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Hydralazine (Systemic)


VA CLASSIFICATION
Primary: CV402
Secondary: CV900

Commonly used brand name(s): Apo-Hydral; Apo-Hydralazine; Apresoline; Apresoline Injection; Novo-Hylazin.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihypertensive—

vasodilator, congestive heart failure—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hypertension (treatment)—Hydralazine is indicated orally for the treatment of hypertension {01}. Hydralazine is indicated intravenously when oral therapy cannot be given or when there is an urgent need to lower blood pressure, {22} such as in hypertensive crisis {27} {28} {29} or pre-eclampsia or eclampsia {23} {24} {25} {31}.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

[Congestive heart failure (treatment) ]1
—Hydralazine combined with isosorbide dinitrate (nonspecific vasodilator therapy) has been used as a supplement to the traditional congestive heart failure treatment of digitalis and diuretics {09} {10}. Although the hydralazine-isosorbide combination has demonstrated beneficial effects {09}, its use remains controversial because of the results of the Veterans Administration Cooperative Vasodilator–Heart Failure Trials (V-HeFT I and II) that evaluated the effects of this combination in patients with mild to moderate congestive heart failure {09} {10}. In V-HeFT I, treatment of patients with hydralazine-isosorbide resulted in a favorable effect on left ventricular (LV) function (interpreted as a delay in the progression of LV dysfunction) and a 28% reduction in overall mortality when compared with treatment of patients receiving placebo {09}. In V-HeFT II, treatment of patients with the angiotensin-converting enzyme (ACE) inhibitor enalapril resulted in a significantly lower average 2-year mortality rate (18%) than treatment of patients with hydralazine-isosorbide (25%), although treatment of patients with hydralazine-isosorbide resulted in a significant improvement in exercise performance and LV function when compared with those treated with enalapril {10}. Since the conclusion of these trials, the statistical methods used in the V-HeFT I trial have been questioned, and the results, according to some scientists, are considered borderline significant {06} {50}. Although ACE inhibitors are considered the basis of treatment for heart failure, isosorbide dinitrate and hydralazine may be considered for the treatment of New York Heart Association (NYHA) class II and III heart failure when ACE inhibitors are not tolerated, as determined by the occurrence of symptomatic hypotension, azotemia, hyperkalemia, cough, rash, or angioneurotic edema {43}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Hydralazine hydrochloride: 196.64 {04}

pKa—
    7.3

Mechanism of action/Effect:

Antihypertensive—Although the exact mechanism of antihypertensive action is not fully understood, hydralazine is thought to lower blood pressure by acting directly on arterial smooth muscle to cause vasodilation {01}. By altering cellular calcium metabolism, hydralazine interferes with the movement of calcium, thereby affecting the contractile state of vascular smooth muscle {01}. Vasodilation and a reduction in total peripheral vascular resistance occur, resulting in an increase in heart rate, stroke volume, and cardiac output {01}.

Vasodilator, congestive heart failure—The beneficial effects of hydralazine in the treatment of congestive heart failure are thought to be due to a direct increase in cardiac output secondary to decreased systemic resistance and to the associated afterload reduction when hydralazine is used in combination with isosorbide dinitrate (additionally, isosorbide dinitrate decreases preload by decreasing resistance in venous capacitance vessels) {37}.


Other actions/effects:

Hydralazine increases renin activity in plasma, possibly resulting from an increase in the secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge {01}. Increased renin activity leads to the production of angiotensin II, which stimulates the production of aldosterone, causing a reabsorption of sodium {01}. Hydralazine also maintains or increases renal and cerebral blood flow {01}.

Absorption:

Hydralazine is rapidly and extensively absorbed (up to 90%) from the gastrointestinal tract and undergoes extensive first-pass metabolism by genetic polymorphic acetylation {13}. Oral bioavailability of hydralazine is dependent upon acetylator phenotype {17}. Bioavailability is approximately 31% in slow acetylators and 10% in fast acetylators {17}.

Protein binding:

High (87%) {01}.

Biotransformation:

Hydralazine, when administered orally, undergoes extensive first-pass metabolism by genetic polymorphic acetylation, which is responsible for a threefold range of oral bioavailability {16} {18}. Intravenously administered hydralazine does not undergo first-pass metabolism and, therefore, is not affected by acetylator phenotype {30}. After the drug reaches the systemic circulation, it is combined with endogenous aldehydes and ketones, including pyruvic acid, to form hydrazone metabolites {17}. The active metabolites, hydralazine acetonide hydrazone and hydralazine pyruvate hydrazone, are equipotent with the parent, hydralazine {13}.

Half-life:


Apparent hydralazine (using nonselective assays):

3 to 7 hours {01} {15} {17}.



Hydralazine (using urine specific assay):

Approximately 90 minutes {15} {17} {44}.


Some references state a difference in half-life between slow and fast acetylators, but there is generally thought to be little difference {13} {17}.

The half-life of antihypertensive action is much longer than the plasma half-life, possibly because hydralazine persists within arteriolar walls.


