Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pharmaceutical industry wikipedia , lookup
Pharmacognosy wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Drug interaction wikipedia , lookup
Prescription costs wikipedia , lookup
Neuropharmacology wikipedia , lookup
Psychopharmacology wikipedia , lookup
Adherence (medicine) wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Eisai Co., Ltd. 1 Revised: October 2014 (5th version) Standard Commodity Classification No. of Japan 871129 - Therapeutic agent for Insomnia - Lunestap Tablets 1 mg Lunestap Tablets 2 mg Lunestap Tablets 3 mg < Eszopiclone preparation > Habit-forming drug , Prescription drug Storage LUNESTA should be stored at room temperature. LUNESTA tablets should be protected from moisture after opening the aluminum bag of the press-through package, or the cap of the bottle package. Expiration date LUNESTA should be used by the expiration date indicated on the package or label. Approval No. Date of listing in the NHI reimbursement price Date of initial marketing in Japan International birth date Tablets 1mg Tablets 2mg Tablets 3mg 22400AMX00027000 22400AMX00028000 22400AMX00029000 Apr 2012 Apr 2012 Dec 2004 Caution: LUNESTA has a habit-forming effect. Caution: Use only as directed by a physician. WARNINGS Twilight state and parasomnias (somnambulism etc.) may occur after taking LUNESTA. Failure to remember events before falling asleep or during arousal from sleep may also occur. Caution should thus be exercised. CONTRAINDICATIONS (LUNESTA is contraindicated in the following patients) 1. Patients with a history of hypersensitivity to any of the ingredients of LUNESTA or to zopiclone 2. Patients with myasthenia gravis [Symptoms may be aggravated due to the muscle-relaxing effects of LUNESTA.] 3. Patients with acute narrow-angle glaucoma [Symptoms may be aggravated due to increased intraocular pressure.] RELATIVE CONTRAINDICATIONS (As a general rule, LUNESTA is contraindicated in the following patients. If the use of LUNESTA is considered essential, it should be administered with care.) Patients with severely decreased respiratory function due to cor pulmonale, pulmonary emphysema, bronchial asthma, or acute-phase cerebrovascular disorders, etc. [Carbon dioxide narcosis is likely to occur.] hypromellose, macrogol 4000, and anhydrous dibasic calcium phosphate. LUNESTA Tablets 2 mg: Each light yellow, film-coated tablet contains 2 mg of eszopiclone. Inactive ingredients consist of yellow ferric oxide, croscarmellose sodium, light anhydrous silicic acid, microcrystalline cellulose, titanium oxide, magnesium stearate, triacetin, lactose hydrate, hypromellose, macrogol 4000, and anhydrous dibasic calcium phosphate. LUNESTA Tablets 3 mg: Each light red, film-coated tablet contains 3 mg of eszopiclone. Inactive ingredients consist of croscarmellose sodium, light anhydrous silicic acid, microcrystalline cellulose, titanium oxide, red ferric oxide, magnesium stearate, triacetin, lactose hydrate, hypromellose, macrogol 4000, and anhydrous dibasic calcium phosphate. 2. Product description Brand name LUNESTA Tablets 1 mg DESCRIPTION 1. Composition LUNESTA Tablets 1 mg: Each white, film-coated tablet contains 1 mg of eszopiclone. Inactive ingredients consist of croscarmellose sodium, light anhydrous silicic acid, microcrystalline cellulose, titanium oxide, magnesium stearate, triacetin, lactose hydrate, LUNESTA Tablets 2 mg LUNESTA Tablets 3 mg Dosage form and identification code Appearance Face Reverse Lateral Description White Film-coated tablets Diameter (mm) 6.45 Weight Thickness (mg) (mm) 104.5 3.2 Light yellow Film-coated tablets Diameter (mm) 6.45 Weight Thickness (mg) (mm) 104.5 3.2 Light red Film-coated tablets Diameter (mm) 6.45 Weight Thickness (mg) (mm) 104.5 3.2 2 Eisai Co., Ltd. INDICATIONS Insomnia DOSAGE AND ADMINISTRATION The usual dosage of eszopiclon is 2 mg per dose for adults and 1 mg per dose for elderly patients, taken orally before bedtime. The dosage may be adjusted according to the patient's symptoms, but a single dose should not exceed 3 mg in adults and 2 mg in elderly patients. <Precautions> 1. Dose escalation beyond the standard dose should be performed with care while closely observing the condition of the patient, and dose reduction should be attempted as symptoms improve. 