Dextromethorphan hydrobromide and quinidine sulfate (DM/Q) 20mg/10mg is FDA approved to treat pseudobulbar affect (PBA), a neurological condition characterized by sudden, frequent, involuntary crying or laughing. Although the total dose of quinidine (20 mg) from twice daily DM/Q for PBA is well below the antiarrhythmic dose (600-1600 mg/day), clinicians may be reticent to use DM/Q due to concerns for cardiac safety.

DM/Q cardiac safety was evaluated in two thorough QTc (TQT) studies and by ECG monitoring in DM/Q phase 3 clinical trials. In the TQT studies, twice daily DM/Q 30mg/10mg (Study 08-AVR-126; N=50 enrolled) and supratherapeutic doses 30mg/30mg and 60mg/60mg (Study 05-AVR-119; N=36 enrolled) were studied in healthy volunteers. In phase 3 controlled clinical trials, the effects of DM/Q on Fridericia’s corrected QT intervals (QTcF) were assessed, as was the incidence of ECG outliers. Adverse events (AEs) were monitored in all clinical trials.

Overall, 47/50 participants completed TQT study 08-AVR-126 and 36/36 completed TQT study 05-AVR-119. Time-matched, placebo-corrected mean maximal changes in QTcF for DM/Q 30mg/10mg and 30mg/30mg occurred 3h post-dose (10.3 and 10.1ms, respectively) vs moxifloxacin (12.2 and 14.4ms at 1.5 and 1.0h). For the supratherapeutic DM/Q 60/60 mg dose, mean maximal QTcF change was 18.8ms. No participant had a QTcF >480 ms or QTc increase >60 ms. In PBA phase 3 controlled trials, mean changes in QTcF were similar for DM/Q containing Q 10 mg (0.4 to 3.5 ms; n=217) andplacebo (0.4 to 3.1 ms; n=183), but greater for DM/Q with Q 30 mg (2.9 to 7.6 ms; n=146). In an outlier analysis, a similar percentage of DM/Q-treated participants (3.9%) had a QTcF shift from <450 ms at baseline to ≥450 ms during treatment vs placebo (2.9%). No participant with PBA had a QTc change from baseline >60 ms or an absolute QTc interval >480 ms. No dose- or time-related trends in cardiac arrhythmias or other cardiac-related AEs were observed.

Of 2552 DM/Q-treated patients and healthy participants across all controlled and open-label trials for any indication, 11 deaths due to any cardiovascular AE have been reported; none were attributable to DM/Q treatment and none occurred in placebo-controlled PBA clinical trials in any treatment group. Overall 16 patients had a QTcF that exceeded 500 ms at any ECG measurement.

The TQT studies demonstrated that DM/Q has the potential to prolong the QT interval in a dose-dependent manner, but that the risk for QTc prolongation and arrhythmias with Q 10 mg formulations is low. In clinical trials with PBA patients, the cardiac safety profile of DM/Q 20mg/10mg or 30/10 mg was indistinguishable from placebo.

Avanir Pharmaceuticals, Inc.