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Publication Date: July 2005
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LUNESTAm: A NEW NON-
BENZODIAZEPINE FOR THE
TREATMENT OF INSOMNIA

Kimberly Fleming, Pharm.D. Candidate



Approximately 33% to 55% of adults suffer
from insomnia during their lifetime. An estimated
10% to 15% of adults complain of chronic insom-
nia, while 25% to 35% complain of transient in-
somnia.1 Although the diagnosis of insomnia is
somewhat subjective, the consequences of un-
treated insomnia are transparent. Untreated, insom-
nia can lead to decreased work productivity and
health care costs exceeding one billion per year,
partly due to increased car accidents and comorbid-
ities, such as depression.2'4
The subjective complaints associated with
insomnia include daytime drowsiness, increased
sleep latency, and/or nighttime awakenings. The
number of hours that any given individual sleeps at
night may not be enough to correctly diagnose in-
somnia. The amount of time an average person
sleeps varies from 3 to 10 hours.3 Thus, some per-
sons that meet the recommended eight hours of
sleep per night may be sleep deprived due to indi-
vidual variations in sleep requirements.1 Insomnia
can not be presumptively diagnosed in a patient
simply based on a complaint of daytime somno-
lence or "not getting enough sleep". A patient must
also complain of increased sleep latency and/or
nighttime awakenings. The Diagnostic and Statisti-


cal Manual of Mental Disorders, 4th edition (DSM-
IV) lists five criteria for the diagnosis of insomnia
(Table 1).11
Primary insomnia can be further divided into
transient or short-term, and long-term or chronic.3
However, there is much contention about the precise
definition of these subtypes. In general, the major
distinction is based on the duration of symptoms.
Transient insomnia lasts anywhere from a few days
to three weeks. According to the DSM-IV criteria,
the complaint must last for at least one month in or-
der to fit the diagnosis of chronic insomnia.4,11 This
leaves a gap between three to four weeks of symp-
toms in which a patient does not fit either category.
Although the best treatment for insomnia is
better sleep hygiene through lifestyle modification,
pharmacological therapy is indicated in some cir-
cumstances. The ideal hypnotic would possess all of
the characteristics listed in Table 2; however, all of
the medications currently approved by the FDA for
treatment of short-term insomnia display one or more
limitations. (Table 3)
Diphenhydramine, and other sedating antihis-
tamines which are available over-the-counter, fre-
quently cause daytime drowsiness and xerostomia. In
recent studies, diphenhydramine has shown superior-
ity over placebo for treating transient insomnia; how-




INSIDE THIS ISSUE:

LUNESTATM: A NEW NON-BENZODIAZEPINE FOR
THE TREATMENT OF INSOMNIA


mm
PharmaNote Volume 20, Issue 10, 2005


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VOLUME 20, ISSUE 10 JULY 2005


Volume 20, Issue 10, 2005


PharmaNote







Table 1. DSM-IV Diagnostic Criteria for Primary Insomnia
A. The predominant complaint is difficulty initiating or
maintaining sleep, or non-restorative sleep, for at least 1
month.
B. The sleep disturbance (or associated daytime fatigue)
causes clinically significant distress or impairment in
social, occupational, or other important areas of func-
tioning.
C. The sleep disturbance does not occur exclusively during
the course of narcolepsy, breathing-related sleep disor-
der, circadian rhythm sleep disorder, or a parasomnia.
D. The disturbance does not occur exclusively during the
course of another mental disorder (e.g., major depressive
disorder, generalized anxiety disorder, a delirium).

E. The disturbance is not due to the direct physiological
effects of a substance (e.g., a drug of abuse, a medica-
tion) or a general medical condition.

