Drug Interaction Report

Coadministration with mild or moderate inhibitors of CYP450 3A4 may modestly increase the plasma concentrations of ruxolitinib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of a single 10 mg dose of ruxolitinib following pretreatment with the moderate CYP450 3A4 inhibitor erythromycin (500 mg twice daily for four days) resulted in an 8% increase in ruxolitinib peak plasma concentration (Cmax) and a 27% increase in systemic exposure (AUC) compared to administration of ruxolitinib alone. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding exposure information. No dosage adjustment is recommended when ruxolitinib is coadministered with mild or moderate CYP450 3A4 inhibitors. However, clinical data for topical ruxolitinib are not available. Consultation with individual package labeling, as well as relevant institutional protocols, may be advisable for further guidance.

ADJUST DOSING INTERVAL: Administration of lomitapide with food may increase the risk of common gastrointestinal adverse reactions such as diarrhea, nausea, vomiting, dyspepsia, abdominal pain or discomfort, abdominal distension, constipation, and flatulence. Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of lomitapide. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Weak CYP450 3A4 inhibitors can increase lomitapide exposure (AUC) by approximately 2-fold according to the product labeling. Ketoconazole, a potent CYP450 3A4 inhibitor, has been shown to increase lomitapide AUC by 27-fold .

GENERALLY AVOID: Coadministration with alcohol may increase the risk of hepatotoxicity associated with the use of lomitapide. In a premarketing clinical trial, 34% (10/29) of patients treated with lomitapide had at least one elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3 times the upper limit of normal (ULN) or greater, and 14% (4/29) had at least one elevation in ALT or AST 5 times ULN or greater. There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or alkaline phosphatase. Lomitapide also increases hepatic fat, with or without concomitant increases in transaminases. In the same study, the median absolute increase in hepatic fat was 6% after both 26 and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy. Hepatic steatosis associated with lomitapide may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with lomitapide, although the long-term consequences are unknown.

MANAGEMENT: Lomitapide should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal. Strict adherence to a low-fat diet (<20% of total calories from fat) and gradual dosage titration may also help to reduce gastrointestinal intolerance. Patients should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract during treatment with lomitapide. Since alcohol may increase levels of hepatic fat and induce or exacerbate liver injury, the manufacturer recommends that patients taking lomitapide not consume more than one alcoholic drink per day.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ruxolitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients treated with ruxolitinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ruxolitinib may be administered with or without food.