Dextromethorphan/quinidine

Dextromethorphan/quinidine, sold under the brand name Nuedexta, is a fixed-dose combination medication for the treatment of pseudobulbar affect. It contains dextromethorphan and the class I antiarrhythmic agent quinidine.
Dextromethorphan/quinidine was approved for medical use in the United States in October 2010, and is marketed by Avanir Pharmaceuticals.

Medical uses

DXM/quinidine is used in the treatment of PBA. In a 12-week randomized, double-blind trial, amyotrophic lateral sclerosis and multiple sclerosis patients with significant PBA were given either Nuedexta 20/10 mg or placebo. In 326 randomized patients, the PBA-episode daily rate was 46.9% lower for Nuedexta than for placebo. The three deaths in each of the two drug treatment arms and the single death in the placebo arm of the study were believed to be due to the natural course of the disease. DMX/quinidine has been reported to reduce bulbar symptoms such as dysarthria and dysphagia in patients with amyotrophic lateral sclerosis, with positive patient-reported outcomes in a multicenter study.

Contraindications

Atrioventricular block, complete, without implanted pacemaker or at high risk of complete AV block
Concomitant use with drugs containing quinidine, quinine, or mefloquine
Concomitant use with drugs that both prolong the QT interval and are metabolized by CYP2D6 ; effects on QT interval may be increased
Concomitant use with MAOIs or use of MAOIs within 14 days; risk of serious, potentially fatal, drug interactions including serotonin syndrome
Heart failure
Hypersensitivity to dextromethorphan
Hypersensitivity to quinine, mefloquine, quinidine, or dextromethorphan/quinidine with a history of thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome induced by these drugs
QT interval, prolonged or congenital long QT syndrome or a history suggesting torsades de pointes

Adverse effects

Common risks and side effects include:

Interactions

Desipramine levels increase 8-fold with co-administration
Paroxetine
Memantine

Pharmacology

Pharmacodynamics

Dextromethorphan acts as a σ₁ receptor agonist, serotonin–norepinephrine reuptake inhibitor, and NMDA receptor antagonist, while quinidine is an antiarrhythmic agent acting as a CYP2D6 inhibitor. Quinidine prevents the metabolism of dextromethorphan into its active metabolite dextrorphan, which is a much more potent NMDA receptor antagonist but much less potent serotonin reuptake inhibitor than dextromethorphan. The mechanism of action of dextromethorphan/quinidine in the treatment of PBA is unknown.

Research

Dextromethorphan/quinidine was investigated for the treatment of agitation associated with dementia, diabetic neuropathy, drug-induced dyskinesia, migraine, and neuropathic pain, but development for these indications was discontinued. Another formulation, deudextromethorphan/quinidine, is still under investigation for various indications. These include agitation, schizophrenia, and major depressive disorder, among others.