Drug Interactions between clofarabine and Kisqali Femara Co-Pack

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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.