HYDRALAZINE HCL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer consistently with regards to timing around meals/food to ensure consistent oral absorption.
Extemporaneous Compounding-Oral
-Hydralazine is stable in mannitol or sorbitol for approximately 21 days. Hydralazine is unstable in dextrose, fructose, lactose, and maltose.

Extemporaneous hydralazine 1.25 mg/mL oral suspension
-Crush seventy-five 50 mg tablets into a fine powder.
-Add 250 mL of distilled water to dissolve the drug.
-Slowly add 2,250 g of Lycasin (a syrup vehicle that is 75% w/w maltitol).
-Dissolve 3 g of edetate disodium and 3 g of sodium saccharin in 50 mL of distilled water, then add to hydralazine mixture.
-Add 30 mL of a paraben stock solution containing methylparaben (10% w/v) and propylparaben 2% (w/v) in propylene glycol to the hydralazine mixture.
-Add 3 mL orange flavoring.
-Add distilled water to bring volume to 3 L. Adjust pH to 3.7 with glacial acetic acid.
-Store in an amber-colored glass bottle and refrigerate at 5 degrees C. Drug is stable for 2 weeks.

Extemporaneous hydralazine 1 mg/mL or 10 mg/mL oral suspension
-Dissolve either 100 mg (for 1 mg/mL suspension) or 1 g (for 10 mg/mL suspension) of hydralazine hydrochloride in 30 mL of purified water.
-Add 50 mg aspartame. Shake or stir until solids dissolve.
-Add 40 g of 70% sorbitol solution.
-In a separate container, dissolve 65 mg of methylparaben and 35 mg of propylparaben in 10 g propylene glycol. Add to hydralazine mixture. Mix well.
-Add sufficient purified water to bring to volume to 100 mL.
-Quantitatively transfer the solution to a suitable tight and light-resistant glass or plastic bottle with a child-resistant closure.
-Store the preparation under refrigeration between 2 to 8 degrees C. The beyond-use date is 30 days from the date of compounding.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Administer dose immediately after opening the vial.
-Do not dilute.
-Do not add hydralazine to any IV solutions.
-Hydralazine changes color after contact with metal. Discard any discolored hydralazine solution.
-Check blood pressure frequently following administration of injectable hydralazine.
Intravenous Administration
IV Push
-Inject over 1 to 2 minutes.

Intramuscular Administration
-Inject undiluted solution deeply into a large muscle.

Difficulty in urination (specific reactions not specified) has been reported with hydralazine treatment. The frequency of occurrence and drug causality are not established.

Gastrointestinal adverse effects associated with hydralazine administration include anorexia, nausea, vomiting, constipation, and diarrhea. Paralytic ileus has also been reported. Many adverse reactions may subside if the drug dosage is decreased; however, in some cases the drug may need to be discontinued.

Hydralazine is a potent vasodilator and can result in hypotension including orthostatic hypotension, dizziness, syncope, peripheral vasodilation, peripheral edema, and fluid retention. Hydralazine-induced fluid retention can cause edema and weight gain. These effects usually can be alleviated by concomitant administration of a thiazide diuretic. Due to the pharmacology of hydralazine, a paradoxical pressor response, palpitations, sinus tachycardia, angina, and ECG changes of myocardial ischemia may also occur. The drug has also been associated with myocardial infarction. Initiation of therapy with low doses and a gradual increase until a satisfactory antihypertensive effect is obtained will help to minimize adverse reactions.

Hypersensitivity and lupus-like symptoms, manifested by fever, chills, sore throat, myalgia, arthralgia, pericarditis, pleuritis, cutaneous vasculitis (skin blisters), glomerulonephritis, rash (unspecified), pruritus, urticaria, eosinophilia, and erythema can occur with hydralazine. Hepatitis has been reported rarely with hydralazine. Hydralazine is implicated in producing lupus-like symptoms. Hydralazine is metabolized by acetylation. The patient's acetylation phenotype will affect the plasma concentration of hydralazine. Patients who are slow acetylators as well as patients with decreased renal function are more likely than fast acetylators to develop lupus-like symptoms. Patients with decreased renal function, patients receiving more than 200 mg/day, and patients with a family history of autoimmune disease are also more likely to develop this condition. Although some manifestations are similar, drug-induced lupus occurs via a different mechanism than idiopathic disease. Patients should be instructed to report adverse symptoms of joint pain, muscle pain, angina, fever, or continued weakness to their physician. If hydralazine-induced lupus syndrome is suspected, the drug should be discontinued. Symptoms usually regress with discontinuation. Long-term steroid treatment may be necessary.

