Drug Interactions between mitotane and Sohonos

GENERALLY AVOID: Grapefruit, pomelo, grapefruit hybrids, and juices or supplements containing these fruits may increase the plasma concentrations of palovarotene. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with these fruits. Concomitant use of erythromycin, a moderate CYP450 3A4 inhibitor, with palovarotene at steady-state plasma levels increased its peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.6 and 2.5-fold, respectively. 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 concentrations of palovarotene may increase the risk of adverse effects such as dry skin, dry lips, alopecia, pruritus, erythema, paronychia, cellulitis, decubitus ulcer, xerophthalmia, night blindness, depression, mood alterations, and pseudotumour cerebri (benign intracranial hypertension).

ADJUST DOSE: Food increases oral absorption of palovarotene.

MANAGEMENT: The manufacturer advises that concomitant use of palovarotene with grapefruit, pomelo, grapefruit hybrids and juices or supplements containing these fruits should be avoided. To ensure maximal absorption, palovarotene should be administered with food.

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.