Drug Interactions between mitotane and Tazverik

GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during tazemetostat therapy may significantly increase the plasma concentrations of tazemetostat. The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism of tazemetostat by certain compounds in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). According to the product labeling, coadministration of tazemetostat (400 mg twice daily) with the moderate CYP450 3A4 inhibitor fluconazole increased the tazemetostat steady state exposure (AUC 0 to 8 hours) by 3.1-fold and peak plasma concentration by 2.3-fold. 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. Clinically, this interaction may result in an increased risk of the frequency or severity of adverse reactions due to tazemetostat such as hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.

MANAGEMENT: The manufacturer advises that patients treated with tazemetostat should avoid consumption of grapefruit or grapefruit juice.

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ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.

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