Hydralazine can cause peripheral neuropathy, evidenced by paresthesias (numbness, pain, and tingling in the hands and feet). Significant increases in urinary xanthurenic acid may indicate pyridoxine deficiency; therefore, an antipyridoxine mechanism has been suggested. If symptoms do develop, the addition of pyridoxine to the regimen is suggested. Tremor, muscle cramps, and headache have also been associated with hydralazine use.

Blood dyscrasias such as agranulocytosis, leukopenia, anemia (defined as reduction of hemoglobin and red cell count), and purpura have been reported during hydralazine therapy. Complete blood counts should be undertaken before therapy with hydralazine and periodically thereafter, especially during prolonged therapy. Hydralazine therapy should be discontinued if there is evidence of blood dyscrasias.

There have been occasional reports of dyspnea, lacrimation, conjunctivitis, flushing, lymphadenopathy, splenomegaly, and nasal congestion with hydralazine therapy.

Depression, anxiety, and disorientation (confusion) have been reported as adverse reactions with hydralazine therapy. Many adverse reactions may subside if the drug dosage is decreased; however, in some cases the drug may need to be discontinued.

Hydralazine may produce a clinical picture simulating systemic lupus erythematosus (SLE) including glomerulonephritis. Hydralazine is extensively metabolized in the liver and is subject to polymorphic acetylation; patients with slow acetylation status have higher plasma levels of hydralazine and these patients require lower doses to maintain control of blood pressure. Thus, the patient's acetylation phenotype will affect the plasma concentration of hydralazine. Patients who are slow acetylators as well as patients with decreased renal function are more likely than fast acetylators to develop lupus-like symptoms or other hydralazine toxicity. Patients with decreased renal function, patients receiving more than 200 mg/day, and patients with a family history of autoimmune disease, are also more likely to develop this condition. It is difficult to provide guidelines regarding administration of hydralazine to patients with preexisting systemic lupus erythematosus (SLE). Although hydralazine has been administered safely to these patients, with no exacerbation of underlying disease, and the mechanism of hydralazine-induced lupus syndrome appears to be distinct from idiopathic lupus, hydralazine should nevertheless be used cautiously in this population. Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy, even if the patient does not have any symptoms; these tests are also indicated if a patient develops arthralgia, fever, chest pain, continued malaise, or other unexplained symptoms. If hydralazine-induced SLE occurs, the drug should be discontinued, unless the benefit of continued antihypertensive therapy with this drug outweighs the risk. Signs and symptoms of lupus usually regress when the drug is discontinued; however, residual signs and symptoms have been detected many years later. Long-term treatment with systemic steroids may be necessary.

Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine. In hypertensive patients with normal kidneys who are treated with hydralazine, there is evidence of increased renal blood flow and maintenance of glomerular filtration rate (GFR). In some instances where control values were below normal, improved renal function has been noted after the administration of the drug. However, as with any antihypertensive agent, hydralazine should be used with caution in patients with advanced renal damage. Some references state to consider extended dose intervals in patients with renal impairment (CrCl 10 to 50 mL/minute). Patients with renal impairment should receive the drug every 8 hours. Patients with renal failure (CrCl less than 10 mL/minute) should receive the drug every 8 to 16 hours; based on patient response, intervals of 12 to 24 hours may be needed.

Hydralazine is contraindicated in patients with mitral valve rheumatic heart disease because it can increase pulmonary artery pressure. Additionally, it has been implicated in causing angina and myocardial infarction secondary to reflex sympathetic nervous system stimulation (i.e., reflex tachycardia); therefore, hydralazine is contraindicated in patients with coronary artery disease as reflex tachycardia increases myocardial oxygen demand and can aggravate angina and ischemia and precipitate acute myocardial infarction. Because hydralazine can cause sodium and fluid retention, its use is generally not recommended in patients with heart failure, although it has been used in patients with intractable left ventricular dysfunction.

Use hydralazine cautiously in patients with acute stroke or cerebral vascular accident as hydralazine in this setting can further worsen brain function. When hydralazine is used in the presence of increased intracranial pressure, lowering of the blood pressure may result in increased cerebral ischemia.

Hydralazine can induce disorientation or confusion. Caution should be exercised during activities requiring coordination and concentration.

Description: Hydralazine is an oral and parenteral antihypertensive agent. Pediatric indications for the drug include hypertension, hypertensive emergency or urgency, and treatment of congestive heart failure with systolic dysfunction. Oral and intravenous dosage forms are available; intravenous treatment is only indicated when oral treatment is not feasible. Due to a lack of pediatric clinical trials of comparing the effects of antihypertensive drugs on clinical outcomes, drug choice typically is influenced by physician preference; as such, the benefits of hydralazine treatment should be weighed against potential adverse effects including unpredictable falls in blood pressure and reflex tachycardia. Although not FDA approved, hydralazine is used off-label for hypertension in pediatric patients as young as neonates.

