Effective Date

Date of Origin   

07-01-2024           

Northera®

(droxidopa)

Capsule*

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 should be assessed periodically.    

* Generic available

1

Orthostatic Hypotension

Orthostatic hypotension (OH) is defined as a blood pressure decrease greater than or equal to 20mmHg systolic or greater than or equal to 10mmHg diastolic recorded within 3 minutes after that patient stands.(2-6) OH can impair perfusion to organs above the heart, resulting in symptoms of hypoperfusion in these tissues. OH is a frequent problem in the general population, especially in the elderly.(2-4,6) The overall prevalence of OH in patients greater than 65 years is approximately 20%.(2) It can result from a variety of medical conditions, such as IV volume depletion, blood pooling from varicose veins, severe anemia, medications, and physical deconditioning. In these cases, OH usually improves once the underlying cause is treated. In a minority of patients, OH occurs due to decreased norepinephrine release from sympathetic nerves, which leads to defective vasoconstriction when in the upright position. This is referred to as neurogenic orthostatic hypotension (nOH). nOH occurs frequently in patients with neurodegenerative disorders such as Parkinson’s disease, Lewy Body dementia, multiple system atrophy, and pure autonomic failure, dopamine beta-hydroxylase deficiency and nondiabetic autonomic neuropathy.(2-6) An estimated 30-50% of Parkinson’s disease patients have nOH.(2,4) When present, symptoms are similar to those observed with OH. However, in contrast to vasovagal (neutrally mediated) syncope, syncope in nOH occurs without signs of autonomic activation such as diaphoresis, tachycardia, nausea, or abdominal discomfort.(2)  

The goal of nOH treatment is not to normalize standing blood pressure, but to reduce symptom burden so as to improve quality of life. The steps in management include: 1) correcting aggravating factors, 2) implementing non-pharmacological measures, and 3) drug therapies. The correction of aggravating factors includes management of medications contributing to the nOH through the reduction of IV volume, induction of vasodilation, and interference with norepinephrine. The correction of anemia and vitamin deficiencies is also included. Non-pharmacological management includes insuring proper blood volume, adjusting sodium intake, physical conditioning, avoid increased core body temperature, compression garments, and head-up position while sleeping.(2) Pharmacological options include midodrine and droxidopa, as well as off-label use of fludrocortisone and pyridostigmine for nOH.(2-6) One of the challenges associated with treating nOH pharmacologically is the limited availability of clinical evidence and lack of comparative effectiveness studies. Once initial therapy has begun, symptomatic benefit, including impact on activities of daily living, and changes in blood pressure need to be assessed frequently. Little data exists to determine efficacy and safety of different combinations of therapy compared to monotherapy for nOH. Based on the experience of the consensus panel, the recommendation is to appropriately titrate to maximum tolerable dose of a single agent and then, if symptomatic benefit is not obtained, consider switching to a different therapy or adding a second agent and titrate from its lowest starting dose.(3)

Efficacy

Clinical studies examined the efficacy of Northera in the short-term (1-2 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 two weeks of treatment. 

Study 301: Patients with symptomatic neurogenic orthostatic hypotension (nOH) participated in this multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study. Patients were required to have a clinical diagnosis of symptomatic nOH due to one of the following: Parkinson’s disease, pure autonomic failure, multiple system atrophy, non-diabetic autonomic neuropathy, or dopamine-beta-hydroxylase deficiency. After the initial screening, patients went through open-label dose titration period followed by a seven-day wash-out period (n=263).(1,7)

Of the 263 patients who participated in dose randomization, 162 (61.6%) were identified as responders and entered the double-blind phase of the study. Responders were defined as demonstrating improvement on the Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 score by at least one point and an increase in systolic blood pressure of at least 10 mmHg upon standing. The OHSA Item #1 referred to dizziness, lightheadedness, feeling faint, and feeling like you might black out (see monograph appendix for more information). Responders were then randomized to a seven-day treatment period with droxidopa (n=82) or placebo (n=80).(1,7)

Patients in the treatment period had an average age of 60 years and a primary diagnosis of Parkinson’s disease (n=60), pure autonomic failure (n=36) or multiple system atrophy (n=26). Patients were allowed to continue taking dopa-decarboxylase inhibitors (45% of patients) and fludrocortisones (29% of patients).(1)

Efficacy was measured utilizing the Orthostatic Hypotension Questionnaire (OHQ, see monograph appendix for more information), which measures the symptoms of nOH and their impact on the patient’s daily activities. The OHQ was administered at baseline, randomization, and at the end of the study. The pre-specified primary efficacy endpoint was the change in overall composite score from randomization to end of study. Secondary endpoints were individual OHQ items and changes in symptom and symptom impact scores. Blood pressure was also measured throughout the study.(1,7)

Results revealed a statistically significant improvement in the OHQ composite score from randomization to the end of the study (p=0.003). Several symptom items revealed differences between droxidopa and placebo including dizziness/lightheadedness (item 1 for randomization), vision disturbance, weakness, and fatigue. Differences from placebo were also observed on all symptom-impact items. Standing systolic blood pressures increased an average of 11.2 mmHg in patients receiving droxidopa versus 3.9 mmHg with placebo.(7)

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 one of treatment, patients showed a mean 0.7 unit decrease in dizziness with NORTHERA versus placebo (P=0.06).(1)

Study 306B: Study 306B was a multi-center, double-blind, randomized, placebo-controlled, parallel-group study that consisted of an initial dose titration period followed by an 8-week treatment period. Patients (n=171) in the study had symptomatic nOH and Parkinson’s disease, and were required to have a decrease of at least 20 mmHg or 10 mmHg, respectively, in systolic or diastolic blood pressure within three minutes after standing. Dosing was titrated to patient response and ranged from 100 mg to 600 mg three times daily. Data was collected throughout an eight-week treatment period. At week one, patients demonstrated a statistically significant decrease (0.9-unit) in dizziness as reported on the OHSA Item #1 11-point scale (p=0.028). This effect did not continue beyond week one.(1)

Safety

Northera has a Boxed Warning for supine hypertension. Supine blood pressure should be monitored 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 droxidopa.(1)

1

Northera prescribing information. Lundbeck LLC. July 2019.