2. Patients should be instructed to take LUNESTA immediately before bedtime. Patients who may need to wake up temporarily for work or other activities during their sleeping time should also be instructed not to take LUNESTA. 3. In patients with severely impaired hepatic or renal function, LUNESTA should be administered in a single dose of 1 mg and should be used with care while observing the condition of the patient. When increasing the dose, a level of 2 mg as a single dose should not be exceeded. [See ‘Careful Administration’ and ‘PHARMACOKINETICS’ sections.] 4. LUNESTA should not be taken with or immediately after a meal. [Blood concentration of LUNESTA may be lowered when administered after a meal compared to when given in a fasting state (See ‘PHARMACOKINETICS’ section).] PRECAUTIONS 1. Careful Administration (LUNESTA should be administered with care in the following patients.) (1) Debilitated patients [Adverse reactions are likely to occur due to enhanced drug action.] (2) Elderly patients [See “Use in the Elderly” and “PHARMACOKINETICS” sections.] (3) Patients with cardiac disorders [Decreased blood pressure may occur, leading to possible aggravation of symptoms.] (4) Patients with cerebral organic disorders [The effects of LUNESTA may be enhanced.] (5) Patients with hepatic or renal function disorders [Blood concentrations of LUNESTA may increase due to reduced clearance (See ‘Precautions’ under ‘DOSAGE AND ADMINISTRATION’ section and ‘PHARMACOKINETICS’ section).] 2. Important Precautions (1) Administration of LUNESTA for the treatment of insomnia should be limited to a short period, and prolonged administration should be avoided. If prolonged use is judged to be essential, administer this product with care after periodically and thoroughly confirming whether the patient has any abnormal conditions or symptoms, etc. (2) The effects of LUNESTA may persist until the next morning (or longer) after ingestion, and this product may induce drowsiness as well as impairment of attention, concentration, and reflex movements, so patients should be cautioned against engaging in potentially hazardous activities such as operating machinery or driving a motor vehicle. 3. Drug Interactions LUNESTA is metabolized mainly by liver drug metabolizing enzyme CYP3A4 (See ‘PHARMACOKINETICS’ section). Precautions for coadministration (LUNESTA should be administered with care when coadministered with the following drugs) Drugs Signs, Symptoms, and Treatment Muscle relaxants Suxamethonium chloride hydrate Tubocurarine chloride hydrochloride hydrate Pancuronium bromide LUNESTA may enhance the effects of these drugs, so avoiding coadministration is recommended. However, if coadministration is deemed essential, these drugs should be administered with care. Anticonvulsant and central nervous depressant effects may be enhanced additively. Alcohol and LUNESTA may enhance the effects of each other. Administer with care as respiratory depression may occur. Alcohol consumption may enhance central nervous depressant effects. LUNESTA may depress respiration, and anesthetics may depress respiration in an additive manner. These drugs induce hepatic metabolizing enzymes and may therefore promote the metabolism of LUNESTA and reduce its effects. These drugs inhibit hepatic metabolizing enzymes and may therefore inhibit the metabolism of LUNESTA and increase its plasma concentration. Central nervous depressants Phenothiazine derivatives