Ramelteon

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 )

2. DOSAGE AND ADMINISTRATION 2.1 Dosage in Adults The recommended dose of ramelteon tablets is 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. • 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 is 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 Precaution ( 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 )].

2.1 Dosage in Adults The recommended dose of ramelteon tablets is 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 Precaution ( 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 )].

3 DOSAGE FORMS AND STRENGTHS Ramelteon tablet is available in an 8 mg strength tablet for oral administration. Ramelteon tablets, 8 mg are yellow colored, circular, biconvex, film-coated tablets, debossed with "RM" on one face and plain on other face with an approximate diameter of 7.00 mm. 8 mg tablets. ( 3 )

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 )

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 AvKARE at 1-855-361-3993 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 tablets in 5,373 subjects, including 722 exposed for six months or longer and 448 subjects for one year. Six percent of the 5,373 individual subjects exposed to Ramelteon tablets in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2,279 subjects receiving placebo. The most frequent adverse events leading to discontinuation in subjects receiving ramelteon tablets were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less. Ramelteon Tablets Most Commonly Observed Adverse Events Table 1 displays the incidence of adverse events reported by the 2,861 patients with chronic insomnia who participated in placebo-controlled trials of ramelteon tablets. 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=1,456) Ramelteon 8 mg (n=1,405) Somnolence 2% 3% Fatigue 2% 3% Dizziness 3% 4% Nausea 2% 3% Insomnia exacerbated 2% 3% To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 tablets 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 tablets 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 tablets and metabolite M-II. Efficacy may be reduced when ramelteon tablets 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 tablets increased by approximately 84% and 36% upon coadministration of ketoconazole with ramelteon tablets. Ramelteon tablets 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 tablets was increased by approximately 150% when ramelteon tablets was coadministered with fluconazole. Ramelteon tablets 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 tablets. Patients should be closely monitored when ramelteon tablets 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 tablets. Patients should be closely monitored when ramelteon tablets is coadministered with doxepin [see Clinical Pharmacology ( 12.5 )]. 7.2 Effect of Alcohol on Ramelteon tablets 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 using ramelteon [see Clinical Pharmacology ( 12.5 )] . Use of the products in combination may have an additive effect. 7.3 Drug/Laboratory Test Interactions Ramelteon is not known to interfere with commonly used clinical laboratory tests. In addition, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro .

12.5 Drug-Drug Interactions Ramelteon tablets has a highly variable intersubject pharmacokinetic profile (approximately 100% coefficient of variation in C max and AUC). As noted above, CYP1A2 is the major isozyme involved in the metabolism of ramelteon tablets; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree. Effects of Other Drugs on Ramelteon tablets Metabolism Fluvoxamine (stro …

8 USE IN SPECIFIC POPULATIONS Pediatric use: Safety and effectiveness not established. ( 8.4 ) Geriatric use: No overall differences in safety and efficacy between elderly and younger adult subjects. ( 8.5 ) Hepatic impairment: Is not recommended in patients with severe impairment; use with caution in moderate impairment. ( 8.8 ) 8.1 Pregnancy Risk Summary Available data from postmarketing reports with ramelteon tablets 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. 8.2 Lactation Risk Summary There are no data regarding the presence of ramelteon or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Ramelteon 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 the mechanism of action of ramelteon, there is a potential risk for somnolence in a breastfed infant (see Clinical Considerations) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ramelteon tablets and any potential adverse effects on the breastfed infant from ramelteon tablets or from the underlying maternal condition. Clinical Considerations Infants exposed to ramelteon tablets through breastmilk 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 ramelteon tablets administration in order to minimize drug exposure to a breastfed infant. 8.4 Pediatric Use Safety and effectiveness of ramelteon tablets in pediatric patients have not been established. Further study is needed prior to determining that this product may be used safely in prepubescent and pubescent patients. 8.5 Geriatric Use A total of 654 subjects in double-blind, placebo-controlled, efficacy trials who received ramelteon tablets were at least 65 years of age; of these, 199 were 75 years of age or older. No overall differences in safety or efficacy were observed between elderly and younger adult subjects. A double-blind, randomized, placebo-controlled study in elderly subjects with insomnia (n=33) evaluated the effect of a single dose of ramelteon tablets on balance, mobility, and memory functi …

12.1 Mechanism of Action Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT 1 and MT 2 receptors and relative selectivity over the MT 3 receptor. The activity of ramelteon at the MT 1 and MT 2 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 pharmacologically active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT 1 and MT 2 receptors, respectively. However, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. 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.

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 an molecular formula of C 16 H 21 NO 2 , molecular weight of 259.34, and the following chemical structure: Ramelteon is a white to cream color powder and it is freely soluble in methanol and practically insoluble in water. Each film-coated tablet contains 8 mg ramelteon and contains following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol, povidone, pregelatinized starch (botanical source: maize), sodium stearyl fumarate, titanium dioxide. Structural Formula

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 tablets. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Ramelteon tablets are yellow colored, circular, biconvex, film-coated tablets, debossed with "RM" on one face and plain on other face with an approximate diameter of 7.00 mm. Bottle of 5 NDC 87063-189-05 (repackaged from NDC 42571-375-XX) Bottle of 10 NDC 87063-189-10 (repackaged from NDC 42571-375-XX) Bottle of 20 NDC 87063-189-20 (repackaged from NDC 42571-375-XX) Bottle of 30 NDC 87063-189-30 (repackaged from NDC 42571-375-XX) Bottle of 60 NDC 87063-189-60 (repackaged from NDC 42571-375-XX) Bottle of 90 NDC 87063-189-90 (repackaged from NDC 42571-375-XX) Bottle of 100 NDC 87063-189-01 (relabeled from NDC 42571-375-01) Store at 20o to 25oC (68o to 77oF); excursions permitted to 15o to 30oC (59o to 86oF) [see USP Controlled Room Temperature]. Keep container tightly closed and protected from moisture and humidity.