Drug Interaction Report

ADJUST DOSE: Coadministration with potent CYP450 3A4 inducers may decrease the systemic exposure and efficacy of pitolisant. The proposed mechanism is induction of CYP450 3A4-mediated metabolism of pitolisant, which has been shown to be metabolized by this isoenzyme. Concomitant use with the potent CYP450 3A4 inducer rifampin decreased the mean peak plasma concentration (Cmax) and area under the plasma concentration-time curve ratio (AUC ratio) by 39% and 50%, respectively.

MANAGEMENT: Patients should be assessed for loss of efficacy of pitolisant following initiation of a potent CYP450 3A4 inducer, and the pitolisant dosage adjusted as necessary. For patients already receiving a stable dose of pitolisant 8.9 mg or 17.8 mg once daily, the dose of pitolisant should be increased to double the original daily dose (i.e., 17.8 mg or 35.6 mg, respectively) over 7 days. The dosage of pitolisant should be reduced by half if concomitant use of a strong CYP450 3A4 inducer is discontinued.

GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.