Download Lunesta

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.
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(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).
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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-
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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
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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)
p”0.0001a)
13.1
(0.5, 91.3)
p”0.0001a)
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.
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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.