Ramelteoninteractions

Rifampin (strong CYP enzyme inducer): Decreases exposure to and effects of ramelteon. Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution. Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution.

Donepezil: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is co-administered with donepezil.

Doxepin: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is co-administered with doxepin.

Alcohol: Causes additive psychomotor impairment; should not be used in combination.

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 Tablets, 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. 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. 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 Tablets. Ramelteon Tablets should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole. Fluconazole (strong CYP2C9 inhibitor) The AUC 0-inf and C max of ramelteon was increased by approximately 150% when Ramelteon Tablets were coadministered with fluconazole. Ramelteon Tablets should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole. 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 are coadministered with donepezil. 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 are coadministered with doxepin.

7.2 Effect of

Alcohol on Ramelteon Tablets Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of Ramelteon Tablets is to promote sleep, patients should be cautioned not to consume alcohol when using Ramelteon Tablets. 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.

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 Tablets, 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. 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. 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 Tablets. Ramelteon Tablets should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole. Fluconazole (strong CYP2C9 inhibitor) The AUC 0-inf and C max of ramelteon was increased by approximately 150% when Ramelteon Tablets were coadministered with fluconazole. Ramelteon Tablets should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole. 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 are coadministered with donepezil. 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 are coadministered with doxepin.

7.2 Effect of

Alcohol on Ramelteon Tablets Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of Ramelteon Tablets is to promote sleep, patients should be cautioned not to consume alcohol when using Ramelteon Tablets. 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.

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 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. 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 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 are used in combination with strong CYP enzyme inducers such as rifampin. Ketoconazole (strong CYP3A4 inhibitor) AUC 0-inf and C max of ramelteon 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 Tablets 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. 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 Tablets should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole. Donepezil Administration of donepezil 10 mg once daily for 26 days resulted in a mean increase of approximately 100% in overall exposure to ramelteon, (AUC 0-inf ) and a mean increase of approximately 87% in maximum exposure to ramelteon (C max ) after a single 8 mg dose of Ramelteon Tablets. No change was seen in M-II exposure. Patients should be closely monitored when Ramelteon Tablets is coadministered with donepezil. Doxepin Administration of doxepin 10 mg once daily for 23 days resulted in a mean increase of approximately 66% in overall exposure to ramelteon, (AUC 0-inf ) and a mean increase of approximately 69% in maximum exposure to ramelteon (Cmax ) after a single 8 mg dose of Ramelteon Tablets. No change was seen in M-II exposure. Patients should be closely monitored when Ramelteon Tablets is coadministered with doxepin. 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 Tablets.