Drug Interaction Report

MONITOR: Coadministration with phenylbutyrate/taurursodiol (ursodoxicoltaurine) may alter the plasma concentrations of drugs that are substrates of CYP450 1A2, 2B6, and/or 3A4. Based on in vitro studies, phenylbutyrate/taurursodiol may decrease clearance via inhibition or increase clearance via induction of these isoenzymes, resulting in increased or decreased plasma concentrations of agents that are metabolized by one or more of these isoenzymes. Clinical and pharmacokinetic data are currently lacking.

MANAGEMENT: Caution is advised if phenylbutyrate/taurursodiol is used concomitantly with drugs that are substrates of CYP450 1A2, 2B6, and/or 3A4, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information for taurursodiol combined with sodium phenylbutyrate recommends avoiding coadministration with CYP450 1A2, 2B6, and/or 3A4 substrates for which minimal concentration changes may lead to therapeutic failure or serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever phenylbutyrate/taurursodiol is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of olaparib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a drug interaction study with 57 patients, mean olaparib systemic exposure (AUC) was increased approximately 2.7-fold by the potent CYP450 3A4 inhibitor itraconazole. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that a moderate inhibitor (fluconazole) may increase the AUC of olaparib by 2.2-fold. The interaction has not been studied with grapefruit juice. 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. Increased exposure to olaparib may increase the risk of adverse effects such as hematologic toxicity, nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain or discomfort.

MANAGEMENT: Food containing grapefruit, grapefruit juice, Seville orange (a citrus relative of the grapefruit), or Seville orange juice should be avoided during treatment with olaparib. Some authorities also recommend avoiding starfruit (carambola) and pomegranate.

ADJUST DOSING INTERVAL: Coadministration with a high-fat meal may reduce the rate and extent of absorption of sodium phenylbutyrate. When a single 3 g-1 g dose of sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine) was administered to healthy volunteers in the presence of a high-fat, high-calorie meal (approximately 800 to 1000 calories; 500 to 600 calories from fat, 250 calories from carbohydrate, 150 calories from protein), sodium phenylbutyrate peak plasma concentration (Cmax) decreased by 75% and systemic exposure (AUC) decreased by 55%. The Cmax for taurursodiol was not significantly affected, but AUC was increased by 46%. The clinical significance of these changes has not been established. In premarketing studies, patients were advised to take the drug before a meal.

MANAGEMENT: The prescribing information recommends administration of sodium phenylbutyrate-taurursodiol before a meal or snack, particularly in patients of low body weight (less than 70 kg).