Ramelteon: uses, dosing, side effects & brands

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 Granules Pharmaceuticals Inc., at 1-877-770-3183 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…

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)

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 tablets 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 and metabolite M-II. Efficacy may be reduced when ramelteon tablets are 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 increased by approximately 84% and 36% upon coadministration of ketoconazole with ramelteon. 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 was increased by approximately 150% when ramelteon 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. Patients should be closely monitored when ramelteon tablets are 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. Patients should be closely monitored when ramelteon tablets are 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 tablets [see Clinical Pharmacology (12.5) ]. Use of the products in combination may have an additive effect. 7.3 Drug/Laboratory Test Interactions Ramelteon tablets are 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.