Pharmacologic class: Uncompetitive N-Methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 agonist + CYP2D6 inhibitor
Active ingredient: Dextromethorphan (DM) HBr 20 mg, quinidine sulfate 10 mg; capsules.
Indication: To treat pseudobulbar affect (PBA).
Pharmacology: DM is a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist. Quinidine increases plasma levels of DM by competitively inhibiting CYP2D6, which catalyzes a major biotransformation pathway for DM. The mechanism by which DM exerts its effects in PBA is unknown.
Clinical trials: The efficacy of Nuedexta was shown in one study in PBA patients with underlying amyotrophic lateral sclerosis or multiple sclerosis. Patients were randomized to receive Nuedexta, DM hydrobromide (HBr) 30 mg/quinidine sulfate 10 mg, or placebo. The primary outcome measure — laughing or crying episodes — was statistically significantly lower in each DM/quinidine arm compared with placebo.
The secondary endpoint was the Center for Neurologic Study-Lability Scale (CNS-LS), a seven-item self-report questionnaire consisting of three items assessing crying and four assessing laughter. The CNS-LS was analyzed based on the difference between the mean scores on Day 84 and baseline, and was also statistically significantly lower in each DM/quinidine arm compared with placebo.
Two studies conducted using a higher dose combination (DM HBr 30 mg/quinidine sulfate 30 mg) provided evidence of Nuedexta efficacy.
Adults: ≥18 years: One capsule daily for seven days, then (starting on Day 8) one capsule every 12 hours. Re-evaluate periodically.
Children: <18 years: not recommended.
Contraindications: Concomitant quinidine, quinine, or mefloquine. History of quinine-, mefloquine-, or quinidine-induced thrombocytopenia; hepatitis; bone-marrow depression; lupuslike syn-drome. Within 14 days of monoamine oxidase inhibitors. Prolonged QT interval. Congenital long QT syndrome. History of torsades de pointes. Heart failure. Drugs that prolong QT interval and are CYP2D6 substrates (e.g., thioridazine, pimozide). Complete atrioventricular (AV) block without pacemaker, or risk of complete AV block.
Warnings/Precautions: Discontinue if quinidine-related thrombocytopenia occurs (continued use may cause fatal hemorrhage); do not restart. Risk of QT prolongation and torsades de pointes (e.g., concomitant drugs that prolong QT interval or that are strong or moderate CYP3A4 inhibitors, left ventricular hypertrophy, left ventricular dysfunction): Do ECG at baseline and three to four hours after first dose; re-evaluate ECG if risk factors for arrhythmia (e.g., electrolyte abnormality, bradycardia, family history of QT abnormality) change during treatment. Correct hypokalemia, hypomagnesemia before starting. Discontinue if arrhythmias occur. Myasthenia gravis. Consider genotyping for poor metabolizers of CYP2D6. Severe renal or hepatic impairment. Pregnancy (Cat. C). Nursing mothers.
Interactions: See Contraindications. May cause serotonin syndrome with concomitant selective serotonin reuptake inhibitors (e.g., fluoxetine) or tricyclic antidepressants (e.g., clomipramine, imipra-mine). Accumulation of parent drug and/or failure of metabolite formation may decrease safety and/or efficacy of concomitant CYP2D6 substrates; adjust dose of CYP2D6 substrate or use alternative treatment. Concomitant desipramine, paroxetine: Reduce dose of these drugs, adjust based on response. Monitor digoxin; may need to reduce dose. Additive central nervous system effects with alcohol.
Adverse reactions: GI upset, dizziness, cough, asthenia, peripheral edema, urinary tract infection, flu, increased gamma-glutamyltransferase, flatulence; thrombocytopenia, hypersensitivity, anticholinergic effects, hepatitis (discontinue if occurs).
How supplied: Caps — 60
For more information, call 949.389.6700 or visit www.Nuedexta.com.