Pharmacology Update

Dextromethorphan Hydrobromide and Quinidine Sulfate Tablets (Nuedexta™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

The FDA has approved the first treatment for pseudobulbar affect (PBA). This condition is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying and is secondary to certain underlying neurologic diseases or injuries. This new combination product contains a N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 agonist, dextromethorphan, and a CYP 450 2D6 inhibitor, quinidine. The product will be marketed by Avanir Pharmaceuticals, Inc., as Nuedexta™ in the first quarter of 2011.

Indications

Dextromethorphan (DEX)/quinidine (QUIN) is indicated for the treatment of pseudobulbar affect.1

Dosage

The recommended dose is 1 capsule daily for 7 days and then 1 capsule every 12 hours.1

The product is available as capsules, each containing DEX 20 mg and QUIN 10 mg.

Potential Advantages

DEX/QUIN reduced laughing and crying episodes compared to placebo in patients with amyotrophic lateral sclerosis and multiple sclerosis.1

Potential Disadvantages

DEX/QUIN may cause dose-dependent QTc prolongation. It is contraindicated in patients with prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, heart failure, or risk of complete atrioventricular block (implanted pacemaker the exception).1 Concomitant use of drugs that prolonged QT interval and are metabolized by CYP 2D6 is contraindicated. Common adverse events, compared to placebo, include diarrhea (13% vs 6%), dizziness (10% vs 5%), cough (5% vs 2%), vomiting (5% vs 1%), asthenia (5% vs 2%), peripheral edema (5% vs 1%), urinary tract infection (4% vs1%), influenza (4% vs 1%), increased gamma-glutamyltransferase (3% vs 0%), and flatulence (3% vs 1%). Thrombocytopenia and lupus-like syndrome have been associated with quinidine.

Comments

Dextromethorphan is a low-affinity, noncompetitive NMDA-receptor antagonist and sigma-1 receptor agonist. Quinidine, a potent CYP P450 2D6 inhibitor, blocks first-pass metabolism resulting in improved systemic exposure of dextromethorphan. The exact mechanism of action in treating pseudobulbar affect is not known. The efficacy was evaluated in a 12-week, randomized, double-blind, placebo-controlled study in patients with amyotrophic lateral sclerosis or multiple sclerosis.1,2 The study randomized patients to DEX/QUIN 30 mg/10 mg (n = 110), DEX/QUIN 20 mg/10 mg (n = 107), or placebo (n = 109). The primary endpoint was patient's change from baseline in the number of PBA episodes of laughing and/or crying per day as recorded in the patient's diary. A secondary endpoint was the patient's change from baseline on Center for Neurologic Studies Lability Scale (CNS-LS). This is a 7-item self-assessment of PBA severity. With no clear clinical advantage with the higher dose, only the 20 mg/10 mg was approved by the FDA. DEX/QUIN 20 mg/10 mg showed a 49% reduction compared to placebo (P < 0.001). The 12-week mean change in daily episodes was -3.9 compared to -3.0 for placebo (P = 0.0099). There was a significant reduction from baseline CNS-LS compared to placebo (8.2 vs 5.7; P = 0.011). Remission was reported in approximately 50% of patients treated with DEX/QUIN compared to approximately 30% for placebo.2 Remission was defined as absence of episodes throughout the final two weeks of the 12-week study. Dizziness and diarrhea were more common with DEX/QUIN compared to placebo (10.3% vs 5.5% and 13.1% vs 6.4%, respectively).2

Clinical Implications

Psuedobulbar affect is a disorder of emotional expression characterized by uncontrollable outbursts of laughing and/or crying.3 This disorder appears to occur in the setting of neurological diseases such as amyotrophic lateral sclerosis and multiple sclerosis. Current therapies include tricyclic antidepressants and selective serotonin reuptake inhibitors and may be considered in patients with depression.3 DEX/QUIN is the first FDA-approved treatment for this condition. Whether the efficacy of this combination of drugs can be generalized to other causes of pseudobulbar affect not related to ALS or MS is not known.

References

1. Nuedexta Prescribing Information. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc.; October 2010.

2. Pioro EP, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol 2010;68:693-702.

3. Rosen H. Dextromethorphan/quinidine sulfate for pseudobulbar affect. Drugs Today (Barc) 2008;44:661-668.