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Proc (Bayl Univ Med Cent). 2006 January; 19(1): 54–59.
Copyright © 2006, Baylor University Medical Center
Eszopiclone (Lunesta): a new nonbenzodiazepine hypnotic agent
Benjamin D. Brielmaier, PharmD, Department of Pharmacy Services,
Baylor University Medical Center, Dallas, Texas.
The complaint of insomnia is defined as the perception of inadequate
or nonrestorative sleep often related to difficulty initiating sleep,
difficulty maintaining sleep, or frequent awakenings (1). It is typically
classified as being either transient or chronic depending on the duration
of a patient's symptoms. Transient insomnia, lasting only a few days,
is often a result of acute stress, acute medical illness, jet lag,
or self-medication(2). Insomnia lasting longer than 3 weeks is considered
chronic and is usually multifactorial, resulting from chronic anxiety,
depression, alcohol or substance abuse or withdrawal, medication use,
or age-related changes in sleep. In hospitalized patients, additional
factors contribute to poor sleep quality, including the anxiety associated
with physical illness, nocturnal isolation from family members, and
the disruptive effects of light, sounds, and procedures in the hospital.
Poor nocturnal sleep quality can have a deleterious impact upon patient
comfort, mood, and ability to cooperate with hospital procedures.
Therefore, ensuring adequate sleep quality within the hospital environment
is a vital component of good patient care. Treatment of insomnia in
hospitalized patients usually consists of both nonpharmacologic and
pharmacologic approaches. Nonpharmacologic measures typically focus
on treatment of the underlying factor(s) contributing to a patient's
insomnia and may include, for example, establishing a regular schedule
of sleeping and waking times (1). Pharmacologic treatment consists
of the short-term use of hypnotic agents, such as benzodiazepines
(e.g., temazepam, lorazepam, estazolam), benzodiazepine omega-1 receptor
agonists (e.g., zolpidem and zaleplon), and trazodone (1). Other agents
with sedative properties, such as antihistamines (e.g., diphenhydramine)
and atypical antipsychotics (e.g., quetiapine), have also been used
as pharmacological therapy for insomnia. The choice of agent should
be based on pharmacokinetic and pharmacodynamic properties of the
medication as well as patient-specific characteristics (1).
The Food and Drug Administration (FDA) approved oral eszopiclone
on December 15, 2004. It is the S-isomer of zopiclone, which has been
available in Europe since 1992. Eszopiclone is the first of several
new agents entering the US market for the treatment of insomnia. Other
recently approved agents include the melatonin receptor agonist ramelteon
(Rozerem) and extended-release zolpidem(Ambien CR). The purpose of
this review is to examine the potential use of eszopiclone in managing
insomnia in hospitalized patients.
Indication
Eszopiclone is indicated for the treatment of insomnia in patients
≥18 years of age. Unlike other nonbenzodiazepine agents, there is
no restriction on its duration of use.
Pharmacology
The precise mechanism of action of eszopiclone as a hypnotic is unknown,
but its effect is believed to result from its interaction with GABA
receptor complexes at binding domains located close to or allosterically
coupled to benzodiazepine receptors. Eszopiclone is a nonbenzodiazepine
hypnotic that is structurally unrelated to pyrazolopyrimidines, imidazopyridines,
benzodiazepines, barbiturates, or other drugs with known hypnotic
properties (6).
Phamacokinetics
Onset of action
In a study conducted by Zammit et al (8) in adults with chronic insomnia,
the average onset of sleep (measured by sleep latency) was 10.4 minutes
faster in the eszopiclone 2 mg group than in the placebo group.
Absorption and distribution
Eszopiclone is rapidly absorbed following oral administration. Peak
plasma concentrations are achieved within 1 hour after oral administration.
It is weakly bound to plasma proteins (52%–59%) (6).
Metabolism
Following oral administration, eszopiclone is extensively metabolized
in the liver by oxidation and demethylation. The primary plasma metabolites
have little to no binding potency to GABA receptors. In vitro studies
have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism
of eszopiclone (6).
Elimination
The mean elimination half-life (t1/2) of eszopiclone is approximately
6 hours. Less than 10% of an oral dose is excreted in the urine as
parent drug (6).
Effect of food
In healthy adults, administration of a 3-mg dose of eszopiclone after
a high-fat meal resulted in no change in area under the curve (AUC),
a 21% reduction in peak concentration (Cmax), and a 1-hour delayed
time to reach peak concentration (tmax). The t1/2 remained unchanged
Clinical Trials
This section summarizes the three published clinical trials on the
safety and efficacy of eszopiclone for the treatment of insomnia.
