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 tablets 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 tablets 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. gov/medwatch. 4% of 72 patients who received 1 mg eszopiclone tablets 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. 8% of 593 patients who received 3 mg eszopiclone tablets 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 tablets 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 tablets 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 Tablets 1 Adverse Reaction Placebo (n=99) Eszopiclone tablets 2 mg (n=104) Eszopiclone tablets 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 tablets 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 tablets 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 tablets 1 mg or 2 mg in which the incidence in patients treated with eszopiclone tablets 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 Tablets 1 Adverse Reactions Placebo (n=208) Eszopiclone tablets 1 mg (n=72) Eszopiclone tablets 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 tablets 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.
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 tablets, 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.
2 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 tablets.
Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.