Journal of the American Society of Hypertension -(-) (2016) 1–8 Research Article Long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension Stuart Isaacson, MDa,*, Steven Vernino, MD, PhDb, Adam Ziemann, MD, PhDc,1, Gerald J. Rowse, PhDc,1, Uwa Kalu, MD, MPH, MBAc, and William B. White, MD, FASHd aParkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA; bDepartment of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA; cLundbeck LLC, Deerfield, IL, USA; and dDivision of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT 06032, USA Manuscript received May 13, 2016 and accepted July 18, 2016 Abstract The long-term safety of droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension in patients with Par- kinson disease, pure autonomic failure, multiple system atrophy, or nondiabetic autonomic neuropathy was evaluated in a phase 3, multinational, open-label study in patients who previously participated in a double-blind, placebo-controlled clinical trial of droxidopa. A total of 350 patients received droxidopa 100 to 600 mg three times daily. Mean duration of droxidopa exposure was 363 days (range, 2–1133 days). Rates of serious adverse events (AEs), cardiac-related AEs, and supine hyper- tension were 24%, 5%, and 5%, respectively. Most AEs, including those of a cardiovascular nature, were not attributed by investigators to droxidopa. In this large cohort of patients with neurogenic orthostatic hypotension, droxidopa was well toler- ated during long-term use. J Am Soc Hypertens 2016;-(-):1–8. Ó 2016 The Authors. Published by Elsevier Inc. on behalf of American Society of Hypertension. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Keyword: Supine hypertension. Introduction Conflict of interest: S.I. has received compensation from Lund- Neurogenic orthostatic hypotension (nOH) refers to beck LLC for consulting, speaking, and research activities. S.V. decreased blood pressure (BP) during head-up posture has received personal compensation from Lundbeck for advisory board and speaker bureau activities, consulting fees from Athena change (ie, standing or head-up tilt) resulting from auto- Diagnostics (Quest), and compensation as an associate editor of nomic failure. Failure of the sympathetic baroreflex results JAMA Neurology. U.K. is an employee of Lundbeck, which in inadequate norepinephrine release from sympathetic 1 funded this study; A.Z. and G.J.R. were Lundbeck employees at nerves innervating the blood vessels and heart. Autonomic the time of contribution. W.B.W. is a safety consultant for Lund- failure occurs in several central and peripheral neurologic beck LLC. No author received compensation for preparation or disorders, including Parkinson disease (PD), multiple sys- writing of this manuscript. tem atrophy (MSA), pure autonomic failure, and peripheral Financial support for research conduct and manuscript prepara- autonomic neuropathy.1,2 Estimates suggest that nOH is tion was provided by Lundbeck LLC. Lundbeck participated in present in 37% to 58% of patients with PD, 75% of patients study design; data analysis and interpretation; and the decision with MSA, and 100% of patients with pure autonomic fail- to submit the article for publication. ure.3 Orthostatic hypotension is associated with significant *Corresponding author: Stuart Isaacson, MD, Parkinson’s Dis- 4 ease and Movement Disorders Center of Boca Raton, 951 NW morbidity and mortality ; patients with nOH have an 13th Street, Bldg 5-E, Boca Raton, FL 33486, USA. Tel: þ1- increased risk of cardiovascular complications as well 561-392-1818; Fax: þ1-561-392-8989. (eg, heart failure, atrial fibrillation), and many have coexist- E-mail: [email protected] ing cardiovascular comorbidities (eg, hypertension, cardiac, 1 At the time the study was conducted and analyzed. or cerebrovascular conditions).4,5 1933-1711/$ - see front matter Ó 2016 The Authors. Published by Elsevier Inc. on behalf of American Society of Hypertension. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jash.2016.07.010 2 S. Isaacson et al. / Journal of the American Society of Hypertension -(-) (2016) 1–8 Droxidopa is an oral norepinephrine prodrug approved in Treatments the United States for the treatment of symptomatic nOH in patients with primary autonomic failure (PD, MSA, pure Droxidopa was administered at doses of 100 to 600 mg autonomic failure), dopamine b-hydroxylase deficiency, in 100-mg increments taken three times daily (TID); doses or nondiabetic autonomic neuropathy (NDAN).6 In short- were taken upon waking and at approximately 4-hour inter- term phase 3 trials, droxidopa significantly improved the vals to allow the last dose to be taken in the late afternoon hallmark symptoms of nOH (eg, orthostatic dizziness, and early enough before bedtime to minimize the risk of lightheadedness, or the ‘‘feeling like you are about to black hypertension during sleep (ie, supine hypertension). Pa- out’’), with patients reporting improved symptom severity tients received individualized doses that had been identified and impact on daily activities compared with placebo.7–9 during the titration period of a previous study, with some Droxidopa also increased standing systolic BP (SBP) in exceptions: all patients who entered the present study these patients.9,10 Short-term treatment with droxidopa from the 8- to 10-week double-blind study underwent was well tolerated in these studies, and most adverse events dose titration in the present study. At the discretion of (AEs) were mild or moderate in severity.7–9 The incidence the treating investigator physician, droxidopa doses could of supine hypertension, defined as SBP >180 mm Hg, be adjusted up or down in single steps for efficacy or ranged from 5% to 14%. Rates of other cardiovascular safety. Dose escalation was stopped if the patient had sus- > > events were low (eg, coronary artery disease, hypertension tained SBP 180 mm Hg or DBP 110 mm Hg in the su- [0%–8%]). pine (or semirecumbent) position was unable to tolerate Previous trials evaluated the efficacy and safety of drox- side effects believed to be related to the study drug or idopa over relatively short treatment durations of 1–2 and reached the maximum dose of droxidopa (600 mg TID; 8–10 weeks.7–9 The objective of the present study was to 1800 mg/d). evaluate the long-term safety of droxidopa for the treatment Scheduled assessments were conducted at months 1 and of symptomatic nOH based on frequency and type of AEs, 3, and every 3 months thereafter. Vasoconstricting agents BP and heart rate, and laboratory findings. (eg, ephedrine, dihydroergotamine, midodrine), tryptamine- based drugs (triptans; eg, sumatriptan), cyclopropane or halogen-containing inhalational anesthetics (eg, halothane), Methods catecholamine-containing preparations (eg, isoproterenol This was a phase 3, multinational, multicenter, open- [isoprenaline]), nonselective monoamine oxidase inhibi- label study in ambulatory patients with symptomatic nOH tors, long-acting antihypertensives, and ergotamine deriva- that assessed the long-term safety of droxidopa tives (except medications for PD) were prohibited during (ClinicalTrials.gov identifier, NCT01132326). Patients the study. Fludrocortisone was permitted, as were all PD entering this long-term study were required to have drugs. participated in a prior short-term,9 8- to 10-week,8,10 or 11,12 1-year double-blind, placebo-controlled droxidopa Assessments trial. This long-term, open-label study was conducted be- tween February 2009 and October 2012. AEs, vital signs, and laboratory testing results were re- corded at each clinic visit. Investigators classified AEs by Patients severity after obtaining the patient’s medical history. Labo- ratory testing included hematology, chemistry, and urinaly- Eligible patients were 18 years of age with symptom- sis; women of childbearing potential underwent a atic nOH (defined as a 20-mm Hg reduction in SBP on pregnancy test at each study visit. Vital sign assessment standing) associated with PD, MSA, pure autonomic fail- included BP (measured using the same calibrated equip- ure, or NDAN. Key exclusion criteria included use of vaso- ment at each visit), heart rate, temperature, and weight. constricting agents or long-acting antihypertensive medications, uncontrolled cardiac arrhythmias, a history Data Analyses of myocardial infarction within the past 2 years, current un- stable angina, uncompensated congestive heart failure All patients who received at least 1 dose of droxidopa (New York Heart Association Class III or IV), or diabetic were evaluated for safety. Continuous variables were sum- autonomic neuropathy. Patients with sustained severe hy- marized descriptively; frequencies and percentages were pertension (defined as SBP 180 mm Hg or diastolic BP calculated for categorical variables. In comparisons with [DBP] 110 mm Hg) were also excluded. To assess for baseline, baseline values reflect evaluations performed the presence of severe hypertension, BP was measured in before the first dose of study treatment in a short-term, dou- a supine (ie, semirecumbent; head and torso elevated ble-blind study unless the last visit in these studies occurred approximately 30-degrees from horizontal) or seated posi- >1