Coverage Policy Manual
Policy #: 2015029
Category: Pharmacy
Initiated: September 2015
Last Review: September 2018
  Droxidopa (Northera™)

Description:
Chronic idiopathic orthostatic hypotension (IOH), or postural hypotension, is a condition in which blood pressure decreases when a person arises from a lying or sitting position.  Orthostatic symptoms, including dizziness, lightheadedness, syncope, and falls are a significant and common problem.  Unfortunately, treatment options are limited.  The etiology is often related to autonomic dysfunction.  Treatment includes hydration, elastic stockings, and lifestyle modification such as sitting on the bedside before arising.  In 2014, droxidopa (Northera) was approved by the FDA for treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” 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 nondiabetic autonomic neuropathy. The package insert notes that “Effectiveness beyond 2 weeks of treatment has not been demonstrated. The continued effectiveness of NORTHERA should be assessed periodically.” Droxidopa is a prodrug which is converted to norepinephrine.  The only other drug approved for symptomatic neurogenic orthostatic hypotension is midodrine, which was approved in 1996, despite any the lack of any convincing studies showing benefit in symptoms.

Policy/
Coverage:
The use of droxidopa for the treatment of orthostatic symptoms or for any other indication does not meet primary coverage criteria for effectiveness.
 
For members with contracts without primary coverage criteria, the use of droxidopa for the treatment of orthostatic symptoms or for any other indication is considered investigational. Investigational services are specific contract exclusion in most member benefit certificates of coverage.
 

Rationale:
Several studies of droxidopa for symptomatic orthostatic hypotension have been completed.  Studies have shown effectiveness compared to control at 7 days and at 14 days, but no longer-term studies have shown statistically significant effectiveness beyond 14 days.  
 
Kaufmann et al reported improvement in the mean OHQ (Orthostatic Hypotension Questionnaire) score and in the drop in mean standing systolic blood pressure with droxidopa vs placebo (Kaufmann, 2014).  It is notable that of 354 patients screened, only 168 were randomized.  Prior to randomization, 263 patients underwent dose titration for tolerability and to document effectiveness of droxidopa.  Only those who tolerated and had successful treatment with the drug were randomized.  The end point was at 7 days, with no longer-term data reported.
 
Biaggioni et al  (NCT00633880) published a randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa (Biaggioni, 2014).  Again, only patients who responded to droxidopa were randomized.  After treating responders with droxidopa and then withdrawing the drug from about half the subjects, at 14 days there was a trend favoring the patients who remained on droxidopa.  However, the study did not reach its primary efficacy end point goal.
 
Hauser et al (Hauser, 2014) published an interim analysis of patients in a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of droxidopa for neurogenic orthostatic hypotension in patients with Parkinson’s disease.  Subjects underwent dosage optimization followed by 8 weeks of maintenance treatment, with the endpoint being change in the OHQ score.  After analysis of data from 51 subjects, the study was stopped based on a pre-planned futility analysis.  There was a trend toward benefit, and there was a statistically non-significant lower rate of reported falls and fall-related injuries in the droxidopa group.  Further trials were thought to be merited.
 
In summary, idiopathic and/or secondary neurogenic orthostatic hypotension are chronic conditions requiring evidence of successful long-term therapy.  The existing evidence is insufficient in demonstrating an improvement in net health outcomes (symptoms, fall, Tilt tests, etc) over extended treatment intervals.  Therefore, droxidopa does not meet primary coverage criteria.  
 
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through August 2017 did not reveal any new information that would prompt a change in the coverage statement.   
 
2018 Update
A literature search conducted through August 2018 did not reveal any new information that would prompt a change in the coverage statement.

References: Biaggioni I, Freeman R, Mathias J, et al.(2014) Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension, 2014;65:101-107.

Hauser RA, Hewitt LA, Issacson S.(2014) Droxidopa in patients with neurogenic orthostatic hypotension associated with parkinson’s disease. J ParkinsonsDis. 2014;4(1):57-65.

Kaufman H, Freeman R, Biaggioni I, et al.(2014) Droxidopa for neurogenic orthostatic hypotension a randomized, placebo-controlled, phase 3 trial. Neurology 2014; 83:328-335.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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