzodiazepines---the "z-sedatives"--has overtaken the older benzodiazepines as the most commonly prescribed sleep medications. The three most popular z-drugs are zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta). The Food and Drug Administration (FDA) also recently approved the production of zolpidem tartrate, a generic form of Ambien. Many dentists prescribe these medications for patients who have difficulty sleeping the night prior to an appointment or as a procedural sedative. With 43 million prescriptions for sleep medications filled in 2005, generating $2.7 billion for pharmaceutical companies, it is important that dentists be aware of these drugs' mechanism of action and potential drug interactions.

Topics: Acetamides; Azabicyclo Compounds; Drug Interactions; Eszopiclone; Humans; Hypnotics and Sedatives; Piperazines; Pyridines; Pyrimidines; Sleep Initiation and Maintenance Disorders; Zolpidem