For the treatment of hypertension*:
Oral dosage:
Neonates: Limited data available; however, 0.25 to 1 mg/kg/dose PO administered 3 to 4 times daily has been suggested. Gradually increase as needed for blood pressure control Max: 7.5 mg/kg/day.
Infants, Children, and Adolescents: 0.75 mg/kg/day PO given in 4 divided doses initially. Max initial dose: 25 mg/dose. Titrate over 3 to 4 weeks up to a Max of 7.5 mg/kg/day (not to exceed 200 mg/day).
Intravenous dosage:
Neonates: Limited data in neonates. A dose of 0.15 to 0.6 mg/kg/dose IV administered every 4 hours has been suggested. Repeat as needed for blood pressure control. Only use IV route if PO is not feasible. Switch to oral antihypertensive therapy as soon as possible, usually within 24 to 48 hours. When switching from IV to oral therapy, the IV dose should generally be doubled and administered orally; titrate the oral dose to response.
Infants, Children, and Adolescents: 0.2 to 0.6 mg/kg/dose (Max: 20 mg/dose) IV every 4 hours as needed for blood pressure control. Max: 1.7 to 3.5 mg/kg/day. Use IV route only if PO is not feasible. Switch to oral therapy as soon as possible, usually within 24 to 48 hours. When switching from IV to oral therapy, the IV dose should generally be doubled and administered orally; titrate the oral dose to response.
Intramuscular dosage:
Infants, Children, and Adolescents: 0.2 to 0.6 mg/kg/dose (Max: 20 mg/dose) IM every 4 hours as needed for blood pressure control. Max: 1.7 to 3.5 mg/kg/day. Use IM route only if PO is not feasible. Switch to oral therapy as soon as possible, usually within 24 to 48 hours.

For the treatment of hypertensive emergency* or hypertensive urgency*:
Intravenous dosage:
Neonates: Limited data. A dose of 0.15 to 0.6 mg/kg/dose IV administered every 4 hours as needed has been suggested. Switch to oral antihypertensive therapy as soon as possible, usually within 24 to 48 hours. When switching from IV to oral therapy, the IV dose should generally be doubled and administered orally; titrate the oral dose to response.
Infants, Children, and Adolescents: 0.1 to 0.2 mg/kg/dose (Max: 20 mg/dose) IV every 4 to 6 hours as needed; may increase the dose slowly up to 0.6 mg/kg/dose (Max: 20 mg/dose). Switch to oral therapy as soon as possible, usually within 24 to 48 hours. When switching from IV to oral therapy, the IV dose should generally be doubled and administered orally; titrate the oral dose to response.
Intramuscular dosage:
Infants, Children, and Adolescents: 0.1 to 0.2 mg/kg/dose (Max: 20 mg/dose) IM every 4 to 6 hours as needed; may increase dose slowly up to 0.6 mg/kg/dose (Max: 20 mg/dose). Switch to oral therapy as soon as possible, usually within 24 to 48 hours.
Oral dosage:
Children and Adolescents: 0.25 mg/kg/dose (Max: 25 mg/dose) PO every 6 to 8 hours as needed.

For the treatment of congestive heart failure* in patients with systolic dysfunction:
Oral dosage:
Infants, Children, and Adolescents: 0.25 to 1 mg/kg/dose PO every 6 to 8 hours; increase as needed. Max: 7 mg/kg/day. The incidence of systemic lupus erythematosus is higher in patients receiving doses greater than 200 mg/day.
Intravenous dosage:
Infants, Children, and Adolescents: 0.1 to 0.5 mg/kg/dose IV every 6 to 8 hours. Switch to oral therapy as soon as possible.

Maximum Dosage Limits:
-Neonates
Safety and efficacy not established; however, doses up to 7.5 mg/kg/day PO or 0.6 mg/kg/dose IV have been used.
-Infants
Safety and efficacy not established; however, doses up to 7.5 mg/kg/day PO or 3.5 mg/kg/day IV or IM have been used.
-Children
Safety and efficacy not established; however, doses up to 7.5 mg/kg/day PO or 200 mg/day PO, whichever is less or 3.5 mg/kg/day IV or IM have been used.
-Adolescents
Safety and efficacy not established; however, doses up to 7.5 mg/kg/day PO or 200 mg/day PO, whichever is less or 3.5 mg/kg/day IV or IM have been used.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available. Hydralazine is extensively metabolized in the liver and is subject to polymorphic acetylation; patients with slow acetylation status have higher plasma levels of hydralazine and these patients require lower doses to maintain control of blood pressure.

Patients with Renal Impairment Dosing
CrCl more than 50 mL/minute: no dosage adjustment needed.
CrCl 10 to 50 mL/minute: administer every 8 hours.
CrCl less than 10 mL/minute: administer every 8 to 16 hours. Interval may be extended to 12 to 24 hours based on patient response.

