Drug Criteria & Outcomes: Eszopiclone (Lunesta) Formulary Evaluation
Drug Criteria & Outcomes
Eszopiclone (Lunesta) Formulary Evaluation
By Eeron Edwards, Pharm D Candidate
Harrison School of Pharmacy
Auburn (AL) University
Eszopiclone (Lunesta) is the first member of a new drug class known as a pyrrolopyrazine derivative of the cyclopyrrolone class. It is a nonbenzodiazepine hypnotic agent with a chemical structure unrelated to any other drugs with known hypnotic properties.
Mechanism of action
The precise mechanism of action of eszopiclone as a hypnotic is unknown, but its effectis believed to result from its interaction with GABA-receptor complexes at binding sites located close to or allosterically coupled to benzodiazepine receptors.
Temazepam (the comparison agent in this evaluation) binds to stereo-specific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system (CNS), including the limbic system, reticular formation.
Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions; this shift in chloride ions results in a less excitable state and stabilization.
Indications (FDA-approved)
Eszopiclone is approved for treatment of short-term and chronic insomnia.
Temazepam is approved for short-term treatment of insomnia.
Pharmacokinetics
The pharmacokinetics of eszopiclone and temazepam are summarized in Table 1.
Dosage and administration
Eszopiclone is a film-coated tablet available in 1 mg, 2 mg, and 3 mg. Temazepam is an oral capsule available in 7.5 mg, 15 mg, 22.5 mg, and 30 mg.
The dose of eszopiclone should be individualized. The recommended starting dose is 2 mg immediately before bedtime, but dosing can be initiated at or raised to 3 mg. The 3 mg dose has been shown to be more effective for sleep.
The recommended adult dose for temazepam is 15 mg before bedtime, but doses ranging from 7.5 mg to 30 mg also are used.
Special populations
- Geriatric patients
For difficulty falling asleep, the starting dose should be 1 mg immediately before bedtime and may be increased to 2 mg if indicated. For difficulty staying asleep, the recommended dose is 2 mg before bedtime.
In elderly patients, it is recommended that temazepam be initiated at a dose of 7.5-15 mg. - Pediatric patients
Safety and efficacy in children has not been established in eszopiclone or temazepam. - Renal impairment
No dosage adjustment of eszopiclone or temazepam is necessary in renal impairment. - Hepatic impairment
The dose of eszopiclone should be decreased to 1 mg in severe hepatic impairment, but no dose adjustment is necessary with mild-to-moderate hepatic impairment.
With temazepam, no dosage adjustment is necessary, but monitoring is suggested.
Adverse drug events
Some adverse reactions that frequently are seen when using eszopiclone are headache, migraine, unpleasant taste, chest pain, and peripheral edema. CNS effects such as drowsiness, headache, and anxiety also may be seen with eszopiclone, but these side effects are rare with eszopiclone. The adverse reactions seen most often with temazepam are drowsiness, headache, fatigue, nervousness, lethargy, dizziness, nausea, hangover, and anxiety.
Drug-drug interactions
Eszopiclone is metabolized via CYP3A4, so coadministration with ketoconazole causes an increase in the levels of eszopiclone, and other CYP3A4 inhibitors are expected to cause the same interaction. The CYP3A4 inducer rifampicin caused an 80% decrease in exposure of racemic zopiclone, so a similar effect would be expected with eszopiclone. An additive effect on psychomotor performance was seen with coadministration of eszopiclone with alcohol or olanzapine. The full extent of eszopiclone’s drug interaction profile is not known due to lack of clinical experimentation.
Alcohol’s effects also intensify temazepam’s actions. CNS depressants such as antihistamines, barbiturates, narcotics, antipsychotics, and antidepressants will increase the CNS-depressing effects of temazepam. Temazepam also may interfere with oral contraceptives.
Drug-food interactions
The effects of eszopiclone on sleep onset may be reduced if it is taken with or immediately after a high-fat or heavy meal. Grapefruit juice may increase the effects of temazepam.
Warnings and precautions
Eszopiclone and temazepam are not recommended in patients with depressive disorders or psychosis. A variety of abnormal thinking and behavior changes also have been reported with eszopiclone use. Use temazepam with caution in patients with sleep apnea, and respiratory, renal, or hepatic disease. Eszopiclone and temazepam should be used with extreme caution in patients at risk of falls and traumatic injury. Temazepam may cause physical or psychological dependence, and withdrawal symptoms may be seen upon discontinuation.
Contraindications
Eszopiclone has no known contraindications, but temazepam is contraindicated in patients who have narrow-angle glaucoma and patients who are pregnant.
Pregnancy/lactation information
Eszopiclone is classified as pregnancy Category C, and it is not known whether it is excreted in breast milk, and as such should be used cautiously. Temazepam is classified as pregnancy category X and is contraindicated in patients who are pregnant. It also is excreted in the breast milk and is not recommended for use in nursing mothers.
Overdose
One overdose in the clinical trials was seen with a dose of 36 mg, and the patient fully recovered. Acute overdose with temazepam amplifies the CNS effects of the drug, but large doses must be taken to be fatal.
