rinciple enzyme that metabolizes S-warfarin and modulates the in vivo activity of warfarin is CYP2C9. However, CYP1A2 and CYP3A4, and to a lesser extent CYP2C19, metabolize the R-isomer which has less anticoagulant activity and slower clearance.
Yohimbine: (Moderate) Use caution if coadministration of ribociclib with yohimbine is necessary, as the systemic exposure of yohimbine may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a CYP3A4 inhibitor and yohimbine is a CYP3A4 substrate.
Zafirlukast: (Moderate) Use caution if coadministration of ribociclib with zafirlukast is necessary, as the systemic exposure of ribociclib may be increased resulting in an increase in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is extensively metabolized by CYP3A4. Zafirlukast is a weak CYP3A4 inhibitor in vitro.
Ziprasidone: (Severe) Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsade de pointes (TdP) including ribociclib. Systemic exposure of ziprasidone 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. Ziprasidone has also been associated with a possible risk for QT prolongation and TdP. Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and ziprasidone is a CYP3A4 substrate.
Zolpidem: (Moderate) Use caution if coadministration of ribociclib with zolpidem is necessary, as the systemic exposure of zolpidem may be increased resulting in increase in treatment-related adverse reactions; adjust the dose of zolpidem if necessary. Ribociclib is a moderate CYP3A4 inhibitor and zolpidem is a CYP3A4 substrate.
PREGNANCY AND LACTATION
Pregnancy
Avoid use of ribociclib; letrozole during pregnancy and for at least 3 weeks after the last dose. The product label of letrozole (single ingredient) contraindicated use in pregnancy. Although there are no available human data, both ribociclib and letrozole can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving ribociclib; letrozole should be apprised of the potential hazard to the fetus.
When given to pregnant rats at exposures approximately 0.6 times what would be achieved at the recommended human dose, reduced maternal body weight gain and reduced fetal weights were accompanied by skeletal changes related to the lower fetal weights. Increased incidences of fetal abnormalities (malformations and external, visceral, and skeletal variants) as well as lower fetal weights occurred in rabbits treated at exposures of 1.5 times what would be achieved at the recommended human dose; there was no maternal toxicity at this dose. Fetal abnormalities included reduced/small lung lobes, additional vessel on the descending aorta |
