indication

For the treatment of insomnia characterized by difficulty with sleep onset.

pharmacology

Ramelteon is the first selective melatonin agonist. It works by mimicking melatonin (MT), a naturally occuring hormone that is produced during the sleep period and thought to be responsible for the regulation of circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has a high affinity for the MT₁ and MT₂ receptors. The MT₁ and MT₂ receptors are located in the brain's suprachiasmatic nuclei (SCN),which is known as the body's "master clock" because it regulates the 24-hour sleep-wake cycle. Ramelteon has an active metabolite that is less potent but circulates in higher concentrations than the parent compound. The metabolite also has weak affinity for the 5HT2b receptor.

mechanism of action

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT₁ and MT₂ receptors, and lower selectivity for the MT₃ receptor. Melatonin production is concurrent with nocturnal sleep, meaning that an increase in melatonin levels is related to the onset of self-reported sleepiness and an increase in sleep propensity. MT₁ receptors are believed to be responsible for regulation of sleepiness and facilitation of sleep onset, and MT₂ receptors are believed to mediate phase-shifting effects of melatonin on the circadian rhythm. While MT₁ and MT₂ receptors are associated with the sleep-wake cycle, MT₃ has a completely different profile, and therefore is not likely to be involved in the sleep-wake cycle. Remelteon has no appreciable affinity for the gamma-aminobutyric acid (GABA) receptor complex or receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.

biotransformation

Hepatic

absorption

Rapid, total absorption is at least 84%.

half life

~1-2.6 hours

route of elimination

Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound.

drug interactions

Atazanavir: Atazanavir increases levels/toxicity of ramelteon

Ciprofloxacin: Ciprofloxacin increases levels/toxicity of ramelteon

Enoxacin: Enoxacin increases levels/toxicity of ramelteon

Fluconazole: Fluconazole may increase the serum levels and toxcity of ramelteon.

Fluvoxamine: Fluvoxamine may increase the serum level and toxicity of ramelteon.

Ketoconazole: Ketoconazole may increase the serum levels and toxicity of ramelteon.

Mexiletine: Mexiletine increases levels/toxicity of ramelteon

Rifampin: Rifampin reduces the levels/effect of ramelteon

Tacrine: Tacrine increases levels/toxicity of ramelteon

Thiabendazole: Thiabendazole increases levels/toxicity of ramelteon

Triprolidine: The CNS depressants, Triprolidine and Ramelteon, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Zileuton: Zileuton increases levels/toxicity of ramelteon