CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ROZEREM (ramelteon) is a melatonin receptor agonist with both
high affinity for melatonin MT1 and MT2
receptors and selectivity over the MT3 receptor.
Ramelteon demonstrates full agonist activity in
vitro in cells expressing human MT1
or MT2 receptors.
The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting
properties, as these receptors, acted upon by endogenous melatonin, are thought
to be involved in the maintenance of the circadian rhythm underlying the normal
sleep-wake cycle.
Ramelteon has no appreciable affinity for the GABA receptor complex or for
receptors that bind neuropeptides, cytokines, serotonin, dopamine,
noradrenaline, acetylcholine, and opiates. Ramelteon also does not interfere
with the activity of a number of selected enzymes in a standard panel.
The major metabolite of ramelteon, M-II, is active and has approximately one
tenth and one fifth the binding affinity of the parent molecule for the human
MT1 and MT2 receptors,
respectively, and is 17- to 25-fold less potent than ramelteon in in
vitro functional assays.
Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at
higher concentrations than the parent producing 20- to 100-fold greater mean
systemic exposure when compared to ramelteon. M-II has weak affinity for the
serotonin 5-HT2B receptor, but no appreciable affinity
for other receptors or enzymes. Similar to ramelteon, M-II does not interfere
with the activity of a number of endogenous enzymes.
All other known metabolites of ramelteon are inactive.
12.3 Pharmacokinetics
The pharmacokinetic profile of ROZEREM has been evaluated in
healthy subjects as well as in subjects with hepatic or renal impairment. When
administered orally to humans in doses ranging from 4 to 64 mg, ramelteon
undergoes rapid, high first-pass metabolism, and exhibits linear
pharmacokinetics. Maximal serum concentration (Cmax) and
area under the concentration-time curve (AUC) data show substantial intersubject
variability, consistent with the high first-pass effect; the coefficient of
variation for these values is approximately 100%. Several metabolites have been
identified in human serum and urine.
Absorption
Ramelteon is absorbed rapidly, with median peak concentrations occurring at
approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral
administration. Although the total absorption of ramelteon is at least 84%, the
absolute oral bioavailability is only 1.8% due to extensive first-pass
metabolism.
Distribution
In vitro protein binding of ramelteon is
approximately 82% in human serum, independent of concentration. Binding to
albumin accounts for most of that binding, since 70% of the drug is bound in
human serum albumin. Ramelteon is not distributed selectively to red blood
cells.
Ramelteon has a mean volume of distribution after intravenous administration
of 73.6 L, suggesting substantial tissue distribution.
Metabolism
Metabolism of ramelteon consists primarily of oxidation to hydroxyl and
carbonyl derivatives, with secondary metabolism producing glucuronide
conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of
ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor
degree.
The rank order of the principal metabolites by prevalence in human serum is
M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a
monophasic decline and rapid elimination. The overall mean systemic exposure of
M-II is approximately 20- to 100-fold higher than parent drug.
Elimination
Following oral administration of radiolabeled ramelteon, 84% of total
radioactivity was excreted in urine and approximately 4% in feces, resulting in
a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and
feces as the parent compound. Elimination was essentially complete by 96 hours
post-dose.
Repeated once daily dosing with ROZEREM does not result in significant
accumulation owing to the short elimination half-life of ramelteon (on average,
approximately 1- 2.6 hours).
The half-life of M-II is 2 to 5 hours and independent of dose. Serum
concentrations of the parent drug and its metabolites in humans are at or below
the lower limits of quantitation within 24 hours.
Effect of Food
When administered with a high-fat meal, the AUC0-inf
for a single 16 mg dose of ROZEREM was 31% higher and the Cmax was 22% lower than when given in a fasted state. Median
Tmax was delayed by approximately 45 minutes when ROZEREM
was administered with food. Effects of food on the AUC values for M-II were
similar. It is therefore recommended that ROZEREM not be taken with or
immediately after a high-fat meal [see
Dosage and Administration
(2.1)
].