All three trials enrolled patients who reported no more than 6.5 hours
of sleep per night and who required more than 30 minutes to fall asleep
each night for at least 1 month. Patients also met the criteria for
primary insomnia given by the Diagnostic and Statistical Manual of
Mental Disorders—4th Edition, Text Revision (DSM-IV):
- The predominant complaint is difficulty initiating or maintaining
sleep, or nonrestorative sleep, for at least 1 month.
- The sleep disturbance (or associated daytime fatigue) causes
clinically significant distress or impairment in social, occupational,
or other important areas of functioning.
- The sleep disturbance does not occur exclusively during the course
of Narcolepsy, Breathing-Related Sleep Disorder, Circadian Rhythm
Sleep Disorder, or a Parasomnia.
- The disturbance does not occur exclusively during the course
of another mental disorder (e.g., Major Depressive Disorder, Generalized
Anxiety Disorder, a delirium).
- The disturbance is not due to the direct physiological effects
of a substance (e.g., a drug of abuse, a medication) or a general
medical condition (9).
Efficacy and safety of eszopiclone over 2 weeks in elderly patients
A randomized, double-blind, multicenter, placebo-controlled trial
of eszopiclone was conducted in elderly patients, aged 65 to 85 years
(10). A total of 231 patients were assigned to one of three treatment
groups: placebo (n = 80), eszopiclone 1 mg (n = 72), or eszopiclone
2 mg (n = 79) nightly for 2 weeks. Patients reported results from
a questionnaire each morning and evening through an interactive voice
response system. Participants also returned to the clinic for weekly
follow-up. The primary endpoint was sleep latency averaged over the
double-blind period, and the primary analysis was the comparison between
the eszopiclone 2 mg and placebo groups. Secondary endpoints included
wake time after sleep onset, number of awakenings, sleep quality,
sleep depth, total sleep time averaged over the double-blind period,
and daytime function variables.
The eszopiclone 2 mg group had a significantly shorter sleep latency
period compared with the placebo group over the double-blind period
(P = 0.0034). The eszopiclone 2 mg group also had significantly longer
total sleep time (P = 0.0003) compared with the placebo group. The
eszopiclone 1 mg group had significantly shorter sleep latency (P
≤ 0.012) compared with the placebo group, but there was no significant
difference in total sleep time or any other secondary endpoint. Secondary
analyses indicated that the eszopiclone 2 mg group had significantly
less waking after sleep onset; significantly fewer and shorter daytime
naps; and significantly higher ratings of sleep quality and depth,
daytime alertness, and sense of physical well-being compared with
the placebo group (P < 0.05). Based on these data, eszopiclone
1 mg was effective at inducing but not maintaining sleep, whereas
the 2-mg dose was effective at both inducing and maintaining sleep.
Although both eszopiclone dose groups had shorter median sleep latencies
at week 2 than at week 1, neither dose was significantly different
from placebo at week 2 (eszopiclone 1 mg, P = 0.10; eszopiclone 2
mg, P = 0.07). This difference appeared to be due to improvement in
the median sleep latency for the placebo group from week 1 to week
2 rather than a diminished effect for the eszopiclone 2 mg group.
Eszopiclone 2 mg significantly increased patient-reported total sleep
time compared with placebo at weeks 1 and 2 (P ≤ 0.002). The eszopiclone
2 mg group had significantly higher quality (P < 0.05) and depth
of sleep (P < 0.05) compared with the placebo group at weeks 1
and 2.
The most common (≥5%) treatment-related adverse event was unpleasant
taste (eszopiclone 1 mg, 8.3%; eszopiclone 2 mg, 11.4%;placebo, 15.0%).
Fewer subjects discontinued treatment because of adverse effects in
the treatment groups than in the placebo group (eszopiclone 1 mg,
1.4%; eszopiclone 2 mg, 2.5%; placebo, 6.3%). There were no reported
adverse events related to accidental falls, amnesia, or hallucinations.
Efficacy and safety of eszopiclone over 6 weeks
A randomized, double-blind, multicenter, placebo-controlled, parallel
group trial conducted in adults aged 21 to 64 years assigned a total
of 308 patients to one of three treatment groups: placebo (n = 99),
eszopiclone 2 mg (n = 104), or eszopiclone 3 mg (n = 105) nightly
for 44 consecutive days (8). This was followed by 2 nights of placebo
to assess the occurrence of rebound
insomnia. Patients reported results nightly via an interactive
voice response system and had overnight stays in the sleep laboratory
for polysomnography recording. The primary endpoint was poly-somnography-determined
latency to persistent sleep. Secondary endpoints were mean sleep efficiency
and wake time after sleep onset. Polysomnography data were reported
as averages from nights 1, 15, and 29. Patient-reported sleep data
were obtained from nights 1, 15, 29, and 43/44.
