What is the recommended treatment and dosage for neurogenic orthostatic hypotension (NOH) using Droxidopa?

Droxidopa for Neurogenic Orthostatic Hypotension

Droxidopa is beneficial for treating symptomatic neurogenic orthostatic hypotension (nOH), with a starting dose of 100 mg three times daily, titrated by 100 mg increments every 24-48 hours up to a maximum of 600 mg three times daily, though effectiveness beyond 2 weeks remains unestablished and requires periodic reassessment. 1

Dosing Algorithm

Initial Dosing

• Start at 100 mg orally three times daily: upon arising in the morning, at midday, and in the late afternoon at least 3 hours prior to bedtime 1
• Administer consistently either with or without food 1
• Take capsules whole, do not crush or open 1

Titration Schedule

• Increase by 100 mg three times daily every 24-48 hours based on symptomatic response 1
• Maximum dose: 600 mg three times daily (total daily dose of 1,800 mg) 2, 1
• Monitor supine blood pressure before each dose increase 1

Clinical Indications

Droxidopa improves symptoms of nOH specifically in:

• Parkinson disease 2
• Multiple system atrophy 2
• Pure autonomic failure 2
• Dopamine beta-hydroxylase deficiency 1
• Non-diabetic autonomic neuropathy 1

Droxidopa may reduce falls according to small studies, though this requires further validation 2

Efficacy Evidence

Symptom Improvement

• Significant reduction in dizziness/lightheadedness compared to placebo (-3.0 vs -1.8 units, P < 0.001) 3
• Improvement in composite symptom scores (-2.68 vs -1.82 units, P < 0.001) 3
• Benefits observed in visual disturbances, weakness, and fatigue 3

Blood Pressure Effects

• Standing systolic BP increases by approximately 11.5 mmHg versus 4.8 mmHg with placebo (P < 0.001) 3
• Supine systolic BP increases by 7.6-15.5 mmHg 4, 3

Duration of Benefit

• FDA approval based on short-term efficacy (≤2 to 10 weeks) 3
• Open-label data suggests sustained benefit through 12 weeks with continued improvement in symptom scores (P < 0.0001) 4
• Effectiveness beyond 2 weeks has not been formally established, requiring periodic reassessment 1

Critical Safety Considerations

Supine Hypertension (PRIMARY CONCERN)

This is the most important limiting factor with droxidopa therapy:

• Elevate the head of the bed when resting or sleeping to reduce supine hypertension risk 1
• Monitor blood pressure in both supine position and head-elevated sleeping position 1
• If supine hypertension persists despite head elevation, reduce or discontinue droxidopa 1
• Supine systolic BP >180 mmHg occurred in 4.9% of droxidopa recipients versus 2.5% with placebo 5
• Uncontrolled supine hypertension may increase cardiovascular risk, particularly stroke 1

Other Serious Warnings

• Hyperpyrexia and confusion resembling neuroleptic malignant syndrome reported postmarketing 1
• Observe carefully when changing droxidopa dose or reducing/discontinuing concomitant levodopa, especially with concurrent neuroleptics 1
• May exacerbate ischemic heart disease, arrhythmias, and congestive heart failure 1

Common Adverse Events

• Headache (7.4-13%) 1, 4, 6
• Dizziness (3.7-10.1%) 1, 4, 6
• Falls (17%) 4
• Nausea 2

Important Drug Interactions

Carbidopa and other DOPA decarboxylase inhibitors (DDCI) may decrease droxidopa effectiveness 2, 1

• Droxidopa is converted to norepinephrine by DOPA decarboxylase 3
• In patients with Parkinson disease taking carbidopa, droxidopa efficacy is numerically reduced though still present 3
• Dose adjustments may be required when using DDCIs 1

Position in Treatment Algorithm

According to ACC/AHA/HRS guidelines, droxidopa is positioned alongside other pharmacologic options:

First-Line Considerations

• Midodrine (α1-adrenergic agonist, 2.5-10 mg three times daily) 2
• Droxidopa (100-600 mg three times daily) 2

Alternative/Adjunctive Options

• Fludrocortisone (0.1-1.0 mg daily) - avoid if supine hypertension present 2
• Pyridostigmine (30-60 mg 2-3 times daily) - less likely to cause supine hypertension, for refractory cases 2

Non-Pharmacologic Measures (Should Always Be Implemented)

• Acute water ingestion (≥240-480 mL) for temporary relief 2
• Physical counter-pressure maneuvers (leg crossing, squatting) 2
• Compression garments (thigh-high, preferably including abdomen) 2
• Increased salt (6-9 g/day) and fluid intake if not contraindicated 2

Special Populations

Renal Impairment

Dosing recommendations cannot be provided for patients with GFR <30 mL/min 1

Heart Failure

May be poorly tolerated in heart failure patients due to increased afterload from sympathomimetic effects 2

Contraindications

• History of hypersensitivity to droxidopa or its ingredients 1

Monitoring Requirements

• Supine blood pressure prior to initiation 1
• Blood pressure monitoring after each dose increase 1
• Measure BP in head-elevated sleeping position 1
• Periodic reassessment of continued effectiveness given lack of long-term efficacy data 1