Ramelteon, sold under the brand name Rozerem among others, is a sleep agent medication 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. It appears to speed the onset of sleep and alter the total amount of sleep a person gets. It is approved by the US 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 is approved in the United States for the treatment of insomnia characterized by difficulty with sleep onset. A systematic review, published in 2014, concluded "ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo."
Adverse effects
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. Six percent of ramelteon-treated patients in clinical trials discontinued due to an adverse event, compared with 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 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.
