Brands, Medical Use, Clinical Data
Brands / Synonyms
For the treatment of insomnia characterized by difficulty with sleep onset.
Ramelton is the first selective melatonin agonist. It works by mimicing melatonin (MT), a naturally occuring hormone that is produced during the sleep period. It has a high affinity for the MT1 and MT2 receptor. The MT1 and MT2 receptors are located in the brain's suprachiasmatic nuclei (SCN). The SCN is known as the body's "master clock" because it regulates the 24-hour sleep-wake cycle. Ramelton has an active metabolite that is less potent but circulates in higher concentrations than the parent compound. The metabolite also has weak affinity for the 5HT2b receptor.
Mechanism of Action
Ramelton 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, and high selectivity for human MT 1 and MT2 receptors compared to the MT3 receptor.
Rapid, total absorption is at least 84%.
Biotrnasformation / Drug Metabolism
ROZEREM is contraindicated in patients with a hypersensitivity to ramelteon or any components of the ROZEREM
ROZEREM has a highly variable inter-subject 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.
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 32mg 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
Effect of Alcohol on Rozerem
Alcohol: With single-dose, daytime co-administration of ROZEREM 32mg 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.
Drug/Laboratory Test Interactions
ROZEREM is not known to interfere with commonly used clinical laboratory tests. In addition, in vitro data
indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine,
cannabinoids, or amphetamines in two standard urine drug screening methods in vitro.