Patient education
Patients should take eszopiclone at bedtime because it will make them drowsy, dizzy, lightheaded, and uncoordinated. They should not take eszopiclone with alcohol or other sleep medications because it will exacerbate these effects. Sleep medicines may cause a special type of memory loss or amnesia. When this occurs, a person may not remember what has happened for several hours after taking the medication. This is usually not a problem because most people fall asleep after taking the medicine.
Clinical trials
Trial 1: Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over six months of nightly treatment. Sleep 2002;26:793-799.
Study design
A randomized, double-blind, placebo-controlled clinical trial conducted in 70 sites in the United States to determine the safety and efficacy of eszopiclone 3 mg administered nightly to patients with chronic insomnia for 12 months.
For the first six months, patients (ages 21-65) were instructed to take the double-blind medication at bedtime each night. Patients completing the double-blind period entered the six-month open-label extension and received eszopiclone 3 mg. A termination visit occurred five to seven days after the last dose of study medication.
Patient population
Almost 1,200 patients were assessed for eligibility. Of the 788 patients who were randomized, 471 completed the double-blind portion of the trial.
Monitoring
Each subject telephoned the interactive voice response system once each week on a regularly scheduled day between 8 p.m. and midnight to report average nightly values during that week for: sleep latency, wake time after sleep onset (WASO), total sleep time, number of awakenings, number of nights awakened, sleep quality, daytime ability to function, daytime alertness, and sense of physical well-being (see Table 2).
Strengths/weaknesses
- Randomized controlled, double-blind trial.
- Intention-to-treat analysis.
- Long duration.
- Placebo and eszopiclone have different tastes, so patients may have been aware of their treatment, which may have led to bias.
- High dropout rate.
- Not a head-to-head study.
- Did not treat individuals older than age 65.
- Races other than Caucasian were not adequately represented.
Conclusion
Nightly use of eszopiclone 3 mg resulted in statistically significant differences in patient-reported measures of sleep onset, maintenance, quality, and next-day function compared with placebo in patients with chronic insomnia with no evidence of tolerance.
Trial 2: Zammit GK, McNabb LJ, Caron J, et al. Efficacy and safety of eszopiclone across six weeks of treatment for primary insomnia. Curr Med Res Opin 2004;20:1,979-1,991.
Study design
A randomized, double-blind, placebo-controlled, parallel-group trial of eszopiclone 2 mg and 3 mg in patients with primary insomnia conducted at centers in the United States.
Patient population and regimen
Before randomization, there was a two-night single-blind placebo lead-in period. A total of 308 patients (ages 21-64) were randomized to take the double-blind medication at bedtime each night for 44 consecutive nights. The double-blind period was followed by two nights of single-blind placebo.
Monitoring
Efficacy was evaluated with polysomnography on nights 1, 15, and 29, and with patient reports on nights 1, 15, 29, and 43/44. Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST).
Results
- Eszopiclone 3 mg, when compared to placebo, resulted in significantly less time to sleep onset (P < 0.0001), more total sleep time and sleep efficiency(P < 0.0001), better sleep maintenance (P < 0.01), and enhanced quality and depth of sleep (P < 0.05).
- Eszopiclone 2 mg resulted in significantly less time to sleep onset (P < 0.001), more total sleep time (P < 0.01) and sleep efficiency (P < 0.001), and enhanced quality and depth of sleep (P < 0.05) compared with placebo, but did not improve sleep maintenance.
- No evidence of tolerance or rebound insomnia after therapy discontinuation was seen with eszopiclone.
- Median DSST scores showed no decrease in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group.
- Treatment was well tolerated with the most common adverse event in the eszopiclone group being an unpleasant taste.
Strengths/weaknesses
- Randomized controlled, double-blind trial.
- Intention-to-treat analysis.
- Inclusion/exclusion criteria.
- Placebo and eszopiclone have different tastes, so patients may have been aware of their treatment, which may have lead to bias.
- Trial of short duration to prove efficacy for chronic insomnia.
- Not a head-to-head study.
- Did not treat patients older than age 65.
Conclusion
- This study’s results demonstrate that nightly use of eszopiclone 3 mg indicate efficacy using both polysomnography and patient reports across four major domains of insomnia including sleep onset, sleep maintenance, sleep duration, and restorative sleep.
- The eszopiclone 2 mg group had significantly reduced sleep latency and improved sleep efficiency.
- In most patients, there was no evidence of daytime residual effects in the patient reports or the DSST.
Place in therapy/advantages
Eszopiclone’s advantage is that it is approved for patients with chronic insomnia and is the only sleep medication with this indication. It can be used long term without any risk of tolerance or addiction, and it does not have the hangover symptoms. In addition, this drug is safer for pregnant patients than benzodiazepines such as temazepam and should be considered as an alternative in this situation.
Formulary recommendation
It is recommended that eszopiclone be formulary status, but patients should not be started on the drug in the hospital. This policy will provide continued eszopiclone therapy for chronic patients and assist with maintaining temazepam as the hospital’s cost-effective hypnotic formulary agent for patients simply needing a hypnotic agent during hospitalization.
Eszopiclone (Lunesta) is the first member of a new drug class known as a pyrrolopyrazine derivative of the cyclopyrrolone class. It is a nonbenzodiazepine hypnotic agent with a chemical structure unrelated to any other drugs with known hypnotic properties.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.