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Eszopiclone

FDA Drug Information • Also known as: Eszopiclone, Lunesta

Brand Names
Eszopiclone, Lunesta
Route
ORAL
Dosage Form
TABLET, FILM COATED
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: COMPLEX SLEEP BEHAVIORS WARNING: COMPLEX SLEEP BEHAVIORS Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of eszopiclone tablets. Some of these events may result in serious injuries, including death. Discontinue eszopiclone tablets immediately if a patient experiences a complex sleep behavior [see Contraindications (4) and Warnings and Precautions (5.1) ]. WARNING: COMPLEX SLEEP BEHAVIOUR See full prescribing information for complete boxed warning. Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of eszopiclone tablets. Some of these events may result in serious injuries, including death. Discontinue eszopiclone tablets immediately if a patient experiences a complex sleep behavior ( 4 , 5.1 ).

Description

11 DESCRIPTION Eszopiclone is a hypnotic agent/nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. The chemical name of eszopiclone is (+)-4-Methyl-1-piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5 H pyrrolo[3,4- b ]pyrazin-5-(S)-yl ester. Its molecular weight is 388.81, and its molecular formula is C 17 H 17 ClN 6 O 3 . Eszopiclone has a single chiral center with an ( S )-configuration. It has the following chemical structure: Eszopiclone USP is a white to slight yellowish powder. Eszopiclone USP is soluble in methylene chloride and dilute hydrochloric acid; practically insoluble in water and in alcohol. Eszopiclone is formulated as film-coated tablets for oral administration. Eszopiclone tablets, USP contain 1 mg, 2 mg, or 3 mg eszopiclone USP and the following inactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, hypromellose lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide, and triacetin. In addition, both the 1 mg and 3 mg tablets contain FD&C Blue #2/indigo carmine aluminium lake. eszopiclonestructure

What Is Eszopiclone Used For?

1 INDICATIONS & USAGE Eszopiclone tablets are indicated for the treatment of insomnia. In controlled outpatient and sleep laboratory studies, eszopiclone tablets administered at bedtime decreased sleep latency and improved sleep maintenance. The clinical trials performed in support of efficacy were up to 6 months in duration. The final formal assessments of sleep latency and maintenance were performed at 4 weeks in the 6-week study (adults only), at the end of both 2-week studies (elderly only) and at the end of the 6-month study (adults only). Eszopiclone tablets are indicated for the treatment of insomnia. Eszopiclone tablets has been shown to decrease sleep latency and improve sleep maintenance ( 1 )

Dosage and Administration

2 DOSAGE & ADMINISTRATION Use the lowest effective dose for the patient.

  • Use the lowest dose effective for the patient ( 2 )
  • Recommended initial dose is 1 mg, immediately before bedtime, with at least 7 to 8 hours remaining before the planned time of awakening. May increase dose if clinically indicated, to a maximum of 3 mg ( 2.1 )
  • Geriatric or debilitated patients: Dose should not exceed 2 mg ( 2.2 )
  • Patients with severe hepatic impairment, or taking potent CYP3A4 inhibitors: Dose should not exceed 2 mg ( 2.3 )
  • Do not take with or immediately after a meal ( 2.5 ) 2.1 Dosage in Adults The recommended starting dose is 1 mg. Dosing can be raised to 2 mg or 3 mg if clinically indicated. In some patients, the higher morning blood levels of eszopiclone tablets following use of the 2 mg or 3 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [ see Warnings and Precautions (5.1) ]. The total dose of eszopiclone tablets should not exceed 3 mg, once daily immediately before bedtime [ see Warnings and Precautions (5.6) ]. 2.2 Geriatric or Debilitated Patients The total dose of eszopiclone tablets should not exceed 2 mg in elderly or debilitated patients. 2.3 Patients with Severe Hepatic Impairment, or Taking Potent CYP3A4 Inhibitors In patients with severe hepatic impairment, or in patients coadministered eszopiclone tablets with potent CYP3A4 inhibitors, the total dose of eszopiclone tablets should not exceed 2 mg [ see Warnings and Precautions (5.7) ]. 2.4 Use with CNS Depressants Dosage adjustments may be necessary when eszopiclone tablets are combined with othercentral nervous system (CNS) depressant drugs because of the potentially additive effects [ see Warnings and Precautions (5.1) ]. 2.5 Administration with Food Taking eszopiclone tablets with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of eszopiclone tablets on sleep latency [see Clinical Pharmacology (12.3) ].

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following are described in more detail in the Warnings and Precautions section of the label:

