Drug Interactions between mitotane and Zepzelca

GENERALLY AVOID: Grapefruit and Seville oranges may increase the plasma concentrations of lurbinectedin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit or Seville oranges, but pharmacokinetic data are available for potent and moderate CYP450 3A4 inhibitors. In a clinical drug interaction study, coadministration of itraconazole, a potent CYP450 3A4 inhibitor, increased the systemic exposure (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4-fold. In a Phase 1 study, coadministration of aprepitant, a moderate CYP450 3A4 inhibitor, decreased lurbinectedin plasma clearance by 33% compared to lurbinectedin alone. In general, the effect of grapefruit and Seville oranges is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice and Seville oranges (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 may increase the incidence and severity of adverse reactions of lurbinectedin, such as myelosuppression and hepatotoxicity.

MANAGEMENT: Patients should avoid consumption of grapefruit, grapefruit juice, and Seville oranges during treatment with lurbinectedin.

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.