Drug Interactions between adagrasib and codeine / phenylephrine / promethazine

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.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: Drugs that are inhibitors of CYP450 2D6 may interfere with the analgesic effect of codeine. The mechanism is decreased in vivo conversion of codeine to morphine, a metabolic reaction mediated by CYP450 2D6. If an inhibitor is started after a stable dose of codeine is achieved, reduced analgesia and possible opioid withdrawal may result. Conversely, ceasing CYP450 2D6 inhibitor therapy may lead to increased morphine levels, increasing the risk of opioid-related adverse effects.

MANAGEMENT: The possibility of reduced or inadequate pain relief should be considered in patients receiving codeine with drugs that inhibit CYP450 2D6. An increase in the codeine dosage or a different analgesic agent may be necessary in patients requiring therapy with CYP450 2D6 inhibitors. If concurrent therapy is used and the CYP450 2D6 inhibitor is stopped, the dose of codeine may need to be reduced and the patient should be monitored for signs and symptoms of respiratory depression or sedation. In addition, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may interfere with the analgesic effects of codeine for at least 28 days after administration of rolapitant. The manufacturer's prescribing information should be consulted for further information.

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