Version July 2025
Heart failure with reduced ejection fraction: Note: Alternative therapy for patients with persistent NYHA class III or IV heart failure with reduced ejection fraction (HFrEF) who cannot tolerate an angiotensin II receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker or additional therapy in patients who have residual symptoms despite an optimal medical regimen for HFrEF (Ref).
Oral: Initial: One tablet (containing 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine) 3 times daily; titrate dose as tolerated in 2 to 4 weeks to a target dose of 2 tablets (containing a total of 40 mg of isosorbide dinitrate and 75 mg of hydralazine) 3 times daily (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
If patient experiences intolerable side effects, dose may be reduced to as little as one-half tablet 3 times daily; dose should be titrated upward as soon as tolerated.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
The following events were reported in the A-HeFT Study using the combination isosorbide dinitrate/hydralazine product. See individual drug monographs for additional information.
>10%:
Cardiovascular: Chest pain (16%)
Central nervous system: Headache (50%), dizziness (32%)
Neuromuscular & skeletal: Weakness (14%)
1% to 10%:
Cardiovascular: Hypotension (8%), palpitations (4%), ventricular tachycardia (4%), tachycardia (2%)
Central nervous system: Paresthesia (4%), drowsiness (1%), malaise (1%)
Dermatologic: Alopecia (1%), diaphoresis (1%)
Endocrine & metabolic: Hyperglycemia (4%), hyperlipidemia (3%), hypercholesterolemia (1%)
Gastrointestinal: Nausea (10%), vomiting (4%), cholecystitis (1%)
Hypersensitivity: Angioedema (1%), hypersensitivity reaction (1%)
Neuromuscular & skeletal: Arthralgia (1%), myalgia (1%), tendinopathy (1%)
Ophthalmic: Amblyopia (3%)
Respiratory: Bronchitis (8%), rhinitis (4%), sinusitis (4%)
Hypersensitivity to organic nitrates or any component in the formulation; concomitant use with phosphodiesterase 5 inhibitors (eg, avanafil, sildenafil, tadalafil, vardenafil); concomitant use with riociguat.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Drug-induced lupus-like syndrome: Hydralazine may cause a drug-induced lupus-like syndrome (more likely on larger doses, longer duration).
• Fluid/sodium retention: Hydralazine-induced fluid and sodium retention may require addition or increased dosage of diuretics.
• Hypotension/bradycardia: Severe hypotension can occur; paradoxical bradycardia and increased angina pectoris can accompany hypotension. Use with caution in volume or salt depletion and/or moderate hypotension; use with extreme caution with inferior wall MI and suspected right ventricular infarctions. Symptomatic hypotension, particularly with upright posture, may occur with even small doses.
• Intracranial pressure increased: Nitrates may precipitate or aggravate increased intracranial pressure and subsequently may worsen clinical outcomes in patients with neurologic injury (eg, intracranial hemorrhage, traumatic brain injury) (Rangel-Castilla 2008).
• Peripheral neuritis: Hydralazine has been associated with peripheral neuritis (eg, paresthesia, numbness, and tingling), possibly due to an antipyridoxine effect. Pyridoxine therapy should be initiated with onset of such symptoms.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with coronary artery disease (CAD); tachycardia and hypotension (due to hydralazine) may potentiate myocardial ischemia and angina, especially in patients with hypertrophic cardiomyopathy.
• Hypertrophic cardiomyopathy: Avoid use in patients with hypertrophic cardiomyopathy with left ventricular outflow tract obstruction; nitrates may reduce preload, exacerbating obstruction and cause hypotension or syncope and/or worsening of heart failure (AHA/ACC [Ommen 2024]).
• Pulmonary hypertension: Use with caution in pulmonary hypertension; may cause hypotension.
Other warnings/precautions:
• Tolerance: When nitrates are used in combination with hydralazine for HF, tolerance to nitrate therapy is less of a concern (Gogia 1995).
Tablet, oral:
BiDil: Isosorbide dinitrate 20 mg and hydralazine hydrochloride 37.5 mg
No
Tablets (BiDil Oral)
20-37.5 mg (per each): $5.50
Tablets (Isosorb Dinitrate-hydrALAZINE Oral)
20-37.5 mg (per each): $0.67 - $4.19
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Heart failure with reduced ejection fraction: Treatment of heart failure as an adjunct to standard therapy.
