Drug Interactions between mobocertinib and Promethazine VC with Codeine

GENERALLY AVOID: Mobocertinib can cause concentration-dependent, life-threatening prolongation of the QT interval. 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. In a subset of 250 patients who had electrocardiograms (ECGs) during clinical studies with mobocertinib 160 mg orally once daily, 1.2% of patients had a QTc interval greater than 500 msec and 11% of patients had a change-from-baseline QTc interval greater than 60 msec. Torsades de pointes occurred in 1 patient (0.4%). Clinical trials of mobocertinib did not include patients with baseline QTc greater than 470 msec. From cardiac electrophysiology studies, the largest mean increase in QTc was 23.0 msec following administration of mobocertinib 160 mg once 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).

MANAGEMENT: Avoid use of mobocertinib with concomitant drugs which are known to prolong the QT interval. If concomitant use is unavoidable, monitor the QTc interval more frequently with ECGs.

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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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GENERALLY AVOID: Coadministration with mobocertinib may decrease the plasma concentrations and therapeutic effects of drugs that are substrates of CYP450 3A4. The interaction may be significant for sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index. The proposed mechanism is increased clearance due to mobocertinib-mediated induction of CYP450 3A4. Concomitant use of mobocertinib 160 mg once daily with oral or intravenous midazolam (a sensitive CYP450 3A4 substrate) decreased the midazolam systemic exposure (AUC) by 32% and 16%, respectively.

MANAGEMENT: Use of mobocertinib with sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index (e.g., cisapride, ergot alkaloids, colchicine, fentanyl, macrolide immunosuppressants, midazolam, pimozide, triazolam, vinca alkaloids) should generally be avoided. If coadministration is required, patients should be monitored for diminished therapeutic effects. Clinical and laboratory monitoring should be considered whenever mobocertinib is added to or withdrawn from therapy with these drugs, and the dosage of the sensitive CYP450 3A4 substrate drug adjusted in accordance with the approved product label.

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