Version May 2024
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 hypertension 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 2020]).
• 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): $3.33 - $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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect 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 enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Dapoxetine: May enhance the orthostatic hypotensive effect of HydrALAZINE. Risk C: Monitor therapy
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Indoramin: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy
Loop Diuretics: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Vasodilators (Organic Nitrates). Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of HydrALAZINE. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect 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 enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk X: Avoid combination
Prazosin: Antihypertensive Agents may enhance the hypotensive effect of Prazosin. Risk C: Monitor therapy
Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Rilmenidine: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Rilmenidine. Risk C: Monitor therapy
Riociguat: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Riociguat. Risk X: Avoid combination
Rosiglitazone: Vasodilators (Organic Nitrates) may enhance the adverse/toxic effect 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 therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Terazosin: Antihypertensive Agents may enhance the hypotensive effect of Terazosin. Risk C: Monitor therapy
Urapidil: Antihypertensive Agents may enhance the hypotensive effect of Urapidil. Risk C: Monitor therapy
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.
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