Northera Blue Flamingo
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NORTHERA trials, data, and experience

Northera Blue Flamingo
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NORTHERA trials, data, and experience

Clinical Trials

Study 306B:

Study design

  • Study 306B (efficacy population, NORTHERA® [droxidopa] n=69; placebo n=78) was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study in PD patients with symptomatic nOH (mean age of patients, 72 years)1,2
  • The study had a dose titration period that lasted up to 2 weeks in which patients received placebo or NORTHERA (100 mg to 600 mg) 3 times daily, followed by an 8-week stable-dose treatment period1,2
Primary efficacy endpoint

The primary endpoint was change in Item 1 on the Orthostatic Hypotension Symptom Assessment (OHSA) scale at Week 1. Item 1 assessed patients’ self-reported symptom ratings for dizziness, lightheadedness, feeling faint, or “feeling like you might black out.”1,2

Key inclusion criteria2

Number 1 icon

Clinical diagnosis of PD with symptomatic nOH

Number 2 icon

Documented decrease in systolic blood pressure (SBP) ≥20 mm Hg or diastolic blood pressure (DBP) ≥10 mm Hg within 3 minutes of standing

Key exclusion criteria2,3

  • Taking vasoconstricting agents (e.g., ephedrine, dihydroergotamine, or midodrine) within 2 days or 5 half-lives (whichever was longer) of study entry
  • Taking long-acting antihypertensive medication (use of short-acting antihypertensive medications at bedtime was permitted)
  • Sustained severe hypertension (SBP ≥180 mm Hg or DBP ≥110 mm Hg in the seated or supine position, which was observed in 3 consecutive measurements over an hour)
  • Significant uncontrolled cardiac arrhythmia, unstable angina, congestive heart failure, or a history of myocardial infarction
  • A score of ≤23 on the Mini-Mental State Examination

Discontinuations

  • There were more premature discontinuations in the NORTHERA group (28%)a vs the placebo group (20%)b during the study2
    • 24 randomized patients (18 NORTHERA, 6 placebo) dropped out of the study prior to the efficacy assessment at Week 12
    • 18 randomized patients (7 NORTHERA, 11 placebo) dropped out of the study after the efficacy assessment at Week 12
  • The most common reason for discontinuation from all randomized patients (NORTHERA n=89; placebo n=85) was adverse events: 10 patients (11.2%) in the NORTHERA group and 6 patients (7.1%) in the placebo group2

a Based on 89 patients; 2 patients on NORTHERA were randomized but never treated.2

b Based on 85 patients; 1 patient on placebo was randomized but never treated.2

Concomitant medications

Concomitant medication use was common in Study 306B for patients taking both droxidopa and placebo.2

  • 88% of NORTHERA patients and 94% of placebo-treated patients were taking dopa-decarboxylase inhibitors1
  • 26% of NORTHERA patients and 17% of placebo-treated patients were taking fludrocortisone1

Concomitant Medications in Phase 3 Trials Included1:

  • Levodopa/Carbidopa
  • Dopamine Agonists
  • Monoamine oxidase B (MAO-B) Inhibitors
  • Catechol-O-methyltransferase (COMT) Inhibitors
  • Other Medications Used to Treat PD

No dedicated drug-drug interaction studies were performed for droxidopa.1

DRUG INTERACTIONS

  • 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.
  • Dopa-decarboxylase inhibitors may require dosing adjustments for NORTHERA.
  • The concomitant use of selective MAO-B inhibitors, such as rasagiline or selegiline, was permitted in the NORTHERA clinical trials. However, based on mechanism of action, the use of non-selective MAO inhibitors and linezolid should be avoided as there is a potential for increased blood pressure when taken with NORTHERA.

