Included as part of the PRECAUTIONS section.
CNS Depressant Effects And Next-Day Impairment
LUNESTA is a central nervous system (CNS) depressant and
can impair daytime function in some patients at the higher doses (2 mg or 3
mg), even when used as prescribed. Prescribers should monitor for excess
depressant effects, but impairment can occur in the absence of symptoms (or
even with subjective improvement), and impairment may not be reliably detected by
ordinary clinical exam (i.e., less than formal psychomotor testing). While
pharmacodynamic tolerance or adaptation to some adverse depressant effects of
LUNESTA may develop, patients using 3 mg LUNESTA should be cautioned against
driving or engaging in other hazardous activities or activities requiring
complete mental alertness the day after use.
Additive effects occur with concomitant use of other CNS
depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants,
alcohol), including daytime use. Downward dose adjustment of LUNESTA and
concomitant CNS depressants should be considered [see DOSAGE AND
The use of LUNESTA with other sedative-hypnotics at
bedtime or the middle of the night is not recommended.
The risk of next-day psychomotor impairment is increased
if LUNESTA is taken with less than a full night of sleep remaining (7- to 8
hours); if higher than the recommended dose is taken; if coadministered with
other CNS depressants; or co-administered with other drugs that increase the blood
levels of eszopiclone [see DOSAGE AND ADMINISTRATION and Clinical
Need To Evaluate For Co-Morbid Diagnoses
Because sleep disturbances may be the presenting
manifestation of a physical and/or psychiatric disorder, symptomatic treatment
of insomnia should be initiated only after a careful evaluation of the patient.
The failure of insomnia to remit after 7 to 10 days of treatment may
indicate the presence of a primary psychiatric and/or medical illness that
should be evaluated. Worsening of insomnia or the emergence of new thinking
or behavior abnormalities may be the consequence of an unrecognized psychiatric
or physical disorder. Such findings have emerged during the course of treatment
with sedative/hypnotic drugs, including LUNESTA. Because some of the important adverse
effects of LUNESTA appear to be dose-related, it is important to use the lowest
possible effective dose, especially in the elderly [see DOSAGE AND
Severe Anaphylactic And Anaphylactoid Reactions
Rare cases of angioedema involving the tongue,
glottis or larynx have been reported in patients after taking the first or
subsequent doses of sedative-hypnotics, including LUNESTA. Some patients have
had additional symptoms such as dyspnea, throat closing, or nausea and vomiting
that suggest anaphylaxis. Some patients have required medical therapy in the
emergency department. If angioedema involves the tongue, glottis or larynx,
airway obstruction may occur and be fatal. Patients who develop angioedema
after treatment with LUNESTA should not be rechallenged with the drug.
Abnormal Thinking And Behavioral Changes
A variety of abnormal thinking and behavior changes have
been reported to occur in association with the use of sedative/hypnotics. Some
of these changes may be characterized by decreased inhibition (e.g.,
aggressiveness and extroversion that seem out of character), similar to effects
produced by alcohol and other CNS depressants. Other reported behavioral
changes have included bizarre behavior, agitation, hallucinations, and
depersonalization. Amnesia and other neuropsychiatric symptoms may occur
unpredictably. In primarily depressed patients, worsening of depression,
including suicidal thoughts and actions (including completed suicides), has
been reported in association with the use of sedative/hypnotics.
Complex behaviors such as “sleep-driving” (i.e., driving
while not fully awake after ingestion of a sedative-hypnotic, with amnesia for
the event) have been reported. These events can occur in sedative-hypnotic-naÃ¯ve
as well as in sedative-hypnotic-experienced persons. Although behaviors such as
sleep-driving may occur with LUNESTA alone at therapeutic doses, the use of alcohol
and other CNS depressants with LUNESTA appears to increase the risk of such behaviors,
as does the use of LUNESTA at doses exceeding the maximum recommended dose. Due
to the risk to the patient and the community, discontinuation of LUNESTA should
be strongly considered for patients who report a “sleep-driving” episode. Other
complex behaviors (e.g., preparing and eating food, making phone calls, or
having sex) have been reported in patients who are not fully awake after taking
a sedative-hypnotic. As with sleep-driving, patients usually do not remember
It can rarely be determined with certainty whether a
particular instance of the abnormal behaviors listed above are drug-induced,
spontaneous in origin, or a result of an underlying psychiatric or physical
disorder. Nonetheless, the emergence of any new behavioral sign or symptom of
concern requires careful and immediate evaluation.
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].
Timing Of Drug Administration
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
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
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
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 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
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.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Inform patients and their families about the benefits
and risks of treatment with LUNESTA. Inform patients of the availability of a
Medication Guide and instruct them to read the Medication Guide prior to
initiating treatment with LUNESTA and with each prescription refill. Review the
LUNESTA Medication Guide with every patient prior to initiation of treatment.
