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Efficacy and Safety of Circadin
in the Treatment of Primary Insomnia
maintaining effective bodily concentrations of melatonin
Figure 1: Sleep Quality During Circadin Treatment
throughout the night requires either repeated administration or a
prolonged-release formulation. Circadin is a prolonged-release formulation
containing 2mg melatonin (PR-melatonin 2mg), and releases the hormone
into the gut over an extended period of time, thereby mimicking
physiological patterns of melatonin secretion. Peak plasma concentrations
are reached three hours after dosing, with a plateau time of 3.5 hours,
before gradually declining to reach baseline levels within 10 hours. The drug ’ or 40
is primarily metabolised by cytochrome P450 1A2 (CYP1A2) (into the
inactive metabolite 6-SMT), and concomitant use of CYP1A2 inhibitors such
as fluvoxamine increases its plasma levels.
Nights rated ‘good
Early double-blind, randomised, placebo-controlled studies in insomnia
10203040 50 60 70
patients over 55 years of age demonstrated the beneficial effects of seven
Treatment time (weeks)
to 21 days of treatment with 2mg per night of Circadin on sleep quantity
Circadin Withdrawal 6 months Withdrawal 12 months
parameters (latency, wake after sleep onset).
Mean % nights rated good/very good (diary card data) during six to 12 months of treatment
controlled cross-over studies indicated comparable hypnotic effects of with Circadin 2mg and two weeks of withdrawal in patients over 55 years of age (n=133).
PR-melatonin 2mg to those of the most frequently prescribed hypnotics in
aircrew for sleep induction and maintenance.
In line with the current placebo (p=0.014). A significant and clinically relevant shortening of sleep
sleep medicine recommendations, Circadin’s clinical development focused latency, similar to most frequently used sleep medications, was also found
on demonstrating quality of sleep and next-day functioning beyond the (-24.3 versus -12.9 minutes; p=0.028), and was consistent with that
facilitation of sleep onset. Given the age-dependent decline in melatonin previously found in the sleep laboratory trial.
In addition, self-reported
production, the target population comprised patients suffering from quality of sleep, number of awakenings and morning alertness of patients
primary insomnia above 55 years of age. In a sleep laboratory trial of significantly improved with PR-melatonin 2mg compared with placebo.
PR-melatonin 2mg with a run-in of two weeks (single-blind with placebo Quality of life improved significantly with PR-melatonin 2mg compared with
treatment), followed by a treatment period of three weeks (double-blind, placebo (p=0.034). The incidence of adverse events was low and most side
placebo-controlled, parallel group design) and a three-week withdrawal, effects were judged to be of minor severity.
A pooled analysis indicated
polysomnographically (PSG) assessed sleep latency was shortened by nine that clinical response – defined as a ‘substantial improvement’ for both
minutes compared with placebo.
There were no modifications of sleep quality of sleep and morning alertness – was 32.4% with PR-melatonin 2mg
architecture and no effect on rapid eye movement (REM) sleep duration versus 18.7% with placebo (p=0.0003). The percentage of patients with a
using PR-melatonin 2mg. Significant improvements of diurnal clinically relevant improvement in quality of sleep or morning alertness was
psychomotor skills (measured using critical flicker fusion [CFF] and total 48 versus 34.5% (p=0.0017) and 40.3 versus 30% (p=0.012), respectively.
reaction t ime tests) were observed with PR-melatonin 2mg compared
with placebo. The PSG recording indicated return of all sleep variables to Clinical Safety
baseline values one day after ending treatment. No withdrawal or Pre-clinical data on melatonin have not revealed any effects to
rebound effects were observed in the sleep variables, psychomotor prompt concern over its long-term use in humans at the clinical dose
performance or safety measures.
of PR-melatonin 2mg. Unlike commonly prescribed hypnotic drugs,
PR-melatonin 2mg has no deleterious effect on psychomotor
Two pivotal clinical studies assessed the effects of PR-melatonin 2mg on performance after single
or repeated doses.
The total exposure of
sleep quality and subsequent morning alertness.
In a study of 170 patients to PR-melatonin 2mg comprised 1,926 patients in short-term
outpatients with a two-week run-in with placebo, a randomised, double- studies, 373 patients who received the compound for six months and 146
blind, placebo-controlled, parallel-group treatment period of three weeks patients who received PR-melatonin for one year or longer.
and a two-week withdrawal with placebo, the rate of patients who concerns were raised. The most common adverse events (>2%) were
showed a clinically significant improvement in both quality of sleep and headache, pharyngitis, back pain and asthenias, and were probably not
morning alertness was 47% with PR-melatonin 2mg compared with 27% related to treatment. When normalised for exposure period (100 patient-
with placebo (p=0.009). In addition, quality of sleep and morning alertness weeks), there were fewer adverse events with PR-melatonin 2mg than
significantly improved with PR-melatonin 2mg compared with placebo. with placebo (3.17 versus 8.21, respectively). PR-melatonin 2mg
The complete response was developed within six days and maintained potentiates the hypnotic effects of benzodiazepines and non-
throughout the three-week treatment period. During the two-week benzodiazepines. Discontinuation of PR-melatonin 2mg after 21 nights
withdrawal period, sleep variables gradually returned to baseline, with no did not produce rebound or withdrawal phenomena.
rebound and no increase in adverse events or withdrawal symptoms.
A dose-ranging study in 257 insomnia outpatients aged between 20 and
In a second study of 354 outpatients with a two-week run-in with placebo 80 years with a two-week run-in (placebo), six weeks of treatment
and a randomised, double-blind, placebo-controlled, parallel-group (randomised, double-blind, placebo-controlled, parallel-group), six to 12
treatment period of three weeks, the percentage of patients who showed a months of PR-melatonin 2mg (single-blind) and a two-week withdrawal
clinically significant improvement in both quality of sleep and morning period demonstrated an optimal dose of 2mg with a significantly greater
alertness was 26% with PR-melatonin 2mg compared with 15% with benefit in patients above 55 years of age (Lemoine P, Zisapel N, et al.,
EUROPEAN PSYCHIATRIC REVIEW 41