Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate to potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations and pharmacologic effects of leniolisib. The proposed mechanism is accelerated clearance of leniolisib due to induction of the CYP450 3A4 isoenzyme, which is the primary route of elimination of leniolisib. Pharmacokinetic-based physiologic modeling predicts that concomitant use of leniolisib with the potent CYP450 3A4 rifampin or moderate CYP450 3A4 inducer efavirenz may decrease the systemic exposure (AUC 0-12h) of leniolisib by 78% and 58%, respectively. Loss of therapeutic efficacy may occur; however, clinical data are not available.

MANAGEMENT: The use of leniolisib with moderate to potent CYP450 3A4 inducers should generally be avoided. Alternative therapeutic agents with less enzyme induction potential should be considered whenever possible.

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

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

MONITOR: Coadministration with inhibitors of CYP450 3A4 including grapefruit or grapefruit juice may increase the plasma concentrations of leniolisib, which undergoes extensive CYP450 3A4-mediated first-pass metabolism in the gut wall and liver. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of leniolisib. Some authorities recommend to avoid grapefruit products during leniolisib treatment (UK).