FDA approves droxidopa to treat neurogenic orthostatic hypotension

Kevin ChamberlinNeurogenic orthostatic hypotension (NOH) is a rare, chronic, and debilitating drop in blood pressure upon standing that is associated with Parkinson’s disease, multiple-system atrophy, and pure autonomic failure. Droxidopa (Northera, Chelsea Therapeutics) is a synthetic amino acid precursor of norepinephrine indicated for the treatment of orthostatic dizziness or lightheadedness in adult patients with symptomatic NOH caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Droxidopa was approved as oral therapy in February 2014 under the FDA’s accelerated approval program. 

Efficacy

As a norepinephrine precursor, droxidopa is metabolized to norepinephrine by dopa-decarboxylase, causing an increase in blood pressure by inducing peripheral and venous vasoconstriction.  Clinical studies examined the efficacy of droxidopa in both short- and long-term periods. Two studies in the package insert showed a treatment effect of droxidopa at week one, but none of the studies demonstrated continued efficacy beyond two weeks of treatment. 

Study 306B was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 147 subjects with symptomatic NOH and Parkinson’s disease. Eligible patients had symptoms of NOH and a decrease of at least 20 mm Hg systolic or 10 mm Hg diastolic within three minutes after standing.  A two-week dose titration period, in which subjects received either placebo or 100 or 600 mg of droxidopa three times a day, was followed by an eight-week treatment period. Efficacy was measured using the Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 score (dizziness, lightheadedness, feeling faint, and feeling like you might black out) at week one.  At week one, subjects showed a statistically significant mean 0.9-unit decrease in dizziness with droxidopa versus placebo (p=0.028); however, the effect did not persist beyond week one.

Study 301 was a multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study that included an initial open-label dose titration period, a seven-day washout period, and a randomized, double-blind, seven-day treatment period. Eligibility criteria were the same as for study 306B, but subjects also had to be considered a responder. Efficacy was measured using the Orthostatic Hypotension Questionnaire (OHQ), a patient-reported outcome that measures symptoms of NOH and their impact on the patient’s ability to perform daily activities that require standing and walking.  A statistically significant treatment effect was not demonstrated on OHQ (treatment effect of 0.4 unit, p=0.19).  Patients showed a 0.7-unit decrease in their dizziness score on OHSA Item #1 with droxidopa versus placebo (p=0.06).

Safety

Droxidopa has a black box warning for supine hypertension and supine blood pressure needs to be monitored prior to and during treatment, especially when increasing doses. Elevating the head of the bed lessens the risk, and blood pressure should be measured in that position. 

Falls (24%), urinary tract infections (15%), headache (13%), syncope (13%), and dizziness (10%) were the most commonly reported adverse effects with droxidopa. In post-marketing cases, droxidopa was found to induce a symptom complex resembling that of neuroleptic malignant syndrome (NMS). Patients taking droxidopa should be observed closely and carefully when dose adjustments are made, or when concomitant levodopa is reduced or discontinued. Additionally, droxidopa was found to potentiate existing ischemic heart disease, arrhythmias, and congestive heart failure, and these patients should be given special consideration prior to initiating droxidopa therapy.

Droxidopa is a pregnancy category C with no adequate or well-controlled published trials in pregnant women.  Likewise, insufficient data for lactating women exists.Pediatric safety data has not been established.  No overall differences in safety or efficacy were observed in geriatric patients with NOH taking droxidopa.

Dosing

Droxidopa is supplied as 100-, 200-, and 300-mg hard gelatin capsules in 90-count bottles for oral use only. Droxidopa should be taken whole with or without food at the same times each day, starting as 100 mg three times a day (morning, midday, and three hours before bedtime). The last dose should be taken at least three hours before bedtime as a means of reducing the risk of supine hypertension. Dosing may be titrated by 100-mg increments every 24-48 hours, with a maximum dose of 600 mg three times a day.  Droxidopa does not have enough data for use in patients with hepatic impairment.

Kevin W. Chamberlin, PharmD, is assistant clinical professor and assistant department head, pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.