Barbiturate derivatives, etc. Alcohol During anesthesia Thiamylal sodium Sodium thiopental, etc. Drugs that induce These drugs enhance metaboCYP3A4 lism of LUNESTA and may Rifampicin, etc. therefore attenuate its effects. Drugs that inhibit These drugs inhibit the metabCYP3A4 olism of LUNESTA and may Itraconazole, etc. therefore enhance its effects. Mechanism and Risk Factors 4. Adverse Reactions Adverse reactions were reported in 156 (48.0%) of 325 insomnia patients treated with 1, 2, or 3 mg of eszopiclone in a parallel-group comparative study conducted in Japan prior to approval. The main adverse reactions were taste abnormality (36.3%) and somnolence (3.7%). Adverse reactions were also reported in 819 (50.0%) of 1,637 primary insomnia patients treated with 1, 2, or 3 mg of eszopiclone in a parallel-group comparative study conducted overseas. The main adverse reactions were taste abnormality (21.0%), headache (10.7%), somnolence (7.8%), and dizziness (5.1%). The following adverse reactions of unknown incidence were observed in overseas studies or spontaneous reports. Eisai Co., Ltd. (1) Clinically significant adverse reactions 1) Shock and anaphylactoid symptoms (incidence unknown) Shock and anaphylactoid symptoms may occur, so the patient must be carefully monitored. If abnormal findings such as urticaria or angioedema are observed, administration should be discontinued and appropriate measures taken. 2) Dependence (incidence unknown) Drug dependence may occur with prolonged use of LUNESTA, so administration should be undertaken with care while closely observing the condition of the patient. Discontinuation of LUNESTA may cause withdrawal symptoms such as anxiety, abnormal dreams, nausea, upset stomach and rebound insomnia, and should therefore be done carefully by gradually reducing the dose, etc. 3) Respiratory depression (incidence unknown) Respiratory depression may occur. Administration of LUNESTA to patients with severely decreased respiratory function may cause carbon dioxide narcosis, in which case appropriate measures, such as airway management and ventilation, should be taken. 4) Hepatic function disorder Hepatic function disorder associated with increases in AST (GOT), ALT (GPT), ALP or Ȗ-GTP, etc. (< 1%), or jaundice (incidence unknown) may occur. The patient should therefore be carefully monitored and, if any abnormal findings are observed, appropriate measures, such as discontinuation of LUNESTA, should be taken. 5) Psychiatric symptoms and disturbed consciousness Psychiatric symptoms and disturbance of consciousness such as nightmares (abnormal dreams), depressed level of consciousness (< 1%), excitement (agitation), confusion (confusional state), hallucination, somnambulism, aggressiveness, delirium and abnormal behavior (incidence unknown) may occur. The patient should therefore be carefully monitored, and, if any abnormal findings are observed, administration should be discontinued. 6) Transient anterograde amnesia, twilight state (incidence unknown) Transient anterograde amnesia (i.e., the patient does not recall events during arousal from sleep, etc.) and twilight state may occur. LUNESTA should therefore be administered with care by starting at a low dose, etc. There have been reports of patients treated with zopiclone preparations who did not recall having driven a car or eaten a meal while in a state of incomplete arousal. Administration of this product should therefore be discontinued if any abnormal findings are observed. 3 (2) Other adverse reactions 3% SomnoNeuropsychiatric lence 1 - < 3% Headache and dizziness <1% Anxiety, disturbance in attention, abnormal dreams and depression Hepatic Others Nervousness, memory impairment, paresthesia, abnormal thinking, affect lability and confusional state Rash and pruritus Hypersensitivity Note) Gastrointestinal Incidence Unknown Taste abnormality Thirst Oral discomfort, dry mouth, diarrhea, constipation and nausea Dyspepsia and vomiting Increased AST (GOT), ALT (GPT), Al-P, ȖGTP and bilirubin Malaise, eczema, glucose urine present and blood urine present Decreased libido, myalgia, migraine, back pain, hypertension and peripheral edema Note) Discontinue treatment if any of these symptoms are observed. 