Drug Interaction Report

MONITOR: Coadministration of glycerol phenylbutyrate may lead to increased concentrations of CYP450 2D6 substrates. The proposed mechanism is inhibition of CYP450 2D6 by phenylbutyrate, the active moiety of glycerol phenylbutyrate, which has been shown to be an in vitro inhibitor of this isoenzyme. In in vitro studies, administration of phenylbutyrate at a concentration of 800 mcg/mL caused greater than 60% reversible inhibition of CYP450 2D6, 2C9, and 3A4/5. The clinical significance of these results has not been established; however, the manufacturer states that a potential interaction with CYP450 2D6 substrates cannot be ruled out.

MANAGEMENT: Caution is recommended if glycerol phenylbutyrate is administered with medicines that are substrates of CYP450 2D6, such as codeine, dextromethorphan, and some beta blockers (including metoprolol, carvedilol, labetalol, propranolol, and nebivolol). Dosage adjustments as well as clinical and laboratory monitoring may be appropriate.

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

Administration with food may increase the bioavailability of paliperidone from the extended release tablets. In healthy ambulatory subjects, administration of a 12 mg paliperidone extended release tablet with a standard high-fat/high-caloric meal resulted in 60% and 54% increases, respectively, in the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of paliperidone compared to administration under fasting conditions. The clinical significance of these changes is unknown.

MANAGEMENT: Patients receiving paliperidone should be advised to avoid the consumption of alcohol. Since clinical trials establishing the safety and efficacy of paliperidone were carried out without regard to the timing of meals, presumably paliperidone may be administered with or without food.