Drug Interactions between imatinib and Nuedexta

GENERALLY AVOID: Coadministration with potent CYP450 2D6 inhibitors (e.g., quinidine, terbinafine) may significantly increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Studies in humans have shown an increase in systemic exposure of dextromethorphan of up to 43-fold when given concurrently with quinidine. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. However, this interaction has also been used clinically, with dextromethorphan in combination with quinidine indicated by some authorities for the treatment of pseudobulbar affect. Data evaluating the impact of this interaction in patients who are poor metabolizers of CYP450 2D6 are limited; most studies include extensive metabolizers of this isoenzyme. It is expected that poor metabolizers would have elevated dextromethorphan levels without concurrent quinidine

MANAGEMENT: The combination of dextromethorphan with potent CYP450 2D6 inhibitors should be generally avoided. Some manufacturers consider the concomitant use of dextromethorphan and selective serotonin reuptake inhibitors contraindicated. If use is considered necessary, the patient should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.

MONITOR: Imatinib is a substrate of the CYP450 3A4 isoenzyme as well as a potent competitive inhibitor of the CYP450 2C9, 2D6 and 3A4 isoenzymes. Some drugs that are known inhibitors of CYP450 3A4 are also metabolized by one or more of the isoenzymes inhibited by imatinib. Theoretically, coadministration of imatinib with those drugs may result in mutually elevated plasma drug concentrations due to competitive and noncompetitive inhibition of CYP450 activities.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of imatinib, including serious adverse effects such as edema, hematologic toxicity and immunosuppression, should be considered during concomitant therapy, particularly with potent CYP450 3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nefazodone, and erythromycin. In addition, clinical and laboratory monitoring for potentially increased pharmacologic effects of coadministered medications is recommended, especially those with a narrow therapeutic range.

MONITOR: Coadministration with CYP450 2D6 inhibitors may increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. Coadministration of dextromethorphan (60 mg orally, once) with the CYP450 2D6 inhibitor panobinostat (20 mg orally once a day on days 3, 5, and 8) in 14 patients with advanced cancer had a highly variable effect on dextromethorphan levels, increasing the peak plasma concentration (Cmax) of dextromethorphan by 20% to 200%, and total systemic exposure (AUC 0 to infinity) by 20% to 130%, compared to dextromethorphan given alone. The moderate CYP450 2D6 inhibitor asunaprevir, given at 200 mg twice daily, also increased Cmax and AUC of a single 30 mg dose of dextromethorphan by 2.7- and 3.9-fold, respectively, in 17 study subjects.

MANAGEMENT: Caution should be exercised if these drugs must be used together. Patients should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.