Drug Interactions between cobicistat / darunavir 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.

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MONITOR CLOSELY: Coadministration with cobicistat may significantly increase the plasma concentrations of certain antiarrhythmic agents such as amiodarone, bepridil, disopyramide, flecainide, propafenone, and quinidine. The mechanism involves inhibition of CYP450 2D6 (flecainide, propafenone) and/or 3A4 (amiodarone, bepridil, disopyramide, quinidine) metabolism, as cobicistat is a potent inhibitor of both isoenzymes. The interaction has not been specifically studied, but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities if levels are significantly increased. The use of these antiarrhythmic agents has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death.

MANAGEMENT: Caution is advised if cobicistat must be used concomitantly with antiarrhythmic agents that are primarily metabolized by CYP450 2D6 and/or 3A4. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever cobicistat is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

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MONITOR: Coadministration with darunavir may increase the plasma concentrations of amiodarone, bepridil, systemic lidocaine, and quinidine. The proposed mechanism is darunavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these antiarrhythmic agents. The interaction has not been studied but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities.

MANAGEMENT: Caution is advised if darunavir must be used with amiodarone, bepridil, systemic lidocaine, or quinidine. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever darunavir is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

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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. In addition, multiple doses of the potent CYP450 2D6 inhibitor cinacalcet (50 mg daily), increased the AUC of a single 30 mg dextromethorphan dose by 11-fold in extensive metabolizers of this isoenzyme. 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.

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