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 )

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 .

8.1 Pregnancy Risk Summary Available data from post marketing reported 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) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

5 WARNINGS AND PRECAUTIONS • Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.1) • Need to evaluate for comorbid diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment. (5.2) • Abnormal thinking, behavioral changes, complex behaviors: May include "sleep-driving" and hallucinations. Immediately evaluate any new onset behavioral changes. (5.3) • Depression: Worsening of depression or suicidal thinking may occur. (5.3) • CNS effects: Potential impairment of activities requiring complete mental alertness such as operating machinery or driving a motor vehicle, after ingesting the drug. (5.4) • Reproductive effects: Include decreased testosterone and increased prolactin levels. 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.