12.4 Pharmacokinetics in Special Populations
Age
: In a group of 24 elderly subjects aged 63 to 79 years
administered a single ROZEREM 16 mg dose, the mean Cmax
and AUC0-inf values were 11.6 ng/mL (SD, 13.8) and 18.7
ng·hr/mL (SD, 19.4), respectively. The elimination half-life was 2.6 hours (SD,
1.1). Compared with younger adults, the total exposure (AUC0
-inf) and Cmax
of ramelteon were 97% and 86% higher, respectively, in elderly subjects. The
AUC0-inf and Cmax of M-II were
increased by 30% and 13%, respectively, in elderly subjects.
Gender
: There
are no clinically meaningful gender-related differences in the pharmacokinetics
of ROZEREM or its metabolites.
Hepatic Impairment
: Exposure to ROZEREM was increased almost 4-fold in
subjects with mild hepatic impairment after 7 days of dosing with 16 mg/day;
exposure was further increased (more than 10-fold) in subjects with moderate
hepatic impairment. Exposure to M-II was only marginally increased in mildly and
moderately impaired subjects relative to healthy matched controls. The
pharmacokinetics of ROZEREM have not been evaluated in subjects with severe
hepatic impairment (Child-Pugh Class C). ROZEREM should be used with caution in
patients with moderate hepatic impairment [see
Warnings and Precautions (5.6)
].
Renal Impairment
: The pharmacokinetic characteristics of ROZEREM were
studied after administering a 16 mg dose to subjects with mild, moderate, or
severe renal impairment based on pre-dose creatinine clearance (53 to 95, 35 to
49, or 15 to 30 mL/min/1.73 m2, respectively), and in
subjects who required chronic hemodialysis. Wide intersubject variability was
seen in ROZEREM exposure parameters. However, no effects on Cmax or AUC0-t of parent drug or M-II
were seen in any of the treatment groups; the incidence of adverse events was
similar across groups. These results are consistent with the negligible renal
clearance of ramelteon, which is principally eliminated via hepatic metabolism.
No adjustment of ROZEREM dosage is required in patients with renal impairment,
including patients with severe renal impairment (creatinine clearance of
≤ 30 mL/min/1.73 m2) and patients who require chronic
hemodialysis.
12.5 Drug
-
D
rug
I
nteractions
ROZEREM has a highly variable intersubject pharmacokinetic
profile (approximately 100% coefficient of variation in Cmax and AUC). As noted above, CYP1A2 is the major isozyme
involved in the metabolism of ROZEREM; the CYP2C subfamily and CYP3A4 isozymes
are also involved to a minor degree.
Effects of Other Drugs on ROZEREM
Metabolism
Fluvoxamine (strong CYP1A2 inhibitor): When
fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose
co-administration of ROZEREM 16 mg and fluvoxamine, the AUC0-inf for ramelteon increased approximately 190-fold, and the
Cmax increased approximately 70-fold, compared to ROZEREM
administered alone. ROZEREM should not be used in combination with fluvoxamine.
Other less strong CYP1A2 inhibitors have not been adequately studied. ROZEREM
should be administered with caution to patients taking less strong CYP1A2
inhibitors [see
Contraindications
].
Rifampin (strong CYP enzyme inducer):
Administration of rifampin 600 mg once daily for 11 days resulted in a mean
decrease of approximately 80% (40% to 90%) in total exposure to ramelteon and
metabolite M-II, (both AUC0
-inf
and Cmax) after a single 32 mg dose of ROZEREM. Efficacy
may be reduced when ROZEREM is used in combination with strong CYP enzyme
inducers such as rifampin.
Ketoconazole (strong CYP3A4 inhibitor): The
AUC0-inf and Cmax of ramelteon
increased by approximately 84% and 36%, respectively, when a single 16 mg dose
of ROZEREM was administered on the fourth day of ketoconazole 200 mg twice daily
administration, compared to administration of ROZEREM alone. Similar increases
were seen in M-II pharmacokinetic variables. ROZEREM should be administered with
caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole.
