FDA

Eszopiclone

Approved 15 Apr 2014OralTablet

The FDA lists this product in 42 strengths and forms.

Indications

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 have been shown to decrease sleep latency and improve sleep maintenance ( 1 ).

Contraindications

Eszopiclone tablets are contraindicated in patients who have experienced complex sleep behaviors after taking eszopiclone tablets [see Warnings and Precautions ( 5.1 )] . Eszopiclone tablets are contraindicated in patients who have experienced complex sleep behaviors after taking eszopiclone tablets [see Warnings and Precautions ( 5.1 )] . Eszopiclone tablets are 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 )

Warnings and precautions

CNS Depressant Effects: Impaired alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Caution patients taking 3 mg dose against driving and against activities requiring complete mental alertness during the morning after use. ( 5.2 ) Evaluate for Comorbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use ( 5.3 ) Severe Anaphylactic/Anaphylactoid Reactions (angioedema and anaphylaxis have been reported): Do not rechallenge if such reactions occur ( 5.4 ) Abnormal Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation and depersonalization have been reported.

Immediately evaluate any new onset of behavioral changes ( 5.5 ) Worsening of Depression or Suicidal Thinking may occur: Prescribe the least number of tablets feasible to avoid intentional overdose ( 5.5 , 5.8 ) Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation ( 5.6 , 9.3 ) Elderly Patients: Use lower dose due to impaired motor, cognitive performance and increased sensitivity ( 2.2 , 5.8 ) Patients with Hepatic Impairment, Impaired Respiratory Function, Impaired Drug Metabolism or Hemodynamic Responses: Use with caution ( 5.8 )

At a glance

Brand name: Eszopiclone
Route: Oral
Dosage form: Tablet
Applicant: Glenmark Pharms LTD
Status: Prescription
FDA approval: 15 Apr 2014
Application: ANDA091166-003

Indications

Eszopiclone tablets are indicated for the treatment of insomnia. Eszopiclone tablets have been shown to decrease sleep latency and improve sleep maintenance ( 1 ).

Contraindications

Warnings and precautions

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 ( 7.2 ) Ketoconazole: Combination use increases exposure and effect of eszopiclone. Dose reduction of eszopiclone is needed ( 7.2 )

7.1CNS 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 is needed for patients co administered eszopiclone 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. Drug Interactions Eszopiclone is metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation. There were no pharmacokinetic or pharmacodynamic interactions between eszopiclone and paroxetine.

When eszopiclone was coadministered with olanzapine, no pharmacokinetic interaction was detected in levels of eszopiclone or olanzapine, but a pharmacodynamic interaction was seen on a measure of psychomotor function. Eszopiclone and lorazepam decreased each other’s C max by 22%. Coadministration of eszopiclone 3 mg to subjects receiving ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days, resulted in a 2.2-fold increase in exposure to eszopiclone.

C max and t 1/2 were increased 1.4-fold and 1.3-fold, respectively. Eszopiclone would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes [see Warnings and Precautions ( 5.7 ), Dosage and Administration ( 2.3 )] . Paroxetine: Coadministration of single dose of eszopiclone and paroxetine produced no pharmacokinetic or pharmacodynamic interaction. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.

Lorazepam: Coadministration of single doses of eszopiclone and lorazepam did not have clinically relevant effects on the pharmacodynamics or pharmacokinetics of either drug. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.

Pregnancy and breastfeeding

8.1Pregnancy 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 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 times the MRHD on a mg/m 2 basis. Eszopiclone had no effects on other developmental measures or reproductive function in the offspring.

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 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 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 Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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, and 1.4% of 72 patients who received 1 mg eszopiclone 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 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 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 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 1 Adverse Reaction Placebo (n=99) Eszopiclone 2 mg (n=104) Eszopiclone 3 mg (n=105) Body as a Whole Headache 13 21 17 Viral Infection 1 3 3 Digestive System Dry Mouth 3 5 7 Dyspepsia 4 4 5 Nausea 4 5 4 Vomiting 1 3 0 Nervous System Anxiety 0 3 1 Confusion 0 0 3 Depression 0 4 1 Dizziness 4 5 7 Hallucinations 0 1 3 Libido Decreased 0 0 3 Nervousness 3 5 0 Somnolence 3 10 8 Respiratory System Infection 3 5 10 Skin and Appendages Rash 1 3 4 Special Senses Unpleasant Taste 3 17 34 Urogenital System Dysmenorrhea * 0 3 0 Gynecomastia ** 0 3 0 1 Reactions for which the eszopiclone incidence was equal to or less than placebo are not listed on the table, but included the following: abnormal dreams, accidental injury, back pain, diarrhea, flu syndrome, myalgia, pain, pharyngitis, and rhinitis. * Gender-specific adverse reaction in females ** Gender-specific adverse reaction in males Adverse reactions from Table 1 that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste.

Table 2 shows the incidence of adverse reactions from combined Phase 3 placebo-controlled studies of eszopiclone at doses of 1 or 2 mg in elderly adults (ages 65 to 86). Treatment duration in these trials was 14 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 1 mg or 2 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients.

Table 2: Incidence (%) of Adverse Reactions in Elderly Adults (Ages 65 to 86 Years) in 2-Week Placebo-Controlled Trials with Eszopiclone 1 Adverse Reactions Placebo (n=208) Eszopiclone 1 mg (n=72) Eszopiclone 2 mg (n=215) Body as a Whole Accidental Injury 1 0 3 Headache 14 15 13 Pain 2 4 5 Digestive System Diarrhea 2 4 2 Dry Mouth 2 3 7 Dyspepsia 2 6 2 Nervous System Abnormal Dreams 0 3 1 Dizziness 2 1 6 Nervousness 1 0 2 Neuralgia 0 3 0 Skin and Appendages Pruritus 1 4 1 Special Senses Unpleasant Taste 0 8 12 Urogenital System Urinary Tract Infection 0 3 0 1 Reactions for which the eszopiclone incidence was equal to or less than placebo are not listed on the table, but included the following: abdominal pain, asthenia, nausea, rash, and somnolence.

Adverse reactions from Table 2 that suggest a dose-response relationship in elderly adults include pain, dry mouth, and unpleasant taste, with this relationship again clearest for unpleasant taste. These figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice because patient characteristics and other factors may differ from those that prevailed in the clinical trials.

Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contributions of drug and nondrug factors to the adverse reaction incidence rate in the population studied. Other Reactions Observed During the Premarketing Evaluation of Eszopiclone Following is a list of modified COSTART terms that reflect adverse reactions as defined in the introduction to the Adverse Reactions section and reported by approximately 1550 subjects treated with eszopiclone at doses in the range of 1 to 3.5 mg/day during Phase 2 and 3 clinical trials throughout the United States and Canada.

All reported reactions are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor reactions common in the general population, and reactions unlikely to be drug related. Although the reactions reported occurred during treatment with eszopiclone, they were not necessarily caused by it. Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those that occurred in fewer than 1/100 patie

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Eszopiclone

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Eszopiclone

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Complex Sleep

5.2CNS Depressant Effects and Next-Day Impairment

5.3Need to Evaluate for Comorbid Diagnoses

5.4Severe Anaphylactic and Anaphylactoid Reactions

5.5Abnormal Thinking and Behavioral Changes

5.6Withdrawal Effects

5.7Timing of Drug Administration

Interactions

7.1CNS Active Drugs Ethanol:

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience Adverse Reactions Resulting in Discontinuation of Treatment

Composition

Strengths and forms

Official product information