Drug Interactions between Nuedexta and tamsulosin

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: Coadministration with inhibitors of CYP450 3A4 and/or 2D6 may increase the plasma concentrations of tamsulosin, which is primarily metabolized in the liver by these isoenzymes. In 24 healthy volunteers, administration of a single 0.4 mg dose of tamsulosin with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 5 days) resulted in a 2.2-fold increase in tamsulosin peak plasma concentration (Cmax) and a 2.8-fold increase in systemic exposure (AUC) compared to administration alone. Likewise, concomitant treatment with the potent CYP450 2D6 inhibitor paroxetine (20 mg once daily for 9 days) resulted in an increase in the Cmax and AUC of a single 0.4 mg dose of tamsulosin by a factor of 1.3 and 1.6, respectively. The effects of concomitant administration of a moderate CYP450 3A4 inhibitor such as erythromycin or a moderate CYP450 2D6 inhibitor such as terbinafine on the pharmacokinetics of tamsulosin have not been evaluated. The effects of coadministration of both a CYP450 3A4 and a CYP450 2D6 inhibitor have also not been evaluated. However, there is a potential for significant increase in tamsulosin exposure relative to coadministration with either inhibitor alone. Similarly, a significant increase in exposure may occur when tamsulosin is administered with a CYP450 3A4 inhibitor to individuals who have genetic polymorphisms of CYP450 2D6 resulting in reduced or absent enzyme activity, or so-called CYP450 2D6 poor metabolizers (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent).

MANAGEMENT: Caution is advised if tamsulosin is used concomitantly with moderate CYP450 3A4 inhibitors (e.g., amiodarone, aprepitant, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fusidic acid, imatinib, isavuconazonium, verapamil) and/or moderate to potent CYP450 2D6 inhibitors (e.g., abiraterone, bupropion, celecoxib, cinacalcet, darifenacin, dronedarone, duloxetine, fluoxetine, lorcaserin, paroxetine, propafenone, quinidine, ranolazine, rolapitant, terbinafine), particularly at a dosage higher than 0.4 mg/day. The potential for increased risk of adverse effects such as postural hypotension, syncope, and priapism should be considered. It should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, can increase plasma concentrations and the risk of adverse effects of tamsulosin for at least 28 days after administration of rolapitant. Patients should be advised to avoid rising abruptly from a sitting or recumbent position, and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medication affects them.