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Ramelteon
CB0496858 · Rozerem · N-[2-[(8S)-1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propanamide · (S)-N-(2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethyl)propionamide · DF883 · CS-1962 · TAK-375 · RAMELTEON
Identifikatoren & physikalische Daten
| CAS No. | 196597-26-9 |
|---|---|
| Summenformel | C16H21NO2 |
| Durchschnittliche Molmasse | 259,34 g/mol |
| Monoisotopische Masse | 259,15722891 g/mol |
| SMILES | CCC(=O)NCC[C@@H]1CCc2ccc3c(c21)CCO3 |
| InChIKey | YLXDSYKOBKBWJQ-LBPRGKRZSA-N |
| PubChem CID | 208902 |
| ChEMBL | CHEMBL1218 |
| ChEBI | CHEBI:109549 |
| EC No. | 688-929-3 |
| DTXSID | DTXSID6045951 |
Chemische & physikalische Eigenschaften
| XLogP | 2,7 |
|---|---|
| Polarare Oberfläche (TPSA) | 38,3 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 2 |
| Frei drehbare Bindungen | 4 |
| Schwere Atome | 19 |
| Formalladung | 0 |
| Komplexität | 331 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | 2.42.57 |
| Color/Form | Crystals from ethyl acetate |
| Löslichkeit | 1.64e-02 g/LDimethyl Sulfoxide, Ethanol, Methanol, |
| Human Drugs | Breast FeedingLactationMilk, HumanCentral Nervous System DepressantsFDA approved drugs -> Active ingredient |
| Schmelzpunkt | 113-115 °C113-1150C |
| Optical Rotation | Specific optical rotation: -57.8 deg at 20 °C/D (concentration = 1.004 g/100 mL in chloroform) |
| Physical Description | Solid |
| Siedepunkt | 455.3±24.0 °C(Predicted) |
| Dichte | 1.119±0.06 g/cm3(Predicted) |
| Flammpunkt | 2℃ |
| Lagerbedingungen | Sealed in dry,Store in freezer, under -20°C |
| Aggregatzustand | Solid |
| pKa (Säurekonstante) | 16.37±0.46(Predicted) |
| Farbe | Crystalline |
| InChI | InChI=1S/C16H21NO2/c1-2-15(18)17-9-7-12-4-3-11-5-6-14-13(16(11)12)8-10-19-14/h5-6,12H,2-4,7-10H2,1H3,(H,17,18)/t12-/m0/s1 |
| InChIKey | YLXDSYKOBKBWJQ-LBPRGKRZSA-N |
| SMILES | C(NCC[C@H]1C2=C3CCOC3=CC=C2CC1)(=O)CC |
| CAS Datenbank | 196597-26-9(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH302 (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.H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral] |
|---|---|
| FDA-Anforderungen | 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. |
| Hazard Classes and Categories | Repr. 2 (100%)Acute Tox. 4 (97.6%) |
| Entsorgungsverfahren | 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. |
| Wechselwirkungen | 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. |
| Hepatotoxicity | 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. |
| Milk Concentrations | Distributed into milk in rats |
| Human Toxicity Excerpts | 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 impairmentavoid use in those with severe hepatic impairment.There is a potential risk of anaphylaxis and angioedema in patients receiving ramelteonsuch 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 | Drug Induced Liver Injury Rank (DILIrank 2.0)RamelteonvNo-DILI-concernNo matchDOI:10.1016/j.drudis.2016.02.015 |
| Non-Human Toxicity Excerpts | /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. |
| Populations at Special Risk | 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 apneause 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 impairmentavoid use in those with severe hepatic impairment. |
| Antidote and Emergency Treatment | 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/ |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| Wassergefährdungsklasse (WGK) | 2 |
| UN-Transportnummer | UN 1648 3 / PGII |
| Zollcode | 2932.99.7000 |
| R-Sätze (R) | 11-20/21/22-36 |
| Gefahrensymbole | F,Xn |
| Sicherheitshinweise (S) | 16-36/37 |
| Lagerklasse | 11 - Combustible Solids |
| Gefahrstoffdaten | 196597-26-9(Hazardous Substances Data) |
| Gefahrenklasse | Acute Tox. 4 Oral |
Anwendungen & Verwendung
Beschreibung
Ramelteon, also known as N-[2-[(8S)-1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propanamide, is a melatonin agonist developed by Takeda Pharmaceuticals, Inc. It was approved by the FDA for marketing in the United States in September 2005 and is marketed under the name Rozerem. It is used to treat difficult-to-sleep and short-term insomnia. Ramelteon is effective for both chronic and short-term insomnia. Unlike most treatments of insomnia that target the GABA (g-aminobutyric acid) receptor complex, ramelteon is an agonist of the melatonin receptor. In particular, it has high selectivity for the MT1 and MT2 subtypes, which have been implicated in the maintenance of circadian rhythms, over the MT3 receptor responsible for other melatonin functions. Its lack of affinity for not only the GABA receptor complex but also neurotransmitter, dopaminerigic, opiate, and benzodiazepine receptors suggests an improved safety profile devoid of the abuse potential of the hypnotic drugs that target these receptors. As such, ramelteon is not a scheduled drug.
Verwenden
Ramelteon is a selective melatonin receptor agonist of MT1 and MT2 approved for the treatment of insomnia (trouble in sleeping). It acts as a sedative and hypnotic agent. Ramelteon is the only prescription sleep aid not designated as a Schedule IV controlled substance.