Intermittent hemodialysis
Administer every 12 to 24 hours depending on patient blood pressure.

Peritoneal dialysis
Administer every 12 to 24 hours depending on patient blood pressure.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Hydralazine is a peripheral vasodilator; it causes relaxation of arteriolar smooth muscle via a direct effect. The molecular explanation of hydralazine's mechanism is not fully understood; however, similar to organic nitrates and nitroprusside, it is thought that hydralazine interferes with the calcium movements within vascular smooth muscle that are responsible for initiating and maintaining the contractile state. In contrast to organic nitrates and sodium nitroprusside, however, hydralazine is selective for arterioles. The peripheral vasodilating effects of hydralazine result in decreased arterial blood pressure (diastolic more than systolic) and peripheral vascular resistance. In addition, the hydralazine-induced reflex autonomic response increases heart rate, stroke volume, cardiac output, and left ventricular ejection fraction. The preferential dilation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output even though the hypotensive effects of hydralazine are diminished somewhat by this increase in cardiac output. There is also evidence suggesting hydralazine exerts a positive inotropic effect on the failing human ventricle. As an antihypertensive, hydralazine does not lead to improvements in left ventricular hypertrophy (LVH). Hydralazine may actually worsen LVH, potentially due to reflex tachycardia and sympathetic stimulation, which may counteract the benefits of afterload reduction.

Animal and limited human data indicate that nitric oxide (NO) may be generated from hydralazine that also has an antioxidant quality to enhance the effects of nitrates and to mitigate the tolerance associated with chronic nitrate therapy. The antioxidant effect of hydralazine can be attributed to its ability in inhibiting oxidase formation. The accumulation of oxidative free radicals creates an environment where chronic reductions in NO bioavailability contribute to a loss of skeletal muscle microvessels. This effect, in turn, leads to impaired muscle perfusion with elevated metabolic demand. Studies show that treatment with hydralazine markedly inhibits oxidase which plays a role in regulating the bioactivity of NO, produced either endogenously or when administered exogenously.

Cerebral, coronary, splanchnic, and renal blood flow usually increase following administration of hydralazine, while urinary parameters are generally unaffected. Hydralazine increases renin activity in plasma, presumably by the renal juxtaglomerular cells in response to sympathetic nervous system stimulation; the increase in renin activity leads to the production of angiotensin II, which stimulates aldosterone and thus, sodium reabsorption. Due to fluid retention, plasma volume increases. As a result, tolerance can develop, which may account for the absence of improvement in some patients receiving the drug for prolonged periods of time.

Pharmacokinetics: Hydralazine is administered orally and parenterally. Hydralazine distributes throughout the body tissues and has a particularly high affinity for arterial walls. The drug is 87% bound to plasma proteins. The drug is mainly eliminated as its metabolites in the urine; approximately 10% of a dose is excreted in the feces. The half-life of the drug in a normal adult patient is 3 to 7 hours.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Oral Route
Although hydralazine is approximately 90% absorbed following oral administration, systemic bioavailability is considerably lower after oral versus intramuscular or intravenous administration due to extensive first-pass metabolism. Oral bioavailability is also dependent on the acetylation phenotype of the patient. In kinetic studies in adults, bioavailability is approximately 50% in 'slow' acetylators and 30% in 'fast' acetylators. Although food in the gut enhances absorption of hydralazine, food-related reductions in hydralazine blood concentrations have been associated with reduced antihypertensive effects, possibly due to an increase in intravascular conversion of the drug to hydralazine pyruvic acid hydrazone. For this reason, it has been suggested that patients take this medication at a fixed time in relationship to meals. Hypotensive effects occur 20 to 30 minutes following an oral dose. Peak plasma concentrations occur in 1 to 2 hours. The antihypertensive effects of an oral hydralazine dose last about 2 to 4 hours.

Intravenous Route
Hypotensive effects occur 5 to 30 minutes after an IV dose. Maximal decrease in blood pressure occurs 10 to 80 minutes following injection. The antihypertensive effects of an IV dose last 2 to 6 hours on average, although the effects of a parenteral dose can last up to 12 hours; the affinity of hydralazine for arterial walls may partially explain the prolonged effect.

Intramuscular Route
Hypotensive effects occur 10 to 30 minutes after an IM dose. Maximal decrease in blood pressure occurs 10 to 80 minutes following injection. The antihypertensive effects of an IM dose last 2 to 6 hours on average, although the effects of a parenteral dose can last up to 12 hours possibly due to the affinity of hydralazine for arterial walls.


-Special Populations
Renal Impairment
The half-life of hydralazine can be prolonged in patients with renal impairment or renal failure.