1.  S-zopiclone
2.  S(+)-zopiclone
3.  Esopiclone
4.  Estorra

• 1. Eszopiclone tablets should be stored at 25 degrees Celsius (C) (77 degrees Fahrenheit (F)) with excursions permitted to 15 to 30 degrees C (59 to 86 degrees F) (Prod Info Lunesta(TM), 2004).

• A. ORAL
  
  • 1. INSOMNIA
    
    • a. A oral starting dose of 2 milligrams (mg) immediately before bedtime is recommended in non-elderly patients; dosing may be initiated at or increased to 3 mg as clinically indicated. All doses of eszopiclone should be individualized (Prod Info Lunesta(TM), 2004).
    • b. An oral nighttime dose of 3 milligrams (mg) has shown efficacy in chronic insomnia (Anon, 2002). This dose was effective in a model of transient insomnia involving healthy subjects (Rosenberg et al, 2002).
    • c. Similar to zopiclone, withdrawal symptoms may occur with eszopiclone after prolonged administration (eg, 1 to 2 weeks); gradual withdrawal is indicated.

• A. No dosage adjustment is necessary for patients with renal impairment (Prod Info Lunesta(TM), 2004).

• A. No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment; use with caution. In patients with severe hepatic impairment or patients coadministered potent CYP3A4 inhibitors, the starting dose should be 1 milligram (mg) (dose can be increased to 2 mg) (Prod Info Lunesta(TM), 2004).

• A. Elderly patients (65 years and older) having a difficult time falling asleep should start therapy at 1 mg immediately before bedtime, while those with difficulty staying asleep should start at a 2 mg dose. Patients should not exceed a 2 mg dose secondary to an increase in total exposure (41% increased area under the curve) and a prolonged half-life (9 hours) (Prod Info Lunesta(TM), 2004).

• A. The safety and effectiveness of eszopiclone in children less than 18 years of age have not been established (Prod Info Lunesta(TM), 2004).

• A. INITIAL RESPONSE :
  
  • 1. INSOMNIA, ORAL
    
    • a. Sleep onset (measured by latency to persistent sleep) after doses of 2 or 3 mg was 8 minutes faster than with placebo in a model of transient insomnia involving healthy subjects (approximately 10 versus 18 minutes) (Rosenberg et al, 2002). Data from studies in patients with diagnosed insomnia are unavailable.

• A. SINGLE DOSE :
  
  • 1. INSOMNIA, ORAL : up to 6 hours (Georgiev, 2001).
    • a. Total sleep time (subjective) after doses of 2 or 3 mg was 20 minutes longer than with placebo in a model of transient insomnia involving healthy subjects (approximately 460 versus 440 minutes); this difference reached significance (Rosenberg et al, 2002). Data from studies in patients with diagnosed insomnia are unavailable.
    • b. In pharmacodynamic studies (daytime), the duration of psychomotor impairment and sleepiness did not exceed 6 hours after oral doses of 1 to 3 mg (Leese et al, 2002), suggesting a low propensity for morning hangover effects when used to treat insomnia.

• A. THERAPEUTIC DRUG CONCENTRATION :
  
  • 1. Plasma level monitoring is not used clinically.
• B. TIME TO PEAK CONCENTRATION :
  
  • 1. ORAL : 1 to 1.5 hours (Prod Info Lunesta(TM), 2004; Leese et al, 2002).
    • a. After single oral doses of up to 7.5 milligrams (mg) and daily administration of 1, 3, and 6 mg for seven days in healthy subjects, time to peak plasma concentrations of eszopiclone were achieved within 1 hour. Sleep effects may be reduced if eszopiclone is administered with or immediately after a high fat/heavy meal (Prod Info Lunesta(TM), 2004).

• A. BIOAVAILABILITY (F) :
  
  • 1. ORAL
    
    • a. Eszopiclone is rapidly absorbed (within 1 hour) following oral administration (Prod Info Lunesta(TM), 2004).
    • b. Specific bioavailability data for eszopiclone are unavailable. Racemic zopiclone is well-absorbed, with a bioavailability of at least 75%.
• B. EFFECTS OF FOOD :
  
  • 1. Administration of a 3 mg dose after a high-fat meal resulted in a 21% reduction in the mean maximum concentration and a delay in the time to maximum concentration by approximately 1 hour. The area under the concentration-time curve (AUC) and the elimination half-life were essentially unchanged. Sleep onset may be reduced when eszopiclone is taken with or shortly after a high-fat meal (Prod Info Lunesta(TM), 2004).

