Dosing Information

The recommended starting dose of NORTHERA is 100 mg, taken orally three times daily: upon arising in the morning, at midday, and in the late afternoon at least 3 hours prior to bedtime (to reduce the potential for supine hypertension during sleep). Administer NORTHERA consistently, either with food or without food. Take NORTHERA capsule whole. Titrate to symptomatic response, in increments of 100 mg three times daily every 24 to 48 hours up to a maximum dose of 600 mg three times daily (i.e., a maximum total daily dose of 1,800 mg).

Monitor supine blood pressure prior to initiating NORTHERA and after increasing the dose.

Patients who miss a dose of NORTHERA should take their next scheduled dose.

Pregnancy

Risk Summary

Thereare no available data on use of NORTHERA in pregnant women and risk of majorbirth defects or miscarriage. NORTHERAdid not produce significant reproductive toxicity in pregnant female rats or rabbitsor in their fetuses. However, when pregnant female rats were dosed during days7-17 of gestation (the period of fetal organogenesis) with doses of NORTHERAcorresponding to 0.3, 1 and 3 times the maximum recommended daily dose of 1,800mg in a 60 kg patient, based on body surface area, and when their male andfemale offspring (who were exposed only during fetal life) were subsequentlybred, the female offspring exhibited a dose-dependent reduction in the numberof live fetuses across all three doses and an increased number ofembryonic/fetal deaths at the two higher doses (see Data).

The estimatedbackground risk of major birth defects and miscarriage in the indicatedpopulation is unknown. Inthe U.S. general population, the estimated background risk of major birthdefects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15to 20%, respectively.

Data

Animal Data

During a multigenerational reproductivetoxicity study in rats, pregnant females were dosedduring days 7-17 of gestation (the period of fetal organogenesis) with doses ofNORTHERA corresponding to 0.3, 1 and 3 times the maximum recommended daily doseof 1,800 mg in a 60 kg patient. Reduced weight gain, renal lesions, and a smallnumber of deaths were observed in females treated with the two higher doses.When their male and female offspring (who were exposed to NORTHERA only duringfetal life) were subsequently bred, the female offspring exhibited adose-dependent reduction in the number of live fetuses across all three dosesand an increased number of embryonic/fetal deaths at the two higher doses.

Lactation

Risk Summary

Thereis no information regarding the presence of NORTHERA or its activemetabolite(s) in human milk, the effects of NORTHERA on the breastfed child, northe effects of NORTHERA on milk production/excretion. Droxidopa is present in rat milk with peak concentrations seen 4 hours after oral drug administration and drug excretion into milk still occurring 48 hours after administration (see Data). However, due to species-specificdifferences in lactation physiology, animal lactation data typically do notreliably predict levels in humans. Because of the potential for seriousadverse reactions, including reduced weight gain in breastfed infants, advise awoman not to breastfeed during treatment with NORTHERA.

Data

Animal Data

Inrats, oral administration of droxidopa resulted in excretion into breast milkwith peak concentrations seen 4 hours after administration, and excretion stilloccurring 48 hours after administration. When the drug was administered tonursing dams during the period of lactation at a dose correspondingto 3 times the maximum recommended daily dose of 1,800 mg in a 60 kg patientwhen based on body surface area, reduced weight gain and reduced survival wereobserved in the offspring. Despite the observed decreased weight gain, physicaldevelopment was normal (with respect to timing and organ morphology).

Pediatric Use

The safety and effectiveness of NORTHERA in pediatric patients have not been established.

Geriatric Use

A total of 197 patients with symptomatic nOH aged 75 years or above were included in the NORTHERA clinical program. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment

NORTHERA and its metabolites are primarily cleared renally. Patients with mild or moderate renal impairment (GFR greater than 30 mL/min) were included in clinical trials and did not have a higher frequency of adverse reactions. Clinical experience with NORTHERA in patients with severe renal function impairment (GFR less than 30 mL/min) is limited.

Supine Hypertension

NORTHERA therapy may cause or exacerbate supine hypertension in patients with nOH. Patients should be advised to elevate the head of the bed when resting or sleeping. Monitor blood pressure, both in the supine position and in the recommended head-elevated sleeping position. Reduce or discontinue NORTHERA if supine hypertension persists. If supine hypertension is not well-managed, NORTHERA may increase the risk of cardiovascular events, particularly stroke.

Hyperpyrexia and Confusion

Postmarketing cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported with NORTHERA use during postmarketing surveillance. Observe patients carefully when the dosage of NORTHERA is changed or when concomitant levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes. The early diagnosis of this condition is important for the appropriate management of these patients.

Ischemic Heart Disease, Arrhythmias, and Congestive Heart Failure

NORTHERA may exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure. Careful consideration should be given to this potential risk prior to initiating therapy in patients with these conditions.

Allergic Reactions

Hypersensitivity reactions including anaphylaxis, angioedema,bronchospasm, urticaria and rash have been reported in postmarketingexperience. Some of these reactions resulted in emergency treatment. If ahypersensitivity reaction occurs, discontinue the drug and initiate appropriate therapy.

This product contains FD&C Yellow No. 5 (tartrazine) which may also cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity [see Contraindications ].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety evaluation of NORTHERA is based on two placebo-controlled studies 1 to 2 weeks in duration (Studies 301 and 302), one 8-week placebo-controlled study (Study 306), and two long-term, open-label extension studies (Studies 303 and 304). In the placebo-controlled studies, a total of 485 patients with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or non-diabetic autonomic neuropathy were randomized and treated, 245 with NORTHERA and 240 with placebo [see Clinical Studies ]. 

