Drug Interactions between adagrasib and Meprozine

GENERALLY AVOID: Adagrasib can cause concentration-dependent, prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias including torsade de pointes and sudden death. According to cardiac electrophysiology data provided by the manufacturer, the mean (90% CI) QTcF change from baseline was 18 ms at the mean steady-state maximum concentration (Cmax,ss) after administration of adagrasib 600 mg twice daily. 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).

GENERALLY AVOID: Adagrasib may increase the plasma concentrations and adverse effects of sensitive CYP450 2C9, 2D6 or P-glycoprotein (P-gp) substrates. Adagrasib is an inhibitor of CYP450 2C9, 2D6, and P-gp. In pharmacokinetic studies, adagrasib 600 mg twice daily is predicted to increase warfarin (a sensitive CYP450 2C9 substrate) peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.1-fold and 2.9-fold, respectively. Also, adagrasib 600 mg twice daily is predicted to increase dextromethorphan (a sensitive CYP450 2D6 substrate) Cmax and AUC by 1.7-fold and 2.4-fold, respectively. In addition, adagrasib 600 mg twice daily is predicted to increase digoxin (a P-gp substrate) Cmax and AUC by 1.9-fold and 1.5-fold, respectively.

MANAGEMENT: Coadministration of adagrasib with other drugs that can prolong the QT interval and/or are sensitive substrates of CYP450 2C9, 2D6 or P-gp should generally be avoided.

ADJUST DOSE: The central nervous system and respiratory depressant effects of meperidine may be potentiated by concomitant use of other agents with CNS depressant effects. An increased risk of serious adverse reactions such as respiratory depression, hypotension, profound sedation, syncope, coma, and even death should be considered, particularly in elderly or debilitated patients.

MANAGEMENT: Caution and dosage adjustments are advisable when meperidine is used in combination with other narcotic analgesics, general anesthetics, phenothiazines, sedative-hypnotics, tranquilizers, tricyclic antidepressants, or other CNS depressants such as alcohol. A lower dosage of meperidine should be considered initially, then titrated carefully according to pain level and clinical response. Meperidine dosage reductions of 25% to 50% have been recommended for patients receiving phenothiazines and other tranquilizers. Patients should be advised to avoid rising abruptly from a sitting or recumbent position, and to notify their physician if they experience dizziness, lightheadedness, orthostasis, syncope, tachycardia, or excessive CNS effects that interfere with their normal activities. Patients should also avoid driving or operating hazardous machinery until they know how these medications affect them.

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.