2

Palma JA, Kaufmann H. Epidemiology, Diagnosis, and Management of Neurogenic Orthostatic Hypotension. Mov Disord Clin Pract. 2017 May-Jun;4(3):298-308. 

3

Gibbons CH, Schmidt P, Biaggioni I, et al. The Recommendations of a Consensus Panel for the Screening, Diagnosis, and Treatment of Neurogenic Orthostatic Hypotension and Associated Supine Hypertension. J Neurol. 2017;264(8):1567-1582.

4

2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients with Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol. 2017 Aug;70(5):e39-e110.

5

Brignole M, Moya A, de Lange FJ, et al. 2018 European Society of Cardiology (ESC) Guidelines for the Diagnosis and Management of Syncope. Eur Heart J. 2018 June;39(21):1883-1948.

6

Kalra DK, Raina A, Sohal S. Neurogenic Orthostatic Hypotension: State of the Art and Therapeutic Strategies. Clin Med Insights Cardiol. 2020;14:1-12.

7

A Clinical Study for Patients With Neurogenic Orthostatic Hypotension (NOH) Using Droxidopa (NOH301). Chelsea Therapeutics. https://clinicaltrials.gov/study/NCT00782340?term=northera&page=4&rank=36&a=12. September 2010.

Northera

droxidopa cap

100 MG ; 200 MG ; 300 MG

M ; N ; O ; Y

O ; Y

Northera

Droxidopa Cap 100 MG

100 MG

450

Capsules

30

DAYS

Northera

Droxidopa Cap 200 MG

200 MG

180

Capsules

30

DAYS

Northera

Droxidopa Cap 300 MG

300 MG

180

Capsules

30

DAYS

Northera

droxidopa cap

100 MG ; 200 MG ; 300 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Northera

Droxidopa Cap 100 MG

100 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Northera

Droxidopa Cap 200 MG

200 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Northera

Droxidopa Cap 300 MG

300 MG

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Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The patient has a diagnosis of neurogenic orthostatic hypotension (nOH) AND ALL of the following:
      1. The prescriber has performed baseline (prior to therapy with the requested agent) blood pressure readings while the patient is sitting or supine (laying face up) AND also within 3 minutes of standing from a supine position AND 
      2. The patient has a decrease of at least 20 mmHg in systolic blood pressure or 10 mmHg diastolic blood pressure within three minutes after standing AND
      3. The patient has persistent and consistent symptoms of neurogenic orthostatic hypotension (nOH) caused by ONE of the following:
         1. Primary autonomic failure (Parkinson's disease [PD], multiple system atrophy, or pure autonomic failure) OR
         2. Dopamine beta-hydroxylase deficiency OR
         3. Non-diabetic autonomic neuropathy AND
      4. The prescriber has assessed the severity of the patient’s baseline (prior to therapy with the requested agent) symptoms of dizziness, lightheadedness, feeling faint, or feeling like the patient may black out AND
      5. The prescriber has assessed and adjusted, if applicable, any medications known to exacerbate orthostatic hypotension (e.g., diuretics, vasodilators, beta-blockers) AND
      6. ONE of the following:
         1. The patient has tried and had an inadequate response to midodrine OR
         2. The patient has an intolerance or hypersensitivity to therapy with midodrine OR
         3. The patient has an FDA labeled contraindication to midodrine OR
   2. The patient has another FDA labeled indication for the requested agent AND
2. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
3. If the request is for one of the following brand agents with an available generic equivalent (listed below), then ONE of the following:

3. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
4. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
5. There is support for the use of the requested brand agent over the generic equivalent AND
6. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
7. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  1 month

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [NOTE: Patients not previously approved for the requested agent will require initial evaluation review] AND
2. ONE of the following:
   1. The patient has a diagnosis of neurogenic orthostatic hypotension (nOH) AND BOTH of the following:
      1. The patient has had improvement in severity from baseline symptoms (prior to therapy with the requested agent) of dizziness, lightheadedness, feeling faint, or feeling like the patient may black out AND
      2. The patient had an increase in systolic blood pressure from baseline (prior to therapy with the requested agent) of at least 10 mmHg upon standing from a supine (laying face up) position OR
   2. BOTH of the following:
      1. The patient has another FDA labeled indication for the requested agent AND
      2. The patient has had clinical benefit with the requested agent AND
3. If the request is for one of the following brand agents with an available generic equivalent (listed below), then ONE of the following:

3. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
4. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
5. There is support for the use of the requested brand agent over the generic equivalent AND
6. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
7. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 3 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
3. ALL of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
   3. There is support for therapy with a higher dose for the requested indication

Length of Approval: Initial - Up to 1 month; Renewal - Up to 3 months