Placebo-Controlled Experience

The most commonly observed adverse reactions (those occurring at an incidence of greater than 5%  in the NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group) in NORTHERA-treated patients during the three placebo-controlled trials were headache, dizziness, nausea, and hypertension. The most common adverse reactions leading to discontinuation from NORTHERA were hypertension or increased blood pressure and nausea.

Note: n=number of patients. Adverse reactions that were reported in greater than 5% of patients in the NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group were from Study 306.

Long-Term, Open-Label Trials with NORTHERA
In the long-term, open-label extension studies, a total of 422 patients, mean age 65 years, were treated with NORTHERA for a mean total exposure of approximately one year. The commonly reported adverse events were falls (24%), urinary tract infections (15%), headache (13%), syncope (13%), and dizziness (10%).

 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NORTHERA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders:  Chest pain
Eye Disorders:  Blurred vision
Gastrointestinal Disorders: Pancreatitis, abdominal pain, vomiting, diarrhea
General Disorders and Administration Site Conditions:  Fatigue
Nervous System Disorders:  Cerebrovascular accident
Psychiatric Disorders:  Psychosis,hallucination, delirium, agitation, memory disorder

Drugs that Increase Blood Pressure

Administering NORTHERA in combination with other agents that increase blood pressure (e.g., norepinephrine, ephedrine, midodrine, and triptans) would be expected to increase the risk for supine hypertension.

Parkinson's Medications

Dopa-decarboxylase inhibitors may require dose adjustments for NORTHERA. 

Non-selective MAO Inhibitors

The concomitant use of selective MAO-B inhibitors,such as rasagiline or selegiline, was permitted in the NORTHERA clinicaltrials. However, based on mechanism of action, the use of non-selective MAOinhibitors and linezolid should be avoided as there is a potential forincreased blood pressure when taken with NORTHERA.

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 dopa­-decarboxylase, 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.

Elimination

The total clearance of droxidopa after oral administration (CL/F) wasapproximately 400 mL/hr following administration of a single 300 mg dose.

Metabolism

The metabolism of droxidopa is mediated by catecholamine pathway and notthrough the cytochrome P450 system. Droxidopais initially converted to methoxylated dihydroxyphenylserine (3-OM-DOPS), amajor metabolite, by catechol-O-methyltransferase (COMT), to norepinephrine byDOPA decarboxylase (DDC), or to protocatechualdehyde by DOPS aldolase. Afteroral dosing in humans, plasma norepinephrine levels peak within 3 to 4 hoursbut are generally very low (less than 1 ng/mL) and variable with no consistentrelationship with dose. The contribution of the metabolites of droxidopa otherthan norepinephrine to its pharmacological effects is not well understood.

Excretion

The mean elimination half-life of droxidopa is approximately2.5 hours in humans. The major route of elimination of droxidopa and itsmetabolites is via the kidneys in both animals and in humans. Studies inanimals with radiolabeled drug showed that ~75% of the administeredradioactivity was excreted in urine within 24 hours of oral dosing.  

Specific Populations

There are no clinically relevant effects of age, body mass index, or sex onthe pharmacokinetics of droxidopa. A population pharmacokinetic analysissuggests that hepatic function, assessed by aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin, did not influence the 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 Interaction Studies

No dedicated drug-drug interaction studies were performed for droxidopa. Patientsin the Phase 3 trials with NORTHERA received concomitant levodopa/carbidopa,dopamine agonists, MAO-B inhibitors, COMT inhibitors and other medications usedto treat Parkinson’s disease. Carbidopa,a peripheral dopa-decarboxylase inhibitor, could prevent the conversion ofNORTHERA to norepinephrine outside of the central nervous system (CNS). Patients taking NORTHERA withL-DOPA/dopa-decarboxylase inhibitor combination drugs had decreased clearanceof NORTHERA, an increase in overall exposure (AUC) to droxidopa of approximately100%, and an increase in overall exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was foundthat the decreased clearance was not associated with a significant need for adifferent 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 doseadjustments are required.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies have been conducted at dosages up to 1,000 mg/kg/day in mice and up to 100 mg/kg/day in rats with no indication of carcinogenic effects. Based on dose per unit body surface area, these two doses correspond to approximately 3 and 0.5 times, respectively, the maximum recommended total daily dose of 1,800 mg in a 60 kg patient. Droxidopa was clastogenic in Chinese hamster ovary cells (chromosome aberration assay), but was not mutagenic in bacteria (Ames assay), and was not clastogenic in a mouse micronucleus assay.

Studies in rats show that droxidopa has no effect on fertility.

Animal Toxicology and/or Pharmacology

In long-term chronic toxicity studies, rats and mice treated for 52 and 80 weeks, respectively, at doses up to 300 mg/kg/day in rats and 1,000 mg/kg/day in mice had increased incidences of renal and cardiac lesions (rats and mice) and deaths (rats only). The doses at which these effects were not seen represented 0.2 and 0.3 times, in rats and mice, respectively, the maximum recommended total daily dose of 1,800 mg in a 60 kg patient, when based on body surface area.

No signs of toxicity were observed in monkeys or dogs given droxidopa for 13 weeks at doses 32 times (3,000 mg/kg/day) and 37 times (2,000 mg/kg/day), respectively, the maximum human dose.

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 mm Hg or 10 mm Hg, 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 mm Hg; P=0.032).

Figure 1. Mean Change in OHSA Item 1 Score by Week in Study 306B 

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

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. 

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 mm Hg, 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 mm Hg 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 dopa-decarboxylase 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=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.