Drug Interaction Report

GENERALLY AVOID: The liver is a known target organ for clofarabine toxicity, and concomitant use of other potentially hepatotoxic agents may increase the risk of liver injury. Severe and fatal hepatotoxicity has occurred with the use of clofarabine alone. In clinical studies, grade 3 to 4 liver enzyme elevations were frequently observed in pediatric patients during treatment, with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations reported in 36% and 44% of patients, respectively. Liver enzyme elevations typically occurred within 10 days of clofarabine administration and returned to grade 2 or lower within 15 days. Grade 3 or 4 bilirubin elevations occurred in 13% of patients, with 2 cases reported as grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation and the other in multi-organ failure and death. Eight patients (7%) had grade 3 or 4 elevations in serum bilirubin at the last time point measured, all of whom died due to sepsis and/or multi-organ failure.

MANAGEMENT: Concomitant use of clofarabine with other potentially hepatotoxic agents should be avoided whenever possible (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Hepatic function should be monitored during clofarabine administration, and therapy discontinued if grade 3 to 4 liver enzyme or bilirubin elevations occur. 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: Grapefruit juice may increase the plasma concentrations of panobinostat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to panobinostat may increase the risk of adverse effects such as nausea, vomiting, diarrhea, anorexia, peripheral edema, cardiotoxicity, ECG abnormalities, electrolyte disturbances, bleeding complications, hepatotoxicity, and myelosuppression.

Food may delay the rate of absorption of panobinostat, but does not significantly affect the overall extent of absorption. When a single oral dose of panobinostat was administered to 36 patients with advanced cancer 30 minutes after a high-fat meal, panobinostat peak plasma concentration (Cmax) and systemic exposure (AUC) were approximately 44% and 16% lower, respectively, compared to administration under fasting conditions. The median time to maximum concentration (Tmax) was prolonged by 2.5 hours.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice during treatment with panobinostat. The manufacturer also recommends avoiding star fruit, Seville oranges, pomegranate, and pomegranate juice. Panobinostat may be administered with or without food.