Ramelteon, marketed as Rozerem by Takeda Pharmaceuticals North America, is the
first in a new class of sleep agents that selectively binds to the MT1 and
MT2 receptors in the suprachiasmatic nucleus, instead of binding to GABAA
receptors, such as with drugs like zolpidem. Ramelteon is approved by the
U.S. Food and Drug Administration for long-term use.
Ramelteon does not show any appreciable binding to GABAA receptors, which are
associated with anxiolytic, myorelaxant, and amnesic effects.
Medical uses Ramelteon can be used for insomnia,
particularly delayed sleep onset. Ramelteon has not been shown to produce
dependence and has shown no potential for abuse, and the withdrawal and
rebound insomnia that is typical with GABA modulators is not present in
ramelteon. Some clinicians also use ramelteon for the treatment of Delayed
sleep phase syndrome. A systematic review, published in 2014,
concluded "ramelteon was found to be beneficial in preventing delirium in
medically ill individuals when compared to placebo."
In a double-blind multicenter trial, ramelteon did reduce the time to fall
asleep by approximately 15–20 minutes after four weeks compared to placebo
Total sleep time improved about 40 minutes, however, this was identical to
improvement with placebo at the end of trial. Subjective reported sleep time
was greater in ramelteon treated persons. Ramelteon, when compared to
placebo, had a much faster onset of effects: one or two weeks. However, the
effects were roughly equivalent to placebo at four weeks.
Adverse effects Six percent of ramelteon-treated
patients in clinical trials discontinued due to an adverse event, compared to 2%
in the placebo arms. The most frequent adverse events leading to
discontinuation were somnolence, dizziness, nausea, fatigue, headache,
and insomnia. The United States official Prescribing Information warns of rare
cases of anaphylactic reactions, abnormal thinking, and suicide in
patients with pre-existing depression. In mice treated with ramelteon for two
years, increases in liver and testicular tumors were observed, but only at doses
at least 20 times greater than the recommended human dose on a
milligram/kilogram basis. Drug interactions
Ramelteon has been evaluated for potential drug interactions with the
following medications and showed no significant effects: omeprazole,
theophylline, dextromethorphan, and midazolam, digoxin and warfarin. There
were no clinically meaningful effects when ramelteon was coadministered with
any of these drugs. A drug interaction study showed that
there were no clinically meaningful effects or an increase in adverse events
when ramelteon and the SSRI Prozac were coadministered. When coadministered with
ramelteon, fluvoxamine increased AUC approximately 190-fold, and the Cmax
increased approximately 70-fold, compared to ramelteon administered
alone. Ramelteon and fluvoxamine should not be coadministered.
Ramelteon has significant drug-drug interaction with the following drugs:
Amiodarone, Ciprofloxacin, Fluvoxamine, Ticlopidine.
Ramelteon should be administered with caution in patients taking other CYP1A2
inhibitors, strong CYP3A4 inhibitors such as ketoconazole, and strong CYP2C9
inhibitors such as fluconazole. Efficacy may be reduced when ramelteon
is used in combination with potent CYP enzyme inducers such as rifampin, since
ramelteon concentrations may be decreased.
Mechanism of action 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, and high
selectivity for human MT1 and MT2 receptors compared to the MT3 receptor.
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 opioids. 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 17–25-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 20–100-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.
No published studies have indicated whether ramelteon, in humans, is more or
less safe or effective than the hormone melatonin which it mimics; melatonin is
much less expensive and is widely available over-the-counter in the US and
Canada. The biological action of melatonin is similar to that of
ramelteon. Ramelteon has been directly compared to melatonin in cats, and
Ramelteon had a significant longer effect and had a more profound effect on
the EEG of the sleeping cats. See also
Discovery and development of melatonin receptor agonists
References Sources and external links
Safety and Efficacy Study of Ramelteon Tablets for Sublingual Administration in
Adults With Bipolar 1 Disorder: NCT01677182 on ClinicalTrials.gov
Kato, K; Hirai, K; Nishiyama, K; Uchikawa, O; Fukatsu, K; Ohkawa, S;
Kawamata, Y; Hinuma, S; Miyamoto, M. "Neurochemical properties of ramelteon,
a selective MT1/MT2 receptor agonist.". Neuropharmacology 48: 301–10.
doi:10.1016/j.neuropharm.2004.09.007. PMID 15695169.
Roth, T; Stubbs, C; Walsh, JK. "Ramelteon, a selective MT1/MT2-receptor
agonist, reduces latency to persistent sleep in a model of transient insomnia
related to a novel sleep environment.". Sleep 28: 303–7. PMID 16173650.
Rozerem Official Website Prescribing Information Data Sheet
RxList.com Clinical Pharmacokinetic Monitoring of
Midazolam in Critically Ill Patients in relation to midazolam as a drug-drug
interaction to Rozerem