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Isosorbide Dinitrate and Hydralazine

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: Treatment of heart failure as an adjunct to standard therapy in self-identified African American patients

American College of Cardiology/American Heart Association heart failure guidelines recommendations (ACCF/AHA [Yancy, 2013]). Patients who are African-American (self-identified) with heart failure with reduced ejection fraction (HFrEF) NYHA class III-IV remaining symptomatic despite optimal guideline-directed medical therapy; Patients with HFrEF who do not tolerate an ACE inhibitor or an angiotensin receptor blocker (ARB)

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: Oral:

Initial: One tablet 3 times daily.

Maintenance: May titrate in 3 to 5 days to a maximum dose of 2 tablets 3 times daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

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. Monitor therapy

Barbiturates: 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. Monitor therapy

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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. 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. Monitor therapy

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. 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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. 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. 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. 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. Monitor therapy

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. 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

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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 Risk Factor

C

Pregnancy Considerations

See individual agents.

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 nausea or vomiting. Have patient report immediately to prescriber severe headache, severe dizziness, passing out, angina, joint pain, joint edema, tachycardia, burning or numbness feeling, or severe loss of strength and energy (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 healthcare 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.

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