Drug Interactions between betrixaban and dextromethorphan / quinidine

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.

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ADJUST DOSE: Coadministration with inhibitors of P-glycoprotein (P-gp) may significantly increase the plasma concentrations of betrixaban, which is a substrate of the efflux transporter. When administered with the potent P-gp inhibitor verapamil, betrixaban peak plasma concentration (Cmax) increased by nearly 5-fold and systemic exposure (AUC) increased by approximately 3-fold compared to betrixaban administered alone. When given with ketoconazole, another P-gp inhibitor, betrixaban Cmax and AUC increased by a little more than 2-fold each. In the Acute Medically Ill Prevention with Extended Duration Betrixaban (APEX) Study, use of betrixaban at a 50% dosage reduction in combination with P-gp inhibitors or in the presence of severe renal impairment was associated with increased relative risks of bleeding, including major bleeding, compared to treatment with enoxaparin.

MANAGEMENT: When used with P-gp inhibitors, the recommended dosage of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. Patients should be routinely evaluated for signs and symptoms suggesting blood loss such as a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress (in pregnant women). Concomitant use of betrixaban with P-gp inhibitors should be avoided in patients with severe renal impairment (CrCl<30 mL/min).

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