Jane S. Ricciuti, RPh, MS


February 07, 2005

In This Article

Sedative and Hypnotic Agents

Manufacturer: Sepracor Inc.

Drug Approval Classification: Original New Drug Application (Approval Date: 12/15/04)

Indication: Lunesta (eszopiclone) tablets are indicated for the treatment of insomnia. In controlled outpatient and sleep laboratory studies, eszopiclone administered at bedtime decreased sleep latency and improved sleep maintenance.

Dosing: The recommended starting dose for eszopiclone for most non-elderly adults is 2 mg immediately before bedtime. Dosing can be initiated at or raised to 3 mg if clinically indicated, since 3 mg is more effective for sleep maintenance.

The recommended starting dose of eszopiclone for elderly patients whose primary complaint is difficulty falling asleep is 1 mg immediately before bedtime. For these patients, the dose may be increased to 2 mg if clinically indicated. For elderly patients whose primary complaint is difficulty staying asleep, the recommended dose is 2 mg immediately before bedtime.

Clinical Summary: Eszopiclone is a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. Eszopiclone's mechanism of action is believed to result from its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors.

In clinical trials, eszopiclone was studied in 2100 patients (ages 18-86) with chronic and transient insomnia in 6 placebo-controlled trials of up to 6 months' duration. Two of these trials were in elderly patients (n = 523). Overall, at the recommended adult dose (2-3 mg) and elderly patient dose (1-2 mg), eszopiclone significantly decreased sleep latency and improved measures of sleep maintenance (objectively measured as wake time after sleep onset [WASO] and subjectively measured as total sleep time).

Adverse Effects: Eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Eszopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, but it shares some of the pharmacologic properties of benzodiazepines. Eszopiclone, like other hypnotics, has CNS-depressant effects. Because of the rapid onset of action, eszopiclone should only be ingested immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep. Patients receiving eszopiclone should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination (eg, operating machinery or driving a motor vehicle) after ingesting the drug, and be cautioned about potential impairment of the performance of such activities on the day following ingestion of eszopiclone.

The most frequently reported adverse events in the nonelderly population studied who took eszopiclone 2 mg or 3 mg were headache (21% and 17%, respectively), unpleasant taste (17% and 34%, respectively), and somnolence (10% and 8%, respectively). In the elderly population, headache was the most frequently reported adverse event (15%, 13%).

Pharmacokinetics: In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Eszopiclone is rapidly absorbed, with a time to peak concentration (tmax) of approximately 1 hour and a terminal-phase elimination half-life (t1/2) of approximately 6 hours. In healthy adults, eszopiclone does not accumulate with once-daily administration, and its exposure is dose proportional over the range of 1 to 6 mg.

In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.

Eszopiclone exposure was increased 2-fold in severely hepatically impaired patients compared with healthy volunteers. The dose of eszopiclone should not be increased above 2 mg in patients with severe hepatic impairment.

No dose adjustment is necessary in patients with renal impairment, since less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.


Lunesta (eszopiclone) Tablets Labeling

Manufacturer: Schwarz Pharma, Inc.

Drug Approval Classification: Original New Drug Application (Approval Date: 1/19/05)

Indication: Niravam (alprazolam) orally disintegrating tablets have 2 labeled indications.

  • Anxiety disorders: Niravam is indicated for the management of anxiety disorder or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

  • Panic disorder: Niravam is indicated for the treatment of panic disorder, with or without agoraphobia.

Dosing: Treatment for patients with anxiety should be initiated with a dose of 0.25 to 0.5 mg given 3 times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses.

Treatment for patients with panic disorder has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean dosage employed was approximately 5 to 6 mg daily.

Clinical Summary: Niravam is an orally administered formulation of alprazolam that rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing.

For the anxiety disorder indication, Niravam was compared to placebo in double-blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Niravam was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician's Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient's Global Impressions, and Self-Rating Symptom Scale.

For the panic disorder indication, Niravam was assessed on the basis of data from 3 short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder. The average dose of Niravam was 5-6 mg/day in 2 of the studies, and the doses of Niravam were fixed at 2 and 6 mg/day in the third study. In all 3 studies, Niravam was superior to placebo with regard to a variable defined as "the number of patients with zero panic attacks" (range, 37% - 83% met this criterion), as well as on a global improvement score.

Pharmacokinetics: Following oral administration, alprazolam is readily absorbed. The peak plasma concentration is reached about 1.5 to 2.0 hours after administration of Niravam given with or without water. When taken with water, mean Tmax occurs about 15 minutes earlier than when taken without water with no change in Cmax or AUC. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL are observed. The elimination half-life of alprazolam is approximately 12.5 hours (range, 7.9 to 19.2 hours) after administration of Niravam in healthy adults.


Niravam (alprazolam) Orally Disintegrating Tablets Labeling