Ramelteon
FDA Drug Information • Also known as: Ramelteon, Rozerem
- Brand Names
- Ramelteon, Rozerem
- Drug Class
- Melatonin Receptor Agonist [EPC]
- Route
- ORAL
- Dosage Form
- TABLET
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Ramelteon is an orally active hypnotic chemically designated as ( S )- N -[2-(1,6,7,8- tetrahydro-2 H -indeno-[5,4- b ]furan-8-yl)ethyl]propionamide and containing one chiral center. The compound is produced as the ( S )-enantiomer, with the molecular formula of C 16 H 21 NO 2 , molecular weight of 259.34, and the following chemical structure: Ramelteon is white to off-white powder soluble in methanol and practically insoluble in water. Each ramelteon tablet includes the following inactive ingredients: copolyvidone, hyperomellose, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch (maize), and titanium dioxide. str
What Is Ramelteon Used For?
1 INDICATIONS AND USAGE Ramelteon tablets are indicated for the treatment of insomnia characterized by difficulty with sleep onset. The clinical trials performed in support of efficacy were up to six months in duration. The final formal assessments of sleep latency were performed after two days of treatment during the crossover study (elderly only), at five weeks in the six week studies (adults and elderly), and at the end of the six month study (adults and elderly) [see Clinical Studies (14) ] . Ramelteon tablets are indicated for the treatment of insomnia characterized by difficulty with sleep onset. ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Adult dose: 8 mg taken within 30 minutes of going to bed. ( 2.1 ) Should not be taken with or immediately after a high-fat meal. ( 2.1 ) Total daily dose should not exceed 8 mg. ( 2.1 ) 2.1 Dosage in Adults The recommended dose of ramelteon tablets are 8 mg taken within 30 minutes of going to bed. It is recommended that ramelteon tablets not be taken with or immediately after a high-fat meal. The total ramelteon tablets dose should not exceed 8 mg per day. 2.2 Dosing in Patients with Hepatic Impairment Ramelteon tablets are not recommended in patients with severe hepatic impairment. Ramelteon tablets should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions (5.6) , Clinical Pharmacology (12.4) ] . 2.3 Administration with Other Medications Ramelteon tablets should not be used in combination with fluvoxamine. Ramelteon tablets should be used with caution in patients taking other CYP1A2 inhibiting drugs [see Drug Interactions (7) , Clinical Pharmacology (12.5) ].
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections: Severe anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.1) ] Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions (5.3) ] CNS effects [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥3% and more common than with placebo) are: somnolence, dizziness, fatigue, nausea, and exacerbated insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Adverse Reactions Resulting in Discontinuation of Treatment The data described in this section reflect exposure to ramelteon in 5373 subjects, including 722 exposed for six months or longer, and 448 subjects for one year. Six percent of the 5373 individual subjects exposed to ramelteon in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2279 subjects receiving placebo. The most frequent adverse events leading to discontinuation in subjects receiving ramelteon were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less. Ramelteon Most Commonly Observed Adverse Events Table 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of ramelteon. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Table 1. Incidence (% of subjects) of Treatment-Emergent Adverse Events MedDRA Preferred Term Placebo (n=1456) Ramelteon 8 mg (n=1405) Somnolence 2% 3% Fatigue 2% 3% Dizziness 3% 4% Nausea 2% 3% Insomnia exacerbated 2% 3%
Drug Interactions
7 DRUG INTERACTIONS Rifampin (strong CYP enzyme inducer): Decreases exposure to and effects of ramelteon. ( 7.1 ) Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution. ( 7.1 ) Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution. ( 7.1 ) Donepezil: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is coadministered with donepezil. ( 7.1 ) Doxepin: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is coadministered with doxepin. ( 7.1 ) Alcohol: Causes additive psychomotor impairment; should not be used in combination. ( 7.2 ) 7.1 Effects of Other Drugs on Ramelteon Fluvoxamine (strong CYP1A2 inhibitor) AUC 0-inf for ramelteon increased approximately 190-fold, and the C max increased approximately 70- fold upon coadministration of fluvoxamine and ramelteon, compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine [see Contraindications (4), Clinical Pharmacology (12.5) ] . Other less strong CYP1A2 inhibitors have not been adequately studied. Ramelteon should be administered with caution to patients taking less strong CYP1A2 inhibitors. Rifampin (strong CYP enzyme inducer) Administration of multiple doses of rifampin resulted in a mean decrease of approximately 80% in total exposure to ramelteon and metabolite M-II. Efficacy may be reduced when ramelteon is used in combination with strong CYP enzyme inducers such as rifampin [see Clinical Pharmacology (12.5) ] . Ketoconazole (strong CYP3A4 inhibitor) The AUC 0-inf and C max of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with ramelteon. Ramelteon should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole [see Clinical Pharmacology (12.5) ] . Fluconazole (strong CYP2C9 inhibitor) The AUC 0-inf and C max of ramelteon was increased by approximately 150% when ramelteon was coadministered with fluconazole. Ramelteon should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Clinical Pharmacology (12.5) ] . Donepezil The AUC 0-inf and C max of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with ramelteon. Patients should be closely monitored when ramelteon is coadministered with donepezil [see Clinical Pharmacology (12.5) ] . Doxepin The AUC 0-inf and C max of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with ramelteon. Patients should be closely monitored when ramelteon is coadministered with doxepin [see Clinical Pharmacology (12.5) ] . 7.2 Effect of Alcohol on Ramelteon Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ramelteon is to promote sleep, patients should be cautioned not to consume alcohol when...
Contraindications
4 CONTRAINDICATIONS Patients who develop angioedema after treatment with ramelteon tablets should not be rechallenged with the drug. Patients should not take ramelteon tablets in conjunction with fluvoxamine [see Drug Interactions (7) ] . History of angioedema while taking ramelteon tablets. ( 4 ) Fluvoxamine (strong CYP1A2 inhibitor): Increases AUC for ramelteon and should not be used in combination. ( 7.1 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Available data from postmarketing reports with ramelteon use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses greater than 36 times the recommended human dose (RHD) of 8 mg/day based on body surface area (mg/m 2 ) (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of ramelteon (10, 40, 150 or 600 mg/kg/day) to pregnant rats during the period of organogenesis was associated with increased incidences of fetal structural abnormalities (malformations and variations) at doses greater than 40 mg/kg/day. The no-effect dose is approximately 50 times the RHD based on mg/m 2 . Treatment of pregnant rabbits during the period of organogenesis produced no evidence of embryo-fetal toxicity at oral doses of up to 300 mg/kg/day (or up to 720 times the RHD based on mg/m 2 ). When rats were orally administered ramelteon (30, 100, or 300 mg/kg/day) throughout gestation and lactation, growth retardation, developmental delay, and behavioral changes were observed in the offspring at doses greater than 30 mg/kg/day. The no-effect dose is 36 times the RHD based on mg/m 2 . Increased incidences of malformation and death among offspring were seen at the highest dose.
Overdosage
10 OVERDOSAGE General symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. 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 ramelteon. Therefore, the use of dialysis in the treatment of overdosage is not appropriate. Poison Control Center As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. Contact a poison control center for current information on the management of overdosage.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Ramelteon Tablets 8 mg are available as pale yellow colored, round, biconvex film-coated tablets, debossed with “RT” on one side and “8” on the other side. They are supplied as follows: Bottles of 30 NDC 59651-505-30 Bottles of 100 NDC 59651-505-01 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep container tightly closed and protected from moisture and humidity.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.