Drug Interaction Report

ADJUST DOSE: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of aripiprazole and its active metabolite, dihydro-aripiprazole. Clinical and in vitro data indicate that aripiprazole is extensively metabolised in the liver primarily via three enzymatic pathways (dehydrogenation, hydroxylation, and N-dealkylation) mediated by CYP450 2D6 and 3A4. When aripiprazole 30 mg once daily was coadministered with the potent CYP450 3A4 inducer carbamazepine at 200 mg twice daily in schizophrenic patients, mean aripiprazole peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 68% and 73%, respectively, compared to administration of aripiprazole alone. Likewise, mean Cmax and AUC of dihydro-aripiprazole were decreased by 69% and 71%, respectively, in the presence of carbamazepine. Reduced efficacy of aripiprazole may occur. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: When aripiprazole is administered orally, the prescribing information recommends doubling the usual dosage over 1 to 2 weeks following the addition of a potent CYP450 3A4 inducer. Additional dosage adjustments should be based on clinical evaluation. Upon discontinuation of the inducer, aripiprazole dosage should be reduced to the original level over 1 to 2 weeks. When given as an immediate-acting intramuscular injection, the aripiprazole dosage should also be doubled in patients receiving potent CYP450 3A4 inducers. For patients receiving extended-release intramuscular formulations of aripiprazole, concomitant use of potent CYP450 3A4 inducers should generally be avoided for greater than 14 days, although some formulations may be administered, with or without a dosage adjustment depending on the dose. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The prescribing information for individual aripiprazole products should be consulted for specific recommendations regarding concomitant use with potent CYP450 3A4 inducers.

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GENERALLY AVOID: An isolated case report suggests that foods containing large amounts of tyramine may precipitate a hypertensive crisis in patients treated with St. John's wort. The mechanism of interaction is unknown, as St. John's wort is not thought to possess monoamine oxidase (MAO) inhibiting activity at concentrations achieved in vivo. The case patient was a 41-year-old man who had been taking St. John's wort for seven days prior to presentation at the emergency room with confusion and disorientation. The patient recalled last eating aged cheese and having a glass of red wine approximately 10 hours prior to admission. No other cause of delirium or hypertension could be identified. In addition, alcohol may potentiate some of the pharmacologic effects of St. John's wort. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Until further information is available, patients treated with St. John's wort should consider avoiding consumption of protein foods in which aging or breakdown of protein is used to increase flavor. These foods include cheese (particularly strong, aged or processed cheeses), sour cream, wine (particularly red wine), champagne, beer, pickled herring, anchovies, caviar, shrimp paste, liver (particularly chicken liver), dry sausage, figs, raisins, bananas, avocados, chocolate, soy sauce, bean curd, yogurt, papaya products, meat tenderizers, fava beans, protein extracts, and dietary supplements. Caffeine may also precipitate hypertensive crisis so its intake should be minimized as well. Patients should also be advised to avoid or limit consumption of alcohol.

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

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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