Drug Interactions between Nuedexta and ubrogepant

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.

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4, breast cancer resistance protein (BCRP), and/or P-glycoprotein (P-gp) may increase the plasma concentrations of ubrogepant based on in vivo and in vitro data. The proposed mechanism involves enhanced oral bioavailability as well as reduced clearance of ubrogepant due to inhibition of CYP450 3A4-mediated metabolism and BCRP/P-gp-mediated efflux in the intestine and liver. When ubrogepant was administered with the potent CYP450 3A4 inhibitor ketoconazole during in vivo studies, ubrogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 5.3- and 9.7-fold, respectively. When administered with the moderate CYP450 3A4 inhibitor verapamil, ubrogepant Cmax and AUC increased by 2.8- and 3.5-fold, respectively. Dedicated drug interaction studies have not been conducted to assess concomitant use of ubrogepant with weak CYP450 3A4 inhibitors and inhibitors of BCRP or P-gp transporters. Ubrogepant exposure is not expected to increase by more than 2-fold when used with weak CYP450 3A4 inhibitors per a conservative prediction from the manufacturer.

MANAGEMENT: The recommended dose of ubrogepant is 50 mg during concomitant treatment with weak CYP450 3A4 inhibitors and/or inhibitors of BCRP or P-gp. If needed, a second 50 mg ubrogepant dose may be administered at least 2 hours after the initial dose.