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Northera

"The U.S. Food and Drug Administration today approved Northera capsules (droxidopa) for the treatment of neurogenic orthostatic hypotension (NOH). NOH is a rare, chronic and often debilitating drop in blood pressure upon standing that is associate"...

Northera

CLINICAL PHARMACOLOGY

Mechanism Of Action

The exact mechanism of action of NORTHERA in the treatment of neurogenic orthostatic hypotension is unknown. NORTHERA is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopadecarboxylase, which is extensively distributed throughout the body. 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. NORTHERA in humans induces small and transient rises in plasma norepinephrine.

Pharmacodynamics

Peak droxidopa plasma concentrations are associated with increases in systolic and diastolic blood pressures. Droxidopa has no clinically significant effect on standing or supine heart rates in patients with autonomic failure.

Cardiac Electrophysiology

No prolongation of the QTc interval was observed with NORTHERA at single oral doses up to 2,000 mg, as shown in a dedicated thorough QT study.

Pharmacokinetics

Absorption

Peak plasma concentrations (Cmax) of droxidopa were reached by 1 to 4 hours post-dose (mean of approximately 2 hours) in healthy volunteers. High-fat meals have a moderate impact on droxidopa exposure with Cmax and area under the plasma concentration-time curve (AUC) decreasing by 35% and 20% respectively. The Cmax was delayed by approximately 2 hours with a high-fat meal.

Distribution

Pre-clinical studies suggest that droxidopa can cross the blood brain barrier. Droxidopa exhibits plasma protein binding of 75% at 100 ng/mL and 26% at 10,000 ng/mL. The estimated apparent volume of distribution of droxidopa is about 200 L in humans.

Metabolism

The metabolism of droxidopa is mediated by catecholamine pathway and not through the cytochrome P450 system. Droxidopa is initially converted to methoxylated dihydroxyphenylserine (3-OM-DOPS), a major metabolite, by catechol-O-methyltransferase (COMT), to norepinephrine by DOPA decarboxylase (DDC), or to protocatechualdehyde by DOPS aldolase. After oral dosing in humans, plasma norepinephrine levels peak within 3 to 4 hours but are generally very low (less than 1 ng/mL) and variable with no consistent relationship with dose. The contribution of the metabolites of droxidopa other than norepinephrine to its pharmacological effects is not well understood.

Excretion

The mean elimination half-life of droxidopa is approximately 2.5 hours in humans. The major route of elimination of droxidopa and its metabolites is via the kidneys in both animals and in humans. Studies in animals showed that ~75% of the radiolabeled dose was excreted in urine within 24 hours of oral dosing.

Special Populations

There are no clinically relevant effects of age, body mass index or sex on the pharmacokinetics of droxidopa. A population pharmacokinetic analysis suggests that hepatic function, assessed by aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin, did not influence t h e exposure to droxidopa. The controlled clinical trials included patients with mild to moderate renal impairment. No dose adjustments are required in patients with mild to moderate renal impairment.

Drug Interactions

No dedicated drug-drug interaction studies were performed for droxidopa. Patients in the Phase 3 trials with NORTHERA received concomitant levodopa/carbidopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors and other medications used to treat Parkinson's Disease. Carbidopa, a peripheral dopa-decarboxylase inhibitor, could prevent the conversion of NORTHERA to norepinephrine outside of the central nervous system (CNS). Patients taking NORTHERA with L-DOPA/dopa-decarboxylase inhibitor combination drugs had decreased clearance of NORTHERA, an increase in exposure (AUC) to droxidopa of approximately 100%, and an increase in exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events. Dopamine agonists, amantadine derivatives, and MAO-B inhibitors do not appear to affect NORTHERA clearance, and no dose adjustments are required.

Animal Toxicology And Pharmacology

Rats and mice treated for 52 and 80 weeks, respectively, at doses similar to human doses (100-300 mg/kg/day for rats and 300-1000 mg/kg/day for mice) had increased incidences of renal and cardiac lesions (rats and mice) and deaths (rats only). No signs of toxicity were observed in monkeys or dogs given droxidopa for 13 weeks at doses 32 times (3000 mg/kg/day) and 37 times (2000 mg/kg/day), respectively, the maximum recommended total daily dose of 1800 mg in a 60 kg patient, when based on body surface area.

Clinical Studies

Studies In Neurogenic Orthostatic Hypotension

Clinical studies (described below) examined the efficacy of NORTHERA in the short-term (1 to 2 weeks) and over longer-term periods (8 weeks; 3 months). Studies 301 and 306B showed a treatment effect of NORTHERA at Week 1, but none of the studies demonstrated continued efficacy beyond 2 weeks of treatment. Study 306B was a multi-center, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic NOH and Parkinson's disease. Patients 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 2 weeks in which patients 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 patients who had completed titration and 1 week of maintenance therapy. A total of 171 patients were enrolled, and 147 patients were included in the efficacy analysis. The mean age was 72 years, and patients were mostly Caucasian. During the study, 94% of placebo treated patients and 88% on NORTHERA were taking dopa-decarboxylase inhibitors; 17% of placebo-treated patients and 26% on NORTHERA were taking fludrocortisone. There were more premature discontinuations in the NORTHERA group (28%) than in the placebo group (20%).

In both groups, the mean baseline dizziness score was 5.1 on an 11-point scale. At Week 1, patients 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. The data at all time points are shown in Figure 1.

Patients 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).

Figure 1: Mean Change in OHSA Item 1 score by week in Study 306B

Mean Change in OHSA Item 1 score by week - Illustration

Note: The graph is based on observed data only. The error bars are the 95% confidence interval of the mean change from baseline in OHSA Item 1 scores.

Figure 2 shows the distribution of changes from Baseline to Week 1 in the OHSA Item #1 score. Overall the figure shows that patients treated with NORTHERA improved more than those treated with placebo.

Figure 2: Distribution of Patients by Change in OHSA Item 1, Baseline to Week 1, in Study 306B

Distribution of Patients by Change in OHSA Item 1, Baseline to Week 1 - Illustration

Study 301 was a multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic neurogenic orthostatic hypotension. The 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, patients 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 patients 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.

Patients who dropped out during the titration period because of side effects or other reasons were also not included in the double-blind portion of the study.

Patients had a primary diagnosis of Parkinson's Disease (n=60), pure autonomic failure (n=36), or multiple system atrophy (n=26). The mean age was 60 years, and most were Caucasian. 45% of patients were taking dopadecarboxylase inhibitors, and 29% were taking fludrocortisone.

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 (n=101) was a placebo-controlled 2-week randomized withdrawal study of NORTHERA in patients with symptomatic NOH. Study 303 (n=75) was an extension of studies 301 and 302, where patients 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 patients should be evaluated periodically to determine whether NORTHERA is continuing to provide a benefit.

Last reviewed on RxList: 2/27/2014
This monograph has been modified to include the generic and brand name in many instances.

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