Adapted from Reference 11

ever tolerance to its' sedative effects may occur after
a few nights of consistent use.1'5 Therefore, use of
diphenhydramine may not be appropriate for chronic
insomnia. Barbiturates, such as phenobarbital, have
been replaced by benzodiazepines which are less
likely to cause tolerance, dependence, and rebound
insomnia. Benzodiazepines also decrease sleep la-
tency and increase duration of sleep. However, ac-
cording to a recent meta-analysis, benzodiazepines
also cause daytime drowsiness, respiratory depres-
sion, dizziness, and impairment of cognitive func-
tion.6 These effects limit the use of benzodiazepines
in many patients. In addition, practitioners should
consider the risk of dependence with this class of
drugs and the possibility of rebound insomnia when
the medication is discontinued.4 Chloral hydrate has
fallen out of favor for the treatment of insomnia due
to drug interactions, GI distress, and fatalities associ-


ated with overdose. Although not FDA-approved for
insomnia, antidepressants that have sedative proper-
ties are often utilized in clinical practice. Trazodone
has been widely used to treat insomnia associated
with depression.4 However, this class of drugs has
anticholinergic side effects that limit their use. A
newer class of drugs, non-benzodiazepines such as
zolpidem (Ambien) and zaleplon (Sonata), have
emerged. This class, also known as the selective ben-
zodiazepine agonists, have fewer drug interactions
and cause less rebound insomnia. Due to a rapid on-
set and short half-life, they decrease sleep latency
with minimal daytime drowsiness.1
Eszopiclone (LunestaTM), a new non-
benzodiazepine hypnotic agent marketed by Sepra-
cor, was approved by the FDA in December 2004. In
contrast to zolpidem and zaleplon which are ap-
proved for short-term insomnia, eszopiclone is ap-
proved for long-term use. This article will examine
the safety, efficacy, and tolerability of eszopiclone.

Pharmacology/Pharmacokinetics of Eszopiclone
Benzodiazepines bind non-selectively to the
omega 1 and 2 sites on the GABA-A chloride iono-
phore. Binding results in an influx of chloride ions
which suppresses excitatory activity. Omega 1 is re-
sponsible for the hypnotic effects of the drug,
whereas omega 2 is responsible for the CNS effects
such as memory loss. Eszopiclone is believed to bind
to a location near the GABA receptor complex that is
allosterically coupled to benzodiazepine receptors.
Its' chemical structure is unrelated to other hypnotic
drugs.7
Eszopiclone is the S-isomer of the racemic
compound, zopiclone. Zopiclone (Imovane) is cur-
rently marketed in Canada by Sanofi-Aventis.
Eszopiclone is rapidly absorbed, reaching maximum


Table 2: Characteristics of the Ideal Hypnotic*
Desirable Undesirable
Rapid and complete absorption Residual daytime effects
Rapid sleep induction Memory loss
Preserved physiological sleep architecture Altered sleep architecture
Optimal duration of action Respiratory depression
Addresses the underlying condition causing insomnia Tolerance and/or physical dependence
Rebound insomnia
Interaction with ethanol or other medications
*Adapted from Reference 2

PharmaNote 10 Volume 20, Issue 10, 2005







Table 3: Drugs Approved by the FDA for the Treatment of Insomnia


Generic Name


Proorietarv Name


Aprobarbital
Butabarbital
Pentobarbital
Phenobarbital
Secobarbital
Estazolam
Flurazepam
Lorazepam
Quazepam
Temazepam
Triazolam


Antihistamines (H1 Receptor Antagonists)


Nonbenzodiazepines


Diphenhydramine


Doxylamine
Eszopiclone
Zaleplon
Zolpidem

Ethchlorvynol


Psychotropics


Paraldehyde
Sedqative Hypnotic Chloral Hydrate


Amytal
Alurate
Butisol, Buticaps
Nembutal


Luminal
Seconal
ProSom
Dalmane
Ativan
Doral
Restoril
Halcion

Benadryl


Unisom, Equate, Nytol
LunestaTM
Sonata
Ambient


Placidyl
Paral
Aquachloral


concentration in about 1 hour and does not accumu-
late when given once daily. Eszopiclone is exten-
sively metabolized by CYP3A4 and CYP2E1 via
oxidation and demethylation but does not inhibit any
of the major CYP450 pathways. Zopiclone is elimi-
nated primarily as metabolites in the urine. It is as-
sumed that eszopiclone follows the same route of
elimination. Less than 10% of the parent drug is ex-
creted in the urine. Food delays the onset of action of
eszopiclone by about an hour. The half-life, 6 hours,
is substantially longer than either zopiclone or zolpi-
dem. This may serve to increase total sleep time by
preventing "wearing off' but could also increase re-
sidual effects of the drug. Patients greater than 65
years experience a 41% increase in total exposure
and a prolonged elimination of about 9 hours, sug-
gesting the importance of a lower starting dose in
this population. When administered with paroxetine,
digoxin, or warfarin, no apparent pharmacokinetic or
pharmacodynamic drug interactions were observed.