• 2.3.2.1 DISTRIBUTION SITES
  • A. TOTAL PROTEIN BINDING :
    
    • 1. Eszopiclone is weakly bound to plasm proteins and has a low blood-to-plasma ratio (Prod Info Lunesta(TM),2004).

• 2.3.3.1 METABOLISM SITES AND KINETICS
  • A. LIVER
    • 1. Eszopiclone is extensively metabolized by oxidation and demethylation. Based on in vitro data, CYP450 3A4 and 2E1 are involved the metabolism of eszopiclone; however, inhibitory potential on CYP450 enzymes was not apparent in cryopreserved human hepatocytes.
• 2.3.3.2 METABOLITES
  • A. (S)-zopiclone-N-oxide
    
    • 1. (S)-zopiclone-N-oxide is a primary metabolite of eszopiclone with no significant binding to the GABA receptors (Prod Info Lunesta(TM), 2004).
  • B. (S)-N-desmethylzopiclone
    
    • 1. (S)-N-desmethylzopiclone is a primary plasma metabolite of eszopiclone with less potency for the GABA receptors (Prod Info Lunesta(TM), 2004).

• 2.3.4.1 BREAST MILK
  • A. BREASTFEEDING: Unknown (Prod Info Lunesta(TM), 2004)
• 2.3.4.2 KIDNEY
  • A. RENAL EXCRETION :
    
    • 1. Data for eszopiclone are unavailable. Most of a dose of racemic zopiclone is excreted in the urine (about 5% unchanged).

• 2.3.5.1 PARENT COMPOUND
  • A. ELIMINATION HALF-LIFE : 5 to 6 hours (Prod Info Lunesta(TM), 2004; Leese et al, 2002).
    • 1. After single oral doses of up to 7.5 milligrams (mg) and daily administration of 1, 3, and 6 mg for seven days in healthy subjects, the mean half-life was 6 hours. In elderly patients, the half-life was increased to 9 hours (Prod Info Lunesta(TM), 2004).

• A. CENTRAL NERVOUS SYSTEM EFFECTS
  
  • 1. Adult patients receiving oral eszopiclone 1 milligram (mg) or 2 mg experienced (less than 10%) ANXIETY, CONFUSION, DEPRESSION, DECREASED LIBIDO, HEADACHE, MIGRAINE, and NERVOUSNESS; DIZZINESS, and HALLUCINATIONS appeared to have a dose-response relationship (Prod Info Lunesta(TM), 2004).
  • 2. Nighttime administration of eszopiclone for insomnia has not been associated with significant residual effects (morning hangover) in unpublished studies (Anon, 2003; Rosenberg et al, 2001; Georgiev, 2001).
  • 3. Sedative effects (sleepiness) and psychomotor impairment did not persist beyond 6 hours postdose (1 to 3 mg) in healthy subjects in a daytime study (Leese et al, 2002).

• A. GASTROINTESTINAL EFFECTS
  
  • 1. Adult patients receiving oral eszopiclone 1 milligram (mg) or 2 mg reported (less than 10%) DYSPEPSIA, NAUSEA, and VOMITING; DRY MOUTH appeared to have a dose-response relationship (Prod Info Lunesta(TM), 2004).
  • 3. Preclinical data have suggested a lower propensity for anticholinergic effects, especially dry mouth, with eszopiclone compared to the R(-)-enantiomer (Georgiev, 2001).
• B. TASTE DISORDER
  
  • 1. UNPLEASANT TASTE, in a dose-response relationship, has been reported in adult patients receiving oral eszopiclone 1 milligram (mg) (3%), 2 mg (17%), and 3 mg (34%) (Prod Info Lunesta(TM), 2004).
  • 2. An unpleasant taste has been reported in limited studies (liquid formulation); it is unclear if this was related to the drug (Leese et al, 2002; Rosenberg et al, 2002). Taste disturbances have been reported with racemic zopiclone.

