Systematic (IUPAC) name
Clinical data
Trade names Rozerem
  • US: C (Risk not ruled out)
Legal status
Routes of
Pharmacokinetic data
Bioavailability 1.8%
Protein binding ~82%
Metabolism Hepatic (CYP1A2-mediated)
Biological half-life 1-2.6 hours
Excretion Renal (84%) and fecal (4%)
CAS Registry Number  Y
ATC code N05
PubChem CID:
DrugBank  Y
ChemSpider  Y
Chemical data
Formula C16H21NO2
Molecular mass 259.343 g/mol

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), instead of binding to GABAA 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.


  • Medical uses 1
  • Adverse effects 2
  • Drug interactions 3
  • Mechanism of action 4
  • See also 5
  • References 6
  • Sources and external links 7

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.

Ramelteon was recently found to significantly reduce delirium in hospitalized at-risk patients.[1] This multicenter prospective, blinded, randomized, placebo-controlled study found that "Ramelteon was associated with a lower risk of delirium (3% vs 32%; P = .003)". A systematic review, published in 2014, concluded "ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo."[2]

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 (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. 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.[3]

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 20x greater than the recommended human dose on a milligram/kilogram basis.[4]

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 (fluoxetine) were coadministered. Ramelteon and fluvoxamine should not be coadministered.

Ramelteon has significant drug-drug interaction with the following drugs: .

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.[5]

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.[6] 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.[7]

See also


  1. ^ Hatta, K; Kishi, Y; Wada, K; Takeuchi, T; Odawara, T; Usui, C; Nakamura, H; Deliria-j, Group (2014). "Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial". JAMA Psychiatry 71 (4): 397–403.  
  2. ^ Chakraborti D, Tampi DJ, Tampi RR (March 2015). "Melatonin and melatonin agonist for delirium in the elderly patients". Am J Alzheimers Dis Other Demen 30 (2): 119–129.  
  3. ^ 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.  
  4. ^ "www.accessdata.fda.gov" (PDF). 
  5. ^ Owen RT (April 2006). "Ramelteon: profile of a new sleep-promoting medication". Drugs Today 42 (4): 255–63.  
  6. ^ Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (May 2012). "Melatonin and its analogs in insomnia and depression". J. Pineal Res. 52 (4): 365–75.  
  7. ^ 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.  

Sources and external links

  • Safety and Efficacy Study of Ramelteon (TAK-375) Tablets for Sublingual Administration (SL) 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 (Feb 2005). "Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist.". Neuropharmacology 48 (2): 301–10.  
  • Roth, T; Stubbs, C; Walsh, JK (Mar 2005). "Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment." (PDF). Sleep 28 (3): 303–7.  
  • 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