Instruct patients or caregivers that LUNESTA should be taken only as
CNS Depressant Effects And Next-Day Impairment
Tell patients that LUNESTA can cause next-day impairment
even when used as prescribed, and that this risk is increased if dosing
instructions are not carefully followed. Caution patients taking the 3 mg dose
against driving and other activities requiring complete mental alertness the
day after use. Inform patients that impairment can be present despite feeling
Severe Anaphylactic And Anaphylactoid Reactions
Inform patients that severe anaphylactic and
anaphylactoid reactions have occurred with eszopiclone. Describe the
signs/symptoms of these reactions and advise patients to seek medical attention
immediately if any of them occur.
Sleep-Driving And Other Complex Behaviors
Instruct patients and their families that sedative
hypnotics can cause abnormal thinking and behavior change, including
“sleep driving” and other complex behaviors while not being fully awake
(preparing and eating food, making phone calls, or having sex). Tell patients
to call you immediately if they develop any of these symptoms.
Tell patients to immediately report any suicidal
Alcohol And Other Drugs
Ask patients about alcohol consumption, medicines they
are taking, and drugs they may be taking without a prescription. Advise
patients not to use LUNESTA if they drank alcohol that evening or before bed.
Tolerance, Abuse, And Dependence
Tell patients not to increase the dose of LUNESTA on
their own, and to inform you if they believe the drug “does not
Patients should be counseled to take LUNESTA right before
they get into bed and only when they are able to stay in bed a full night (7–8
hours) before being active again. LUNESTA tablets should not be taken with or
immediately after a meal. Advise patients NOT to take LUNESTA if they drank
alcohol that evening.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a carcinogenicity study in rats, oral administration
of eszopiclone for 97 (males) or 104 (females) weeks resulted in no increases
in tumors; plasma levels (AUC) of eszopiclone at the highest dose tested (16
mg/kg/day) are approximately 80 (females) and 20 (males) times those in humans
at the maximum recommended human dose (MRHD) of 3 mg/day. However, in a 2- year
carcinogenicity study in rats, oral administration of racemic zopiclone (1, 10,
or 100 mg/kg/day) resulted in increases in mammary gland adenocarcinomas
(females) and thyroid gland follicular cell adenomas and carcinomas (males) at
the highest dose tested. Plasma levels of eszopiclone at this dose are
approximately 150 (females) and 70 (males) times those in humans at the MRHD of
eszopiclone. The mechanism for the increase in mammary adenocarcinomas is
unknown. The increase in thyroid tumors is thought to be due to increased levels
of TSH secondary to increased metabolism of circulating thyroid hormones, a
mechanism not considered relevant to humans.
In a 2-year carcinogenicity study in mice, oral
administration of racemic zopiclone (1, 10, or 100 mg/kg/day) produced
increases in pulmonary carcinomas and carcinomas plus adenomas (females) and
skin fibromas and sarcomas (males) at the highest dose tested. The skin tumors were
due to skin lesions induced by aggressive behavior, a mechanism not relevant to
humans. A carcinogenicity study of eszopiclone was conducted in mice at oral
doses up to 100 mg/kg/day. Although this study did not reach a maximum
tolerated dose, and was thus inadequate for overall assessment of carcinogenic
potential, no increases in either pulmonary or skin tumors were seen at doses
producing plasma levels of eszopiclone approximately 90 times those in humans
at the MRHD of eszopiclone (and 12 times the exposure in the racemate study). Eszopiclone
did not increase tumors in a p53 transgenic mouse bioassay at oral doses up to 300 mg/kg/day.
Eszopiclone was clastogenic in in vitro (mouse lymphoma
and chromosomal aberration) assays in mammalian cells. Eszopiclone was negative in the in
vitro bacterial gene mutation (Ames) assay and in an in vivo micronucleus
(S)-N-desmethyl zopiclone, a metabolite of eszopiclone,
was positive in in vitro chromosomal aberration assays in mammalian cells. (S)-N-desmethyl
zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and
in an in vivo chromosomal aberration and micronucleus assay.
Impairment Of Fertility
Oral administration of eszopiclone to rats prior to and
during mating, and continuing in females to day 7 of gestation (doses up to 45
mg/kg/day to males and females or up to 180 mg/kg/day to females only) resulted
in decreased fertility, with no pregnancy at the highest dose tested when both
males and females were treated. In females, there was an increase in abnormal
estrus cycles at the highest dose tested. In males, decreases in sperm number
and motility and increases in morphologically abnormal sperm were observed at
the mid and high doses. The no-effect dose for adverse effects on fertility (5
mg/kg/day) is 16 times the MRHD on a mg/m² basis.
Use In Specific Populations
Available pharmacovigilance data with LUNESTA use in
pregnant women are insufficient to identify a drug-associated risk of major
birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal
reproduction studies conducted in pregnant rats and rabbits throughout organogenesis,
there was no evidence of teratogenicity. Administration of eszopiclone to rats throughout
pregnancy and lactation resulted in offspring toxicities at all doses tested;
the lowest dose was approximately 200 times the maximum recommended human dose
(MRHD) of 3 mg/day based on mg/m² body surface area (See Data).
