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Ramelteon: Wikis


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Systematic (IUPAC) name
(S)-N-[2-(1,6,7,8-tetrahydro-2 H-indeno-[5,4-b]
CAS number 196597-26-9
ATC code N05CH02
PubChem 208902
DrugBank APRD01213
Chemical data
Formula C 16H21NO2  
Mol. mass 259.343 g/mol
Pharmacokinetic data
Bioavailability 1.8%
Protein binding ~82%
Metabolism Hepatic (CYP1A2-mediated)
Half life 1-2.6 hours
Excretion Renal (84%) and fecal (4%)
Therapeutic considerations
Pregnancy cat. C(US)
Legal status -only (US)
Routes Oral
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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 (SCN), versus binding to GABA A receptors, such as with drugs like zolpidem, eszopiclone, and zaleplon. Ramelteon is approved by the U.S. Food and Drug Administration (FDA) for long-term use.

Ramelteon does not show any appreciable binding to GABAA receptors, which are associated with anxiolytic, myorelaxant, and amnesic effects.



Ramelteon is 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 other GABA modulators is not present in ramelteon. It is currently the only non-scheduled prescription drug for the treatment of insomnia available in the United States.[1] Some clinicians also use ramelteon for the treatment of Delayed sleep phase disorder.

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.[2]

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 significance of ramelteon's lack of affinity for the MT3 receptor is not clear, despite the manufacturer's emphasis of this fact in commercial advertisements. The MT3 receptor appears almost exclusively in the gut and might not have any relationship to sleep or wakefulness.

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.

All other known metabolites of ramelteon are inactive.

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 (3x) longer effect and had a more profound effect on the EEG of the sleeping cats.[3]

Clinical efficacy

In a double-blind multicenter trial[4], ramelteon did reduce the time to fall asleep by approximately 15-20 minutes, at 8 mg and 16 mg doses after four weeks compared to placebo (approx. 29-32 versus 48 minutes) 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. The main thing to note is ramelteon compared to placebo had a much faster onset of effects, one or two weeks, but the effects were roughly equivalent to placebo at four weeks.

Adverse effects

Ramelteon caused hyperprolactinaemia two to three times more often than placebo in clinical trials. Studies of rats and mice showed a dose-dependent increase in cancer. The long-term safety in humans is unknown. Ramelteon was teratogenic in rats.

Drug interactions

Ramelteon has been studied in combination with omeprazole, theophylline, dextromethorphan, and midazolam. Other such drug-drug interactions include 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 (fluoxetine) were coadministered. Ramelteon and fluvoxamine should not be coadministered.

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.

Advertising campaign

Rozerem has become known for the surreal humor of its television advertisements, particularly one involving an insomniac chatting with Abraham Lincoln and a talking beaver over a chess board, while a hard-hat diver stands silently in the background. As of October, 2007, the most recent spot was framed as a late-night talk show, with the beaver as host, Lincoln as sidekick, a Rozerem expert as guest, and the diver as bandleader.


  1. ^
  2. ^ Owen RT (April 2006). "Ramelteon: profile of a new sleep-promoting medication". Drugs Today 42 (4): 255–63. doi:10.1358/dot.2006.42.4.970842. PMID 16703122.  
  3. ^ Miyamoto M, Nishikawa H, Doken Y, Hirai K, Uchikawa O, Ohkawa S (November 2004). "The sleep-promoting action of ramelteon (TAK-375) in freely moving cats". Sleep 27 (7): 1319–25. PMID 15586784.  
  4. ^ Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T (August 2007). "Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia". J Clin Sleep Med 3 (5): 495–504. PMID 17803013.  

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