Co-administration of eszopiclone with olanzapine
results in a change in psychomotor function beyond
that expected with either agent alone, suggesting that
the CNS effects of eszopiclone may be additive with
other drugs. Co-administration of lorazepam and
eszopiclone resulted in a 22% decrease in the maxi-
mum serum concentration (Cmax) of both drugs. Ke-
toconazole potentiates a 2.2-fold increase in expo-
sure to eszopiclone.7 Table 4 compares the pharma-
cokinetics of the non-benzodiazepine hypnotics.

Clinical Trials

Transient Insomnia
Eszopiclone's effect on transient insomnia
was evaluated in a randomized, double-blind, pla-
cebo-controlled study.8 Four hundred thirty-six eligi-
ble patients aged 25-50 years were randomized to
receive either eszopiclone 1, 2, 3, 3.5 mg, or placebo.


PharmaNote Volume 20, Issue 10, 2005


Drug Class


Barbiturates


Amobarbital


Benzodiazepines


Generc Nam


Volume 20, Issue 10, 2005


PharmaNote







Table 4: Pharmacokinetics of the Non-Benzodiazepines

Eszopiclone Zolpidem Zaleplon
Onset 1 hour 1.5 hours 1 hour
t2 6 hours 2.5-2.6 hours 1 hour

Dose Adjustments Elderly or hepatic impairment Elderly or hepatic impairment Elderly or hepatic impairment

Route of elimination Hepatic Hepatic Hepatic
CYP involvement CYP3A4, CYP2E1 CYP3A4, CYP2C9 CYP3A4 (minor)


The primary endpoint was latency to persistent
sleep (LPS), defined as the duration of time from
when the participant began trying to fall asleep to
the time immediately before 10 minutes of uninter-
rupted sleep. Secondary endpoints included wake
time after sleep onset (WASO), sleep efficiency,
number of nighttime awakenings, and amount of
time spent in each stage of sleep. Using polysom-
nography (PSG), a statistically significant shorter
LPS (p < 0.0001) was found in participants receiv-
ing doses of 2, 3, and 3.5 mg of eszopiclone com-
pared to placebo. Those receiving the 2 and 3 mg
dose had a mean LPS of 10 minutes, and those re-
ceiving the 3.5 mg dose had a mean LPS of 8 min-
utes. The WASO was significantly shorter (p <
0.05) and sleep efficiency was significantly higher
(p < 0.02) in subjects treated with eszopiclone,
where as nighttime awakenings were significantly
reduced with the 3 and 3.5 mg doses only (p <
0.005). Self-reported sleep efficacy results were
similar to objective measures: shorter LPS (p <
0.05), fewer nighttime awakenings (p < 0.05),
shorter WASO (3 and 3.5 mg only, p < 0.05), more
total sleep time (all except the 1 mg group, p <
0.01), more reports of very deep sleep (p < 0.01),
and more reports of excellent quality sleep (all but
1 mg, p < 0.0001). Significant differences in sleep
architecture were seen in participants treated with
eszopiclone 3.5 mg compared to placebo. This
group showed a decrease in Rapid Eye Movement
(REM) sleep (p < 0.05), a decrease in stage 1 (p <
0.05), and an increase in stage 2 (p < 0.01). The
incidence of adverse events was similar to placebo
with the exception of dysguesia, which was re-
ported at a higher frequency in all groups receiving
eszopiclone. Somnolence was reported in all
groups, ranging from 6.2 % in the 2 mg group to
4.1% in the placebo group.