Both doses of eszopiclone significantly reduced the average latency
to persistent sleep compared with placebo (P < 0.001). Secondary
supportive analyses indicated that these treatment effects were consistent
across nights 1, 15, and 29 (P < 0.001). Both doses of eszopiclone
significantly improved the average sleep efficiency relative to placebo
(3 mg, P < 0.001; 2 mg, P < 0.01). Additionally, 68% of patients
in the eszopiclone 3 mg group (P < 0.001 vs placebo) and 53% of
patients in the eszopiclone 2 mg group (P < 0.03 vs placebo) had
polysomnography-defined total sleep time ≥7 hours (the double-blind
average), compared with 37% of patients in the placebo group. These
treatment effects were consistent across nights 1, 15, and 29 (P <
0.01) for the 3-mg dose.
Eszopiclone 3 mg, but not 2 mg, significantly reduced the double-blind
average wake time after sleep onset relative to placebo (P < 0.01).
Supportive analyses of eszopiclone 3 mg indicated that wake time after
sleep onset was significantly less compared with placebo on nights
1 and 29, but not on night 15. The polysomnography-defined number
of awakenings was not significantly different between treatment groups.
Results of the double-blind average and nightly patient-reported sleep
endpoints were consistent with the polysomnography findings. Eszopiclone
3 mg and 2 mg produced significantly less sleep latency (P < 0.0001
for both doses), higher quality of sleep (P = 0.007 and 0.04, respectively),
and better depth of sleep (P = 0.046 and 0.005, respectively)relative
to placebo. Eszopiclone 3 mg (P = 0.02 vs placebo), but not 2 mg,
resulted in significantly less patient-reported wake time after sleep
onset.
There was no evidence of tolerance or rebound insomnia after therapy
discontinuation. Median digit symbol substitution test (DSST) scores
showed no decrement in psychomotor performance relative to baseline
and did not differ from placebo in either eszopiclone group.
The most common treatment-related adverse event was unpleasant taste,
which was greatest in the eszopiclone 3 mg group. The rates of dizziness
and somnolence in the eszopiclone 3 mg group were similar to those
in the placebo group. No patient in the eszopiclone 3 mg group or
the placebo group discontinued treatment due to adverse events; 3
patients in the 2 mg group discontinued for adverse events that may
or may not have been related to the study drug. Rates of new adverse
events occurring during the single-blind placebo run-out phase were
lower in the eszopiclone groups (11.5% in the eszopiclone 2 mg group,
15.2% in the eszopiclone 3 mg group) than in the placebo group (18.2%).
There were no differences between eszopiclone and placebo for central
nervous system (CNS) and potentially CNS-related adverse events, the
most commonly noted symptoms of hypnotic withdrawal.
Efficacy and safety of eszopiclone over 6 months
A randomized, double-blind, multicenter, placebo-controlled trial
was conducted in patients aged 21 to 69 years and assigned a total
of 788 patients to receive either eszopiclone 3 mg (n = 593) or placebo
(n = 195) nightly for 6 months (11). Patients reported results weekly
via an interactive voice response system. Monthly office visits were
also scheduled for safety and compliance assessments. Endpoints included
sleep latency; total sleep time;number of awakenings;wake time after
sleep onset;quality of sleep; and next-day ratings of ability to function,
daytime alertness, and sense of physical well-being. Seven time points
(week 1 and months 1–6) during the study were analyzed. Data from
week 1 were intended to measure short-term efficacy, while the remaining
time points assessed sustained efficacy.
Compared with placebo, eszopiclone produced a statistically significant
improvement (P < 0.05)in all of the aforementioned endpoints. These
differences were evident at the first measured time point (week 1),
as well as the subsequent 6 time points. At week 1, patients taking
eszopiclone fell asleep a mean of 37.2 minutes faster, had 0.6 fewer
nightly awakenings, experienced 0.9 fewer nights awake per week, and
slept 50.2 minutes longer than patients in the placebo group. At 6
months, patients treated with eszopiclone fell asleep 16.1 minutes
faster, had 0.7 fewer nightly awakenings, experienced 0.8 fewer nights
awake per week, and slept 39 minutes longer.