  • Complex Sleep Behaviors [see Boxed Warning and Warnings and Precautions (5.1) ]
  • CNS Depressant Effects and Next-Day Impairment [see Warnings and Precautions (5.2) ]
  • Need to Evaluate for Comorbid Diagnoses [see Warnings and Precautions (5.3) ]
  • Severe Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions (5.4) ]
  • Abnormal Thinking and Behavioral Changes [see Warnings and Precautions (5.5) ]
  • Withdrawal Effects [see Warnings and Precautions (5.6) ]
  • Timing of Drug Administration [see Warnings and Precautions (5.7) ]
  • Special Populations [see Warnings and Precautions (5.8) ] 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 eszopiclone tablets 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 eszopiclone tablets 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. Most commonly observed adverse reactions (incidence ≥2%) were unpleasant taste, headache, somnolence, respiratory infection, dizziness, dry mouth, rash, anxiety, hallucinations, and viral infections ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or ww.fda.gov/medwatch. 6.1 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 eszopiclone tablets, and 1.4% of 72 patients who received 1 mg eszopiclone tablets 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 eszopiclone tablets 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 eszopiclone tablets at doses of 2 or 3 mg in nonelderly adults. Treatment duration in this trial was 44 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone tablets 2 mg or 3 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients. Table 1: Incidence (%) of Adverse Reactions in a 6-Week Placebo-Controlled Study in Nonelderly Adults with Eszopiclone Tablets 1 Adverse Reaction Placebo (n=99) Eszopiclone tablets 2 mg (n=104) Eszopiclone tablets 3 mg (n=105) Body as a Whole Headache 13...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • CNS Depressants Additive CNS-depressant effects with combination use. Use with ethanol causes additive psychomotor impairment ( 7.1 )
  • Rifampicin Combination use may decrease exposure and effects of eszopiclone tablets ( 7.2 )
  • Ketoconazole Combination use increases exposure and effect of eszopiclone tablets. Dose reduction of eszopiclone tablet is needed ( 7.2 ) 7.1 CNS Active Drugs Ethanol: An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol [see Warnings and Precautions (5.1 , 5.2) ]. 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. 7.2 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 eszopiclone tablet is needed for patient co-administered eszopiclone tablets with potent CYP3A4 inhibitors [see Dosage and Administration (2.3) ] . 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 eszopiclone tablets.

    • Contraindications

    4 CONTRAINDICATIONS

  • Eszopiclonetablet is contraindicated in patients who have experienced complex sleep behaviors after taking eszopiclone tablets [see Warnings and Precautions (5.1) ].
  • Eszopiclone tablet is contraindicated in patients with known hypersensitivity to eszopiclone. Hypersensitivity reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.3) ].
  • Patients who have experienced complex sleep behaviors after taking eszopiclone tablets ( 4 )
  • Known hypersensitivity to eszopiclone ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Available pharmacovigilance data with eszopiclone use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies conducted in pregnant rats and rabbits throughout organogenesis, there was no evidence of teratogenicity. Administration of eszopiclone to rats throughout pregnancy and lactation resulted in offspring toxicities at all doses tested; the lowest dose was approximately 200 times the maximum recommended human dose (MRHD) of 3 mg/day based on mg/m 2 body surface area (See Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of eszopiclone to pregnant rats (62.5, 125, or 250 mg/kg/day) and rabbits (4, 8, or 16 mg/kg/day) throughout organogenesis showed no evidence of teratogenicity up to the highest doses tested. In rats, reduced fetal weight and increased incidences of skeletal variations and/or delayed ossification were observed at the mid and high doses. The no-observed-effect dose for adverse effects on embryofetal development is 200 times the maximum recommended human dose (MRHD) of 3 mg/day on a mg/m 2 basis. No effects on embryofetal development were observed in rabbits; the highest dose tested is approximately 100 times the MRHD on a mg/m 2 basis. Oral administration of eszopiclone (60, 120, or 180 mg/kg/day) to pregnant rats throughout the pregnancy and lactation resulted in increased post-implantation loss, decreased postnatal pup weights and survival, and increased pup startle response at all doses. The lowest dose tested is approximately 200...

    8.2 Lactation Risk Summary There are no data on the presence of eszopiclone in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for eszopiclone and any potential adverse effects on the breastfed infant from eszopiclone or from the underlying maternal condition.

    Overdosage

    10 OVERDOSAGE In clinical trials with eszopiclone, one case of overdose with up to 36 mg of eszopiclone was reported in which the subject fully recovered. Since commercial marketing began, spontaneous cases of eszopiclone overdoses up to 270 mg (90 times the maximum recommended dose of eszopiclone) have been reported, in which patients have recovered. Fatalities related to eszopiclone tablets overdoses were reported only in combination with other CNS drugs or alcohol. 10.1 Signs and Symptoms Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. Impairment of consciousness ranging from somnolence to coma has been described. Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agents. Methemoglobinemia in association with overdoses of racemic zopiclone has been reported. 10.2 Recommended Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may be useful. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Consider monitoring methemoglobin in the setting of high-dose overdosage. The value of dialysis in the treatment of overdosage has not been determined. As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Eszopiclone tablets USP, 3 mg are dark blue to blue, round, biconvex, film-coated tablets debossed with ‘H’ on one side and ‘E16’ on the other side. Bottles of 30 tablets NDC 31722-857-30 Bottles of 100 tablets NDC 31722-857-01 Eszopiclone tablets USP, 2 mg are white to off-white, round, biconvex, film-coated tablets debossed with ‘H’ on one side and ‘E15’ on the other side. Bottles of 30 tablets NDC 31722-856-30 Bottles of 100 tablets NDC 31722-856-01 Eszopiclone tablets USP, 1 mg are light blue, round, biconvex, film-coated tablets debossed with ‘H’ on one side and ‘E14’ on the other side. Bottles of 30 tablets NDC 31722-855-30 Bottles of 100 tablets NDC 31722-855-01 Store at 20° to 25° C (68° to 77° F) [see USP Controlled Room Temperature].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.