• A. GENITOURINARY EFFECTS
  
  • 1. DYSMENORRHEA and GYNECOMASTIA have been reported in adult patients receiving oral eszopiclone 2 milligrams (Prod Info Lunesta(TM), 2004).

• A. RESPIRATORY EFFECTS
  
  • 1. VIRAL INFECTION (less than 10%) has been reported in adult patients receiving oral eszopiclone 1 milligram (mg) or 2 mg (Prod Info Lunesta(TM), 2004).
  • 2. Eszopiclone (up to 7 milligrams (mg) orally) lacked respiratory depressant effects in a small randomized comparison with codeine and placebo in healthy subjects (Powchick & Cohn, 2001).

• A. RASH (less than 5%) has been reported in adult patients receiving oral eszopiclone 1 milligram (mg) or 2 mg (Prod Info Lunesta(TM), 2004).

• A. OVERDOSE
  
• B. DEPENDANCE AND TOLERANCE
  
  • 1. Dependance to eszopiclone was not demonstrated in clinical trials. No evidence of serious WITHDRAWAL SYNDROME was reported. However, symptoms of withdrawal (anxiety, abnormal dreams, nausea and upset stomach) were reported in patients (less than 2%). Tolerance, as assessed over six months, was not observed (Prod Info Lunesta(TM), 2004).
• C. PAIN
  
  • 1. Pain has been reported in elderly adult patients receiving oral eszopiclone 1 milligram (mg) or 2 mg (Prod Info Lunesta(TM), 2004).

• A. PHYSICAL EXAMINATION
  
  • 1. Sleep onset, duration, and quality (office questioning)

• A. LABORATORY PARAMETERS
  
  • 1. Liver function tests pre- and posttreatment in patients with preexisting liver disease; initial doses should be reduced in these patients
• B. PHYSICAL EXAMINATION
  
  • 1. Signs/symptoms of toxicity: confusion; daytime sleepiness (hangover effects); mood changes; daytime restlessness and/or anxiety (withdrawal phenomena); rash (hypersensitivity); severe lethargy, confusion, or ataxia (overdose symptoms)

• 1. Although the exact mechanism of action of eszopiclone is unknown, its effects are thought to be modulated from an interaction with gamma aminobutyric acid (GABA) at the GABA-A-receptor complex (Prod Info Lunesta(TM), 2004; Georgiev, 2001; McMahon et al, 2003).

• 1. Eszopiclone (S-zopiclone) is a nonbenzodiazepine hypnotic agent indicated for the treatment of insomnia. It is the S(+)-enantiomer of racemic zopiclone (Prod Info Lunesta(TM), 2004; Anon, 2002; McMahon et al, 2003; Georgiev, 2001).
• 2. Preclinical studies have demonstrated that S(+)-zopiclone is more active than R(-)-zopiclone at the benzodiazepine receptor complex, and provides most of the hypnotic activity of the racemic compound (McMahon et al, 2003; Georgiev, 2001); about 50-fold higher affinity for the benzodiazepine receptor was demonstrated with S(+)-zopiclone in one study (Georgiev, 2001). The S(+)-enantiomer was significantly more potent than R(-)-zopiclone in producing behavioral effects in rodents (McMahon et al, 2003).
• 3. Eszopiclone appears to have a short duration of action, which could minimize or prevent residual hangover effects (Leese et al, 2002; Anon, 2002). Preclinical data suggest a significantly lower propensity for anticholinergic effects (eg, dry mouth) than the R(-)-enantiomer (Georgiev, 2001); this would represent an advantage of the drug over racemic zopiclone, which is not always seen with development of single-isomers, developed mainly for financial gain.
• 4. Eszopiclone in doses of up to 7 milligrams (mg) lacked respiratory depressant effects in a small randomized comparison with codeine and placebo in healthy subjects (Powchick & Cohn, 2001).

• 1. Review of available/investigational psychopharmacologic agents (Mealy et al, 2002).

