General Information

Northera (droxidopa) is a synthetic amino acid precursor of norepinephrine. Norepinephrine increases blood pressure by inducing peripheral arterial and venous vasoconstriction.

Northera is specifically indicated for the treatment of orthostatic dizziness or lightheadedness in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (Parkinson's disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy.

Northera is supplied as a capsule for oral administration. The recommended starting dose is 100 mg three times during the day. It may be titrated by 100 mg three times daily, up to a maximum dose of 600 mg three times daily. Northera should be administered consistently with or without food. To reduce the potential for supine hypertension, elevate the head of the bed and give the last dose at least 3 hours prior to bedtime. The effectiveness of Northera beyond 2 weeks is uncertain, and patients should be evaluated periodically to determine whether Northera is continuing to provide a benefit.

Mechanism of Action

Northera (droxidopa) is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which is extensively distributed throughout the body. The exact mechanism of action of Northera in the treatment of neurogenic orthostatic hypotension is unknown. Northera is believed to exert its pharmacological effects through norepinephrine and not through the parent molecule or other metabolites. Norepinephrine increases blood pressure by inducing peripheral arterial and venous vasoconstriction.

Side Effects

Adverse events associated with the use of Northera may include, but are not limited to, the following:

• headache
• dizziness
• nausea
• hypertension
• fatigue

The Northera drug label comes with the following Black Box Warning: Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses. Elevating the head of the bed lessens the risk of supine hypertension, and blood pressure should be measured in this position. If supine hypertension cannot be managed by elevation of the head of the bed, reduce or discontinue Northera.

Clinical Trial Results

The FDA approval of Northera was based on short-term (1 to 2 weeks) and longer-term period (8 weeks; 3 months) studies. Thee studies showed a treatment effect of Northera at Week 1, but none of the studies demonstrated continued efficacy beyond two weeks of treatment.
Study 306B
This was a multi-center, double-blind, randomized, placebo-controlled, parallel-group study in subjects with symptomatic NOH and Parkinson’s disease. Subjects entering the study were required to have a decrease of at least 20 mmHg or 10 mmHg, respectively, in systolic or diastolic blood pressure, within 3 minutes after standing, as well as symptoms associated with neurogenic orthostatic hypotension. The study had an initial dose titration period that lasted up to two weeks in which subjects received placebo or 100 to 600 mg of Northera three times daily, followed by an 8-week treatment period. Efficacy was measured using the OHSA Item #1 score (dizziness, lightheadedness, feeling faint, and feeling like you might black out) at Week 1, in subjects who had completed titration and 1 week of maintenance therapy. A total of 171 subjects were enrolled, and 147 were included in the efficacy analysis. In both groups, the mean baseline dizziness score was 5.1 on an 11-point scale. At Week 1, subjects showed a statistically significant mean 0.9-unit decrease in dizziness with Northera versus placebo (p = 0.028), but the effect did not persist beyond Week 1. Subjects receiving Northera also had a greater increase, compared to placebo, in the Week 1 lowest standing systolic blood pressure within 3 minutes after standing (5.6 mmHg; p = 0.032).
Study 301
This multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study included an initial open-label dose titration period, a 7-day washout period, and a randomized double-blind 7-day treatment period. To be eligible for enrollment, subjects were required to have a decrease in systolic or diastolic blood pressure of at least 20 or 10 mmHg, respectively, within 3 minutes after standing. The study was enriched, such that only subjects who had been identified as ‘responders’ during the titration period were randomized to Northera or placebo. To be considered a responder, a patient had to demonstrate improvement on the OHSA Item #1 score by at least 1 point, as well as an increase in systolic blood pressure of at least 10 mmHg post-standing, during the open-label dose titration period. 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. The OHQ includes OHSA Item #1 as one of several components. A statistically significant treatment effect was not demonstrated on OHQ (treatment effect of 0.4 unit, p-value=0.19). The mean baseline dizziness score on OHSA Item #1 (dizziness, lightheadedness, feeling faint, and feeling like you might black out) was 5.2 units on an 11-point scale. At Week 1 of treatment, patients showed a mean 0.7 unit decrease in dizziness with Northera versus placebo (p=0.06).
Study 302 was a placebo-controlled 2-week randomized withdrawal study of Northera in 101 subjects with symptomatic NOH. Study 303 was an extension of studies 301 and 302, where 75 subjects received their titrated dose of Northera for 3 months and then entered a 2-week randomized withdrawal phase. Neither study showed a statistically significant difference between treatment arms on its primary endpoint. Considering these data, the effectiveness of Northera beyond 2 weeks is uncertain, and subjects should be evaluated periodically to determine whether Northera is continuing to provide a benefit.