5. Use in the Elderly Pharmacokinetic studies in elderly patients have revealed a tendency towards elevated blood concentration, suggesting that adverse reactions such as ataxia are likely to occur in such patients. Therefore, in elderly patients, LUNESTA should be administered at a single dose of 1 mg and the dose should not be increased above 2 mg. [See ‘DOSAGE AND ADMINISTRATION’ and ‘PHARMACOKINETICS’ sections.] 6. Use during Pregnancy, Delivery or Lactation (1) Pregnancy etc.: LUNESTA should be used in pregnant women or in women who may possibly be pregnant only if the expected therapeutic benefits are considered to outweigh the potential risks associated with treatment. [The safety of this product in pregnant and nursing women has not been established. Neonates born from women treated with this drug in the third trimester of pregnancy are likely to experience withdrawal symptoms such as respiratory depression, convulsion, tremor, irritability, and feeding difficulty. These symptoms may be reported as neonatal asphyxia.] (2) Nursing mothers Avoiding administration of LUNESTA to nursing mothers is recommended. However, if use of this product is judged to be essential, breastfeeding must be discontinued during treatment. [This product may be excreted in human breast milk and cause lethargy in neonates.] 7. Pediatric Use The safety of LUNESTA has not been established in low birth weight infants, neonates, nursing infants, or children (no clinical experience in Japan). 4 Eisai Co., Ltd. 8. Overdosage (1) Signs and Symptoms Overdosage of LUNESTA is likely to cause somnolence, confusion and lethargy, as well as ataxia, decreased muscle tone, decreased blood pressure, methemoglobinemia, decreased respiratory function and coma, etc. Overdosage of this product in combination with other central nervous depressants or alcohol may result in death. Presence of risk factors such as complications or debility may cause the symptoms to become more severe and, in rare cases, result in fatal clinical consequences. (2) Treatment Monitor respiration, pulse and blood pressure, and take appropriate measures such as induced vomiting, gastric lavage, administration of adsorbents/cathartics, fluid infusion and airway management, etc. When flumazenil (benzodiazepine receptor antagonist) is administered to treat apparent or suspected overdosage of LUNESTA, be sure to read the precautions of flumazenil (contraindications, careful administration, drug interactions, etc.) before administration. It should be noted that hemodialysis is not effective for removal of LUNESTA. and the dose on Day 7. Both Cmax and AUC0-last of eszopiclone increased in a dose-dependent manner 1). Changes in mean plasma drug concentration in healthy Japanese men at initial dose with repeated oral administration of LUNESTA (Mean ± SD; 1 and 3 mg, n = 8; 2 mg, n = 9) Pharmacokinetic parameters after repeated doses Dose Dose timing Cmax (ng/ mL) Day 1 14.52±4.46 Day 7 14.71±3.97 Day 1 25.40±7.40 Day 7 27.02±5.22 Day 1 37.03±5.70 Day 7 37.59±5.54 1 mg 2 mg 9. Precautions concerning Use Caution when handing over drug (tablets) For drugs that are dispensed in a press-through package (PTP), patients should be instructed to remove the drugs from the package prior to use. [Swallowing the PTP sheet by mistake has been reported to cause puncture in the esophageal mucosa due to sharp corners of the sheet, resulting in perforation and in serious complications such as mediastinitis.] 