Drug Interactions between idelalisib and Kisqali Femara Co-Pack

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: Coadministration with idelalisib may increase the plasma concentrations of drugs that are substrates of CYP450 3A4. Idelalisib has been shown to be a potent inhibitor of this isoenzyme. In healthy volunteers, administration of a single 5 mg dose of midazolam, a CYP450 3A4 probe substrate, with idelalisib 150 mg for 15 doses increased mean midazolam peak plasma concentration (Cmax) by 2.4-fold and systemic exposure (AUC) by 5.4-fold.

MANAGEMENT: Use of idelalisib should generally be avoided with drugs that are primarily metabolized by CYP450 3A4, particularly those with a narrow therapeutic range (e.g., antiarrhythmics, anticonvulsants, antineoplastics, immunosuppressants) or those that are considered sensitive substrates (e.g., ergot derivatives, statins, oral midazolam, triazolam). Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever idelalisib is added to or withdrawn from therapy, if coadministration is required.

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.