Drug Interactions between clozapine and Kisqali Femara Co-Pack

MONITOR CLOSELY: Coadministration of clozapine with other agents that can cause granulocytopenia, neutropenia, or agranulocytosis (severe neutropenia) may increase the risk and/or severity of hematologic toxicity. Clozapine alone is associated with a significant risk of severe neutropenia, defined as an absolute neutrophil count (ANC) of less than 500/µL (0.5 x 10^9/L), and its development appears independent of dose and treatment duration. The exact mechanism by which clozapine leads to neutropenia is unknown; however, several test systems using animal bone marrow cells suggest that clozapine has a suppressant effect on cell division. Some authorities estimate the incidence of neutropenia and severe neutropenia from clozapine therapy at 3% and 0.7%, respectively, with more severe cases occurring during the first 18 to 26 weeks of treatment. Fatal cases of clozapine-induced neutropenia have been rarely reported, and the majority of these cases occurred prior to the recognition of the risk of clozapine-induced neutropenia and the need for routine blood monitoring during clozapine therapy.

MANAGEMENT: If clozapine is used concurrently with an agent known to cause neutropenia (e.g., antineoplastic drugs, some anticonvulsant and antirheumatic medications, albendazole, chloramphenicol, colchicine, dapsone, interferons, linezolid, pentamidine, procainamide, and zidovudine), consider monitoring patients more closely than the standard guidelines suggested in the product labeling. If a patient is receiving concomitant chemotherapy, the treating oncologist should be consulted. Some authorities consider this combination to be contraindicated.

MONITOR CLOSELY: Clozapine has the potential to prolong QT interval of the electrocardiogram. Theoretically, coadministration with other agents that can cause QT prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. Clozapine treatment alone has been associated with ventricular arrhythmia, torsade de pointes, cardiac arrest, and sudden death. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if clozapine is used in combination with other drugs that can prolong the QT interval. Serum electrolytes, including potassium, magnesium and calcium, should be measured at baseline and periodically during treatment, and any abnormalities corrected prior to initiating clozapine. Routine ECG assessment may detect QTc prolongation, but is not always effective in preventing arrhythmias. Clozapine treatment should be discontinued if the QTc interval exceeds 500 msec. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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.