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: The risk and/or severity of diarrhea may be increased when idelalisib is used with other agents that cause diarrhea. In premarketing trials, serious and fatal diarrhea or colitis (Grade 3 or higher) occurred in 14% of patients receiving idelalisib. Diarrhea may occur at any time and responds poorly to antimotility agents. The median time to resolution across trials ranged from one week to one month following interruption of idelalisib therapy and, in some instances, use of corticosteroids. Serious and fatal intestinal perforation has also been reported with idelalisib. At the time of perforation, some patients had moderate to severe diarrhea.

MANAGEMENT: The use of idelalisib with other agents that can induce hepatotoxicity and/or diarrhea should be avoided whenever possible. Patients treated with idelalisib should be monitored for development of severe diarrhea or colitis and have serum ALT, AST, and bilirubin measured prior to initiation of treatment and regularly during treatment in accordance with the product labeling, and the dosing adjusted or interrupted as necessary. Permanent discontinuation of idelalisib is recommended in those who experience recurrent hepatotoxicity following dosage reduction and/or life-threatening diarrhea or intestinal perforation. 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. Patients should also contact their physician immediately if the number of bowel movements per day increases by six or more, or if they have new or worsening abdominal pain, chills, fever, nausea, or vomiting.

GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice. If coadministration is unavoidable, monitor for prolonged and/or increased pharmacologic effects of imatinib, including edema, hematologic toxicity and immunosuppression.