• 1. OVERVIEW :

  
  FDA APPROVAL:  Adult, yes; pediatric, no
  EFFICACY:  Adult, effective
  DOCUMENTATION:  Adult, good
  

• 2. SUMMARY :

  
   - Efficacy reported in patients with transient or 
     chronic insomnia
  
   - 6-month course of ESZOPICLONE induced 
     significant improvements in sleep patterns
     compared with placebo in patients who suffered
     from chronic insomnia
  
   - Tolerance to the drug was not apparent over
     a 6-month course and withdrawal symptoms were
     not observed after the drug was stopped
  
   - Studies have been manufacturer sponsored 
  

• 3. ADULT :
  
  • a. In a double-blind parallel-group trial, eszopiclone (2 or 3 milligrams (mg)) was superior to placebo on latency to persistent sleep and wake time after sleep onset (3 mg dose). Adult patients with chronic insomnia (n=308) received eszopiclone 2 mg, 3 mg, or placebo for 6 weeks; objective endpoints were measured at 4 weeks (Prod Info Lunesta(TM), 2004).
  • b. Among patients with CHRONIC INSOMNIA, a 6-month course of ESZOPICLONE provided improvements in time to sleep onset, sleep maintenance, and sleep quality compared with placebo, with no evidence indicating that eszopiclone-treated patients developed tolerance to the drug. Significant differences were seen beginning in the first week and continuing to study end-point. These findings emanated from a double-blind, randomized trial (n=788; 3:1 ratio, eszopiclone 593; placebo 195). Enrollees met DSM IV criteria for PRIMARY INSOMNIA and reported less than 6.5 hours (hr) of sleep per night and/or a sleep latency of more than 30 minutes (min) each night for at least 1 month. Eszopiclone was administered as 3 milligrams orally at bedtime. After 6 months of treatment, median sleep latency was 30 min and 45 min for the eszopiclone and placebo groups, respectively (p less than 0.0001). Comparable sleep latency times during the first week of treatment were 30 and 60 min, respectively. At endpoint, wake time after sleep onset was median 21 min and 30 min for those receiving eszopiclone and placebo, respectively (p less than 0.0032). Median number of nightly awakenings was 1.6 and 2.0 for the same 2 groups, respectively (p less than 0.0001). Median length of sleep time was 382 min and 345 min, respectively (p less than 0.0001). Quality of sleep (patient self-rated on a 10-point scale) improved from a median score of 4 at baseline in both groups to 6.5 in the eszopiclone group and 5.5 in the control group (p less than 0.0001). Patient ratings with respect to next-day functioning, alertness, and sense of physical well-being were significantly better among those given eszopiclone. By comparing outcomes during the first week with those at endpoint, the investigators determined that tolerance to the medication did not develop. There were no withdrawal symptoms exhibited following discontinuation of eszopiclone. Patients with adverse events considered probably or definitely related to study drug were 22.6% and 7.2% for the eszopiclone and control groups, respectively, with unpleasant taste of eszopiclone accounting for the major difference. Because the discontinuation rates were so high (39.5% and 43.4%, eszopiclone and placebo), several statistical analyses using varying data sets were performed; overall pattern and significance were maintained (Krystal et al, 2003).
  • c. Limited unpublished data released from phase II and III studies suggest the efficacy of eszopiclone in both transient and chronic insomnia compared to placebo, including improved time to sleep onset and total sleep time (maintenance of sleep), with no significant morning hangover effects (Anon, 2003; Anon, 2002; Georgiev, 2001). Efficacy and good tolerability were reported in elderly patients with chronic insomnia in these studies.
  • d. According to a published abstract, eszopiclone was investigated in a model of transient insomnia (healthy subjects) (Rosenberg et al, 2002). Oral eszopiclone (liquid formulation) 2 or 3 milligrams (mg) significantly shortened the latency to persistent sleep (about 10 minutes with both doses versus 18 minutes with placebo). The duration and quality of sleep were improved significantly by eszopiclone, except for objective number of awakenings, which were similar with 2-mg doses (5.4) and placebo (6). Subjective morning sleepiness was significantly less only with eszopiclone 3 mg versus placebo. In this study, all significant differences were only at the 5% level (p less than 0.05).