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HydrALAZINE

Pronunciation

Pronunciation

(hye DRAL a zeen)

Index Terms

  • Apresoline
  • Hydralazine HCl
  • Hydralazine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection, as hydrochloride:

Generic: 20 mg/mL (1 mL)

Tablet, Oral, as hydrochloride:

Generic: 10 mg, 25 mg, 50 mg, 100 mg

Pharmacologic Category

  • Antihypertensive
  • Vasodilator

Pharmacology

Direct vasodilation of arterioles (with little effect on veins) with decreased systemic resistance

Absorption

Oral: Rapidly absorbed

Metabolism

Hepatically acetylated; extensive first-pass effect (oral)

Excretion

Urine (as metabolites)

Onset of Action

IV: 10 to 80 minutes

Time to Peak

Plasma: Oral: 1 to 2 hours

Duration of Action

IM, IV: Up to 12 hours (Marik 2007); Note: Duration may vary depending on acetylator status of patient. Hypotension due to hydralazine may last longer even though the circulating half-life is much shorter (Marik, 2007; O’Malley, 1975).

Half-Life Elimination

3 to 7 hours

Protein Binding

87%

Special Populations Note

Slow acetylators: Patients will generally have higher plasma levels of hydralazine and require lower doses to maintain control of BP.

Use: Labeled Indications

Hypertension: Management of moderate to severe hypertension

Note: According to the Eighth Joint National Committee (JNC 8) guidelines, hydralazine is not recommended for the initial treatment of hypertension (James, 2013).

Use: Unlabeled

Patients with heart failure with reduced ejection fraction (HFrEF) who do not tolerate an ACE inhibitor or an angiotensin receptor blocker (ARB) (in combination with isosorbide dinitrate); African-American (self-identified) patients with HFrEF NYHA Class III-IV remaining symptomatic despite optimal guideline directed medical therapy (in combination with isosorbide dinitrate); hypertensive emergency (with or without pre-eclampsia/eclampsia) in pregnancy; postoperative hypertension.

Contraindications

Hypersensitivity to hydralazine or any component of the formulation; coronary artery disease; mitral valve rheumatic heart disease

Dosing: Adult

Hypertension: Oral: Initial: 10 mg 4 times daily for the first 2 to 4 days; increase to 25 mg 4 times daily for the balance of the first week; further increase to 50 mg 4 times daily; for maintenance, adjust dose to the lowest effective dose (up to 300 mg daily may be required in resistant patients)

Heart failure (off-label use): Oral: Initial dose: 25 to 50 mg 3 or 4 times daily; use in combination with isosorbide dinitrate; maximum dose: 300 mg daily in divided doses (ACCF/AHA [Yancy, 2013])

Hypertensive emergency (off-label dose): Note: Use is generally not recommended due to unpredictable and prolonged antihypertensive effects (Marik, 2007): IM, IV: 10 to 20 mg every 4 to 6 hours as needed (Rhoney, 2009)

Hypertensive emergency in pregnancy (systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg) (off-label dose): IM, IV: Initial: 5 or 10 mg; may repeat dose in 20 to 40 minutes with 5 to 10 mg if blood pressure continues to exceed thresholds (ACOG, 2015; Magee, 2014; Too, 2013). Also refer to administration protocols developed by the American College of Obstetricians and Gynecologists (ACOG, 2015). A maximum total cumulative dose of 20 mg (IV) or 30 mg (IM) is recommended (Magee, 2014). Note: After the initial dose, may initiate a continuous infusion of 0.5 to 10 mg/hour instead of intermittent dosing (Magee, 2014).

Perioperative hypertension (off-label dose): IV: 3 to 20 mg every 20 to 60 minutes as needed (Varon, 2008). Note: The lower end of the dosage range is preferred in the immediate perioperative period and in patients with renal failure. The use of hydralazine in this setting especially in patients with ischemic heart disease, aortic dissection, or an intracranial process is best avoided due to unpredictable and prolonged antihypertensive effects (Lien, 2012; Varon, 2008).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Children and Adolescents: Note: Individualize dose; titrate gradually to patient response.