Chronic Insomnia
Two randomized, double-blind, multicenter,
placebo-controlled trials have evaluated eszopiclone
in chronic insomnia. Zammit et al.9 randomized
adults, aged 21-64 years old, to either eszopiclone 2
mg, eszopiclone 3 mg, or placebo for 44 days. As
compared to placebo, eszopiclone reduced sleep la-
tency (2 mg p<0.001, 3 mg p< 0.0001), increased
total sleep time (2 mg p<0.01, 3 mg p<0.0001), in-
creased sleep efficiency (2 mg p<0.001, 3 mg
p<0.0001), and increased quality and depth of sleep
(2 mg and 3 mg p<0.05). The 3 mg dose significantly
improved sleep maintenance (p<0.01). The results
showed no evidence of rebound insomnia, tolerance,
or decreased performance in the morning. Sleep ar-
chitecture was preserved in all stages except for
Stage 2, which increased 25 minutes and 37 minutes
for the 2 mg and 3 mg dose of eszopiclone, respec-
tively, versus placebo (p<0.05). Treatment-related
adverse effects that differed from placebo included
abnormal dreams, nervousness, back pain, dizziness,
xerostomia, somnolence, headache, and dysguesia.
In the study used to justify chronic use, Krys-
tal et al.10 randomized 788 patients aged 21 to 69
years to eszopiclone 3 mg or placebo every night for
6 months. Compared to placebo, eszopiclone 3 mg
decreased sleep latency (p<0.0001), WASO
(p=.0032), nighttime awakenings (p< 0.001), and
increased total sleep time (p<0.0001) and sleep qual-
ity scores (p<0.0001). There was no evidence of tol-
erance to eszopiclone and daytime effects, such as
alertness and ability to function, were actually im-
proved. Adverse event rates were similar to the
aforementioned study with dysguesia being reported
most frequently. Table 5 summarizes the clinical tri-
als with eszopiclone.

Dosing and Administration
Eszopiclone should be taken immediately be-


PharmaNote Volume 20, Issue 10, 2005


Volume 20, Issue 10, 2005


PharmaNote







Table 5: Summary of Clinical Trials


Study *


Rosenberg et al.8


Drus/Dose


Placebo


Number of Sleep Latency,
patients min (Median)
98 15


Total Sleep Time,
min (Median)
460


Nighttime awaken-
ings (Median)
2


Eszopiclone Img

Eszopiclone 2mg

Eszopiclone 3mg

Eszopiclone 3.5mg


Zammit et al.9


Placebo


Eszopiclone 2mg

Eszopiclone 3mg


Krystal et al.10


Placebo


Eszopiclone 3mg


*The study by Rosenberg et al. enrolled patients wit transient insomnia, whereas the studies by Zammit and Krystal were in patients with chronic insomnia.


fore bedtime and should not be taken with food due
to an increased time to peak plasma concentrations.
The recommended starting dose for most adults is 2
mg at bedtime, with the option to increase the dose
to a maximum of 3 mg if necessary. For elderly pa-
tients who are at increased risk of adverse effects, a
starting dose of 1 mg/day is suggested in patients
with a primary complaint of increased sleep latency,
whereas 2 mg can be used if nighttime awakenings
are bothersome. In patients with severe hepatic im-
pairment or patients taking potent CYP3A4 inhibi-
tors, the starting dose should be 1 mg at bedtime. A
lower dose should be considered in patients with a
disease or condition that might decrease the metabo-
lism of eszopiclone, although there is no clinical evi-

Table 6: Average Retail Cost of Non-Benzodiazepines
Drug Dose Average Montly (30 day) Cost*
Eszopiclone 1 mg $111.00-$114.90
2mg $111.00-$114.90

3 mg $111.00-$114.90
Zolpidem 5 mg $45.00-$59.70
10 mg $45.00-$59.70
Zaleplon 5 mg $45.00-$59.70
10 mg $60.00-$89.70

* Cost represents average retail cost of LunestaTM, AmbienTM, and SonataTM
from 3 major retail pharmacies in Gainesville, FL.


dence of such interactions. No dosage adjustment is
necessary in patients with renal impairment.
Eszopiclone has not been studied in children
younger than 18 years old or in pregnant or nursing
7
women.

