ers. Finally, crizotinib is primarily metabolized by CYP3A4/5 and ribociclib is a moderate CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of crizotinib (single dose) by 3.2-fold and 1.4-fold, respectively; moderate CYP3A4 inhibitors may also increase crizotinib exposure. The effect of CYP3A4 inhibitors on steady-state crizotinib exposure has not been eva luated.
Cyclobenzaprine: (Major) Avoid coadministration of ribociclib with cyclobenzaprine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of cyclobenzaprine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Cyclobenzaprine is associated with a possible risk of QT prolongation and TdP, particularly in the event of acute overdose. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and cyclobenzaprine is a CYP3A4 substrate in vitro.
Cyclophosphamide: (Moderate) Use caution if coadministration of ribociclib with cyclophosphamide is necessary, as the systemic exposure of cyclophosphamide may be altered, affecting either efficacy or toxicity. The clinical significance of this interaction is unknown. Ribociclib is a moderate CYP3A4 inhibitor. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. It is not yet completely clear what effect inhibitors of CYP2B6 or CYP3A4 have on the activation and/or toxicity of cyclophosphamide; it has been postulated that the use of CYP3A4 inhibitors might attenuate neurotoxic effects of the drug in some patients, but no clinically reliable data are available to support this hypothesis. In vitro, coadministration with a CYP3A4 inhibitor had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with both strong and moderate CYP3A4 inhibitors in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
Cyclosporine: (Moderate) Use caution if coadministration of ribociclib with cyclosporine is necessary, as the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions including neutropenia and QT prolongation. Monitor cyclosporine concentrations and adjust the dose of cyclosporine if necessary. Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; cyclosporine is a moderate CYP3A4 inhibitor and a CYP3A4 substrate with a narrow therapeutic window. .
Dabrafenib: (Major) Coadministration of ribociclib and dabrafenib may decrease exposure to ribociclib. If another agent cannot be substituted and coadministration of these agents is unavoidable, closely monitor for a decreased response to ribociclib. The systemic exposure of dabrafenib may also increase resulting in an increase of treatment-related adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; dabrafenib is a CYP3A4 inducer and a substrate of CYP3A4 and CYP2 |
