ROZEREM™ (ramelteon) is an orally active hypnotic chemically designated as
and containing one chiral center. The compound is produced as the (
tiomer, with an empirical formula of C
, molecular weight of 259.34,
and the following chemical structure:
Ramelteon is freely soluble in organic solvents, such as methanol, ethanol,
and dimethyl sulfoxide; soluble in 1-octanol and acetonitrile; and very slightly
soluble in water and in aqueous buffers from pH 3 to pH 11.
Each ROZEREM tablet includes the following inactive ingredients: lactose
monohydrate, starch, hydroxypropyl cellulose, magnesium stearate,
hypromellose, copovidone, titanium dioxide, yellow ferric oxide, polyethylene
glycol 8000, and ink containing shellac and synthetic iron oxide black.
Pharmacodynamics and Mechanism of Action
ROZEREM (ramelteon) is a melatonin receptor agonist with both high affinity
for melatonin MT
receptors and selectivity over the MT
Ramelteon demonstrates full agonist activity
in cells expressing
receptors, and high selectivity for human MT
receptors compared to the MT
The activity of ramelteon at the MT
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, noradren-
aline, 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
receptors, respectively, and is 17 – 25-fold less potent than
functional assays. Although the potency of M-II at MT
receptors is lower than the parent drug, M-II circulates at higher
concentrations than the parent producing 20 – 100-fold greater mean systemic
exposure when compared to ramelteon. M-II has weak affinity for the serotonin
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
All other known metabolites of ramelteon are inactive.
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