10. Other Precautions (1) If LUNESTA is newly administered to patients who have been treated with flumazenil (benzodiazepine receptor antagonist) without first identifying the previously administered drug, the sedative and anticonvulsive effects of this product may be altered or delayed. (2) This product is one of the two enantiomers ((S)-enantiomer) of racemic zopiclone. In studies of mice and rats treated with zopiclone for 2 years, higher incidences of subcutaneous tumors in male mice, pulmonary tumors in female mice, thyroid tumors in male rats, and mammary gland tumors in female rats were reported at doses approximately 800 times the clinical dose (100 mg/kg/day) compared to the respective control groups. PHARMACOKINETICS 1. Blood concentrations The following figure shows changes in mean plasma drug concentrations in healthy Japanese men on Day 1 when oral LUNESTA 1-3 mg was administered repeatedly once daily for 7 days. Moreover, the subsequent table shows the pharmacokinetic parameters after the first dose on Day 1 3 mg tmax (hr) 1.3 (0.5 – 1.5) 1.0 (0.5 – 1.5) 1.0 (0.5 – 2.0) 1.0 (0.5 – 2.0) 1.5 (0.5 – 2.0) 0.8 (0.5 – 2.0) AUC0-last (ng·hr/ mL) t1/2 (hr) 79.60±36.17 - 88.71±36.33 4.83±0.89 147.89±57.47 - 168.69±67.54 5.08±1.62 222.25±36.95 - 252.63±59.17 5.16±0.85 Mean ± SD; however, tmax values are shown as medians (minimum maximum). AUC0-last: area under plasma concentration-time curve from time zero to last quantifiable sample. 1 and 3 mg, n = 8; 2 mg, n = 9 2. Effect of Food Single oral administration of LUNESTA 3 mg in healthy Japanese men after a meal resulted in a 30% reduction in Cmax of eszopiclone, while AUC0-24 was unchanged compared to administration in the fasting state. In addition, the median tmax was delayed by 2.5 hours 2). 3. Metabolism Following oral administration, eszopiclone is metabolized by various oxidations. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the former compound shows no receptor binding capacity while the latter compound binds to central benzodiazepine receptors, although with an affinity approximately 21 times less than that of eszopiclone. In vitro metabolism studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. 4. Excretion After single oral administration of 14C-labeled-zopiclone 7.5 mg to healthy, non-Japanese men, 74.8% of the radioactivity was excreted in urine within 120 hours, of which approximately 85% was recovered within 24 hours. A fur- Eisai Co., Ltd. ther 15.8% of radioactivity was excreted in feces 3). 5. Elderly Patients Compared with non-elderly healthy adults, elderly Japanese (average age of 69 years) showed a 32% increase in both Cmax and AUC0-24 and a 64% prolongation of t1/2 after repeated administration of LUNESTA 3 mg Note) for 7 days 4). 6. Patients with Hepatic Disorder (data from non-Japanese patients) Compared to healthy adults, Cmax of eszopiclone in patients with mild, moderate and severe hepatic disorder declined by 13%, 29% and 25%, respectively, while AUC0-inf decreased by 4% in the mildly impaired patients, but increased by 5% and 80% in the moderately and severely impaired patients, respectively. Moreover, t1/2 was prolonged by 2%, 66% and 130%, respectively 5). 7. Patients with Renal Impairment (data from non-Japanese patients) Compared to healthy adults, Cmax of eszopiclone in patients with mild, moderate and severe renal disorder increased by 22%, 8% and 25%, AUC0-inf increased by 40%, 28% and 45%, and t1/2 was prolonged by 19%, 24% and 33%, respectively. AUC0-inf of (S)-desmethyl zopiclone increased by 40%, 88% and 127%, respectively 6). 