Drug Interactions between itraconazole and Nuedexta

CONTRAINDICATED: Coadministration with azole antifungal agents may significantly increase the plasma concentrations of quinidine. The proposed mechanism is inhibition of quinidine metabolism via intestinal and hepatic CYP450 3A4. Additionally, itraconazole and ketoconazole are also potent P-glycoprotein inhibitors and may reduce the active renal efflux of quinidine. In nine healthy, nonsmoking volunteers, administration of a single 100 mg oral dose of quinidine sulfate on the last day of itraconazole treatment (200 mg once a day for 4 days) increased quinidine peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 1.6- and 2.4-fold, respectively, compared to administration with placebo. The elimination half-life of quinidine was prolonged 60% by itraconazole, and its renal clearance decreased by 50%. Another study in six healthy subjects reported an approximately 60% decrease each in total and renal clearance and a 35% increase in elimination half-life of a single 200 mg dose of quinidine sulfate when given with itraconazole (100 mg daily for 6 days). Likewise, plasma quinidine levels more than doubled within seven days after initiating ketoconazole 200 mg/day in an elderly man taking quinidine sulfate 300 mg four times a day, although there was no evidence of clinical toxicity in this case. The use of quinidine has been associated with 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. Some azole antifungal agents themselves have also rarely been associated with QT interval prolongation and/or torsade de pointes. Theoretically, additive proarrhythmic effects may occur when used with quinidine. A case of deafness has been associated with quinidine toxicity attributed to a suspected interaction with itraconazole.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of quinidine, concomitant use with azole antifungal agents is considered contraindicated. Some authorities consider concomitant administration of quinidine and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole.

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.