Dextromethorphan/Quinidine Combo Controls PBA in Dementia

Daniel M. Keller, PhD

December 02, 2014

PHILADELPHIA, Pennsylvania — A combination of dextromethorphan and quinidine (Nuedexta, Avanir Pharmaceuticals) significantly reduced symptoms of pseudobulbar affect (PBA) among patients with dementia, a 12-week study shows.

The reduction in symptoms was clinically meaningful, as demonstrated by quality-of-life scores and patient and clinician assessments of improvement.

"The majority of people improved," Rachelle Doody, MD, PhD, director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine in Houston, Texas. Between 30 days and 90 days, she said, "we saw further improvement at the final time point."

The results were presented here at the 7th Clinical Trials Conference on Alzheimer's Disease (CTAD).

PBA manifests as uncontrollable episodes of laughing or crying that are inappropriate to the mood or situation. It can occur in a variety of neurologic conditions, and episodes can be disruptive and distressing.

This drug combination is already approved by the US Food and Drug Administration on the basis of PBA trials in amyotrophic lateral sclerosis and multiple sclerosis. Low-dose quinidine increases the bioavailability of dextromethorphan.

PRISM II

The PRISM II (Pseudobulbar affect Registry Investigating Symptom Management) trial is an ongoing, open-label, multicenter registry to gather additional data on dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg (DM/Q) for the treatment of PBA secondary to dementia, stroke, or traumatic brain injury. DM/Q was administered once daily for the first week and twice daily thereafter. In this presentation, Dr Doody focused on patients with dementia.

Study participants were adults (mean age, 71 years) with clinically diagnosed PBA, Center for Neurologic Study-Lability Scale scores of 13 or greater, and dementia with Mini-Mental State Examination (MMSE) scores of 10 or greater. They could be receiving memantine, acetylcholinesterase inhibitors, antidepressants, or neuropsychiatric medications if doses were stable.

Of 134 patients enrolled, 106 completed the trial. Fourteen withdrew because of adverse events. Most patients were white (88%); 59% were women; 64% had Alzheimer's disease; 19% had vascular dementia; and the rest had frontotemporal, Lewy body, or other dementias.

At baseline, patients experienced fewer than 10 to 90 or more PBA episodes per week. About 35% of patients experienced 10 to 20 episodes per week. At day 30, fewer patients were in the upper end of the range of episodes, and by day 90, about 70% of patients were experiencing 0 to 20 episodes per week.

Table. Reduction in Measures of PBA with Oral Dextromethorphan/Quinidine

Endpoint Baseline Day 30 Day 90
Center for Neurologic Study-Lability Scale score 20.1 15.5 13.0
Reduction in PBA weekly episodes (%) 50.2 67.7

P < .001 vs baseline.

 

Both the patient and the clinician global impression of change scores were in close agreement, differing at most by 2%. Clinicians and patients scored 23% of patients (themselves) as minimally worse or of having no change. About 15% of patients were judged as minimally improved, 48% were much improved, and about 30% were very much improved.

Quality-of-life scores on a visual analogue scale improved by day 90 vs baseline (P < .001), and MMSE scores trended toward improvement but were not significantly different (P = .084).

Most adverse events were mild to moderate and were reported by 49 patients (36.6%). Fourteen patients (10.4%) experienced a serious adverse event, but investigators judged that none was related to treatment. The most common adverse events were headache (7.5% of patients) and urinary tract infection (4.5%). Falls, dizziness, or somnolence each occurred in 2.2% of patients.

Dr Doody concluded that DM/Q significantly reduced the frequency of PBA episodes in this 12-week trial and that the reductions were clinically meaningful, as demonstrated by patient and clinician impressions of improvement as well as by quality-of-life scores. She said the treatment was well tolerated in this largely elderly population.

Heather Snyder, PhD, director of medical and scientific operations at the Alzheimer's Association in Chicago, Illinois, commented to Medscape Medical News that even though the study population was relatively small, "which is what you would expect in a phase 2... There's a benefit for those individuals that are taking this medication."

She said that more than 5 million Americans and more than 40 million people worldwide are living with dementia and of those, "somewhere between 10% to 40% of individuals may experience [PBA] through their progression that can actually be somewhat disruptive to their life and actually lead to isolation because they're not comfortable being in social situations."

"Based on this data, it suggests that it's worth further pursuit" to study DM/Q for PBA, she said.

According to a Wall Street Journal blog, Nuedexta costs between $400 and $600 for a month's treatment. However, of the two components, dextromethorphan is available over the counter in cough preparations, and quinidine is an inexpensive prescription drug. They are available for about $20 per month, the Wall Street Journal estimates.

The doses in Nuedexta are significantly lower than doses of the individual drugs when used for cough suppression (dextromethorphan) and for treating cardiac arrhythmias (quinidine).

As early as 2011, members of the Senate and the House of Representatives asked Avanir, the drug's manufacturer, to justify the price. A recent court decision has upheld Avanir patents, giving it marketing exclusivity for the DM/Q formulation through 2026.

A recent online search showed the branded drug now costs more than $600 a month.

PRISM II is supported by Avanir Pharmaceuticals. Dr Doody reports consulting fees from AbbVie, AC Immune, Avanir, AZ Therapies, Baxter, Biogen, Biotie, Cerespir, GSK, Hoffmann-LaRoche, Merck, Novartis, Nutricia, Pfizer, Shanghai Green Valley, Suven, Targacept, Transition; research support from Accera, Avanir, Genentech, Janssen, Merck, Pfizer, Takeda; stock options from AZ Therapies, QR Pharma, Sonexa, Transition; other: Hoffmann-LaRoche (DSMB), Lilly/UCSD (ADCS_DAPC). Dr Snyder has disclosed no relevant financial relationships.

7th Clinical Trials Conference on Alzheimer's Disease (CTAD): Abstract OC33. Presented November 21, 2014.

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