What is the recommended treatment and management for an adult patient with neurogenic orthostatic hypotension (NOH), likely with a history of neurological disease such as Parkinson's disease or multiple system atrophy, using Droxidopa?

Droxidopa for Neurogenic Orthostatic Hypotension

Droxidopa is a beneficial pharmacologic agent for treating symptomatic neurogenic orthostatic hypotension (nOH) in adults with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy, though its effectiveness beyond 2 weeks remains unestablished and requires periodic reassessment. 1, 2

Indications and Patient Selection

Droxidopa is FDA-approved specifically for treating orthostatic dizziness, lightheadedness, or the "feeling that you are about to black out" in adult patients with symptomatic nOH caused by: 2

• Primary autonomic failure (Parkinson's disease, multiple system atrophy, pure autonomic failure)
• Dopamine beta-hydroxylase deficiency
• Non-diabetic autonomic neuropathy

Dosing and Administration

Start droxidopa at 100 mg three times daily: upon arising in the morning, at midday, and in the late afternoon at least 3 hours prior to bedtime. 2 This timing reduces the risk of supine hypertension during sleep.

Titration Protocol:

• Increase in 100 mg increments three times daily every 24-48 hours based on symptomatic response 2
• Maximum dose: 600 mg three times daily (1,800 mg total daily dose) 2
• Administer consistently either with or without food 2
• Take capsules whole 2
• Monitor supine blood pressure before initiating and after each dose increase 2

Clinical Efficacy

Droxidopa improves symptoms of nOH in the target populations and may reduce falls according to small studies. 1 In patients with Parkinson's disease specifically, integrated analysis demonstrates significant improvements in: 3

• Orthostatic Hypotension Questionnaire composite scores
• Standing systolic and diastolic blood pressure (mean increase of 4.09 mmHg systolic) 4
• Patient-reported symptom assessments

However, the efficacy of droxidopa decreases gradually after 2 weeks, with statistical significance lost after 8 weeks of treatment. 4 The FDA label explicitly states that effectiveness beyond 2 weeks has not been established, requiring periodic reassessment of continued benefit. 2

Critical Warnings and Management

Supine Hypertension (Black Box Warning):

Monitor supine blood pressure prior to and during treatment, with increased frequency when escalating doses. 2

• Elevate the head of the bed when resting or sleeping to reduce supine hypertension risk 2
• Measure blood pressure in the head-elevated sleeping position 2
• If supine hypertension persists despite head elevation, reduce or discontinue droxidopa 2
• Uncontrolled supine hypertension may increase cardiovascular event risk, particularly stroke 2

Other Serious Warnings:

Hyperpyrexia and Confusion: Postmarketing cases resembling neuroleptic malignant syndrome have been reported. 2 Observe patients carefully when changing droxidopa dosage or when abruptly reducing/discontinuing concomitant levodopa, especially in patients receiving neuroleptics. 2

Cardiovascular Considerations: Droxidopa may exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure. 2 Carefully weigh this risk before initiating therapy in patients with these conditions.

Drug Interactions and Special Populations

Important caveat for Parkinson's disease patients: Concurrent use of carbidopa may decrease droxidopa effectiveness. 1 This interaction requires consideration when managing patients already on carbidopa-levodopa combinations.

Common Adverse Effects

Use and titration may be limited by: 1

• Supine hypertension
• Headache
• Dizziness
• Nausea

In long-term safety studies of 350 patients (mean exposure 363 days), serious adverse events occurred in 24%, cardiac-related adverse events in 5%, and supine hypertension in 5%. 5 Most adverse events, including cardiovascular ones, were not attributed to droxidopa by investigators. 5

Integration with Comprehensive nOH Management

According to ACC/AHA/HRS guidelines, droxidopa should be considered within a broader treatment algorithm: 1

First-line non-pharmacologic measures:

• Acute water ingestion (≥240 mL, peak effect at 30 minutes) for temporary relief
• Physical counter-pressure maneuvers (leg crossing, squatting)
• Compression garments (at least thigh-high, preferably including abdomen)

Pharmacologic options (droxidopa is one of several):

• Midodrine (alternative pressor agent)
• Fludrocortisone (when supine hypertension is not present)
• Salt supplementation (6-9 g daily) and increased fluid intake (unless contraindicated by hypertension, renal disease, or heart failure)

Refractory cases:

• Pyridostigmine
• Octreotide (for postprandial hypotension)

Clinical Bottom Line

The number needed to treat (NNT) for droxidopa is less than 10 for improvement in orthostatic symptoms, with a number needed to harm (NNH) of 81 for adverse events leading to discontinuation. 6 Droxidopa is 7.8 times more likely to provide clinical benefit than cause discontinuation due to adverse events at week 1. 6

Given the lack of established long-term efficacy beyond 2 weeks 2, 4, clinicians must periodically reassess whether patients continue to derive meaningful benefit from droxidopa therapy and consider alternative or adjunctive treatments if response wanes.