Ramelteon

2.4

2.57

Breast Feeding; Lactation; Milk, Human; Central Nervous System Depressants

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Warning

H302 (97.6%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 42 reports by companies from 4 notifications to the ECHA C&L Inventory.

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including ramelteon, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Repr. 2 (100%)

Acute Tox. 4 (97.6%)

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Substrates of CYP isoenzymes 1A2 (e.g., theophylline), 2C9 (e.g., warfarin), 2C19 (e.g., omeprazole), 2D6 (e.g., dextromethorphan), or 3A4 (e.g., midazolam): Pharmacokinetic interaction unlikely.

Inducers of CYP isoenzymes: Pharmacokinetic interaction observed during concomitant use with rifampin (decreased concentrations of ramelteon and active metabolite). Possibly reduced ramelteon efficacy when used concomitantly with potent CYP inducers such as rifampin.

Inhibitors of CYP2D6 isoenzyme: Pharmacokinetic interaction with fluoxetine unlikely.

Inhibitors of CYP2C9 isoenzyme: Pharmacokinetic interaction observed during concomitant use with fluconazole (increased concentrations of ramelteon and active metabolite). Caution if used concomitantly with fluconazole or other potent inhibitors of CYP2C9.

For more Interactions (Complete) data for Ramelteon (7 total), please visit the HSDB record page.

In several clinical trials, ramelteon was found to be well tolerated and not associated with serum enzyme elevations or evidence of liver injury. Despite, wide scale use, it has not been convincingly linked to instances of clinically apparent liver injury. A single report of worsening liver disease with jaundice, ascites, bacterial peritonitis and death in a patient with alcoholic liver disease who had started ramelteon therapy a month before has been reported. Ramelteon is not recommended in patients with impaired hepatic function.

Adverse effects reported in 2% or more of patients receiving ramelteon during clinical trials include headache, somnolence, fatigue, dizziness, nausea, exacerbation of insomnia, upper respiratory tract infection, diarrhea, myalgia, depression, dysgeusia, and arthralgia.

Following administration of 16 mg of ramelteon daily for 7 days, exposure to the drug was increased by approximately fourfold in patients with mild hepatic impairment and more than tenfold in those with moderate hepatic impairment.1 The pharmacokinetics of ramelteon have not been evaluated in patients with severe hepatic impairment (Child-Pugh class C). Use with caution in patients with moderate hepatic impairment; avoid use in those with severe hepatic impairment.

There is a potential risk of anaphylaxis and angioedema in patients receiving ramelteon; such reactions may occur as early as with the first dose of the drug.

Studies employing subjective measures (e.g., questionnaires) did not reveal evidence of a withdrawal syndrome (including rebound insomnia) following discontinuance of long-term ramelteon therapy (4, 8, or 16 mg daily for up to 35 days).

In a 35-night randomized study evaluating next-day residual effects of ramelteon, adult patients receiving 8 mg of the drug every night experienced reduced immediate/delayed memory recall and increased sluggishness, fatigue, and irritation at weeks 1 and 3 of treatment compared with those receiving placebo. However, next-day residual effects were not substantially different between ramelteon- and placebo-treated patients at week 5.1 2 A similar study in geriatric patients receiving 4 or 8 mg of ramelteon every night did not produce any substantial differences in measures of residual effects.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ramelteon

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In rats, the incidence of hepatic adenoma and benign Leydig cell tumors of the testis was increased in males at doses = 250 mg/kg/day. In females, the incidence of hepatic adenoma was increased at doses = 60 mg/kg/day. The incidence of hepatic carcinoma was increased in males and female rats at 1000 mg/kg/day. The no-effect dose for tumors in rats (15 mg/kg/day) is approximately 20 times the RHD on a mg/sq m basis

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Ramelteon was administered to mice and rats at oral doses of 0, 30, 100, 300, or 1000 mg/kg/day (mice) and 0, 15, 60, 250, or 1000 mg/kg/day (rats). Mice and rats were dosed for two years, except at the high dose (94 weeks for male and female mice and female rats). In mice, dose-related increases in the incidence of hepatic tumors (adenomas, carcinomas, hepatoblastomas) were observed in males and females. The no-effect dose for hepatic tumors in mice (30 mg/kg/day) is approximately 20 times the recommended human dose (RHD) of 8 mg/day on a body surface area (mg/sq m) basis.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ When ramelteon (doses of 6 to 600 mg/kg/day) was administered orally to male and female rats prior to and during mating and early gestation, alterations in estrus cyclicity and decreased numbers of corpora lutea, implantations, and live embryos were observed at doses greater than 20 mg/kg/day. The no-effect dose is approximately 24 times the recommended human dose of 8 mg/day on a body surface area (mg/sq m) basis. Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.

/GENOTOXICITY/ Ramelteon was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma TK+/- assay, and in in vivo oral micronucleus assays in mouse and rat. Ramelteon was clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells.

The effects of Rozerem were evaluated after administering a 16 mg dose or placebo in a crossover design to subjects (n=26) with mild to moderate obstructive sleep apnea. Treatment with Rozerem 16 mg for one night showed no difference compared with placebo on the Apnea/Hypopnea Index (the primary outcome variable), apnea index, hypopnea index, central apnea index, mixed apnea index, and obstructive apnea index. Treatment with a single dose of Rozerem does not exacerbate mild to moderate obstructive sleep apnea. There is no available information on the respiratory effects of multiple doses of Rozerem in patients with sleep apnea. The effects on exacerbation in patients with mild to moderate sleep apnea cannot be definitively known from this study. Rozerem has not been studied in subjects with severe obstructive sleep apnea; use of Rozerem is not recommended in such patients.

Following administration of 16 mg of ramelteon daily for 7 days, exposure to the drug was increased by approximately fourfold in patients with mild hepatic impairment and more than tenfold in those with moderate hepatic impairment.1 The pharmacokinetics of ramelteon have not been evaluated in patients with severe hepatic impairment (Child-Pugh class C). Use with caution in patients with moderate hepatic impairment; avoid use in those with severe hepatic impairment.

Intravenous fluids should be administered as needed. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed. Hemodialysis does not effectively reduce exposure to Rozerem. Therefore, the use of dialysis in the treatment of overdosage is not appropriate.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including ramelteon, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N - Nervous system

QN - Nervous system

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.

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.

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. 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 opiates. 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- 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. All other known metabolites of ramelteon are inactive

Hepatic

Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree. The rank order of the principal metabolites by prevalence in human serum is M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination. The overall mean systemic exposure of M-II is approximately 20- to 100-fold higher than parent drug.

901AS54I69

RAMELTEON

Established Pharmacologic Class [EPC] - Melatonin Receptor Agonist

Mechanisms of Action [MoA] - Melatonin Receptor Agonists

Ramelteon is a Melatonin Receptor Agonist. The mechanism of action of ramelteon is as a Melatonin Receptor Agonist.

RAMELTEON

Rapid, total absorption is at least 84%.

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.

73.6 L

In vitro protein binding of ramelteon is approximately 82% in human serum, independent of concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound in human serum albumin. Ramelteon is not distributed selectively to red blood cells. Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting substantial tissue distribution.

Ramelteon is absorbed rapidly, with median peak concentrations occurring at approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral administration. Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass metabolism

Distributed into milk in rats; not known whether ramelteon is distributed into human milk.

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

THERAPEUTIC CATEGORY: Sedative, hypnotic

MEDICATION