Dextromethorphan/quinidine

Dextromethorphan/quinidine (trade name Nuedexta) is a combination drug containing dextromethorphan and the class I antiarrhythmic agent quinidine. It is the first FDA-approved drug for the treatment of pseudobulbar affect (PBA).

Clinical studies

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% (p < 0.0001) lower for Nuedexta than for placebo.^[1] 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.^[2]

Nuedexta was approved in February 2011 and is marketed in the United States by Avanir Pharmaceuticals.

Those seemingly unrelated drugs became associated so that low-dose quinidine inhibits dextromethorphan's breakdown. The latter has shown marginal efficacy in pseudobulbar syndrome due to rapid first-pass metabolism that reduces its bioavailability.

Interactions

• Desipramine (CYP2D6 substrate)^[2] levels increase 8-fold with co-administration
• Paroxetine (CYP2D6 inhibitor and substrate)^[2]
• Memantine

Contraindications

• Atrioventricular (AV) 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 (e.g., thioridazine, pimozide); 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 (e.g., rash, hives)
• 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:^[2][3][4]

• Abdominal pain
• Asthenia
• Cough
• Diarrhea (reported in 13% of patients)
• Dizziness
• Elevated gamma glutamyltransferase
• Flatulence
• Influenza
• Prolonged QT interval
• Muscle spasm
• Peripheral edema
• Urinary tract infection
• Vomiting

Other possible indications

In June 2012, drug discovery and development magazine reported that Avanir Pharmaceuticals plans to test the drug for the treatment of agitation associated with Alzheimer's disease.^[5] The drug is also under investigation for the treatment of major depressive disorder.^[6]

References