Hydralazine Plus Isosorbide Dinitrate Dosing
Start with 37.5 mg hydralazine/20 mg isosorbide dinitrate three times daily, then titrate to the target dose of 75 mg hydralazine/40 mg isosorbide dinitrate three times daily (total daily: 225 mg hydralazine/120 mg isosorbide dinitrate). 1
Initial Dosing
- Fixed-dose combination (BiDil): Begin with 1 tablet (37.5 mg hydralazine/20 mg isosorbide dinitrate) three times daily 1
- Separate formulations: If using individual drugs, start with hydralazine 25-50 mg three or four times daily plus isosorbide dinitrate 20-30 mg three or four times daily 1
- Both medications must be administered at least three times daily to achieve the mortality benefit demonstrated in clinical trials 1
Target Maintenance Dosing
- Fixed-dose combination: Increase to 2 tablets three times daily for total daily dose of 225 mg hydralazine and 120 mg isosorbide dinitrate 1
- Separate formulations: Titrate to maximum of 300 mg hydralazine daily in divided doses and 120 mg isosorbide dinitrate daily in divided doses 1
- The mortality benefit in A-HeFT was achieved at these higher doses with three-times-daily administration 2, 3
Titration Strategy
- Increase doses progressively over 3-4 weeks to reach target dosing 1
- Use slower titration if side effects are problematic to enhance tolerance and adherence 1, 2
- The mean doses achieved in clinical trials were approximately 175 mg hydralazine/90 mg isosorbide dinitrate daily 1
Critical Dosing Considerations
Timing and Intervals
- Administer three times daily with consistent spacing 1
- Consider a nitrate-free interval of at least 10 hours to minimize tolerance development 2
- With immediate-release isosorbide dinitrate, at least one 14-hour dose-free interval daily is needed to prevent refractory tolerance 4
Common Pitfalls
- Adherence is notoriously poor due to multiple daily tablets (up to 6 tablets/day at target dose), frequent dosing, and high incidence of adverse effects 1
- Headache, dizziness, and gastrointestinal complaints are frequent but often improve with continued therapy 1, 5
- Do not use lower doses or less frequent administration—the mortality benefit requires the full three-times-daily regimen 6
Patient-Specific Indications
Class I Recommendation (Strongest Evidence)
- Self-identified African American patients with NYHA class III-IV HFrEF already on optimal therapy (ACE inhibitors/ARBs, beta-blockers, aldosterone antagonists) 1, 2
- This combination produced a 43% mortality reduction (NNT=7 for mortality at 36 months) and 33% reduction in heart failure hospitalizations 2, 3
Class IIa Recommendation
- Patients with symptomatic HFrEF who cannot tolerate ACE inhibitors or ARBs due to drug intolerance, hypotension, or renal insufficiency 1, 2
- Evidence is weaker in this population, but the combination may be considered as an alternative 2
Contraindications to Use
- Do not use as first-line therapy in patients who have not tried standard neurohumoral antagonists 1, 2
- Do not substitute for ACE inhibitor/ARB therapy in patients tolerating these medications without difficulty 1
- Avoid hydralazine doses >150 mg daily to prevent drug-induced lupus 6
Monitoring Requirements
- Monitor blood pressure for hypotension, especially during titration 1
- Watch for reflex tachycardia and fluid retention (hydralazine effects) 6
- Consider concurrent beta-blocker and diuretic therapy to counteract these effects 6
- Monitor for blood dyscrasias (reduction in hemoglobin, leukopenia, agranulocytosis) and discontinue if abnormalities develop 7