Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Droxidopa (e.g., 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:

Effective August 2023

The use of droxidopa does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of orthostatic symptoms or for any other indication or circumstance.

For individuals with contracts without primary coverage criteria, the use of droxidopa for the treatment of orthostatic symptoms or for any other indication or circumstance is considered investigational.

Investigational services are specific contract exclusion in most member benefit certificates of coverage.

Effective prior to August 2023

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of droxidopa for the treatment of orthostatic symptoms or for any other indication does not meet primary coverage criteria for effectiveness in improving health outcomes.

For individuals 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.

2019 Update

A literature search conducted through July 2019 did not reveal any new information that would prompt a change in the coverage statement.

2020 Update

McDonell KE, Shibao CA, Biaggioni I, Hartman A, Robertson D, Claassen DO. (2019) presented the results of a retrospective cohort study examining cognitive and behavioral side effects linked to droxidopa therapy.

A review of 101 patients who had been treated with droxidopa at an academic tertiary care center was performed and identified cases of cognitive and behavioral changes associated with the therapy.

Six patients who had developed cognitive and behavioral symptoms, including memory difficulties, confusion, mania, and irritability, shortly after droxidopa initiation were identified. All six patients displayed symptoms of synucleinopathy, manifesting with autonomic failure, rapid eye movement sleep behavior disorder, and parkinsonism. Patients had no significant cognitive or behavioral symptoms before droxidopa initiation. Behavioral disturbances were observed early in the droxidopa titration period and at relatively low doses. Symptoms resolved with dose reduction in four patients, and droxidopa was discontinued in two patients due to persistent irritability. No other medical comorbidities or alternative etiologies were identified to explain the symptoms.

Droxidopa is designed to act peripherally as a pressor agent but may also exert important central effects. McDonell KE, Shibao CA, Biaggioni I, Hartman A, Robertson D, Claassen DO hypothesize that the cognitive and behavioral manifestations observed in the patients with orthostatic hypotension resulted from an "overdose" of key noradrenergic networks linking orbitofrontal and mesolimbic regions.

Biaggioni I, Freeman R, Mathias CJ, et al. (2015) evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100-600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa. Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient's self-reported ability to perform activities requiring standing a short time and standing a long time. Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa. There was no significant difference between groups for standing systolic blood pressure. Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.

References:

Biaggioni I, Freeman R, Mathias CJ, et al.(2015) Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension. 2015;65(1):101-107. doi:10.1161/HYPERTENSIONAHA.114.04035

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.

McDonell KE, Shibao CA, Biaggioni I, Hartman A, Robertson D, Claassen DO.(2019) Cognitive and Behavioral Changes in Patients Treated With Droxidopa for Neurogenic Orthostatic Hypotension: A Retrospective Review. Cogn Behav Neurol. 2019;32(3):179-184. doi:10.1097/WNN.0000000000000198

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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