Isosorbide Dinitrate + Hydralazine Hydrochloride

Approved Indications:

• Heart Failure with Reduced Ejection Fraction (HFrEF):
• Specifically approved for the treatment of chronic heart failure (NYHA Class III–IV) in self-identified Black patients, in combination with standard therapy (including beta-blockers and ACE inhibitors or ARBs), or as an alternative in patients unable to tolerate these agents.
• Demonstrated reduction in mortality and improvement in quality of life.

Clinically Accepted Off-label Uses:

• HFrEF in Non-Black Patients Intolerant to ACEI/ARBs:
• Used in patients with HFrEF who are unable to tolerate ACE inhibitors, ARBs, or ARNI due to adverse effects like angioedema, hyperkalemia, or renal dysfunction.
• Resistant Hypertension (Hydralazine component):
• Hydralazine may be used off-label as part of multi-drug regimens for treatment-resistant hypertension.

Route of Administration:

• Oral

Initial Adult Dosage (Heart Failure):

• Isosorbide Dinitrate 20 mg + Hydralazine 37.5 mg:
• One tablet three times daily, taken with food to reduce gastrointestinal side effects.

Maintenance Dosage:

• Titrate to a maximum of two tablets three times daily, based on patient tolerance and clinical response.
• Maximum recommended daily dose:
• Isosorbide Dinitrate 120 mg + Hydralazine 225 mg

Elderly:

• Start at lower end of the dosage range due to increased risk of hypotension and renal impairment.

Renal Impairment:

• No specific adjustment required, but close monitoring is advised.

Hepatic Impairment:

• Use with caution. Hydralazine undergoes hepatic metabolism and clearance may be reduced.

Pediatrics:

• Not recommended; safety and efficacy have not been established in pediatric populations.

Isosorbide Dinitrate functions as a nitric oxide donor, causing relaxation of vascular smooth muscle, primarily affecting venous capacitance vessels, thereby reducing preload. Hydralazine acts as a direct arteriolar vasodilator, decreasing afterload by relaxing vascular smooth muscle via interference with intracellular calcium and enhancement of nitric oxide bioavailability. The combination leads to balanced vasodilation (arterial and venous), lowering myocardial oxygen demand, improving cardiac output, and reducing ventricular remodeling. Together, they enhance survival and symptom control in patients with HFrEF, particularly in those of African descent.

Isosorbide Dinitrate:

• Absorption: Rapid oral absorption; bioavailability ~20–25% due to first-pass metabolism.
• Onset of Action: 15–30 minutes
• Peak Plasma Time: 1–2 hours
• Metabolism: Hepatic, via denitration to active metabolites (isosorbide mononitrate)
• Half-life: ~1 hour (parent compound)
• Elimination: Primarily renal excretion

Hydralazine Hydrochloride:

• Absorption: Rapid; oral bioavailability 25–50% depending on acetylator phenotype
• Peak Plasma Time: 1–2 hours
• Metabolism: Hepatic acetylation; variability based on acetylator status (fast vs slow)
• Half-life: 3–7 hours (prolonged in slow acetylators)
• Elimination: Renal, mostly as metabolites

Pregnancy:

• Hydralazine: Commonly used in pregnancy for severe hypertension; generally considered safe.
• Isosorbide Dinitrate: No definitive evidence of teratogenicity; use only if clearly needed.
• FDA Classification: Not assigned under current FDA labeling system (formerly Category C). Use only if potential benefits outweigh risks.

Lactation:

• Hydralazine: Present in breast milk in low amounts; generally considered compatible with breastfeeding.
• Isosorbide Dinitrate: Unknown if excreted in breast milk; caution is advised.
• Recommendation: Monitor infant for signs of hypotension, poor feeding, or unusual sleepiness.

• Primary Class: Vasodilators
• Subclasses:
• Isosorbide Dinitrate: Nitrate-type vasodilator (venous)
• Hydralazine Hydrochloride: Direct-acting arteriolar vasodilator
• Combination Type: Fixed-dose vasodilator therapy for heart failure

• Known hypersensitivity to isosorbide dinitrate, hydralazine, or any excipients
• Concomitant use with phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil, tadalafil)
• Severe hypotension or circulatory shock
• Idiopathic systemic lupus erythematosus (Hydralazine-related)
• Known coronary artery disease or valvular rheumatic heart disease (Hydralazine component)
• Increased intracranial pressure

• Symptomatic Hypotension: Risk increased with diuretics or other antihypertensives
• Tachyphylaxis: Nitrate tolerance can develop; include a daily nitrate-free interval of 10–12 hours
• Lupus-like Syndrome: Hydralazine may induce SLE-like symptoms, especially with prolonged high-dose use
• Reflex Tachycardia: Can exacerbate angina or heart failure symptoms
• Peripheral Neuritis: Rare, associated with long-term hydralazine use; may respond to vitamin B6 supplementation
• Renal/Hepatic Impairment: Use with caution; monitor renal and liver function
• Monitoring: Blood pressure, heart rate, ANA (for lupus), CBC (for blood dyscrasias)

Common:

• Cardiovascular: Headache, flushing, hypotension, palpitations, tachycardia
• Gastrointestinal: Nausea, vomiting, diarrhea, loss of appetite
• Neurological: Dizziness, fatigue

Serious:

• Immunologic: Drug-induced lupus erythematosus (Hydralazine)
• Hematologic: Agranulocytosis, thrombocytopenia (rare)
• Neurological: Peripheral neuritis, depression
• Hepatic: Elevated liver enzymes, jaundice

Timing & Severity:

• Headache and flushing occur early and may improve with continued use
• Lupus-like effects and hematologic abnormalities may appear with chronic use

Major Drug Interactions:

• PDE-5 Inhibitors (e.g., Sildenafil, Tadalafil): Risk of life-threatening hypotension; contraindicated
• Beta-Blockers: May be co-administered to control reflex tachycardia caused by hydralazine
• Other Antihypertensives (e.g., ACEIs, ARBs, diuretics): Additive hypotensive effect; monitor blood pressure
• MAO Inhibitors: May increase the hypotensive effect; use with caution
• Tricyclic Antidepressants: Risk of orthostatic hypotension

Enzyme Systems Involved:

• Hydralazine metabolism varies by N-acetyltransferase activity
• No significant interactions with CYP450 isoenzymes reported

• AHA/ACC/HFSA 2022 Heart Failure Guidelines:
• Continue to recommend Isosorbide Dinitrate + Hydralazine as add-on therapy for Black patients with HFrEF (NYHA III–IV) receiving guideline-directed therapy.
• Also recommended as an alternative for any HFrEF patient intolerant to ACEIs/ARBs/ARNIs.
• No recent safety-related label changes or new contraindications reported.

• Storage Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Allowable Excursions: Between 15°C to 30°C
• Humidity/Light: Protect from excessive moisture and direct light
• Container Requirements: Store in tightly closed, light-resistant containers
• Handling Instructions: Do not freeze. Keep away from children.
• Reconstitution/Refrigeration: Not applicable