Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence (9)].
LUNESTA should be taken immediately before bedtime. Taking a sedative/hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.
Use in Elderly and/or Debilitated Patients
Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients [see Dosage and Administration (2.2)].
Use in Patients with Concomitant Illness
Clinical experience with eszopiclone in patients with concomitant illness is limited. Eszopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of eszopiclone. Caution is advised, however, if LUNESTA is prescribed to patients with compromised respiratory function.
The dose of LUNESTA should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of eszopiclone is excreted unchanged in the urine.
The dose of LUNESTA should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking LUNESTA. Downward dose adjustment is also recommended when LUNESTA is administered with agents having known CNS-depressant effects.
Use in Patients with Depression
In primarily depressed patients treated with sedative-hypnotics, worsening of depression, including suicidal thoughts and actions (including completed suicides), have been reported in association with the use of sedative/hypnotics.
Sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
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 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.
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.
1 Reactions for which the LUNESTA 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 Reaction||Placebo (n=99)||LUNESTA 2 mg (n=104)||LUNESTA 3 mg (n=105)|
|Body as a Whole|
|Skin and Appendages|
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.
1 Reactions for which the LUNESTA 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||Placebo (n=208)||LUNESTA 1 mg (n=72)||LUNESTA 2 mg (n=215)|
|Body as a Whole|
|Skin and Appendages|
|Urinary Tract Infection||0||3||0|
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 introduction to the Adverse Reactions section 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.
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