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Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The premarketing development program for LUNESTA included eszopiclone exposures in patients and/or normal subjects from two different groups of studies: approximately 400 normal subjects in clinical pharmacology/pharmacokinetic studies, and approximately 1550 patients in placebo-controlled clinical effectiveness studies, corresponding to approximately 263 patient-exposure years. The conditions and duration of treatment with LUNESTA varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, and short-term and longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while the patient was receiving therapy following baseline evaluation.
Clinical Trials Experience
Adverse Reactions Resulting in Discontinuation of Treatment
In placebo-controlled, parallel-group clinical trials in the elderly, 3.8% of 208 patients who received placebo, 2.3% of 215 patients who received 2 mg LUNESTA, and 1.4% of 72 patients who received 1 mg LUNESTA discontinued treatment due to an adverse reaction. In the 6-week parallel-group study in adults, no patients in the 3 mg arm discontinued because of an adverse reaction. In the long-term 6-month study in adult insomnia patients, 7.2% of 195 patients who received placebo and 12.8% of 593 patients who received 3 mg LUNESTA discontinued due to an adverse reaction. No reaction that resulted in discontinuation occurred at a rate of greater than 2%.
Adverse Reactions Observed at an Incidence of ≥ 2% in Controlled Trials
Table 1 shows the incidence of adverse reactions from a Phase 3 placebo-controlled study of LUNESTA at doses of 2 or 3 mg in non-elderly adults. Treatment duration in this trial was 44 days. The table includes only reactions that occurred in 2% or more of patients treated with LUNESTA 2 mg or 3 mg in which the incidence in patients treated with LUNESTA was greater than the incidence in placebo-treated patients.
Table 1: Incidence (%) of Adverse Reactions in a
6-Week Placebo-Controlled Study in Non-Elderly Adults with LUNESTA1
|LUNESTA 2 mg
|LUNESTA 3 mg
|Body as a Whole|
|Skin and Appendages|
|Gynecomastia * *||0||3||0|
|1Reactions for which the LUNESTA incidence was
equal to or less than placebo are not listed on the
table, but included the following: abnormal dreams, accidental injury, back
pain, diarrhea, flu syndrome, myalgia, pain, pharyngitis, and rhinitis.
* Gender-specific adverse reaction in females
** Gender-specific adverse reaction in males
Adverse reactions from Table 1 that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste.
Table 2 shows the incidence of adverse reactions from combined Phase 3 placebo-controlled studies of LUNESTA at doses of 1 or 2 mg in elderly adults (ages 65-86). Treatment duration in these trials was 14 days. The table includes only reactions that occurred in 2% or more of patients treated with LUNESTA 1 mg or 2 mg in which the incidence in patients treated with LUNESTA was greater than the incidence in placebo-treated patients.
Table 2: Incidence (%) of Adverse Reactions in Elderly
Adults (Ages 65-86) in 2-Week Placebo-Controlled Trials with LUNESTA1
|LUNESTA 1 mg
|LUNESTA 2 mg
|Body as a Whole|
|Skin and Appendages|
|Urinary Tract Infection||0||3||0|
|1Reactions for which the LUNESTA incidence was equal to or less than placebo are not listed on the table, but included the following: abdominal pain, asthenia, nausea, rash, and somnolence.|
Adverse reactions from Table 2 that suggest a dose-response relationship in elderly adults include pain, dry mouth, and unpleasant taste, with this relationship again clearest for unpleasant taste.
These figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice because patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contributions of drug and non-drug factors to the adverse reaction incidence rate in the population studied.
Other Reactions Observed During the Premarketing Evaluation of LUNESTA
Following is a list of modified COSTART terms that reflect adverse reactions as defined in the introduction to the Adverse Reactions section and reported by approximately 1550 subjects treated with LUNESTA at doses in the range of 1 to 3.5 mg/day during Phase 2 and 3 clinical trials throughout the United States and Canada. All reported reactions are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor reactions common in the general population, and reactions unlikely to be drug-related. Although the reactions reported occurred during treatment with LUNESTA, they were not necessarily caused by it.
Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 patients; InFrequent adverse reactions are those that occurred in fewer than 1/100 patients but in at least 1/1,000 patients; Rare adverse reactions are those that occurred in fewer than 1/1,000 patients. Gender-specific reactions are categorized based on their incidence for the appropriate gender.