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and miscarriage
in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Oral administration of eszopiclone to pregnant rats
(62.5, 125, or 250 mg/kg/day) and rabbits (4, 8, or 16 mg/kg/day) throughout
organogenesis showed no evidence of teratogenicity up to the highest doses
tested. In rats, reduced fetal weight and increased incidences of skeletal
variations and/or delayed ossification were observed at the mid and high doses.
The no-observed-effect dose for adverse effects on embryofetal development is
200 times the MRHD of 3 mg/day on a mg/m² basis. No effects on embryofetal
development were observed in rabbits; the highest dose tested is approximately
100 times the MRHD on a mg/m² basis.
Oral administration of eszopiclone (60, 120, or 180
mg/kg/day) to pregnant rats throughout the pregnancy and lactation resulted in
increased post-implantation loss, decreased postnatal pup weights and survival,
and increased pup startle response at all doses. The lowest dose tested is approximately
200 times the MRHD on a mg/m² basis. Eszopiclone had no effects on other developmental
measures or reproductive function in the offspring.
There are no data on the prescence of eszopiclone in
either human or animal milk, the effects on the breastfed infant, or the
effects on milk production. The developmental and health benefits of breastfeeding
should be considered along with the mother's clinical need for LUNESTA and any potential
adverse effects on the breastfed infant from LUNESTA or from the underlying maternal
Safety and effectiveness of LUNESTA have not been
established in pediatric patients. LUNESTA failed to demonstrate efficacy in
controlled clinical studies of pediatric patients with Attention-Deficit/Hyperactivity
(ADHD) associated insomnia.
In a 12-week controlled study, 483 pediatric patients
(aged 6-17 years) with insomnia associated with ADHD (with 65% of the patients
using concomitant ADHD treatments) were treated with oral tablets of LUNESTA (1
or 2 or 3 mg tablets, n=323), or placebo (n=160). LUNESTA did not significantly
decrease latency to persistent sleep, compared to placebo, as measured by polysomnography
after 12 weeks of treatment. Psychiatric and nervous system disorders comprised
the most frequent treatment emergent adverse reactions observed with LUNESTA versus
placebo and included dysgeusia (9% vs. 1%), dizziness (6% vs. 2%), hallucinations
(2% vs. 0%) and suicidal ideation (0.3% vs. 0%). Nine patients on LUNESTA (3%)
discontinued treatment due to an adverse reaction compared to 3 patients on
In studies in which eszopiclone (2 to 300 mg/kg/day) was
orally administered to young rats from weaning through sexual maturity,
neurobehavioral impairment (altered auditory startle response) and reproductive
toxicity (adverse effects on male reproductive organ weights and histopathology)
were observed at doses ≥ 5 mg/kg/day. Delayed sexual maturation was noted
in males and females at ≥10 mg/kg/day. The no-effect dose (2 mg/kg) was
associated with plasma exposures (AUC) for eszopiclone and metabolite
(S)-desmethylzopiclone [(S)-DMZ] approximately 2 times plasma exposures in
humans at the maximum recommended dose (MRHD) in adults (3 mg/day).
When eszopiclone (doses from 1 to 50 mg/kg/day) was
orally administered to young dogs from weaning through sexual maturity,
neurotoxicity (convulsions) was observed at doses ≥ 5 mg/kg/day.
Hepatotoxicity (elevated liver enzymes and hepatocellular vacuolation and degeneration)
and reproductive toxicity (adverse effects on male reproductive organ weights
and histopathology) were noted at dose ≥10 mg/kg/day. The no-effect dose
(1 mg/kg) was associated with plasma exposures (AUC) to eszopiclone and (S)-DMZ
approximately 3 and 2 times, respectively, plasma exposures in humans at the
MRHD in adults.
A total of 287 subjects in double-blind, parallel-group,
placebo-controlled clinical trials who received eszopiclone were 65 to 86 years
of age. The overall pattern of adverse events for elderly subjects (median age
= 71 years) in 2-week studies with nighttime dosing of 2 mg eszopiclone was not
different from that seen in younger adults [see ADVERSE REACTIONS]. LUNESTA
2 mg exhibited significant reduction in sleep latency and improvement in sleep maintenance
in the elderly population. Compared with non-elderly adults, subjects 65 years
and older had longer elimination and higher total exposure to eszopiclone.
Therefore, dose reduction is recommended in the elderly patients [see DOSAGE
AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
No dose adjustment is necessary for patients with
mild-to-moderate hepatic impairment. Exposure was increased in severely
impaired patients compared with the healthy volunteers. The dose of LUNESTA
should not exceed 2 mg in patients with severe hepatic impairment. LUNESTA
should be used with caution in patients with hepatic impairment [see DOSAGE
AND ADMINISTRATION, CLINICAL PHARMACOLOGY].