Drug Interactions between amiodarone and Nuedexta

GENERALLY AVOID: Coadministration of amiodarone and quinidine may increase the risk of new arrhythmias due to additive depressant effects on cardiac conduction. There have been reports of torsade de pointes arrhythmia in association with significantly prolonged QT interval in patients receiving concomitant therapy. Serious exacerbation of preexisting arrhythmia may also be more likely during coadministration relative to either agent alone. Despite the potential toxicities, amiodarone and quinidine have been used together successfully in the treatment of certain arrhythmias.

ADJUST DOSE: Amiodarone may increase the plasma concentrations of quinidine. The mechanism of interaction has not been established, but may involve inhibition of quinidine clearance via CYP450 3A4 metabolism and/or P-glycoprotein efflux. In 11 patients stabilized on quinidine (1.2 to 4.2 gm/day), the addition of amiodarone (600 mg every 12 hours for 5 to 7 days, followed by 600 mg daily) increased mean serum quinidine concentrations by approximately 33%. Signs of toxicity including diarrhea, nausea, vomiting, and hypotension were reported in some patients, necessitating dosage reductions by an average of 37%. Due to the long and variable half-life of amiodarone, potential for interaction may exist even after its discontinuation.

MANAGEMENT: The concurrent use of amiodarone with other antiarrhythmic agents, including quinidine, should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or to amiodarone alone. A dosage reduction for quinidine is recommended during coadministration. In general, if adding or transferring to oral amiodarone, the dosages of previously administered agents should be reduced by 30% to 50% several days after initiation of amiodarone, when onset of arrhythmia suppression is expected to occur. The continued need for other antiarrhythmic agents should be evaluated after the effects of amiodarone have been established, and discontinuation should ordinarily be attempted. If the combination is continued, patients should be monitored closely for adverse effects including conduction disturbances and exacerbation of tachyarrhythmias. Conversely, in amiodarone-treated patients who require additional antiarrhythmic agents, the initial dosage of such agents should be approximately one-half the usual recommended dosage. Patients should be advised to seek medical attention if they experience potential signs of quinidine toxicity such as nausea, vomiting, diarrhea, tinnitus, hearing loss, vertigo, visual disturbances, dizziness, headache and confusion, or symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath and syncope.

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 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. 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.