Eszopiclone

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/m² 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/m² basis. No effects on embryofetal development were observed in rabbits; the highest dose tested is approximately 100 times the MRHD on a mg/m² 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/m² basis. Eszopiclone had no effects on other developmental measures or reproductive function in the offspring.

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.

Carcinogenesis

In a carcinogenicity study in rats, oral administration of eszopiclone for 97 (males) or 104 (females) weeks resulted in no increases in tumors; plasma levels (AUC) of eszopiclone at the highest dose tested (16 mg/kg/day) are approximately 80 (females) and 20 (males) times those in humans at the MRHD of 3 mg/day. However, in a 2-year carcinogenicity study in rats, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) resulted in increases in mammary gland adenocarcinomas (females) and thyroid gland follicular cell adenomas and carcinomas (males) at the highest dose tested. Plasma levels of eszopiclone at this dose are approximately 150 (females) and 70 (males) times those in humans at the MRHD of eszopiclone. The mechanism for the increase in mammary adenocarcinomas is unknown. The increase in thyroid tumors is thought to be due to increased levels of TSH secondary to increased metabolism of circulating thyroid hormones, a mechanism not considered relevant to humans.

In a 2-year carcinogenicity study in mice, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) produced increases in pulmonary carcinomas and carcinomas plus adenomas (females) and skin fibromas and sarcomas (males) at the highest dose tested. The skin tumors were due to skin lesions induced by aggressive behavior, a mechanism not relevant to humans. A carcinogenicity study of eszopiclone was conducted in mice at oral doses up to 100 mg/kg/day. Although this study did not reach a maximum tolerated dose, and was thus inadequate for overall assessment of carcinogenic potential, no increases in either pulmonary or skin tumors were seen at doses producing plasma levels of eszopiclone approximately 90 times those in humans at the MRHD of eszopiclone (and 12 times the exposure in the racemate study).

Eszopiclone did not increase tumors in a p53 transgenic mouse bioassay at oral doses up to 300 mg/kg/day.

Mutagenesis

Eszopiclone was clastogenic in in vitro (mouse lymphoma and chromosomal aberration) assays in mammalian cells. Eszopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo micronucleus assay.

(S)-N-desmethyl zopiclone, a metabolite of eszopiclone, was positive in in vitro chromosomal aberration assays in mammalian cells. (S)-N-desmethyl zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo chromosomal aberration and micronucleus assay.

Impairment of Fertility

Oral administration of eszopiclone to rats prior to and during mating, and continuing in females to day 7 of gestation (doses up to 45 mg/kg/day to males and females or up to 180 mg/kg/day to females only) resulted in decreased fertility, with no pregnancy at the highest dose tested when both males and females were treated. In females, there was an increase in abnormal estrus cycles at the highest dose tested. In males, decreases in sperm number and motility and increases in morphologically abnormal sperm were observed at the mid and high doses. The no-effect dose for adverse effects on fertility (5 mg/kg/day) is 16 times the MRHD on a mg/m² basis.

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

• Complex Sleep Behaviors
• CNS Depressant Effects and Next-Day Impairment
• Need to Evaluate for Comorbid Diagnoses
• Severe Anaphylactic and Anaphylactoid Reactions
• Abnormal Thinking and Behavioral Changes
• Withdrawal Effects
• Timing of Drug Administration
• Special Populations

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.

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, 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:

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 65-86). 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 65-86 Years) in 2-Week Placebo-Controlled Trials with eszopiclone¹:

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 patients but in at least 1/1,000 patients; rare adverse reactions are those that occurred in fewer than 1/1,000 patients. Gender-specific reactions are categorized based on their incidence for the appropriate gender.

Body as a Whole: Frequent: chest pain; Infrequent: allergic reaction, cellulitis, face edema, fever, halitosis, heat stroke, hernia, malaise, neck rigidity, photosensitivity.

Cardiovascular System: Frequent: migraine; Infrequent: hypertension; Rare: thrombophlebitis.

Digestive System: Infrequent: anorexia, cholelithiasis, increased appetite, melena, mouth ulceration, thirst, ulcerative stomatitis; Rare: colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, stomach ulcer, stomatitis, tongue edema, rectal hemorrhage.

Hemic and Lymphatic System: Infrequent: anemia, lymphadenopathy.

Metabolic and Nutritional: Frequent: peripheral edema; Infrequent: hypercholesteremia, weight gain, weight loss; Rare: dehydration, gout, hyperlipemia, hypokalemia.

Musculoskeletal System: Infrequent: arthritis, bursitis, joint disorder (mainly swelling, stiffness, and pain), leg cramps, myasthenia, twitching; Rare: arthrosis, myopathy, ptosis.

Nervous System: Infrequent: agitation, apathy, ataxia, emotional lability, hostility, hypertonia, hypesthesia, incoordination, insomnia, memory impairment, neurosis, nystagmus, paresthesia, reflexes decreased, thinking abnormal (mainly difficulty concentrating), vertigo; Rare: abnormal gait, euphoria, hyperesthesia, hypokinesia, neuritis, neuropathy, stupor, tremor.

Respiratory System: Infrequent: asthma, bronchitis, dyspnea, epistaxis, hiccup, laryngitis.

Skin and Appendages: Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria; Rare: erythema multiforme, furunculosis, herpes zoster, hirsutism, maculopapular rash, vesiculobullous rash.

Special Senses: Infrequent: conjunctivitis, dry eyes, ear pain, otitis externa, otitis media, tinnitus, vestibular disorder; Rare: hyperacusis, iritis, mydriasis, photophobia.

Urogenital System: Infrequent: amenorrhea, breast engorgement, breast enlargement, breast neoplasm, breast pain, cystitis, dysuria, female lactation, hematuria, kidney calculus, kidney pain, mastitis, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, uterine hemorrhage, vaginal hemorrhage, vaginitis; Rare: oliguria, pyelonephritis, urethritis.

Postmarketing Experience

In addition to the adverse reactions observed during clinical trials, dysosmia, an olfactory dysfunction that is characterized by distortion of the sense of smell, has been reported during postmarketing surveillance with eszopiclone. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.