8. Drug Interactions (data from non-Japanese patients) (1) Ketoconazole Cmax and AUC0-IJ increased by 43% and 125%, respectively following coadministration of LUNESTA 3 mg and ketoconazole 400 mg once daily for 5 days to healthy adults, compared to administration of LUNESTA alone. Cmax and AUC0-IJ of ketoconazole decreased by 18% and 12%, respectively 7). (2) Alcohol Additively impaired psychomotor skills were seen up to 4 hours after single coadministration of LUNESTA 3.5 mg Note) with alcohol 0.7 g/kg to healthy adults 8). (3) Olanzapine Single coadministration of LUNESTA 3 mg and olanzapine 10 mg to healthy adults did not cause any change in Cmax but produced a 6.0% increase in AUC0-last, compared to administration of LUNESTA alone. Cmax of olanzapine decreased by 8.4%, while AUC0-last was unchanged. Coadministration of this product and olanzapine also produced a substantial decrease in Digit Symbol Substitution Test (DSST) score, an indicator of the psychomotor skills (psychomotor skills deteriorated) 9). (4) Lorazepam Single coadministration of LUNESTA 3 mg and lorazepam 2 mg to healthy adults caused a 22.6% decrease in Cmax and a 7.0% decrease in AUC0-last, compared to administration of LUNESTA alone. Cmax and AUC0-last of lorazepam decreased by 21.3% and 9.5%, respectively 10). 5 (5) Paroxetine Single coadministration of LUNESTA 3 mg and paroxetine 20 mg to healthy adults yielded an 11.6% increase in Cmax and a 9.3% increase in AUC0-last, compared to administration of LUNESTA alone. Cmax of paroxetine increased by 1.6% and AUC0-last decreased by 3.5% 11). (6) Digoxin Oral administration of digoxin 0.5 mg twice daily on Day 1 and 0.25 mg once daily on Days 2-6 followed by coadministration of LUNESTA 3 mg and digoxin 0.25 mg on Day 7 to healthy adults resulted in a 12.3% decline in Cmax, but no change in AUC0-IJ 12). (7) (R, S)-warfarin Repeated administration of LUNESTA 3 mg once daily for 5 days with coadministration of (R, S)-warfarin 25 mg on Day 5 to healthy adults did not cause any change in Cmax and AUC0-last of either (R)- or (S)-warfarin 13). Note) The approved dosage and administration for LUNESTA is as follows: ‘The usual dosage of eszopiclon is 2 mg per dose for adults and 1 mg per dose for elderly patients, taken orally before bedtime. The dosage may be adjusted according to the patient’s symptoms, but a single dose should not exceed 3 mg in adults and 2 mg in elderly patients. CLINICAL STUDIES 1. Japanese studies (1) Phase II/III trial In a randomized, double-blind, placebo-controlled crossover comparative study, 72 adult patients with primary insomnia were treated with placebo, LUNESTA 1, 2, or 3 mg, or a zolpidem preparation for 2 days. Results of primary endopoints, i.e., sleep latency measured by overnight polysomnography (PSG) and subjective sleep latency, are shown in the following table. LUNESTA 2 and 3 mg treatment periods exhibited statistically significant differences in these endpoints compared to the placebo treatment period 14). Placebo No. of subjects assessed 71 PSG-assessed sleep latency 22.8 (0.8, 194.5) Subjective sleep latency 45.0 (12.5, 210.0) LUNESTA 2 mg 3 mg 69 68 11.3 (0.3, 132.3) p<0.001a) 25.0 (3.0, 120.0) p<0.001a) 10.4 (0.0, 59.3) p<0.001a) 20.0 (3.0, 142.5) p<0.001a) Zolpidem 70 7.0 (0.0, 146.5) 22.5 (0.0, 150.0) Median value (min) (minimum, maximum) a) Mixed-effect model using log-transformed mean value at each period as response variable; drug, order of dosing, and time of dosing as fixed effect; subjects as random effect (nested in order of dosing). (2) Long-term treatment study In a randomized, double-blind, parallel-group comparative study, 325 adult and elderly insomnia patients (including 161 patients with insomnia caused by mental illness [depression, etc.]) were treated with LUNESTA (2 6 Eisai Co., Ltd. or 3 mg in adults and 1 or 2 mg in elderly patients) for 24 weeks. Changes in subjective sleep latency are shown below 15). Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Final evaluation Adults 2 mg group 3 mg group 60.0 60.0 (15, 240) (20, 240) 84 subjects 77 subjects 30.0 30.0 (0, 180) (2, 120) 81 subjects 73 subjects 30.0 20.0 (5, 90) (3, 120) 79 subjects 72 subjects 30.0 20.0 (0, 120) (5, 150) 75 subjects 69 subjects 20.0 20.0 (0, 120) (5, 120) 72 subjects 67 subjects 25.0 20.0 (1, 120) (0, 300) 70 subjects 66 subjects 20.0 20.0 (0, 120) (5, 240) 70 subjects 65 subjects 27.5 20.0 (0, 240) (3, 240) 84 subjects 75 subjects Elderly patients 1 mg group 2 mg group 60.0 60.0 (30, 180) (15, 240) 83 subjects 80 subjects 30.0 30.0 (0, 180) (2, 90) 79 subjects 75 subjects 22.5 30.0 (3, 90) (5, 150) 79 subjects 72 subjects 20.0 20.0 (5, 90) (5, 90) 74 subjects 70 subjects 20.0 25.0 (5, 90) (5, 120) 67 subjects 73 subjects 20.0 20.0 (5, 120) (5, 90) 69 subjects 74 subjects 20.0 20.0 (5, 180) (5, 90) 68 subjects 72 subjects 20.0 20.0 (5, 180) (5, 120) 79 subjects 83 subjects Median value (min) (minimum, maximum) 2. Overseas studies (1) Phase II trial In a randomized, double-blind, placebo-controlled crossover comparative study, 65 adult patients with primary insomnia were treated with placebo, LUNESTA 1, 2, 2.5, or 3 mg, or a zolpidem preparation 10 mg once daily for 2 days. Results of the primary endpoint, i.e., sleep latency measured by polysomnography, are shown in the table below. LUNESTA 2 and 3 mg treatment periods exhibited statistically significant differences in the endpoint compared to the placebo treatment period 16). Placebo LUNESTA 2 mg 3 mg Zolpidem No. of subjects assessed 63 63 64 64 PSG-assessed sleep latency 29.0 (1.5, 143.5) 15.5 (1.8, 99.5) p0.0001a) 13.1 (0.5, 91.3) p0.0001a) 13.1 (1.0, 81.0) Median value (min) (minimum, maximum) a) Mixed-effect model using rank-transformed mean actual value of two consecutive nights at each period as response variable; drug, order of dosing, and time of dosing as fixed effect; subjects as random effect (nested in order of dosing). (2) Phase III trials The primary endpoint results of randomized, double-blind, placebo-controlled, parallel-group comparative studies in primary insomnia patients are shown in the following table. In all 5 trials, LUNESTA produced statistically significant differences in endpoints compared to placebo 17, 18, 19, 20, 21) Adult patients Trial 1 (44 days; mean of Days 1, 15 & 29) No. of subjects assessed PSG-assessed sleep latency (min) Placebo 2 mg 99 104 3 mg 105 29.0 (1.0, 131.9) 15.0 (0.8, 164.0) p<0.0001a) 13.1 (0.8, 85.3) p<0.0001a) Adult patients Placebo Trial 2 (6 months; mean of Months 4-6) Trial 3 (6 months; mean of Months 4-6) 2 mg 3 mg No. of subjects assessed 172 543 Subjective sleep latency (min) 44.8 (4.1, 330.0) 31.7 (2.1, 565.0) p<0.0001a) No. of subjects assessed 226 504 Subjective sleep latency (min) 45.0 (4.0, 315.0) 27.3 (3.4, 196.7) p<0.0001a) Elderly patients Placebo Trial 4 (14 days; mean of Days 1, 2, 13 & 14) No. of subjects assessed PSG-assessed sleep latency (min) 1 mg 2 mg 136 128 14.8 (2.0, 102.1) p<0.0001a) 80.4 (59.3, 92.3) p<0.0001a) 30.4 (4.1, 173.1) Sleep efficiency (%) 74.6 (24.7, 91.6) No. of subjects assessed 79 70 79 52.0 (4.7, 540.0) 35.9 (0.0, 348.0) p=0.0120a) 36.2 (5.4, 410.0) p=0.0034a) Trial 5 (14 day-mean) Subjective sleep latency (min) Median value (min) (minimum, maximum) a) Analysis of variance model on rank transformed data using treatment group & clinical study site as factors. PHARMACOLOGY 1. Mechanism of action LUNESTA is the one enantiomer (i.e., (S)-enantiomer) of racemic zopiclone and is a drug product possessing most of the pharmacological activity of zopiclone. Eszopiclone is believed to enhance the effects of GABA by binding to the benzodiazepine binding domain on GABAAreceptor complexes in central nervous system and promoting chloride ion influx into neurons 22, 23). 