Side Effects of Lunesta (eszopiclone)

Lunesta (eszopiclone) is a non-benzodiazepine, oral, sedative drug (“sleeping pill”) used to treat insomnia. Symptoms of insomnia include difficulty falling asleep, awakening frequently during the night, waking up too early, an inability to fall back to sleep, or awakening in the morning not feeling refreshed. Lunesta was formerly known as Estorra. 

Common side effects of Lunesta include headache, drowsiness, dry mouth, dizziness, unpleasant taste, stomach upset, and loss of coordination.

Serious side effects of Lunesta include anxiety, depression, aggression, agitation, memory problems, unusual thoughts or behavior, thoughts of hurting yourself, confusion, or hallucinations.

Lunesta is a controlled substance. Patients taking Lunesta or any other sedative drug may become dependent on the drug for sleep and experience withdrawal symptoms when Lunesta is discontinued.

Drug interactions of Lunesta include alcohol (which causes sedation) and drugs that have sedating effects because their sedating effects, when added to those of Lunesta, may cause excessive sedation. Drugs that reduce the action of liver enzymes that break down Lunesta (for example, ketoconazole) may increase blood levels of Lunesta and its sedative effects.

Use of Lunesta during pregnancy has not been adequately evaluated. It is unknown if Lunesta is excreted in breast milk. Because many medicines are excreted in breast milk and because the effect of Lunesta on infants has not been studied, breastfeeding is not recommended while taking Lunesta.

What are the common side effects of Lunesta?

The most common side effects of eszopiclone are:

• headache,
• drowsiness,
• dry mouth,
• dizziness,
• unpleasant taste,
• stomach upset, and
• loss of coordination.

Lunesta (eszopiclone) is a controlled substance. Patients taking Lunesta or any other sedative drug may become dependent on the drug for sleep and experience withdrawal symptoms when the drug is discontinued.

CNS Active Drugs

Ethanol

• An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol.

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.

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 Lunesta is needed for patient co-administered Lunesta with potent CYP3A4 inhibitors.

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 Lunesta.

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 Lunesta 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 Lunesta 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 Lunesta, and 1.4% of 72 patients who received 1 mg Lunesta 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 Lunesta 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 Lunesta 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 Lunesta 2 mg or 3 mg in which the incidence in patients treated with Lunesta 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 Lunesta¹

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 Lunesta 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 Lunesta 1 mg or 2 mg in which the incidence in patients treated with Lunesta 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 Lunesta¹

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 Lunesta

Following is a list of modified COSTART terms that reflect adverse reactions as defined in the prescribing information and reported by approximately 1550 subjects treated with Lunesta 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 Lunesta, 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 Lunesta. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.