Ramelteon
Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. It reduces the time taken to fall asleep, but the degree of clinical benefit is small. The medication is approved for long-term use. Ramelteon is taken by mouth.
Side effects of ramelteon include somnolence, dizziness, fatigue, nausea, exacerbated insomnia, and changes in hormone levels. Ramelteon is an analogue of melatonin and is a selective agonist of the melatonin MT1 and MT2 receptors. The half-life and duration of ramelteon are much longer than those of melatonin. Ramelteon is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.
Ramelteon was first described in 2002 and was approved for medical use in 2005. Unlike certain other sleep medications, ramelteon is not a controlled substance in nearly every country and has no known potential for misuse.
Medical uses
Insomnia
Ramelteon is approved for the treatment of insomnia characterized by difficulty with sleep onset in adults. In regulatory clinical trials, it was found to significantly reduce latency to persistent sleep. A 2009 pooled analysis of four clinical trials found that ramelteon at a dose of 8 mg reduced sleep onset by 13 minutes relative to placebo on the first and second nights of use. Subsequent meta-analyses of longer-duration use have found that ramelteon decreases subjective sleep latency by about 4 to 7 minutes. Meta-analyses are mixed on whether ramelteon increases total sleep time. Ramelteon also improves sleep quality and sleep efficiency. The clinical improvement in insomnia with ramelteon is small and of questionable benefit.Ramelteon is approved in the United States but was not approved in the European Union owing to concerns that it lacked effectiveness. The Committee for Medicinal Products for Human Use of the European Medicines Agency noted that ramelteon had only been found to improve sleep onset and not other sleep outcomes, only one of three clinical trials actually found that it improved sleep onset, and that the improvement in sleep onset was too small to be clinically meaningful. The CHMP also noted that the long-term effectiveness of ramelteon had not been demonstrated.
The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended the use of ramelteon in the treatment of sleep-onset insomnia. It rated the recommendation as weak and the quality of evidence as very low but concluded that the potential benefits outweighed the potential harms. The guidelines found that ramelteon reduces sleep latency by 9minutes but does not improve sleep quality. In contrast to ramelteon, the guidelines did not recommend the use of melatonin.
Circadian rhythm sleep disorders
s like melatonin and tasimelteon are considered to be effective in regulating sleep–wake cycles and in the treatment of circadian rhythm sleep disorders like delayed sleep phase disorder. Ramelteon has been assessed in only a few studies in the treatment of circadian rhythm sleep disorders, including jet lag disorder, shift work disorder, and non-24-hour sleep–wake disorder. These studies have been of varying quality and their findings in terms of effectiveness have been mixed. Ramelteon is approved only for treatment of insomnia and is not approved for treatment of circadian rhythm sleep disorders. It was previously under development for treatment of circadian rhythm sleep disorders, but development for these indications was discontinued.Some clinical trials since 2020 have found that dosages much lower than the standard 8 mg tablet may be more effective at advancing the circadian rhythm.
Other uses
Delirium
A systematic review, published in 2014, concluded "ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo." A 2022 systematic review and meta-analysis found that the combination of ramelteon and the orexin receptor antagonist suvorexant may reduce the incidence of delirium in adults hospitalized patients whereas suvorexant alone was ineffective.Bipolar disorder
Ramelteon has received attention in psychiatry as a possible add-on treatment for mania in bipolar disorder. However, to date, the scarce available evidence fails to support the clinical utility of ramelteon and other melatonin receptor agonists such as melatonin for mania.Available forms
Ramelteon is available in the form of 8 mg oral film-coated tablets.Contraindications
Ramelteon is not recommended for use in people with severe sleep apnea.Adverse effects
s of ramelteon include somnolence, fatigue, dizziness, nausea, and exacerbated insomnia. 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 but not in men and to decrease free testosterone levels.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 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 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.
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. Remelteon has a clinically irrelevant affinity for the serotonin 5-HT1A receptor.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. 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.
Ramelteon has no appreciable affinity for the GABA receptors 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.