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. Pharmacology
Pharmacodynamics
Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the non-human 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 non-human MT3 receptor. The affinity of ramelteon for the MT1 and MT2 receptors is 3 to 16 times higher than that of melatonin. Ramelteon has 8-fold higher affinity for the MT1 receptor over the MT2 receptor. The binding profile of ramelteon distinguishes it from melatonin, tasimelteon, and agomelatine.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- to 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- to 100-fold greater mean systemic exposure when compared to ramelteon.
Overall, side effects occurred in 6% with ramelteon and 2% with placebo in clinical trials. Side effects leading to discontinuation occurred in 1% or fewer people. Rarely, anaphylactic reactions, abnormal thinking, and worsening of depression or suicidal thinking in patients with pre-existing depression may occur with ramelteon. Ramelteon has been found to slightly increase prolactin levels in women (+34% vs. –4% with placebo) but not in men and to decrease free testosterone levels (by 3–6% in younger men and by 13–18% in older men).Ramelteon has not been shown to produce dependence and has shown no potential for abuse. The withdrawal and rebound insomnia that is typical with GABAA receptor positive modulators like benzodiazepines and Z-drugs is not present in ramelteon.Increased incidence of liver and testicular tumors have been observed with ramelteon in rodents but only at doses equivalent to at least 20 times greater than the recommended dose in humans. Overdose
Ramelteon has been assessed at doses of up to 64 mg in clinical studies. 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 Cmax increased approximately 70-fold, compared to ramelteon administered alone.