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Isosorbide Dinitrate and Hydralazine

Medically reviewed by Drugs.com. Last updated on Aug 28, 2019.

Pronunciation

(eye soe SOR bide dye NYE trate & hye DRAL a zeen)

Index Terms

  • Hydralazine and Isosorbide Dinitrate

Dosage Forms

Tablet, oral:

BiDil: Isosorbide dinitrate 20 mg and hydralazine hydrochloride 37.5 mg

Brand Names: U.S.

  • BiDil

Pharmacologic Category

  • Antihypertensive
  • Vasodilator

Pharmacology

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.

Time to Peak

1 hour (both agents)

Half-Life Elimination

Hydralazine: 4 hours; Isosorbide dinitrate: 2 hours

Special Populations: Hepatic Function Impairment

Isosorbide dinitrate concentrations increase in patients with cirrhosis.

Special Populations: Elderly

Isosorbide dinitrate, its active metabolites, and hydralazine may be eliminated more slowly in elderly patients.

Use: Labeled Indications

Heart failure with reduced ejection fraction (HFrEF): Treatment of heart failure as an adjunct to standard therapy in self-identified African-American patients. Note: Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of heart failure, isosorbide dinitrate in combination with hydralazine is effective and recommended as additional therapy to optimal medical therapy for self-identified African-American patients with persistent NYHA class III or IV HFrEF or for patients who do not tolerate an ACE inhibitor or an ARB (ACC/AHA [Yancy 2013]). Some experts recommend isosorbide dinitrate in combination with hydralazine in addition to optimal guideline-directed medical therapy for black and nonblack patients with persistent NYHA class III or IV HFrEF, particularly for those with low output states or hypertension, or for patients who do not tolerate an ACE inhibitor, ARB, or angiotensin II-neprilysin inhibitor (Colucci 2018).

Contraindications

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

Dosing: Adult

Heart failure with reduced ejection fraction (HFrEF): Note: As additional therapy for persistent NYHA class III or IV HFrEF despite optimal medical therapies or for patients who cannot tolerate an ACE inhibitor, ARB, or angiotensin II-neprilysin inhibitor (ACCF/AHA [Yancy 2013]; Colucci 2018).

Oral: Initial: One tablet (containing 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine) 3 times daily; titrate dose in 2 to 4 weeks to a maximum dose of 2 tablets (containing a total of 40 mg of isosorbide dinitrate and 75 mg of hydralazine) 3 times daily. Note: May also consider use of hydralazine 3 times daily and isosorbide dinitrate 3 times daily as separate components rather than this combination tablet (ACC/AHA/HFSA [Yancy 2017]; ACCF/AHA [Yancy 2013]; Gottlieb 2018).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

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.

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Alcohol (Ethyl): May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of HydrALAZINE. Monitor therapy

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Vasodilators (Organic Nitrates). Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of HydrALAZINE. 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. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Avoid combination

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. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Rilmenidine: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Rilmenidine. Monitor therapy

Riociguat: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Riociguat. 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. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

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%), tendon disease (1%)

Ophthalmic: Amblyopia (3%)

Respiratory: Bronchitis (8%), rhinitis (4%), sinusitis (4%)

Warnings/Precautions

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 (HCM): Avoid use in patients with HCM with outflow tract obstruction; nitrates may reduce preload, exacerbating obstruction and cause hypotension or syncope and/or worsening of heart failure (ACCF/AHA [Gersh, 2011]).

• Pulmonary hypertension: Use with caution in pulmonary hypertension; may cause hypotension.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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).

Monitoring Parameters

Blood pressure (standing and sitting/supine), heart rate; CBC and antinuclear antibody (ANA) titers (if symptoms of systemic lupus erythematosus occur)

Pregnancy Considerations

Hydralazine crosses the placenta (ESC [Regitz-Zagrosek 2018]).

See individual monographs for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, loss of strength and energy, or nausea. Have patient report immediately to prescriber signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs), severe dizziness, passing out, chest pain, tachycardia, or burning or numbness feeling (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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