Fluconazole (strong CYP2C9 inhibitor): The total
and peak systemic exposure (AUC0-inf and Cmax) of ramelteon after a single 16 mg dose of ROZEREM was
increased by approximately 150% when administered with fluconazole. Similar
increases were also seen in M-II exposure. ROZEREM should be administered with
caution in subjects taking strong CYP2C9 inhibitors such as fluconazole.
Interaction studies of concomitant administration of ROZEREM with fluoxetine
(CYP2D6 inhibitor), omeprazole (CYP1A2 inducer/CYP2C19 inhibitor), theophylline
(CYP1A2 substrate), and dextromethorphan (CYP2D6 substrate) did not produce
clinically meaningful changes in either peak or total exposures to ramelteon or
the M-II metabolite.
Effects of ROZEREM on Metabolism of Other
Drugs
Concomitant administration of ROZEREM with omeprazole (CYP2C19 substrate),
dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline
(CYP1A2 substrate), digoxin (p-glycoprotein substrate) and warfarin (CYP2C9
[S]/CYP1A2 [R] substrate) did not produce clinically meaningful changes in peak
and total exposures to these drugs.
Effect of Alcohol on ROZEREM
With single-dose, daytime co-administration of ROZEREM 32 mg and alcohol (0.6
g/kg), there were no clinically meaningful or statistically significant effects
on peak or total exposure to ROZEREM. However, an additive effect was seen on
some measures of psychomotor performance (i.e., the Digit Symbol Substitution
Test, the Psychomotor Vigilance Task Test, and a Visual Analog Scale of
Sedation) at some post-dose time points. No additive effect was seen on the
Delayed Word Recognition Test. Because alcohol by itself impairs performance,
and the intended effect of ROZEREM is to promote sleep, patients should be
cautioned not to consume alcohol when using ROZEREM.
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Ramelteon was administered to mice and rats at oral doses of 0, 30, 100, 300,
or 1000 mg/kg/day (mice) and 0, 15, 60, 250, or 1000 mg/kg/day (rats). Mice and
rats were dosed for two years, except at the high dose (94 weeks for male and
female mice and female rats). In mice, dose-related increases in the incidence
of hepatic tumors (adenomas, carcinomas, hepatoblastomas) were observed in males
and females. The no-effect dose for hepatic tumors in mice (30 mg/kg/day) is
approximately 20 times the recommended human dose (RHD) of 8 mg/day on a body
surface area (mg/m2) basis.
In rats, the incidence of hepatic adenoma and benign Leydig cell tumors of
the testis was increased in males at doses ≥ 250 mg/kg/day. In females, the
incidence of hepatic adenoma was increased at doses ≥ 60 mg/kg/day. The
incidence of hepatic carcinoma was increased in males and female rats at
1000 mg/kg/day. The no-effect dose for tumors in rats (15 mg/kg/day) is
approximately 20 times the RHD on a mg/m2 basis.
Mutagenesis
Ramelteon was not genotoxic in the in vitro
bacterial reverse mutation (Ames) assay, the in
vitro mouse lymphoma TK+/- assay,
and in in
vivo oral micronucleus assays in mouse and rat. Ramelteon
was clastogenic in the in
vitro chromosomal aberration
assay in Chinese hamster lung cells.
Separate studies indicated that the concentration of the M-II metabolite
formed in the presence of metabolic activation exceeded the concentration of
ramelteon; therefore, the genotoxic potential of the M-II metabolite was also
assessed in the in
vitro
studies.
Impairment of Fertility
When ramelteon (doses of 6 to 600 mg/kg/day) was administered orally to male
and female rats prior to and during mating and early gestation, alterations in
estrus cyclicity and decreased numbers of corpora lutea, implantations, and live
embryos were observed at doses greater than 20 mg/kg/day. The no-effect dose is
approximately 24 times the recommended human dose of 8 mg/day on a body surface
area (mg/m2) basis. Oral administration of ramelteon (up
to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive
performance.
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