Manufacturer:

Avanir Pharmaceuticals

Pharmacological Class:

Uncompetitive NMDA receptor antagonist and sigma-1 agonist + CYP2D6 inhibitor.

Active Ingredient(s):

Dextromethorphan HBr 20mg, quinidine sulfate 10mg; capsules.

Indication(s):

To treat pseudobulbar affect (PBA).

Pharmacology:

Dextromethorphan (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 HBr 30mg/quinidine sulfate 10mg, or placebo. The primary outcome measure, laughing or crying episodes, was statistically significantly lower in each DM/quinidine arm compared to placebo. The secondary endpoint was the Center for Neurologic Studies Lability Scale (CNS-LS), a 7-item self-report questionnaire with 3 items assessing crying and 4 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 to placebo.

Two studies conducted using a higher dose combination (DM HBr 30mg/quinidine sulfate 30mg) provided evidence of Nuedexta efficacy.

Legal Classification:

Rx

Adults:

≥18 years: 1 capsule daily for 7 days, then (starting on Day 8) 1 capsule every 12 hours. Reevaluate periodically.

Children:

<18 years: not recommended.

Contraindication(s):

Concomitant quinidine, quinine, or mefloquine. History of quinine, mefloquine, or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression, lupus-like syn­drome. Within 14 days of MAOIs. Prolonged QT interval. Congenital long QT syndrome. History of torsades de pointes. Heart failure. Drugs that prolong QT interval and are CYP2D6 substrates (eg, thioridazine, pimozide). Complete AV block w/o 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 (eg, concomitant drugs that prolong QT interval or that are strong or moderate CYP3A4 inhibitors, left ventricular hypertrophy, LVD): do ECG at baseline and 3–4 hours after 1^st dose; reevaluate ECG if risk factors for arrhythmia (eg, 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.

Interaction(s):

See Contraindications. May cause serotonin syndrome with concomitant SSRIs (eg, fluoxetine) or TCAs (eg, clomipramine, imipra­mine). 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 CNS effects with alcohol.

Adverse Reaction(s):

GI upset, dizziness, cough, asthenia, peripheral edema, UTI, flu, increased gamma-glutamyltransferase, flatulence; throm­bo­cytopenia, hypersensitivity, anticholinergic effects, hepatitis (discontinue if occurs).

How Supplied:

Caps—60