Drug Interactions between adagrasib and famotidine / ibuprofen

MONITOR: Coadministration with adagrasib may increase the plasma concentrations of drugs that are metabolized by the CYP450 3A4, 2D6 or 2C9 enzymatic pathways or are substrates of the P-glycoprotein (P-gp) efflux membrane transporter. When adagrasib 400 mg twice daily (two-thirds the approved recommended dosage) was administered with midazolam (a sensitive CYP450 3A4 substrate) and dextromethorphan (a sensitive CYP450 2D6 substrate) in pharmacokinetic studies, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.8- and 21-fold, respectively, while dextromethorphan Cmax and AUC increased by 1.9- and 1.8-fold, respectively. Adagrasib at the approved recommended dosage of 600 mg twice daily is predicted to increase midazolam Cmax by 3.1-fold and AUC by 31-fold; dextromethorphan Cmax by 1.7-fold and AUC by 2.4-fold; warfarin (a sensitive CYP450 2C9 substrate) Cmax by 1.1-fold and AUC by 2.9-fold; and digoxin (a P-gp substrate) Cmax by 1.9-fold and AUC by 1.5-fold. These results suggest that adagrasib is a potent inhibitor of CYP450 3A4 and may be a moderate inhibitor of CYP450 2D6 and 2C9 at the approved recommended dosage of 600 mg twice daily.

MANAGEMENT: Caution is advised when adagrasib is used concomitantly with drugs that are substrates of CYP450 3A4, CYP450 2D6, CYP450 2C9 and/or P-gp, particularly sensitive substrates or those with a narrow therapeutic range. Substitution for these medications is recommended when possible, or initiate with lower dosages and monitor patient clinical response/tolerance and titrate accordingly if coadministration is required. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

MONITOR: Famotidine may cause QTc prolongation. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. According to the manufacturer, prolongation of the QT interval has been reported very rarely in patients with impaired renal function whose dose/dosing interval of famotidine may not have been adjusted appropriately. In general, the risk of an individual agent or a combination of these 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 and clinical monitoring are recommended if famotidine is used in combination with other drugs that can prolong the QT interval. 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.

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.