Hypertension, chronic: Oral: Initial: 0.75 mg/kg/day in 2 to 4 divided doses, maximum initial dose: 10 mg/dose; may increase gradually over 3 to 4 weeks up to a maximum of 7.5 mg/kg/day in 2 to 4 divided doses not to exceed 200 mg/day (NHBPEP 2004; NHLBI 2012; Park 2014)

Hypertensive emergency/urgency: IM, IV: Initial: 0.1 to 0.2 mg/kg/dose every 4 to 6 hours; increase as required to suggested usual range: 0.2 to 0.6 mg/kg/dose every 4 to 6 hours as needed; maximum dose: 20 mg/dose (NHBPEP 2004; Park 2014; Thomas 2011); manufacturer labeling suggests a dose range of 1.7 to 3.5 mg/kg/day divided in 4 to 6 doses

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended (Aronoff 2007):

Children and Adolescents: Note: Renally adjusted dose recommendations are based on doses: Oral: 0.75 to 1 mg/kg/day divided every 6 to 12 hours; IV: 0.1 to 0.2 mg/kg/dose every 6 hours:

GFR >50 mL/minute/1.73 m2: No adjustment necessary

GFR 10 to 50 mL/minute/1.73 m2: Administer every 8 hours

GFR <10 mL/minute/1.73 m2: Administer every 12 to 24 hours

Intermittent hemodialysis: Administer every 12 to 24 hours

Peritoneal dialysis: Administer every 12 to 24 hours

Continuous renal replacement therapy: Administer every 8 hours

Adults: Note: Renally adjusted dose recommendations are based on doses of 25 to 50 mg every 8 hours:

GFR ≥10 mL/minute: Administer every 8 hours.

GFR <10 mL/minute: Administer every 8 to 16 hours

Intermittent hemodialysis: Dose after dialysis

Peritoneal dialysis: Administer every 8 to 16 hours

Continuous renal replacement therapy: Administer every 8 hours

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling. However, hydralazine undergoes extensive hepatic metabolism.

Extemporaneously Prepared

A 4 mg/mL oral suspension may be made with tablets and a 1:1 mixture of Ora-Sweet SF and Ora-Plus. Crush four 100 mg tablets in a mortar and reduce to a fine powder. Add 15 mL of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 100 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 100 mL. Label “Shake Well”, “Protect From Light”, “Store in a Refrigerator”. Stable for 2 days when stored in amber plastic prescription bottles in the dark and refrigerated (Allen, 1998).

Note: Stability reduced to 24 hours if Ora-Sweet is substituted for Ora-Sweet SF.

Allen LV Jr, Erickson MA 3rd. Stability of alprazolam, chloroquine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids. Am J Health-Syst Pharm. 1998;55(18):1915-1920.9784772

Administration

Oral: Administer without regard to meals. However, food enhances bioavailability; administer consistently with regard to meals.

Injection: Response may be delayed and unpredictable in some patients; titrate cautiously to response.

IM: Administer undiluted as IM injection.

IV: Administer undiluted as slow IV push; maximum rate in children: 5 mg/minute (Klaus 1989). May also administer as a continuous infusion; refer to indication-specific infusion rates in dosing for detailed recommendations.

Compatibility

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D51/4NS, D51/2NS, D5NS, D10W, LR, 1/2NS, NS; incompatible with D5W.

Y-site administration: Incompatible with aminophylline, ampicillin, furosemide, nesiritide, pantoprazole.

Compatibility in syringe: Incompatible with pantoprazole.

Storage

Tablets: Store at 15ºC to 30ºC (59ºF to 86ºF).

Injection: Store at 20ºC to 25ºC (68ºF to 77ºF); use immediately after vial is opened. Solution may discolor upon contact with metal; discard discolored solutions.

Drug Interactions

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

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

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

Dapoxetine: May enhance the orthostatic hypotensive effect of HydrALAZINE. 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

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

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

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

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. 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

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

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

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

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering 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

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

Adverse Reactions

Frequency not defined.