Over the 6-month study period, adverse events were reported in 81.1%
of patients in the eszopiclone group and 70.8% of patients in the
placebo group. The most common events in both groups were unpleasant
taste, headache, infection, pain, nausea, and pharyngitis. The vast
majority of infections (~85%) were related to the common cold, and
none resulted in discontinuation from the study. Headache was the
only adverse event reported in more than 10% of the patients in both
groups. Over the 6-month period, the rate of discontinuation due to
adverse events was 12.8% in the eszopiclone group and 7.1% in the
placebo group (P < 0.05). The most common reasons were somnolence
(2.2% for eszopiclone, 1.5% for placebo), depression (2.0% and 0%),
unpleasant taste (1.7% and 0.5%), headache (0% and 2%), asthenia (1.0%
and 1.5%), and insomnia (0% and 1.5%).
Following discontinuation of the drug, the overall rates of “new”
events (those not seen during the treatment period or a worsening
of an event) were similar between the eszopiclone group and the placebo
group (11.2% and 10.7%, respectively). There were no reports of seizures,
hallucinations, or perceptual-disturbance events that are commonly
reported as withdrawal symptoms following discontinuation of sedative-hypnotic
medications; there was one report of anxiety in the eszopiclone group.
All of the patients over 64 years of age in the 6-month trial were
part of the eszopiclone 3 mg treatment group. This dose is higher
than the recommended dose (either 1 or 2 mg, depending on clinical
factors) in the prescribing information.
None of the three trials studying the safety and efficacy of eszopiclone
reported a power calculation. Therefore, it is unclear as to whether
enough patients were included in each trial to truly show a difference
between the treatment and placebo groups. Trials of the nature discussed
here typically have a very high attrition rate; therefore, intention-to-treat
analyses are most appropriate for this circumstance. Each of the three
trials included an intention-to-treat population consisting of patients
who received at least 1 dose of study medication.
Each study was sponsored and funded by Sepracor Inc., the manufacturer
of eszopiclone. Several of the investigators were employees, speakers,
or grant recipients of Sepracor Inc.; nonetheless, potential conflicts
of interest were clearly disclosed in each study.
Adverse Effects
Table 1 summarizes the most common adverse events reported from a
phase 3 placebo-controlled study in nonelderly patients treated with
either eszopiclone 2 mg or 3 mg. Treatment duration in this trial
was 44 days.
Table 2 shows the incidence of adverse events reported from combined
phase 3 placebo-controlled studies with either eszopiclone 1 mg or
2 mg in elderly patients (aged 65 to 86 years). Treatment duration
in these trials was 14 days.
The two most frequent adverse events in both treatment durations
were headache and unpleasant taste. Dyspepsia, pain, and diarrhea
were also common in elderly patients treated for 14 days, whereas
somnolence, dry mouth, and nausea were common in adults treated for
44 days.
Warnings/Precautions
While there are no known contraindications to eszopiclone (6), the
drug should be administered with caution in patients exhibiting signs
and symptoms of depression. Suicidal tendencies may be present, and
intentional overdose is more common in such patients. Therefore, the
smallest dose feasible should be prescribed to the patient. In clinical
trials with eszopiclone, one case of overdose with up to 36 mg was
reported in which the subject fully recovered.
In healthy volunteers, a 7-mg oral dose of eszopiclone did not produce
respiratory-depressant effects. However, caution should be exercised
in administration of eszopiclone to patients with compromised respiratory
function.
Use of benzodiazepines and similar agents may lead to physical and
psychological dependence. The risk of abuse and dependence increases
with the dose and duration of treatment and concomitant use of other
psychoactive drugs. The risk is also greater in patients with a history
of alcohol or drug abuse or history of psychiatric disorders.
Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like
agents for a few weeks. However, no evidence of developed tolerance
was seen with eszopiclone over a period of 6 months in clinical trials
(6).
Dosing and Admin
The recommended starting dose for eszopiclone for most nonelderly
adults is 2 mg immediately before bedtime. Dosing can be initiated
at or raised to 3 mg if clinically indicated, since 3 mg is more effective
for sleep maintenance.
Taking eszopiclone with or immediately after a heavy, high-fat meal
results in slower absorption and would be expected to reduce the effect
of eszopiclone on sleep latency.
Dosing in special populations
The elderly: The recommended starting dose for elderly patients whose
primary complaint is difficulty falling asleep is 1 mg immediately
before bedtime. The dose may be increased to 2 mg if clinically indicated.
