Dextromethorphan and Quinidine

NUEDEXTA is indicated for the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurologic conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the underlying emotional state. PBA is a specific condition, distinct from other types of emotional lability that may occur in patients with neurological disease or injury. NUEDEXTA is a combination product containing dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist and sigma-1 agonist) and quinidine sulfate (a CYP450 2D6 inhibitor) indicated for the treatment of pseudobulbar affect (PBA).

Dextromethorphan (DM) is a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist. Quinidine increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6, which catalyzes a major biotransformation pathway for dextromethorphan. The mechanism by which dextromethorphan exerts therapeutic effects in patients with pseudobulbar affect is unknown.

Starting dose: one capsule daily by mouth for 7 days. Maintenance dose: After 7 days, 1 capsule every 12 hours. Recommended Dose The recommended starting dose of NUEDEXTA is one capsule daily by mouth for the initial seven days of therapy. On the eighth day of therapy and thereafter, the daily dose should be a total of two capsules a day, given as one capsule every 12 hours. The need for continued treatment should be reassessed periodically, as spontaneous improvement of PBA occurs in some patients.

Concomitant use with quinidine, quinine, or mefloquine. Patients with a history of quinidine, quinine or mefloquine-induced thrombocytopenia, hepatitis, or other hypersensitivity reactions. Patients with known hypersensitivity to dextromethorphan. Use with an MAOI or within 14 days of stopping an MAOI. Allow 14 days after stopping NUEDEXTA before starting an MAOI. Prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, or heart failure. Complete atrioventricular (AV) block without implanted pacemaker, or patients at high risk of complete AV block.

Thrombocytopenia or other hypersensitivity reactions: Discontinue if occurs. Hepatitis: Discontinue if occurs. QT Prolongation: Monitor ECG if concomitant use of drugs that prolong QT interval cannot be avoided or if concomitant CYP3A4 inhibitors used. Left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD): Monitor ECG in patients with LVH or LVD. CYP2D6 substrate: Nuedexta inhibits CYP2D6. Accumulation of parent drug and/or failure of metabolite formation may decrease safety and/or efficacy of concomitant CYP2D6 metabolized drugs. Adjust dose of CYP2D6 substrate or use alternative treatment when clinically indicated. Dizziness: Take precautions to reduce falls. Serotonin syndrome: Use of NUEDEXTA with selective serotonin reuptake inhibitor (SSRIs) or tricyclic antidepressants increases the risk. Discontinue if occurs.

A total of 946 patients participated in four Phase 3 controlled and uncontrolled PBA studies and received at least one dose of the combination product of dextromethorphan/quinidine in various strengths at the recommended or higher than the recommended dose. Of those patients, 393 patients were exposed for at least 180 days and 294 patients were exposed for at least one year. Median exposure was 168 days. Controlled trials enrolled only patients with either ALS or MS. Uncontrolled studies enrolled 136 patients with PBA secondary to a wide variety of underlying neurological conditions including stroke (45 patients) and traumatic brain injury (23 patients). Consequently, patients with other underlying neurologic diseases may experience other adverse reactions not described below.

Desipramine: Exposure increases 8-fold. Reduce desipramine dose and adjust based on clinical response. Paroxetine: Exposure increases 2-fold. Reduce paroxetine dose and adjust based on clinical response. Digoxin: Increased digoxin substrate plasma concentration may occur.

Storage Store NUEDEXTA capsules at controlled room temperature, 25°C (77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [ s ee USP Controlled Room Temperature].