Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 1A2 and/or 3A4 may increase the plasma concentrations of tasimelteon, which is primarily metabolized by these isoenzymes. When tasimelteon was administered after 6 days of treatment with the potent CYP450 1A2 inhibitor fluvoxamine 50 mg/day, tasimelteon peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2- and 7-fold, respectively, compared to tasimelteon administered alone. When administered after 5 days of treatment with the potent CYP450 3A4 inhibitor ketoconazole 400 mg/day, tasimelteon AUC increased by approximately 50%.

MANAGEMENT: Caution is advised if tasimelteon is prescribed in combination with inhibitors of CYP450 1A2 and/or 3A4. Patients should be monitored for excessive sedation and other side effects.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of tasimelteon. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: Food may delay the absorption and onset of action of tasimelteon. According to the product labeling, administration of tasimelteon with a high-fat meal decreased peak plasma concentration (Cmax) by 44% and delayed the median time to reach Cmax by approximately 1.75 hours compared to administration in the fasted state.

MONITOR: Smoking induces CYP450 1A2 and may reduce the plasma concentrations of tasimelteon, which is metabolized by the isoenzyme. According to the product labeling, tasimelteon systemic exposure was approximately 40% lower in smokers than in nonsmokers.

MANAGEMENT: Patients receiving tasimelteon should be advised to avoid or limit consumption of alcohol. Tasimelteon should be taken without food. Patients who smoke may have a reduced therapeutic response to tasimelteon.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.