For elderly patients whose primary complaint is difficulty staying
asleep, the recommended dose is 2 mg immediately before bedtime.
Hepatic impairment: The starting dose should be 1 mg in patients
with severe hepatic impairment. Eszopiclone should be used with caution
in these patients.
Renal impairment: No dose adjustments are necessary in patients with
any degree of renal insufficiency.
Coadministration with CYP3A4 inhibitors: The starting dose should
not exceed 1 mg in patients coadministered eszopiclone with potent
CYP3A4 inhibitors (see drug interactions section). If needed, the
dose can be raised to 2 mg (6).
Pregnancy/lactation
Pregnancy category C: There are no adequate, well-controlled studies
of eszopiclone in pregnant women. Eszopiclone should be used during
pregnancy only if the potential benefits outweigh the potential risks.
It is not known whether eszopiclone is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised
when eszopiclone is administered to a nursing mother.
DRUG INTERACTIONS CNS-active drugs
Ethanol: An additive impairment of psychomotor performance was seen
with coadministration of eszopiclone and ethanol.
Paroxetine: Coadministration of single doses of eszopiclone 3 mg
and paroxetine 20 mg daily for 7 days produced no pharmacokinetic
or pharmacodynamic interaction.
Lorazepam: Coadministration of single doses of eszopiclone 3 mg and
lorazepam 2 mg did not have clinically relevant effects on the pharmacokinetics
or pharmacodynamics of either drug.
Olanzapine: Coadministration of single doses of eszopiclone 3 mg
and olanzapine 10 mg produced a decrease in DSST scores, resulting
from a pharmacodynamic interaction. The pharmacokinetics of both drugs
were unaltered. No specific recommendation for dose adjustments of
either drug is made by the manufacturer in the prescribing information.
Drugs that inhibit CYP3A4
The AUC of eszopiclone was increased 2- to 3-fold by co-administration
of ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5
days. Cmax and tmax were increased 1.4-fold and 1.3-fold, respectively.
Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin,
nefazodone, ritonavir, nelfinavir) would be expected to behave similarly.
However, no specific recommendations for dose adjustments are made
in the prescribing information.
Drugs that induce CYP3A4
Racemic zopiclone exposure was reduced by 80% by concomitant use of
rifampicin, a potent inducer of CYP3A4. A similar effect would be
expected with eszopiclone. Nonetheless, the manufacturer provides
no recommendations for dose adjustments when the two drugs are coadministered.
Drugs highly bound to plasma proteins
Eszopiclone is not highly bound to plasma proteins; therefore, the
disposition of eszopiclone is not expected to be sensitive to alterations
in protein binding. Administration of eszopiclone 3 mg to a patient
taking another drug that is highly protein bound would not be expected
to alter the free concentration of either drug.
Drugs with a narrow therapeutic index
Digoxin: A single dose of eszopiclone 3 mg did not affect the pharmacokinetics
of digoxin measured at steady state.
Warfarin: Eszopiclone 3 mg administered daily for 5 days did not
affect the pharmacokinetics of warfarin, nor were there any changes
in prothrombin time following a single 25-mg oral dose of warfarin.
Dosage
Eszopiclone is available as 1-mg, 2-mg, and 3-mg tablets. It is a
schedule IV controlled substance under the Controlled Substances Act.
Phamacoeconomics
The Baylor University Medical Center acquisition cost for eszopiclone
($2.88 per tablet, regardless of the strength) is slightly higher
than, but comparable to, the costs of both zolpidem and zaleplon and
is much higher than the costs of older hypnotic agents.
Conclusions
The current data suggest that the use of eszopiclone in hospitalized
patients offers no distinct advantage over other currently available
hypnotics. Like other nonbenzodiazepine agents, eszopiclone has been
shown to be efficacious in sleep induction and maintenance, and its
pharmacokinetic and pharmacodynamic parameters are similar to those
of zolpidem and zaleplon. Dosing should begin at 2 mg for nonelderly
patients and may be initiated at or increased to 3 mg if clinically
appropriate. However, there are currently no efficacy studies that
directly compare eszopiclone with other hypnotic agents, including
zolpidem or zaleplon, or with nonpharmacologic treatments. The acquisition
cost of eszopiclone is comparable to the cost of zolpidem and zaleplon
but much higher than that of older hypnotic agents. Lastly, the distinguishing
feature of eszopiclone—approved labeling for long-term use—is not
an overriding consideration in the decision to administer this medication
to hospitalized patients.
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