Digestive System: InFrequent: anorexia, cholelithiasis, increased appetite, melena, mouth ulceration, thirst, ulcerative stomatitis; Rare: colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, stomach ulcer, stomatitis, tongue edema, rectal hemorrhage.
Nervous System: InFrequent: agitation, apathy, ataxia, emotional lability, hostility, hypertonia, hypesthesia, incoordination, insomnia, memory impairment, neurosis, nystagmus, paresthesia, reflexes decreased, thinking abnormal (mainly difficulty concentrating), vertigo; Rare: abnormal gait, euphoria, hyperesthesia, hypokinesia, neuritis, neuropathy, stupor, tremor.
Skin and Appendages: InFrequent: acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria; Rare: erythema multiforme, furunculosis, herpes zoster, hirsutism, maculopapular rash, vesiculobullous rash.
Urogenital System: InFrequent: amenorrhea, breast engorgement, breast enlargement, breast neoplasm, breast pain, cystitis, dysuria, female lactation, hematuria, kidney calculus, kidney pain, mastitis, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, uterine hemorrhage, vaginal hemorrhage, vaginitis; Rare: oliguria, pyelonephritis, urethritis.
In addition to the adverse reactions observed during clinical trials, dysosmia, an olfactory dysfunction that is characterized by distortion of the sense of smell, has been reported during post-marketing surveillance with LUNESTA. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.
Read the Lunesta (eszopiclone) Side Effects Center for a complete guide to possible side effects
CNS Active Drugs
Ethanol: An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol.
Olanzapine: Coadministration of eszopiclone and olanzapine produced a decrease in DSST scores. The interaction was pharmacodynamic; there was no alteration in the pharmacokinetics of either drug.
Drugs That Inhibit Or Induce CYP3A4
Drugs That Inhibit CYP3A4 (Ketoconazole)
CYP3A4 is a major metabolic pathway for elimination of eszopiclone. The exposure of eszopiclone was increased by coadministration of ketoconazole, a potent inhibitor of CYP3A4. Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly. Dose reduction of LUNESTA is needed for patient co-administered LUNESTA with potent CYP3A4 inhibitors [see DOSAGE AND ADMINISTRATION].
Drugs that Induce CYP3A4 (Rifampicin)
Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4. A similar effect would be expected with eszopiclone. Combination use with CYP3A4 inducer may decrease the exposure and effects of LUNESTA.
Drug Abuse And Dependence
LUNESTA is a Schedule IV controlled substance under the Controlled Substances Act. Other substances under the same classification are benzodiazepines and the nonbenzodiazepine hypnotics zaleplon and zolpidem. While eszopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, it shares some of the pharmacologic properties of the benzodiazepines.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
In a study of abuse liability conducted in individuals with known histories of benzodiazepine abuse, eszopiclone at doses of 6 and 12 mg produced euphoric effects similar to those of diazepam 20 mg. In this study, at doses 2-fold or greater than the maximum recommended doses, a dose-related increase in reports of amnesia and hallucinations was observed for both LUNESTA and diazepam.
The clinical trial experience with LUNESTA revealed no evidence of a serious withdrawal syndrome. Nevertheless, the following adverse events included in DSM-IV criteria for uncomplicated sedative/hypnotic withdrawal were reported during clinical trials following placebo substitution occurring within 48 hours following the last LUNESTA treatment: anxiety, abnormal dreams, nausea, and upset stomach. These reported adverse events occurred at an incidence of 2% or less. Use of benzodiazepines and similar agents may lead to physical and psychological dependence. The risk of abuse and dependence increases with the dose and duration of treatment and concomitant use of other psychoactive drugs. The risk is also greater for patients who have a history of alcohol or drug abuse or history of psychiatric disorders. These patients should be under careful surveillance when receiving LUNESTA or any other hypnotic.
Some loss of efficacy to the hypnotic effect of benzodiazepines and benzodiazepine-like agents may develop after repeated use of these drugs for a few weeks.
No development of tolerance to any parameter of sleep measurement was observed over six months. Tolerance to the efficacy of LUNESTA 3 mg was assessed by 4-week objective and 6-week subjective measurements of time to sleep onset and sleep maintenance for LUNESTA in a placebo-controlled 44-day study, and by subjective assessments of time to sleep onset and WASO in a placebo-controlled study for 6 months.
Read the Lunesta Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/29/2014
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