ADVERSE REACTIONS:
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.
Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, COSTART terminology has been used to classify reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while the patient was receiving therapy following baseline evaluation.
Adverse Findings Observed In Placebo-Controlled Trials
Adverse Events 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 event. In the 6-week parallel-group study in adults, no patients in the 3 mg arm discontinued because of an adverse event. 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 event. No event that resulted in discontinuation occurred at a rate of greater than 2%.
Adverse Events Observed At An Incidence Of ≥2% In Controlled Trials
Table 1 shows the incidence of treatment-emergent adverse events from a Phase 3 placebo-controlled study of LUNESTA at doses of 2 or 3 mg in non-elderly adults. Treatment duration in this trial was 44 days. The table includes only events 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 Treatment-Emergent Adverse Events in a 6-Week Placebo-Controlled Study in Non-Elderly Adults with LUNESTA1 | Adverse Event | Placebo
(n=99) | LUNESTA 2 mg
(n=104) | LUNESTA 3 mg
(n=105) |
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1 Events 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.
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* Gender-specific adverse event in females
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** Gender-specific adverse event in males
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| 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 |
Adverse events 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 treatment-emergent adverse events 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 events 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 Treatment-Emergent Adverse Events in Elderly Adults (Ages 65-86) in 2-Week Placebo-Controlled Trials with LUNESTA1 | Adverse Event | Placebo
(n=208) | LUNESTA 1 mg
(n=72) | LUNESTA 2 mg
(n=215) |
|---|
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1 Events 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.
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| 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 |
Adverse events 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 events 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 non-drug factors to the adverse event incidence rate in the population studied.
Other Events Observed During The Premarketing Evaluation Of LUNESTA
Following is a list of modified COSTART terms that reflect treatment-emergent adverse events 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 events are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor events common in the general population, and events unlikely to be drug-related. Although the events reported occurred during treatment with LUNESTA, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those that occurred on one or more occasions in at least 1/100 patients; infrequent adverse events are those that occurred in fewer than 1/100 patients but in at least 1/1,000 patients; rare adverse events are those that occurred in fewer than 1/1,000 patients. Gender-specific events 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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