Current Medical Research and Opinion ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20 An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions Gary L. Pattee, James P. Wymer, Catherine Lomen-Hoerth, Stanley H. Appel, Andrea E. Formella & Laura E. Pope To cite this article: Gary L. Pattee, James P. Wymer, Catherine Lomen-Hoerth, Stanley H. Appel, Andrea E. Formella & Laura E. Pope (2014) An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions, Current Medical Research and Opinion, 30:11, 2255-2265, DOI: 10.1185/03007995.2014.940040 To link to this article: https://doi.org/10.1185/03007995.2014.940040 © 2014 The Author(s). Published by Taylor & View supplementary material Francis. Accepted author version posted online: 25 Submit your article to this journal Jul 2014. Published online: 28 Jul 2014. Article views: 1684 View related articles View Crossmark data Citing articles: 11 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Download by: ["University at Buffalo Libraries"] Date: 28 November 2017, At: 19:52 Current Medical Research & Opinion Vol. 30, No. 11, 2014, 2255–2265 0300-7995 Article FT-0229.R1/940040 doi:10.1185/03007995.2014.940040 All rights reserved: reproduction in whole or part not permitted Original article An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions Gary L. Pattee Abstract Neurology Associates, Lincoln, NE, USA Background: James P. Wymer Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and The Neurosciences Institute, Albany Medical Center, characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or Albany, NY, USA unrelated to the patient’s emotional state. Clinical trials establishing dextromethorphan and quinidine Catherine Lomen-Hoerth (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple Department of Neurology, University of California, San sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition Francisco, CA, USA affecting the brain. Stanley H. Appel Department of Neurology, Methodist Neurological Objective: Institute, The Methodist Hospital Research Institute, To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA The Methodist Hospital, Houston, TX, USA associated with multiple neurological conditions. Andrea E. Formella Methods: Laura E. Pope Fifty-two-week open-label study of DM/Q 30/30 mg twice daily. Safety measures included adverse events Avanir Pharmaceuticals Inc., Aliso Viejo, CA, USA (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. Address for correspondence: Clinical trial registration: Gary L. Pattee MD, Neurology Associates, PC, 2631 #NCT00056524. South 70th Street, Lincoln, NE 68506, USA. Tel.: +1 402 483 7226; Fax: +1 402 483 5440; [email protected] Results: Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 A total of 553 PBA patients with430 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache Keywords: (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly Dextromethorphan/quinidine – Pseudobulbar affect – Safety – Tolerability mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory Accepted: 26 June 2014; published online: 28 July 2014 failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no Citation: Curr Med Res Opin 2014; 30:2255–65 clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose. Conclusions: DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions. ! 2014 Informa UK Ltd www.cmrojournal.com Safety of dextromethorphan/quinidine in PBA Pattee et al. 2255 Current Medical Research & Opinion Volume 30, Number 11 November 2014 Introduction were instructed to take DM/Q 30/30 mg in the evening for 7 days and then twice daily thereafter. Patients kept a Pseudobulbar affect (PBA) is a neurological condition that diary of dosage times and recorded any adverse events exerts a significant health burden on patients and care- (AEs). Clinic visits occurred at screening, baseline 1 givers . PBA is associated with a wide range of neuro- (Day 1), and after 1, 4, 8, and 12 months of treatment or logical disorders and is characterized by frequent, sudden, at patient discontinuation. During months when no clinic uncontrollable episodes of crying and/or laughing that are visit was scheduled, patients were contacted by telephone greatly exaggerated or contrary to the patient’s emotional and asked about medication compliance and AEs. state2. Available prevalence studies suggest PBA is present in at least 5% of Parkinson’s disease (PD), 10% of multiple sclerosis (MS), stroke, traumatic brain injury (TBI), and Study population Alzheimer’s disease (AD), 20% of progressive supranuclear palsy, and up to 50% of amyotrophic lateral sclerosis Eligible patients were 18 to 75 years of age with a clinical (ALS) patients3–11. diagnosis of PBA. For the purposes of this study, PBA was PBA is thought to arise from disruption of corticobulbar defined as ‘a syndrome characterized by outbursts of crying and cerebellar/pontine pathways controlling emotional and/or laughing that occur spontaneously and inappropri- expression12–14. These pathways may be disrupted by mul- ately given the context in which they occur’. No specific tiple neurological conditions, yet the ensuing clinical threshold for severity of PBA symptoms was required for manifestations of PBA are indistinguishable, consistent study entry. Patients were required to have an electrocar- with a common etiology across disorders12–14. The com- diogram (ECG) with no evidence of rate-corrected QT bination of dextromethorphan and quinidine (DM/Q) is interval (QTc) prolongation (450 msec in men; the first pharmacotherapy approved by the US Food and 470 msec in women), heart block (isolated right bundle Drug Administration (FDA) and European Medicines branch block without clinical history of heart disease was Authority (EMA) for treating PBA15,16. allowable), sinus bradycardia (550 bpm), ventricular Dextromethorphan (DM) has many pharmacological tachycardia, multifocal ventricular ectopic beats (any fre- actions, including uncompetitive N-methyl-D-aspartate quency), or unifocal ventricular ectopic beats (45/min). (NMDA) receptor antagonism17, sigma-1 receptor agon- Patients with ALS were required to have a vital capacity ism18, and serotonin reuptake inhibition, among others; 50% at baseline. Patients completing prior controlled the precise mechanism(s) accounting for PBA suppression studies of twice daily DM/Q 30/30 mg to treat PBA in 23 22 is/are unknown19. DM is co-administered with low-dose MS or ALS were also eligible to participate, provided quinidine, a potent CYP2D6 inhibitor that reduces rapid they met all eligibility requirements at the time of enroll- first-pass metabolism of DM. This inhibition increases DM ment in this study. bioavailability and half-life20,21. The efficacy, safety, and Exclusion criteria were myasthenia gravis; a history of tolerability of DM/Q as PBA treatment was established in ventricular tachycardia or torsades de pointes; sensitivity three controlled clinical trials lasting 422 or 1223,24 weeks, to quinidine or opiate drugs; major psychiatric disturbance; using fixed-dose combinations of twice daily DM/Q 30/ a history of substance abuse in the past 2 years; any major 30 mg22,23, 30/10 mg24, or 20/10 mg24 in patients with systemic disease that would interfere with interpretation of ALS22,24 or MS23,24. The present trial was designed to pro- study results (e.g., malignancy, uncontrolled diabetes, vide long-term safety data using the higher DM/Q 30/ dilated cardiac myopathy, ischemic or valvular heart Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 30 mg dose in patients with PBA, regardless of primary disease); hypotension (systolic blood pressure [BP] neurological condition. 5100 mmHg); a history of postural or any unexplained syncope; renal, hepatic, or pulmonary disease; or clinically significant deviations in standard laboratory tests. Female patients could not be pregnant or breastfeeding; those with Methods child-bearing potential were required to use an established Study design method of birth control.