Cardiovascular: Angina pectoris, flushing, orthostatic hypotension, palpitations, paradoxical hypertension, peripheral edema, tachycardia, vascular collapse

Central nervous system: Anxiety, chills, depression, disorientation, dizziness, fever, headache, increased intracranial pressure (IV; in patient with pre-existing increased intracranial pressure), psychotic reaction

Dermatologic: Pruritus, rash, urticaria

Gastrointestinal: Anorexia, constipation, diarrhea, nausea, paralytic ileus, vomiting

Genitourinary: Dysuria, impotence

Hematologic: Agranulocytosis, eosinophilia, erythrocyte count reduced, hemoglobin decreased, hemolytic anemia, leukopenia, thrombocytopenia (rare)

Neuromuscular & skeletal: Muscle cramps, peripheral neuritis, rheumatoid arthritis, tremor, weakness

Ocular: Conjunctivitis, lacrimation

Respiratory: Dyspnea, nasal congestion

Miscellaneous: Diaphoresis, drug-induced lupus-like syndrome (dose related; fever, arthralgia, splenomegaly, lymphadenopathy, asthenia, myalgia, malaise, pleuritic chest pain, edema, positive ANA, positive LE cells, maculopapular facial rash, positive direct Coombs' test, pericarditis, pericardial tamponade)

Warnings/Precautions

Concerns related to adverse effects:

• Drug-induced lupus-like syndrome: May cause a drug-induced lupus-like syndrome including glomerulonephritis, especially in patients receiving higher doses. If this syndrome occurs, discontinue therapy unless the benefit-to-risk requires continued therapy. Signs and symptoms usually regress after discontinuation of therapy, but residua have been detected many years later. Long-term treatment with steroids may be necessary.

• Hematologic effects: Blood dyscrasias (eg, reduction in hemoglobin and red blood cell count, leukopenia, agranulocytosis, purpura) may occur; discontinue therapy if these hematologic effects occur.

• Hypotension: Postural hypotension may occur.

• 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 is contraindicated in patients with coronary artery disease (CAD). Use with caution in patients with cerebral vascular accidents and suspected CAD; myocardial stimulation produced by hydralazine can cause anginal attacks and electrocardiogram (ECG) changes of myocardial ischemia; has been implicated in the production of myocardial infarction. According to the American Heart Association/American College of Cardiology/American Society of Hypertension 2015 scientific statement for the treatment of hypertension in patients with CAD, hydralazine (without a concomitant nitrate [eg, isosorbide dinitrate]) should be avoided for the treatment of hypertension in patients with heart failure (with reduced ejection fraction) of ischemic origin (AHA/ACC/ASH [Rosendorff, 2015]).

• Mitral valvular disease: Use with caution in patients with mitral valvular disease; may increase pulmonary artery pressure in these patients. Use is contraindicated in patients with mitral valve rheumatic heart disease.

• Renal impairment: Use with caution in patients with advanced renal impairment; dosage adjustment recommended.

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.

Dosage forms related issues:

• Tartrazine sensitivity: May contain tartrazine, which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of tartrazine sensitivity in the general population is low, it is frequently seen in patients who are also hypersensitive to aspirin.

Monitoring Parameters

Blood pressure (monitor closely with IV use), standing and sitting/supine, heart rate, complete blood cell count (CBC), antinuclear antibody (ANA) titer

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Hydralazine crosses the placenta (Liedholm, 1982). Intravenous hydralazine is recommended for use in the management of acute onset, severe hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg) with preeclampsia or eclampsia in pregnant and postpartum women. Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. If treatment for chronic hypertension in pregnancy is needed, other oral agents are preferred as initial therapy (ACOG, 2013; Magee, 2014).

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, diarrhea, lack of appetite, vomiting, 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, angina or shortness of breath, or swelling in the arms or legs), change in amount of urine passed, urinary retention, severe dizziness, passing out, angina, tachycardia, abnormal heartbeat, chills, pharyngitis, burning or numbness feeling, severe loss of strength and energy, bruising, or bleeding (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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