Time to peak concentration:

Oral tablets—1 to 2 hours {01}.

Elimination:
    Renal—52 to 90%, primarily as metabolites {45}.
    Fecal—Approximately 10% {45}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to tartrazine (FD & C Yellow No. 5) may be sensitive to the tablets that contain this dye {01}.

Carcinogenicity

A lifetime study in Swiss male and female albino mice given hydralazine continuously in their drinking water at a dose of about 250 mg per kg of body weight (mg/kg) per day (approximately 80 times the maximum recommended human dose) revealed an increase in the incidence of lung tumors (adenomas and adenocarcinomas) {01}.

Tumorigenicity

In a 2-year carcinogenicity study of rats, hydralazine given at dose levels of 15, 30, and 60 mg/kg per day (about 5 to 20 times the recommended human daily dose) produced a small, but statistically significant, increase in benign neoplastic nodules in male and female rats in the high-dose group and in female rats in the intermediate-dose group {01}. Furthermore, benign interstitial cell tumors of the testes were significantly increased in male rats in the high-dose group {01}.

Mutagenicity

Hydralazine was shown to be mutagenic in bacterial systems (gene mutation and DNA repair). Mutagenicity was also found in one of two rat and one rabbit hepatocyte in vitro DNA repair study. However, in vivo and in vitro studies using mouse lymphoma cells, germinal cells, and fibroblasts, Chinese hamster bone marrow cells, and human cell fibroblasts did not reveal any mutagenic potential of hydralazine {01}.

Pregnancy/Reproduction

Pregnancy—
Although hydralazine is one of the most commonly used drugs for acute blood pressure reduction in severe hypertension in pregnancy {41}, few adequate and well-controlled studies of hydralazine in pregnant women have been done. Adverse effects that have occurred in pregnant women with hydralazine administration include anxiety, epigastric pain, flushing, headaches, hypotension, nausea, palpitations, reduction in placental perfusion, restlessness, tachycardia, tremors, and vomiting {41}. Thrombocytopenia, leukopenia, petechial bleeding, and hematomas have been reported in newborns whose mothers took hydralazine orally, although these symptoms resolved spontaneously in 1 to 3 weeks. In patients with intrauterine growth retardation, intravenous use of hydralazine has caused fetal distress {25} {32} {33} {41}. The risk of fetal distress appears to be greater when vasodilation with hydralazine is undertaken without prior volume expansion {34}. Hydralazine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus {01}.

Studies in mice given hydralazine at 20 to 30 times the maximum daily human dose of 200 to 300 mg revealed teratogenic effects {01}. Furthermore, studies in rabbits indicate teratogenic effects at doses 10 to 15 times the maximum daily human dose. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones {01}. However, hydralazine was not shown to be teratogenic in rats {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

Hydralazine is distributed into breast milk {01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of hydralazine have not been performed in the pediatric population. However, the oral solution contains aspartame, which is metabolized to phenylalanine, and must be used with caution in children with phenylketonuria {39} {40}.


Geriatrics


Although extensive studies on the relationship of age to the effects of hydralazine have not been performed in the geriatric population, geriatrics-specific problems are not expected to limit the usefulness of hydralazine in the elderly. Renal clearance and apparent volume of distribution appear to be decreased and half-life appears to be increased in older hypertensive patients when compared with young healthy volunteers, although confirmation of these differences requires further investigation {45}.


Pharmacogenetics

Acetylator phenotype is responsible for differences in oral bioavailability of hydralazine {01} {17}. Generally, all patients may be divided into two groups, slow and fast acetylators of hydralazine {13}. Eskimo, Oriental, and American Indian populations have the lowest prevalence of slow acetylators, while Egyptian, Israeli, Scandinavian, other Caucasian, and black populations have the highest prevalence of slow acetylators.

In slow acetylators, the oral bioavailability of hydralazine is increased {01} {17}, which may explain why rapid acetylators generally require larger oral doses of hydralazine for the control of blood pressure {17} {45}. Slow acetylators, as a result of increased bioavailability, are exposed to higher plasma hydralazine concentrations than are rapid acetylators when a fixed, weight-adjusted oral dose is administered {45}. This may explain why slow acetylators are more prone to develop adverse effects, such as hydralazine-induced systemic lupus erythematosus (SLE) {45}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin    (may reduce antihypertensive effects of hydralazine; indomethacin, and possibly other NSAIDs, may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention)


» Diazoxide or
Hypotension-producing medications, other (see Appendix II )    (antihypertensive effects may be potentiated when these medications are used concurrently with hydralazine; concurrent use of diazoxide or other potent parenteral antihypertensive agents with hydralazine may result in a severe, additive hypotensive effect; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use {01}; patients should be continuously observed for excessive fall in blood pressure for several hours after concurrent administration of diazoxide or other potent parenteral antihypertensives {01})


