Drug Interactions between asciminib 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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

MONITOR: Coadministration with asciminib may increase the plasma concentrations of drugs that are primarily metabolized by the CYP450 3A4 isoenzyme. The mechanism is reduced clearance due to inhibition of CYP450 3A4 by asciminib. When midazolam, a sensitive CYP450 3A4 substrate, was coadministered with asciminib 40 mg twice daily, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 11% and 28%, respectively. Likewise, the Cmax and AUC of midazolam increased by 17% and 24%, respectively, following coadministration with asciminib at 80 mg once daily, but increased by 58% and 88%, respectively, following coadministration with asciminib at 200 mg twice daily. These results suggest weak inhibition of CYP450 3A4 by asciminib.

MANAGEMENT: Caution is advised when asciminib is used concomitantly with drugs that are substrates of CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever asciminib is added to or withdrawn from therapy. The prescribing information recommends closely monitoring for the development of adverse reactions in patients receiving asciminib therapy at 80 mg total daily dose with certain CYP450 3A4 substrates where minimal concentration changes may lead to serious or life-threatening toxicities, and avoiding coadministration of these drugs with asciminib at the maximum recommended dosage of 200 mg twice daily. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a weak CYP450 3A4 inhibitor like asciminib and for any dosage adjustments that may be required.

MONITOR: It is uncertain whether asciminib causes clinically significant prolongation of the QT interval of the electrocardiogram. In clinical studies, prolongation of the Fridericia-corrected QT interval (QTcF) was reported in 3 of 356 (0.8%) of patients, with one report of QTcF greater than 500 msec together with more than 60 msec QTcF increase from baseline. Asciminib is not reported to prolong the corrected QT (QTc) interval by greater than 20 msec at the maximum recommended clinical dosage (200 mg twice daily); however, a prolongation of up to 10 msec cannot be excluded. 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, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Some authorities recommend caution and clinical monitoring when asciminib is used with drugs that are known to cause QT interval prolongation. An ECG should be obtained at baseline and during treatment as clinically indicated, particularly in patients with a history of cardiac arrhythmias, uncontrolled or significant cardiac disease (including bradycardia), or congenital or family history of long QT syndrome. Serum electrolytes, including potassium and magnesium should also be corrected prior to starting asciminib therapy and monitored during treatment as clinically indicated. Patients should be advised to seek prompt medical attention if they experience symptoms that indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.