Study 301c:

Study design

  • A Phase 3, multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group, induction-design study with an initial open-label dose titration, followed by a 7-day washout period. Patients were then randomized into droxidopa and placebo groups. Randomization to end of study was 1 week (total efficacy population, n=162)2

Primary efficacy endpoint

  • The primary efficacy endpoint was the mean change from randomization to the end of study in the Orthostatic Hypotension Questionnaire (OHQ) composite score, 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 components1,2

Study 302d:

Study design

  • A Phase 3, multicenter, multinational, randomized, placebo-controlled, double-blind, parallel-group withdrawal study. Open-label dose titration of droxidopa (up to 14 days) was followed by 7 days of open-label treatment. Patients were then randomized to droxidopa or placebo for 14 days (total efficacy population, n=101)2

Primary efficacy endpoint

  • The primary efficacy endpoint was mean change from randomization to Day 14 on the OHSA Item 1 (dizziness, lightheadedness, and “feeling like you might black out”)2

Study 303e:

Study design

  • A Phase 3, multicenter, multinational, 12-month, open-label study of the safety and efficacy of droxidopa that included a 2-week, double-blind, randomized-withdrawal, placebo-controlled period (following the first 3-month open-label droxidopa treatment) to evaluate the long-term effects of droxidopa treatment (total efficacy population, n=75). All patients entered this study from a prior droxidopa study (Study 301 or Study 302)2

Primary efficacy endpoint

  • The primary efficacy endpoint was mean change from randomization to Day 14 in the OHQ composite score following 3-month open-label droxidopa treatment2

cStudy 301 included patients with primary autonomic failure and non-diabetic autonomic neuropathy with symptomatic nOH.2
dStudy 302 included patients with primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy with symptomatic nOH.2
eStudy 303 included patients with primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy with symptomatic nOH.2

Results

Studies 301, 302, and 303 failed to reach statistical significance in their primary endpoint analyses. 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.1

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Find out more about adverse reactions reported during clinical trials and other safety considerations.1

 

SEE SAFETY CONSIDERATIONS
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Find out how NORTHERA is metabolized in the body.

SEE PHARMACOLOGY

References:

1. NORTHERA [package insert]. Deerfield, IL: Lundbeck. 2. Data on file. Deerfield, IL: Lundbeck. 3. Hauser RA, Isaacson S, Lisk JP, et al. Mov Disord. 2015;30(5):646-654.

Please see Important Safety Information, including Boxed Warning for supine hypertension.

For more information, see the full Prescribing Information.

Indications and Usage

NORTHERA (droxidopa) is indicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension (nOH) caused by primary autonomic failure (Parkinson’s disease [PD], multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Effectiveness beyond 2 weeks of treatment has not been established. The continued effectiveness of NORTHERA should be assessed periodically.

Important Safety Information

WARNING: SUPINE HYPERTENSION

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.

CONTRAINDICATIONS

  • NORTHERA is contraindicated in patients who have a history of hypersensitivity to the drug or its ingredients.

WARNINGS AND PRECAUTIONS

  • Supine Hypertension: NORTHERA therapy may cause or exacerbate supine hypertension in patients with nOH, which may increase the risk of cardiovascular events if not well managed, particularly stroke.
  • Hyperpyrexia and Confusion: Cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported with NORTHERA use during post-marketing 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 therapy may exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure. Careful consideration should be given to this potential risk prior to initiating therapy.
  • Allergic Reactions: Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, urticaria, and rash have been reported in post-marketing experience, with some resulting in emergency treatment. If a hypersensitivity 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.

ADVERSE REACTIONS

  • The most common adverse reactions (>5% and ≥3% difference compared to placebo) were headache, dizziness, nausea, and hypertension.

DRUG INTERACTIONS

  • 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.
  • Dopa-decarboxylase inhibitors may require dose adjustments for NORTHERA.
  • The concomitant use of selective MAO-B inhibitors, such as rasagiline or selegiline, was permitted in the NORTHERA clinical trials. However, based on mechanism of action, the use of non-selective MAO inhibitors and linezolid should be avoided as there is a potential for increased blood pressure when taken with NORTHERA.

USE IN SPECIFIC POPULATIONS

  • There are no available data on use of NORTHERA in pregnant women and risk of major birth defects or miscarriage. Because of the potential for serious adverse reactions, including reduced weight gain in breastfed infants, advise a woman not to breastfeed during treatment with NORTHERA.
  • The safety and effectiveness of NORTHERA in pediatric patients have not been established. No overall differences in safety or effectiveness were observed between patients aged 75 years and older and younger patients in clinical trials, but greater sensitivity of some older individuals cannot be ruled out.
  • Clinical experience with NORTHERA in patients with severe renal function impairment (GFR <30 mL/min) is limited; therefore, dosing recommendations cannot be provided for these patients.

For more information, please see the full Prescribing Information, including Boxed Warning for supine hypertension.