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May increase vasodilatory effects of Vasodilators (Organic Nitrates). Risk C: Monitor
Alfuzosin: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Amifostine: Blood Pressure Lowering Agents may increase hypotensive effects of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider Therapy Modification
Amisulpride (Oral): May increase hypotensive effects of Hypotension-Associated Agents. Risk C: Monitor
Amphetamines: May decrease antihypertensive effects of Antihypertensive Agents. Risk C: Monitor
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may increase hypotensive effects of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor
Arginine: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Barbiturates: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Benperidol: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Brigatinib: May decrease antihypertensive effects of Antihypertensive Agents. Brigatinib may increase bradycardic effects of Antihypertensive Agents. Risk C: Monitor
Brimonidine (Topical): May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Bromperidol: May decrease hypotensive effects of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may increase hypotensive effects of Bromperidol. Risk X: Avoid
Dapoxetine: May increase orthostatic hypotensive effects of HydrALAZINE. Risk C: Monitor
Dapsone (Topical): May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Risk C: Monitor
Dexmethylphenidate: May decrease therapeutic effects of Antihypertensive Agents. Risk C: Monitor
Diazoxide: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
DULoxetine: Blood Pressure Lowering Agents may increase hypotensive effects of DULoxetine. Risk C: Monitor
Flunarizine: May increase therapeutic effects of Antihypertensive Agents. Risk C: Monitor
Herbal Products with Blood Pressure Increasing Effects: May decrease antihypertensive effects of Antihypertensive Agents. Risk C: Monitor
Herbal Products with Blood Pressure Lowering Effects: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Iloperidone: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Indoramin: May increase hypotensive effects of Antihypertensive Agents. Risk C: Monitor
Isocarboxazid: May increase antihypertensive effects of Antihypertensive Agents. Risk X: Avoid
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may increase hypotensive effects of Levodopa-Foslevodopa. Risk C: Monitor
Local Anesthetics: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor
Loop Diuretics: May increase hypotensive effects of Antihypertensive Agents. Risk C: Monitor
Lormetazepam: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Metergoline: May decrease antihypertensive effects of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may increase orthostatic hypotensive effects of Metergoline. Risk C: Monitor
Methylphenidate: May decrease antihypertensive effects of Antihypertensive Agents. Risk C: Monitor
Molsidomine: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Molsidomine: May increase hypotensive effects of Vasodilators (Organic Nitrates). Risk C: Monitor
Naftopidil: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Nicergoline: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Nicorandil: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Nitric Oxide: May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Nitroprusside: Blood Pressure Lowering Agents may increase hypotensive effects of Nitroprusside. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents: May decrease antihypertensive effects of HydrALAZINE. Risk C: Monitor
Obinutuzumab: May increase hypotensive effects of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider Therapy Modification
Pentoxifylline: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Perazine: May increase hypotensive effects of Antihypertensive Agents. Risk C: Monitor
Pholcodine: Blood Pressure Lowering Agents may increase hypotensive effects of Pholcodine. Risk C: Monitor
Phosphodiesterase 5 Inhibitors: May increase vasodilatory effects of Vasodilators (Organic Nitrates). Risk X: Avoid
Prazosin: Antihypertensive Agents may increase hypotensive effects of Prazosin. Risk C: Monitor
Prilocaine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor
Primaquine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Primaquine. Specifically, the risk for methemoglobinemia may be increased. Management: Avoid concomitant use of primaquine and other drugs that are associated with methemoglobinemia when possible. If combined, monitor methemoglobin levels closely. Risk D: Consider Therapy Modification
Prostacyclin Analogues: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Quinagolide: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Rilmenidine: Vasodilators (Organic Nitrates) may increase hypotensive effects of Rilmenidine. Risk C: Monitor
Riociguat: Vasodilators (Organic Nitrates) may increase hypotensive effects of Riociguat. Risk X: Avoid
Rosiglitazone: Vasodilators (Organic Nitrates) may increase adverse/toxic effects of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. Risk C: Monitor
Silodosin: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Sodium Nitrite: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Terazosin: Antihypertensive Agents may increase hypotensive effects of Terazosin. Risk C: Monitor
Tiapride: May increase hypotensive effects of Vasodilators (Organic Nitrates). Risk C: Monitor
Urapidil: Antihypertensive Agents may increase hypotensive effects of Urapidil. Risk C: Monitor
Hydralazine crosses the placenta (ESC [Regitz-Zagrosek 2018]).
See individual monographs for additional information.
Hydralazine is present in breast milk (ESC [Regitz-Zagrosek 2018]).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
See individual monographs for additional information.
Blood pressure (standing and sitting/supine), heart rate; CBC and antinuclear antibody (ANA) titers (if symptoms of systemic lupus erythematosus occur)
Hydralazine: Direct vasodilation of arterioles (with little effect on veins) resulting in decreased systemic resistance
Isosorbide Dinitrate: Stimulation of intracellular cyclic-GMP results in vascular smooth muscle relaxation of both arterial and venous vasculature with more prominent effects on the veins. Primarily reduces cardiac oxygen demand by decreasing preload (left ventricular end-diastolic pressure); may modestly reduce afterload. Additionally, coronary artery dilation improves collateral flow to ischemic regions.
The following values are from administration of isosorbide dinitrate 40 mg and hydralazine 75 mg in healthy adults. Also see individual drug monographs.
Half-life elimination: Hydralazine: 4 hours; Isosorbide dinitrate: 2 hours
Time to peak, plasma: 1 hour (both agents)
Hepatic function impairment: Isosorbide dinitrate concentrations increase in patients with cirrhosis.
Older adult: Isosorbide dinitrate, its active metabolites, and hydralazine may be eliminated more slowly in elderly patients.