2. Action on EEG in animals Eszopiclone reduced non-REM sleep latency and prolonged non-REM sleep time in mice, rats, and guinea pigs. No clear effect on REM sleep was observed 24, 25, 26) 3. Other CNS actions Eszopiclone exhibited anxiolytic and sedative effects in mice, rats, and monkeys 27, 28, 29, 30, 31). PHYSICOCHEMISTRY Nonproprietary name: Eszopiclone Chemical name: (5S)-6-(5-Chloropyridin-2-yl)-7-oxo-6,7dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate Molecular formula: C17H17ClN6O3 Molecular weight: 388.81 Structural formula: Eisai Co., Ltd. Physiochemical description: Eszopiclone is a white to light yellow crystalline powder. It is sparingly soluble in acetonitrile, N,N-dimethyl formamide, tetrahydrofuran and dichloromethane, slightly soluble in methanol, ethanol (99.5), acetone, 2-butanone, ethyl acetate and toluene, and very slightly soluble in water. Melting point: about 205 °C PACKAGING LUNESTA Tablets 1 mg: 100 tablets (PTP / bottle) 140 tablets (PTP 14 tablets × 10) 500 tablets (PTP) LUNESTA Tablets 2 mg: 100 tablets (PTP) 140 tablets (PTP 14 tablets × 10) 500 tablets (PTP, bottle) LUNESTA Tablets 3 mg: 100 tablets (PTP) 140 tablets (PTP 14 tablets × 10) 500 tablets (bottle) REFERENCES 1) In-house document: Phase I multiple-dose study of eszopiclone in healthy Japanese and Caucasian adults (overseas study). 2) In-house document: Bioequivalence & postprandial effect studies of eszopiclone preparations with different content in healthy Japanese adults (Japanese studies). 3) In-house document: Mass-balance study of eszopiclone in healthy non-Japanese adults (overseas study). 4) In-house document: Phase I multiple-dose study of eszopiclone in healthy elderly Japanese (Japanese study). 5) In-house document: Pharmacokinetic study of eszopiclone in patients with hepatic function disorder (overseas study). 6) In-house document: Pharmacokinetic study of eszopiclone in patients with renal function disorder (overseas study). 7) In-house document: Drug interaction study of eszopiclone and ketoconazole (overseas study). 8) In-house document: Drug interaction study of eszopiclone and alcohol (overseas study). 9) In-house document: Drug interaction study of eszopiclone and olanzapine (overseas study). 10) In-house document: Drug interaction study of eszopiclone and lorazepam (overseas study). 11) In-house document: Drug interaction study of eszopiclone and paroxetine (overseas study). 12) In-house document: Drug interaction study of eszopiclone and digoxin (overseas study). 13) In-house document: Drug interaction study of eszopiclone and warfarin (overseas study). 14) In-house document: Phase II/III study of eszopiclone in primary insomnia patients (Japanese study). 15) In-house document: Phase III study of eszopiclone in insomnia patients (Japanese study). 7 16) In-house document: Dose-response study of eszopiclone in primary insomnia patients (overseas study). 5 17) Zammit, G. K. et al.: Curr. Med. Res. Opin., 20, 1979, 2004. 18) McCall, W. V. et al.: Curr. Med. Res. Opin., 22, 1633, 2006. 19) Scharf, M. et al.: Sleep, 28, 720, 2005. 20) In-house document: Long-term treatment study of eszopiclone in primary insomnia patients (overseas study). 21) Walsh, J. K. et al.: Sleep, 30, 959, 2007. 22) Hanson, S. M. et al.: J. Med. chem., 51, 7243, 2008. 23) In-house document: Enhancing effect of eszopiclone on GABA-induced current in GABAA receptor subtype expressing cells. 24) In-house document: Effects of eszopiclone on EEG in mice. 25) In-house document: Effects of eszopiclone on EEG in rats. 26) Xi, M. and Chase, M. H.: Sleep, 31, 1043, 2008. 27) In-house document: Sedative effects of eszopiclone in mice. 28) In-house document: Anxiolytic effects of eszopiclone in mice (light/dark box test). 29) Carlson, J. N. et al.: Eur. J. Pharmacol., 415, 181, 2001. 30) In-house document: Anxiolytic effects of eszopiclone in monkeys (conflict test). 31) In-house document: Sedative effects of eszopiclone in monkeys. REQUESTS FOR LITERATURE AND PRODUCT INFORMATION SHOULD BE MADE TO: Customer Drug Information Service Free Dial: 0120-419-497 Eisai Co., Ltd. Manufactured and marketed by: Eisai Co., Ltd. 6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, 112-8088 Licensed by: Sunovion Pharmaceuticals Inc.