Drug Interaction Report

MONITOR CLOSELY: Coadministration with potent CYP450 3A4 inhibitors may increase the plasma concentrations and effects of unconjugated DM4, the microtubule inhibitor component of mirvetuximab soravtansine. Mirvetuximab soravtansine is a folate receptor alpha (FR-alpha)-directed antibody-drug conjugate (ADC) that releases DM4 via proteolytic cleavage, and DM4 has been shown to be primarily metabolized by CYP450 3A4. Increased concentrations of unconjugated DM4 may increase the risk of adverse effects including ocular toxicity (e.g., visual impairment, corneal disorders, dry eye, photophobia, eye pain, and uveitis), pneumonitis, and peripheral neuropathy. Clinical data are not available. Other, less potent CYP450 3A4 inhibitors are not expected to interact.

MANAGEMENT: Caution is recommended if mirvetuximab soravtansine is administered in combination with potent CYP450 3A4 inhibitors. Close monitoring for adverse reactions including ocular toxicity, pneumonitis, and peripheral neuropathy is advised. Mirvetuximab soravtansine treatment may need to be discontinued, interrupted, or dosage reduced in patients with serious or life-threatening toxicities in accordance with the product labeling. Alternative treatment that does not interfere with mirvetuximab soravtansine metabolism should be considered whenever possible.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ceritinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ceritinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death. Other, more common side effects such as diarrhea, nausea, vomiting, abdominal pain, hyperglycemia, and bradycardia may also increase.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ceritinib. The mechanism of interaction is unknown. Compared to the fast state, administration of a single 500 mg dose of ceritinib with a high-fat meal (approximately 1000 calories; 58 grams of fat) increased ceritinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 41% and 73%, respectively, and administration with a low-fat meal (approximately 330 calories; 9 grams of fat) increased ceritinib Cmax and AUC by 43% and 58%, respectively. A dose of 600 mg or higher taken with a meal is expected to produce systemic exposure exceeding that from a 750 mg dose taken in the fasted state, which may lead to increased adverse effects.

MANAGEMENT: Patients treated with ceritinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ceritinib should be administered on an empty stomach (i.e., avoid administration within 2 hours of a meal).