RAMELTEON

Ramelteon tablets is an orally active hypnotic chemically designated as (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide and containing one chiral center. The compound is produced as the (S)-enantiomer, and has the following structural formula: Ramelteon is freely soluble in organic solvents, such as methanol, ethanol, and dimethyl sulfoxide; soluble in 1-octanol and acetonitrile; and very slightly soluble in water and in aqueous buffers from pH 3 to pH 11. Each ramelteon tablet for oral administration contains 8 mg ramelteon, and has the following inactive ingredients: hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, pregelatinized corn starch, titanium dioxide, and triacetin. Ramelteon Structural Formula

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 )

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 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 )].

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 Interaction ( 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 )

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 Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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%

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 (strong CYP1A2 inhibitor) When fluvoxamine 100 mg twice daily was administered for three days prior to single-dose coadministration of ramelteon tablets 16 mg and fluvoxamine, the AUC 0-inf for ramelteon tablets increased approximately 190-fold, and the C max increased approximately 70-fold, compared to ramelteon tablets administered alone. Ramelteon tablets should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. Ramelteon tablets should be administered with caution to patients taking less strong CYP1A2 inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7 )] . Rifampin (strong CYP enzyme inducer) Administration of rifampin 600 mg once daily for 11 days resulted in a mean decrease of approximately 80% (40 to 90%) in total exposure to ramelteon tablets and metabolite M-II, (both AUC 0-inf and C max ) after a single 32 mg dose of ramelteon tablets. Efficacy may be reduced when ramelteon tablets is used in combination with strong CYP enzyme inducers such as rifampin [see Drug Interactions ( 7 )]. Ketoconazole (strong CYP3A4 inhibitor) The AUC 0-inf and C max of ramelteon tablets increased by approximately 84% and 36%, respectively, when a single 16 mg dose of ramelteon tablets was administered on the fourth day of ketoconazole 200 mg twice daily administration, compared to administration of ramelteon alone. Similar increases were seen in M-II pharmacokinetic variables. Ramelteon tablets should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole [see Drug Interactions ( 7 )]. Fluconazole (strong CYP2C9 inhibitor) The total and peak systemic exposure (AUC 0-inf and C max ) of ramelteon after a single 16 mg dose of ramelteon tablets was increased by approximately 150% when administered with fluconazole. Similar increases were also seen in M-II exposure. Ramelteon should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Drug Interactions ( 7 )]. Donepezil Administration of donepezil 10 mg once daily for 26 days resulted in a mean increase of approximately 100% in overall exposure to ramelteon tablets, (AUC 0-inf ) and a mean increase of approximately 87% in maximum exposure to ramelteon tablets (C max ) after a single 8 mg dose of ramelteon. No change was seen in M-II exposure. Patients should be closely monitored when ramelteon is coadministered with donepezil [see Drug Interactions ( 7 )] . Doxepin Administration of doxepin 10 mg once daily for 23 days resulted in a mean increase of approximately 66% in overall exposure to ramelteon tablets, (AUC 0-inf ) and a mean increase of approximately 69% in maximum exposure to ramelteon (C max ) after a single 8 mg dose of ramelteon. No change was seen in M-II exposure. Patients should be closely monitored when ramelteon is coadministered with doxepin [see Drug Interactions ( 7 )] . Interaction studies of concomitant administration of ramelteon tablets with fluoxetine (CYP2D6 inhibitor), omeprazole (CYP1A2 inducer/CYP2C19 inhibitor), theophylline (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate), sertraline, venlafaxine, escitalopram, gabapentin, and zolpidem did not produce clinically meaningful changes in either peak or total exposures to ramelteon or the M-II metabolite. Effects of Ramelteon tablets on Metabolism of Other Drugs Zolpidem Administration of ramelteon 8 mg once daily for 11 days resulted in an increase in median T max of zolpidem by approximately 20 minutes and exposure to zolpidem (both AUC 0-inf and C max ) was unchanged after a single 10 mg dose of zolpidem. Ordinarily zolpidem should not be given in a patient taking ramelteon tablets. Concomitant administration of ramelteon tablets with omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), digoxin (p-glycoprotein substrate), warfarin (CYP2C9 [S]/CYP1A2 [R] substrate), venlafaxine, fluvoxamine, donepezil, doxepin, sertraline, escitalopram, and gabapentin did not produce clinically meaningful changes in peak and total exposures to these drugs. Effect of Alcohol on Ramelteon tablets With single-dose, daytime coadministration of ramelteon tablets 32 mg and alcohol (0.6 g/kg), there were no clinically meaningful or statistically significant effects on peak or total exposure to ramelteon tablets. However, an additive effect was seen on some measures of psychomotor performance (i.e., the Digit Symbol Substitution Test, the Psychomotor Vigilance Task Test, and a Visual Analog Scale of Sedation) at some postdose time points. No additive effect was seen on the Delayed Word Recognition Test. Because alcohol by itself impairs performance, and the intended effect of ramelteon tablets is to promote sleep, patients should be cautioned not to consume alcohol when using ramelteon.