Drug Interactions between asciminib and famotidine / ibuprofen

MONITOR: Coadministration with asciminib may increase the plasma concentrations of drugs that are primarily metabolized by the CYP450 2C9 isoenzyme. The mechanism is reduced clearance due to inhibition of CYP450 2C9 by asciminib. When warfarin, a probe substrate for CYP450 2C9, was coadministered with asciminib 40 mg twice daily, peak plasma concentration (Cmax) and systemic exposure (AUC) for the biologically more active S(-) enantiomer of warfarin increased by 8% and 41%, respectively. Likewise, the Cmax and AUC of S(-) warfarin increased by 4% and 52%, respectively, following coadministration with asciminib at 80 mg once daily, but increased by 7% and 314%, respectively, following coadministration with asciminib at 200 mg twice daily. These results suggest weak inhibition of CYP450 2C9 by asciminib at the lower dosages and moderate inhibition at the highest dosage.

MANAGEMENT: Caution is advised when asciminib is used concomitantly with drugs that are substrates of CYP450 2C9, 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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever asciminib is added to or withdrawn from therapy.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 avoiding concomitant use of asciminib with sensitive CYP450 2C9 substrates or certain substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If treatment with CYP450 2C9 substrate(s) is required, closely monitor for the development of adverse reactions and reduce dosage(s) as necessary in patients receiving asciminib therapy at 80 mg total daily dose. Consider alternative therapy with non-CYP450 2C9 substrates in patients receiving 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 moderate CYP450 2C9 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.

H2 antagonists may alter the pharmacokinetic disposition of some nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased or decreased plasma concentrations. Data have been varied, even for the same NSAID. The mechanism may involve inhibition of metabolism, changes in gastric pH resulting in altered absorption, and/or reduced urinary elimination of the affected NSAIDs. Statistically significant changes have been small and of limited clinical significance when interactions have been observed.