Ramelteon

Ramelteon

Systematic (IUPAC) name
(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b] furan-8-yl)ethyl]propionamide
Clinical data
Trade names	Rozerem
AHFS/Drugs.com	monograph
MedlinePlus	a605038
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral (tablets)
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%)
Identifiers
CAS Number	196597-26-9 Y
ATC code	N05CH02 (WHO)
PubChem	CID: 208902
IUPHAR/BPS	1356
DrugBank	DB00980 Y
ChemSpider	9033484 Y
UNII	901AS54I69 Y
KEGG	D02689 Y
ChEMBL	CHEMBL133775 Y
Chemical data
Formula	C16H21NO2
Molecular mass	259.343 g/mol
SMILES CCC(NCC[C@@H]1CCC2=CC=C3OCCC3=C12)=O
InChI InChI=1S/C16H21NO2/c1-2-15(18)17-9-7-12-4-3-11-5-6-14-13(16(11)12)8-10-19-14/h5-6,12H,2-4,7-10H2,1H3,(H,17,18)/t12-/m1/s1 Y Key:YLXDSYKOBKBWJQ-GFCCVEGCSA-N Y
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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), instead of binding to GABA_A receptors, such as with drugs like zolpidem. Ramelteon is approved by the U.S. Food and Drug Administration (FDA) for long-term use.

Ramelteon does not show any appreciable binding to GABA_A 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 (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.

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 (fluoxetine) were coadministered. When coadministered with ramelteon, fluvoxamine (strong CYP1A2 inhibitor) increased AUC approximately 190-fold, and the C_max 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: .

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-HT_2B 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 (3 times) longer effect and had a more profound effect on the EEG of the sleeping cats.

See also

• Discovery and development of melatonin receptor agonists

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
• 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