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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 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 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 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 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.

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%

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-inffor ramelteon increased approximately 190-fold, and the C maxincreased 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-infand C maxof 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-infand C maxof 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-infand C maxof 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-infand C maxof 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 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 vitrodata 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.

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 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)].

9 DRUG ABUSE AND DEPENDENCE

Ramelteon tablets are 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 [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.

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.

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/m 2).

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/m 2.

Mutagenesis

Ramelteon was not genotoxic in the in vitrobacterial reverse mutation (Ames) assay, the in vitromouse lymphoma TK +/-assay, and in in vivooral micronucleus assays in mouse and rat. Ramelteon was clastogenic in the in vitrochromosomal 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.

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/m 2. Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.