Toxicity and Safety
Some of the adverse events associated with
eszopiclone are dose related. Viral infection,
xerostomia, dizziness, hallucinations, infection,
rash, and unpleasant taste were reported more often
with the 3 mg dose compared with the 2 mg dose.
Other adverse events observed at a higher rate with
active drug than with placebo, are headache, nau-
sea, vomiting, anxiety, depression, nervousness,
somnolence, dysmenorrhea, and gynecomastia. Bit-
ter taste was the most frequent side effect with a
reported incidence of 3% with placebo, 17% with
eszopiclone 2 mg/day, and 34% with eszopiclone 3
mg/day. In clinical trials, the discontinuation rate
was less than 2%.7

Cost
The average retail cost of the non-
benzodiazepine hypnotics are depicted in Table 6.

Summary
Eszopiclone is the first agent available in
the United States indicated for the long-term treat-


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Volume 20, Issue 10, 2005


PharmaNote







ment of insomnia. In clinical trials, eszopiclone dem-
onstrated efficacy versus placebo for the treatment of
short-term and long-term insomnia, especially at the
higher end (3 mg) of the dosing range. Studies of
eszopiclone have treated patients for up to six
months. It appears to be well-tolerated with the most
common reported adverse event being unpleasant
taste. The discontinuation rate in all three studies was
low and not related to adverse events. In many ways,
eszopiclone resembles the non-benzodiazepine hyp-
notics currently on the market; however, the avail-
ability of long-term safety and efficacy data with
eszopiclone is encouraging. Long-term studies evalu-
ating zaleplon and zolpidem are needed to confirm
their safety and efficacy in this setting.


References
1. Benca R. Diagnosis and Treatment of Chronic Insomnia:
A Review. Psychiatr Serv 2005;56:332-43.
2. Mendelson W et al. The treatment of chronic insomnia:
drug indications, chronic use and abuse liability. Sum-
mary of a 2001 New Clinical Drug Evaluation Unit Meet-
ing Symposium. Sleep 2004;8:7-17.
3. Kirkwood CK. Management of Insomnia. J Am Pharm
Assoc 1999;39:688-696.
4. Ringdahl E. Treatment of Primary Insomnia. J Am Board
Fam Pract 2004;17:212-9.
5. Richardson GS et al. Tolerance to daytime sedative effects
of HI antihistamines. J Clin Psychopharmacol
2002;22:511-5.
6. Holbrook AM. Meta-analysis of benzodiazepine use in the
treatment of insomnia. CMAJ 2000;162:225-33.
7. Eszopiclone [Package Insert]. Sepracor. 2005.
8. Rosenberg R et al. An assessment of the efficacy and
safety of eszopiclone in the treatment of transient insom-
nia in healthy adults. Sleep 2005;6:15-22.
9. Zammit G et al. Efficacy and safety of eszopiclone across
6-weeks of treatment for primary insomnia. Current Medi-
cal Research and Opinion 2004;20:1979-1991.
10. Krystal A et al. Sustained Efficacy of Eszopiclone Over 6
Months of Nightly Treatment: Results of a Randomized,
Double-Blind, Placebo-Controlled Study in Adults with
Chronic Insomnia. Sleep 2003;26:793-799.
11. American Psychiatric Association. Diagnostic and statisti-
cal manual of mental disorders. American Psychiatric
Association 1994;557.


Labeling Changes

The FDA has asked that manufacturers of all
prescription non-steroidal anti-inflammatory
drugs (NSAIDs) revise their product labeling
to include warnings regarding increased
cardiovascular events and gastrointestinal
bleeding. The warning will come in the form
of a black box warning in the package insert
and a medication guide to be dispensed with
the product. Over-the-counter NSAIDS will
soon add more specific warnings to the
product label, reminding patients of such
risks.




New Drug Approvals

Menactra (Meningococcal [Groups A, C, Y,
and W-135] polysaccharide diphtheria toxoid
conjugate vaccine), a tetravalent conjugate
vaccine (MCV4), is approved for the
prevention of meningococcal disease in adults
and adolescents 11-55 years of age. The
Advisory Committee on Immunization
Practices (ACIP) now recommends routine
vaccination of young adolescents with MCV4
at the preadolescent visit (11-12 years old).




The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D.

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PharmaNote Volume 20, Issue 10, 2005


Volume 20, Issue 10, 2005


PharmaNote




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