Drug Interaction Report

GENERALLY AVOID: Coadministration of idelalisib with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. The use of idelalisib has been associated with elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the upper limit of normal. Serious and fatal hepatotoxicity occurred in 14% of patients treated with idelalisib in premarketing trials. Liver enzyme elevations were generally observed within the first 12 weeks of treatment and were reversible with dose interruption. Following treatment resumption at a lower dose, 26% of patients had recurrence of ALT and AST elevations.

GENERALLY AVOID: Coadministration of ribociclib with a drug that is both a substrate as well as inhibitor of CYP450 3A4, such as idelalisib, may result in increased plasma concentrations of both drugs. Ribociclib itself is also a substrate and moderate inhibitor of CYP450 3A4. Theoretically, competitive and/or noncompetitive metabolic inhibition may occur. In healthy volunteers, administration of a single 400 mg dose of idelalisib with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 4 days) resulted in a 1.8-fold increase in mean idelalisib systemic exposure (AUC). In healthy subjects, administration of a single 400 mg dose of ribociclib with ritonavir (100 mg twice daily for 14 days), a potent CYP450 3A4 inhibitor, resulted in a 1.7-fold and 3.2-fold increase in ribociclib peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to ribociclib administered alone. In addition, administration of erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase ribociclib Cmax and AUC by 1.3-fold and 1.9-fold, respectively. Because ribociclib 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. In addition, with increasing levels of ribociclib, the risk of other adverse effects such as infections, neutropenia, leucopenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, stomatitis, anorexia, alopecia, fatigue, headache, and abnormal liver function may also be increased.

MANAGEMENT: Concomitant use of ribociclib with potent CYP450 3A4 inhibitors, such as idelalisib, should generally be avoided. Alternative agents with no or minimal CYP450 3A4 inhibitory potential are recommended whenever possible. If no alternatives exist, the dose of ribociclib should be reduced to 400 mg once daily. Following discontinuation of the potent CYP450 3A4 inhibitor, the ribociclib dosage should be returned (after at least 5 half-lives of the inhibitor) to that used prior to initiation of the inhibitor. Likewise, clinical and/or laboratory monitoring may be appropriate for idelalisib following the addition or withdrawal of ribociclib, and the dosage adjusted as necessary. The use of idelalisib with other potentially hepatotoxic agents should be avoided whenever possible. In addition, if these agents are CYP450 3A4 inhibitors they may increase the toxicity of idelalisib. Caution is advised if coadministration is required. Patients should be closely monitored for hepatotoxicity and other toxicities of idelalisib such as diarrhea, colitis, intestinal perforation, pneumonitis, neutropenia and thrombocytopenia, and the dosing adjusted or interrupted as necessary. Patients should have serum ALT, AST, and bilirubin measured prior to initiation of treatment and regularly during treatment in accordance with the product labeling. Permanent discontinuation of idelalisib is recommended in those who experience recurrent hepatotoxicity following dosage reduction. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

GENERALLY AVOID: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.