What is Droxidopa used for?

Droxidopa for Orthostatic Hypotension

Droxidopa is FDA-approved specifically for the 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, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. 1

Mechanism and Indication

Droxidopa is a synthetic amino acid precursor of norepinephrine that works by increasing circulating levels of norepinephrine, which helps maintain blood pressure upon standing. It is indicated for:

• Neurogenic orthostatic hypotension (nOH) due to:
  • Primary autonomic failure (Parkinson's disease, multiple system atrophy, pure autonomic failure)
  • Dopamine beta-hydroxylase deficiency
  • Non-diabetic autonomic neuropathy 1

Dosing and Administration

• Starting dose: 100 mg three times daily
• Titration: Increase in increments of 100 mg three times daily every 24-48 hours
• Maximum dose: 600 mg three times daily (1,800 mg total daily dose)
• Timing: Take upon arising in the morning, at midday, and in late afternoon (at least 3 hours before bedtime to reduce risk of supine hypertension)
• Administration: Can be taken with or without food, but should be consistent 1

Efficacy

Droxidopa has been shown to significantly improve:

• Orthostatic Hypotension Questionnaire (OHQ) composite scores
• Dizziness/lightheadedness symptoms
• Standing systolic blood pressure
• Activities of daily living 2

However, it's important to note that the FDA label states "effectiveness beyond 2 weeks of treatment has not been established" 1. Meta-analysis data suggests that efficacy may decrease gradually after 2 weeks, with statistical significance lost after 8 weeks 3.

Safety Considerations

Major Warnings

1. Supine Hypertension: Monitor supine blood pressure prior to and during treatment, especially when increasing doses. Elevating the head of the bed can reduce this risk. If supine hypertension cannot be managed, reduce or discontinue droxidopa 1

2. Hyperpyrexia and Confusion: Cases resembling neuroleptic malignant syndrome have been reported, particularly when changing dosage or when concomitant levodopa is reduced or discontinued 1

3. Cardiovascular Risk: May exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure 1

Common Adverse Effects

The most frequently reported adverse events include:

• Falls (17%)
• Headache (13%)
• Dizziness (9%) 4

Management Algorithm for Orthostatic Hypotension

1. First-line: Non-pharmacological measures

   • Increased salt and fluid intake (unless contraindicated)
   • Physical counter-pressure maneuvers (leg crossing, muscle tensing)
   • Compression garments (thigh-high or waist-high)
   • Elevating head of bed 10° during sleep
   • Avoiding prolonged standing 5

2. Second-line: Pharmacological therapy

   • Midodrine (5-20 mg three times daily) is typically considered first-line pharmacotherapy 6
   • Droxidopa (100-600 mg three times daily) is an alternative first-line option 1
   • Fludrocortisone (0.1-0.3 mg daily) may be considered, especially if volume expansion is needed 5

3. For patients with diabetes and orthostatic hypotension:

   • Both midodrine and droxidopa are approved by the FDA for treatment of orthostatic hypotension 6
   • Pyridostigmine may be considered as it's less likely to cause supine hypertension 6

Clinical Pearls and Pitfalls

• Monitor supine blood pressure: The most significant risk is supine hypertension, which occurs in approximately 5-8% of patients 7, 2

• Timing is crucial: Administer the last dose at least 3 hours before bedtime to minimize supine hypertension risk during sleep 1

• Regular reassessment: The continued effectiveness of droxidopa should be assessed periodically due to potential waning efficacy over time 1, 3

• Special considerations in cardiac amyloidosis: Droxidopa may be poorly tolerated in patients with cardiac involvement and restrictive physiology 6

• Treatment goal: Focus on symptom improvement rather than complete normalization of blood pressure 5

• Drug interactions: Minimal drug interactions have been reported, even with concurrent carbidopa use, though efficacy may be numerically greater in patients not using dopa decarboxylase inhibitors 8, 2

By addressing orthostatic hypotension effectively, droxidopa can significantly improve quality of life and reduce morbidity associated with falls and syncope in patients with neurogenic orthostatic hypotension.