Eszopiclone (Lunesta), manufactured by Sepracor Inc., is a new nonbenzodiazepine hypnotic developed for the treatment of insomnia. Insomnia is characterized as either short-term or transient (lasting a few days to 2 weeks) or chronic (lasting more than 3 weeks). It is estimated that 20% to 40% of adults complain of short-term insomnia and 10% to 15% of chronic insomnia. 1
Insomnia can affect daytime function and represents a significant economic burden to society. Patients experiencing either transient or chronic insomnia often complain of daytime fatigue, impaired mood, general malaise, and impaired mental, physical, social, and occupational functioning. 1 Finding the cause of insomnia is important before prescribing pharmacologic treatments (see Tables : “Management of Persistent or Chronic Insomnia” and “Principles of Sleep Hygiene”).
TABLE. Management of Persistent or Chronic Insomnia 3
TABLE. Principles of Sleep Hygiene 4
Eszopiclone is indicated for the treatment of insomnia and has been studied in clinical trials with patients experiencing both chronic and transient insomnia. When administered at bedtime, eszopiclone is effective in decreasing sleep latency (trouble falling asleep) and improving the patient’s ability to stay asleep.
Mechanism of Action
The precise mechanism of action of eszopiclone as a hypnotic is unknown, but its effect is believed to result from its interaction with GABA-receptor complexes. 2 Eszopiclone is rapidly absorbed after oral administration, and peak concentration is achieved within 1 hour. The drug is minimally bound to plasma proteins and therefore absorption and distribution is minimally affected by other drugs competing for protein binding sites.
In clinical studies, the effect of food on the absorption of eszopiclone was most noticeable when taken concomitantly with a high-fat meal; maximum absorption was delayed by approximately 1 hour, 2 although the half-life remained unchanged. Patients should be advised that a delay of sleep onset may occur if eszopiclone is taken with or soon after a high-fat meal.
Drug Metabolism
Eszopiclone is metabolized by oxidation and demethylation, primarily by plasma metabolites, although some metabolism occurs in the liver via CYP 3A4 and CYP 2E1 enzymes. Drug metabolism in patients with severe hepatic impairment was decreased and resulted in an increased drug exposure in patients with this condition. The half-life of eszopiclone is approximately 6 hours and the metabolites are primarily eliminated though urinary excretion. Less than 10% of the orally administered drug is excreted unchanged. 2
Contraindications
There are no specific contraindications to the use of eszopiclone at this time. Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. 2 Insomnia may be a primary condition or comorbid with a psychiatric, medical, or other sleep disorder. Assessment of insomnia should include a thorough history obtained from both the patient and bed partner, and followed by a physical examination. The primary focus should be on the functional impact, severity, and chronicity of the complaints, with rapid identification of target symptoms to formulate a management strategy. 3
General precautions that should be considered include the timing of drug administration, use in elderly or debilitated patients, use in patients with current illnesses, and use in patients with depression. Specific information related to these special patient populations is presented in the dosage and administration section.
Adverse Events
Eszopiclone was studied in six placebo-controlled clinical trials with 2,100 subjects experiencing both chronic and transient insomnia. Adverse events reported during the clinical trials in at least 2% of the study population were generally mild and resulted in minimal study subjects who discontinued treatment. The most commonly reported adverse reaction with eszopiclone use was unpleasant taste. Other reported adverse events with a dose-related response included viral infection, dry mouth, dizziness, hallucinations, infection, and rash. 2
Tolerance, dependence, and abuse with the use of benzodiazepines have led to concerns in using these types of hypnotics in the treatment of chronic insomnia. However, no tolerance or serious withdrawal syndrome to eszopiclone was observed during the 6-month clinical trials. The risk of patient abuse or dependence while using hypnotics increases with higher doses and duration of use, the concomitant use of other psychoactive drugs, and in patients with a history of drug or alcohol abuse and psychiatric disorders. Unlike most other medications for insomnia, eszopiclone is not just for short-term use only. However, because eszopiclone was used in clinical trials for a maximum of 6 months, practitioners are advised to carefully monitor for tolerance or dependence in patients on long-term drug therapy.
Dosage and Administration
The recommended starting dose of eszopiclone is 2 mg for most nonelderly adult patients with insomnia characterized by sleep latency. For those who also have difficulty with sleep maintenance or do not achieve adequate results with the lower dose, 3 mg has been shown to be more effective. For elderly patients, the recommended starting dose is 1 mg for those with difficulty falling asleep and 2 mg in those with complaints of difficulty staying asleep. In all patients, the drug should be administered immediately before bedtime. As mentioned previously, concomitant intake of a high-fat meal and eszopiclone may prolong the time before the drug becomes effective in inducing sleep.
Patients with severe hepatic impairment should use eszopiclone with caution, and practitioners should start with a 1 mg dose and monitor these patients carefully. In patients also taking potent inhibitors of CYP 3A4 (e.g., ketoconazole, clarithromycin, nefazodone), the dose of eszopiclone should be reduced. Practitioners should prescribe eszopiclone with caution to patients with depression because of a potential for intentional overdose. Because only a minimal amount of the drug is excreted unchanged in the urine, no dose adjustments are considered necessary for patients with renal impairment. 2
Eszopiclone has not been studied in pregnant women and the drug is classified as a Pregnancy Category C. It is also unknown whether the drug is excreted in human milk. Eszopiclone in pregnant or lactating women should be used with caution. Clinical studies completed thus far have studied eszopiclone only in the adult and geriatric population. The safe and effective use of the drug in the pediatric population has not been established.
Special Instructions
Sepracor offers information handouts for patients available through pharmacists during drug dispensing or from the Lunesta Web site ( http://www.lunesta.com ). Most importantly, the patient must be informed to take eszopiclone just before their anticipated bedtime. After first taking eszopiclone and until the full effects of the drug are known, patients are also advised to avoid conducting potentially dangerous activities (driving or operating machinery) the next day. Alcohol and other sleep medications should not be taken along with eszopiclone. In addition, prescribing practitioners should carefully review all prescription and over-the-counter medications currently used by the patient. If a patient has been using eszopiclone for more than a few weeks, he should be instructed not to suddenly stop using the medication to avoid potential withdrawal effects.
Gary Laustsen PhD, APRN, BC
