Ramelteon

Ramelteon is used for: Ramelteon is indicated for the, treatment of insomnia, characterized by difficulty with sleep onset.

Adult: Tablet 8 mg taken within 30 minutes of going to bed. Total daily dose should not exceed 8 mg.

Safety and efficacy not established

Take within 30 min of going to bed. Should not be taken with or immediately after a high-fat meal.

Hypersensitivity Ramelteon is not recommended in patients with severe hepatic impairment. Patients who develop angioedema after treatment with Ramelteon should not be re-challenged with the drug.

In rare cases, severe anaphylactic and anaphylactoid reactions have occurred following use of Ramelteon. Angioedema involving the tongue, glottis, or larynx has been reported. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Reactions may require emergency treatment and may be fatal. Patients who develop such reactions should not be rechallenged. Ramelteon should not be used in patients with severe hepatic impairment or in combination with fluvoxamine. Failure of insomnia to remit after 7–10 days, worsening of insomnia, or emergence of new cognitive or behavioral abnormalities should be medically evaluated, as this may be the result of an unrecognized underlying medical/psychiatric disorder. In primarily depressed patients, worsening of depression, including suicidal ideation and completed suicides, can occur with hypnotics. Hallucinations, as well as behavioral changes such as bizarre behavior, agitation, and mania, have been reported with Ramelteon use. Amnesia, anxiety, and other neuropsychiatric symptoms may also occur unpredictably. Complex behaviors such as “sleep-driving," making or eating food, talking on the phone, sleep-walking, or engaging in other activities while not fully awake, with amnesia for the event, may occur with use of hypnotics, including Ramelteon. The use of alcohol with Ramelteon may increase the risk of such behaviors. Discontinuation of Ramelteon should be strongly considered for patients who report any complex sleep behavior. Patients should avoid engaging in hazardous activities that require concentration (such as operating a motor vehicle or heavy machinery) after taking Ramelteon. Patients should be advised not to consume alcohol in combination with Ramelteon, as alcohol and Ramelteon may have additive effects when used in conjunction. Ramelteon has been associated with decreased testosterone levels and increased prolactin levels. Patients may experience cessation of menses or galactorrhea in females, decreased libido, or fertility problems that are possibly associated with such hormone changes. Ramelteon has not been studied in patients with severe sleep apnea and is not recommended for use in this population. Lactation: no clinical studies, not recommended

Pregnancy Available data from postmarketing reports with use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Animal data In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses greater than 36 times recommended human dose (RHD) of 8 mg/day based on body surface area (mg/m2) Lactation There are no data regarding presence of drug or metabolites in human milk, effects on breastfed infant, or on milk production The drug and/or its metabolites are present in rat milk; when a drug is present in animal milk, it is likely that the drug will be present in human milk; because of mechanism of action of drug, there is a potential risk for somnolence in a breastfed infant; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breastfed infant from drug or from underlying maternal condition Infants exposed to drug through breast milk should be monitored for somnolence and feeding problems; a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 25 hours (approximately 5 elimination half-lives) after drug administration in order to minimize drug exposure to a breastfed infant

Rifampin (strong CYP enzyme inducer): Decreases exposure to and effects of ramelteon. Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution. Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution. Donepezil increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is coadministered with donepezil. Doxepin increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is coadministered with doxepin. Alcohol: Causes additive psychomotor impairment; should not be used in combination.

Side effects of Ramelteon : Most common adverse reactions (≥3% and more common than with placebo) are: somnolence, dizziness, fatigue, nausea, and exacerbated insomnia.

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over 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.