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)]

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

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Ramelteon tablets

Fluvoxamine (strong CYP1A2 inhibitor)

AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax 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 AUC0-inf and Cmax 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 AUC0-inf and Cmax 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 AUC0-inf and Cmax 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 AUC0-inf and Cmax 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.

9 DRUG ABUSE AND DEPENDENCE

Ramelteon tablets is not a controlled substance.

Discontinuation of ramelteon in animals or in humans after chronic administration did not produce withdrawal signs. Ramelteon does not appear to produce physical dependence.

Human Data

A laboratory abuse potential study was performed with ramelteon tablets [see Clinical Studies (14.2)].

Animal Data

Ramelteon did not produce any signals from animal behavioral studies indicating that the drug produces rewarding effects. Monkeys did not self- administer ramelteon and the drug did not induce a conditioned place preference in rats. There was no generalization between ramelteon and midazolam. Ramelteon did not affect rotorod performance, an indicator of disruption of motor function, and it did not potentiate the ability of diazepam to interfere with rotorod performance.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Ramelteon was administered to mice and rats at oral doses of 0, 30, 100, 300, or 1,000 mg/kg/day (mice) and 0, 15, 60, 250, or 1,000 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 based on body surface area (mg/m2).

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 1,000 mg/kg/day. The no-effect dose for tumors in rats (15 mg/kg/day) is approximately 20 times the RHD based on mg/m2basis.

Mutagenesis

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 M-II metabolite was not tested for genotoxicity. However, it was present in the test medium of the parent drug at concentrations higher than those of the parent.

Separate studies indicated that the concentration of the M-II metabolite formed in the presence of metabolic activation exceeded the concentration of ramelteon; therefore, the genotoxic potential of the M-II metabolite was also assessed in the in vitro studies.

Impairment of Fertility

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 RHD of 8 mg/day based on mg/m2. Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Severe Anaphylactic and Anaphylactoid Reactions

Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with ramelteon. Describe the relevant signs/symptoms and advise seeking immediate medical attention if any such things occur.

Sleep-Driving and other Complex Behaviors

There have been reports of people getting out of bed after taking a sleep medication and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sleep medications are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sleep medication. As with sleep-driving, patients usually do not remember these events.

Endocrine Effects

Patients should consult their healthcare providers if they experience one of the following: cessation of menses or galactorrhea in females, decreased libido, or problems with fertility. Describe the relevant signs/symptoms and advise seeking medical attention if any such things occur.

Administration Instructions

• Patients should be advised to take ramelteon tablets within 30 minutes prior to going to bed and should confine their activities to those necessary to prepare for bed.

• Patients should be advised that they should not take ramelteon tablets with or immediately after a high-fat meal.

• Do not break the tablet; it should be swallowed whole.

Lactation

Advise mothers using ramelteon tablets to monitor neonates for signs of somnolence and feeding problems. A lactating woman may consider pumping and discarding breast milk during treatment and for 25 hours after ramelteon administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)].

RX only

Manufactured By:

Dr. Reddy’s Laboratories LA LLC

Shreveport, LA 71106 USA

Distributed By:

Dr. Reddy’s Laboratories Inc.,

Princeton, NJ 08540 USA

Issued: 12/2021