FDA Approves First Treatment for Pseudobulbar Affect

Yael Waknine

November 02, 2010

November 2, 2010 — The US Food and Drug Administration (FDA) has approved dextromethorphan HBr and quinidine sulfate 20 mg/10 mg capsules (Nuedexta; Avanir Pharmaceuticals, Inc) as the first treatment for pseudobulbar affect (PBA).

PBA occurs secondary to brain injury or neurologic conditions such as multiple sclerosis, amyotrophic lateral sclerosis (ALS), and stroke. Also known as emotional incontinence, it is characterized by sudden outbursts of involuntary crying and/or laughing that can cause anxiety and embarrassment in public settings.

"The FDA approval of Nuedexta marks an important milestone for people living with PBA, an under-recognized and debilitating neurologic condition," said Keith Katkin, president and chief executive officer of Avanir, in a company news release. "We expect that Nuedexta will be available by prescription during the first quarter of 2011."

FDA approval of the first-in-class medication was based primarily on data from a clinical trial of 326 patients with ALS and multiple sclerosis with clinically significant PBA, as defined by a baseline score of 13 or greater on the 7-point Center for Neurologic Studies–Lability Scale.

As previously reported by Medscape Medical News, results at 12 weeks showed that dextromethorphan 30 mg/quinidine 10 mg and dextromethorphan 20 mg/quinidine 10 mg significantly decreased the PBA episode daily rate by 46.9% and 49.0%, respectively, relative to placebo (P < .0001 for both comparisons).

Mean Center for Neurologic Studies–Lability Scale scores, a secondary outcome measure of PBA frequency and severity, were likewise significantly decreased by 8.2 points in both treatment groups (vs placebo, 5.7 points; P = .0002 and .0113, respectively).

These findings were supported by data from 2 additional studies of high-dose dextromethorphan 30 mg/quinidine 30 mg: a 4-week study of patients with PBA who had underlying ALS and a 12-week study of patients with underlying multiple sclerosis.

The recommended starting dose for dextromethorphan/quinidine is a single 20 mg/10 mg capsule daily for 7 days, after which patients may receive the maintenance dose of 1 capsule every 12 hours.

Use of dextromethorphan/quinidine is contraindicated in patients with known hypersensitivity to its components; those taking a monoamine oxidase inhibitor or within 2 weeks of discontinuation; patients with prolonged QT interval, congenital long QT syndrome, heart failure, complete atrioventricular block without implanted pacemaker (or at high risk for complete block), or heart failure; and patients taking drugs that both prolong the QT interval and are metabolized by cytochrome P 450 isoenzyme 2D6 (eg, thioridazine and pimozide).

Adverse events most commonly reported with use of dextromethorphan/quinidine in clinical trials include diarrhea (13%), dizziness (10%), cough (5%), vomiting (5%), asthenia (5%), and peripheral edema (5%); urinary tract infection, influenza, increased gamma-glutamyltransferase levels, and flatulence were also reported. Precautions should be taken to reduce the risk for falls resulting from dizziness, particularly in patients with motor impairment affecting gait or a history of falls.

The FDA warns that dextromethorphan/quinidine is linked to a risk for severe and potentially fatal immune-related thrombocytopenia that can be preceded by nonspecific symptoms such as light-headedness, chills, fever, nausea, and vomiting. Treatment should be permanently discontinued if thrombocytopenia develops.

Hepatitis has been reported in patients receiving quinidine, generally during the first few weeks of treatment, and may be accompanied by thrombocytopenia or other signs of hypersensitivity. Most cases remit when quinidine is discontinued.

Treatment with dextromethorphan/quinidine causes dose-dependent QTc prolongation. Electrocardiographic evaluation at baseline and 3 to 4 hours after the first dose is recommended for at-risk patients, including those taking drugs that prolong the QT interval or are strong/moderate cytochrome P 450 isoenzyme 3A4 (CYP 3A4) inhibitors, and patients with left ventricular hypertrophy or dysfunction. Treatment should be discontinued for symptoms suggestive of arrhythmia.

Because quinidine inhibits CYP 2D6, coadministration of dextromethorphan/quinidine with agents that undergo extensive CYP 2D6 metabolism can result in altered effects resulting from drug accumulation and/or failure of metabolite formation. Caution is advised when using CYP 2D6–metabolized agents with a low therapeutic index; dose modifications may be required.

When used with selective serotonin reuptake inhibitors or tricyclic antidepressants, dextromethorphan/quinidine may cause serotonin syndrome. Symptoms may include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.

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