Sympathomimetics, including
Epinephrine{01}    (hydralazine may reduce pressor responses to epinephrine {01}; contrarily, sympathomimetics may reduce the antihypertensive effects of hydralazine; the patient should be monitored carefully when sympathomimetics are used concurrently with hydralazine)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Direct antiglobulin (Coombs') tests    (may produce positive results)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Coronary artery disease{01}    (myocardial stimulation and increased myocardial oxygen demands may cause or aggravate ischemia and angina and reportedly may precipitate myocardial infarction {01})


» Hypersensitivity to hydralazine{01}
» Mitral valvular disease, such as that associated with rheumatic heart disease{01}    (hydralazine may increase pulmonary artery pressure in these patients {01})


Risk-benefit should be considered when the following medical problems exist
Aortic aneurysm or
» Aortic dissection, acute{28}{29}    (reflexive increase in heart rate, cardiac output, and shear stress associated with hydralazine may exacerbate condition)


Cerebrovascular disease or accident    (hydralazine-induced decreases in blood pressure may increase cerebral ischemia)


Phenylketonuria    (the oral solution of hydralazine contains aspartame, which is metabolized to phenylalanine, and may be hazardous to patients with phenylketonuria {39} {40})


Renal function impairment    (high plasma “apparent” hydralazine concentrations have occurred in patients with renal failure and, in one study, the two subjects with the lowest estimated creatinine clearances [39 and 45 mL per minute (mL/min)] had the longest half-lives and lowest clearances of hydralazine {45}. Although evidence of increased hydralazine toxicity in renal failure has not been observed {46}, caution should be used in dosing hydralazine in patients with severe renal function impairment {01})


Note: There is no substantial evidence that use of hydralazine in the treatment of hypertension in patients with systemic vasculitis or systemic lupus erythematosus (SLE) exacerbates the underlying disease process.



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Antinuclear antibody (ANA) titer determinations{01} and
Lupus erythematosus cell preparations    (may be indicated if arthralgia, fever, chest pain, continued malaise, or other unexplained symptoms develop that may be related to drug-induced SLE {01})


» Blood pressure measurements    (periodic monitoring is necessary for titration of dose according to the patient's response {01})


Complete blood counts (CBC)    (periodic monitoring may be necessary {42}; blood dyscrasias, consisting of a reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, and purpura, have been reported {01}; hydralazine should be discontinued if these abnormalities occur {01})




Side/Adverse Effects

Note: Side/adverse effects are rare at lower dosages and are generally reversible.
Hepatotoxicity has been reported in a few patients.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Allergic reaction (skin rash or itching)
    
angina pectoris (chest pain)
    
cutaneous vasculitis (blisters on skin)
    
lymphadenopathy (swelling of lymph glands)
    
peripheral neuritis (numbness, tingling, pain, or weakness in hands or feet)
    
sodium and water retention and edema (swelling of feet or lower legs)
    
systemic lupus erythematosus (SLE)–like syndrome, including glomerulonephritis (blisters on skin; chest pain; general feeling of discomfort, illness, or weakness; muscle pain; joint pain; skin rash or itching; sore throat and fever)

Note: Long-term hydralazine therapy has been associated with a moderate incidence of a condition resembling systemic lupus erythematosus (SLE) {01}. Risk factors for development of hydralazine-induced SLE include high daily doses of hydralazine (greater than 200 mg per day), slow acetylator or HLA-DRw4 phenotype, and family history of autoimmune disease {19} {20}. Clinical symptoms may include adenopathy, arthralgias, arthritis, fever, malaise, myalgias, pericarditis with or without effusions, pleuritis with or without effusions, and, rarely, skin rash and glomerulonephritis {47} {48}. If SLE-like symptoms develop, hydralazine should be discontinued {48}. Clinical symptoms usually resolve within days or weeks after discontinuation of hydralazine, although the resolution of laboratory value changes, such as a positive antinuclear antibody (ANA) titer, may take much longer {19} {20} {21} {47}. Approximately 30% of all patients receiving hydralazine develop a positive ANA within 1 year of continuous therapy {20} {21}. Development of a positive ANA titer is not strongly linked to development of clinical symptoms; therefore, screening asymptomatic patients using serial ANA titers is not recommended {48}.
Attacks of angina pectoris and electrocardiographic changes showing myocardial ischemia have occurred as a result of hydralazine-induced myocardial stimulation {01}.


Incidence rare
    
Blood dyscrasias, including agranulocytosis, leukopenia, and purpura (fever; general feeling of discomfort or illness; sore throat; weakness)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Anorexia (loss of appetite)
    
diarrhea
    
headache
    
nausea or vomiting
    
palpitations (pounding heartbeat)
    
tachycardia (fast heartbeat)

Note: In patients with severe heart failure, sympathetic tone is already high and there will be little or no change in heart rate.


Incidence less frequent
    
Constipation
    
dyspnea (shortness of breath)
    
hypotension (dizziness or lightheadedness)
    
lacrimation (watery eyes)
    
nasal congestion (stuffy nose)
    
redness or flushing of face





Overdose
For specific information on the agents used in the management of hydralazine overdose, see:
   • Beta-adrenergic Blocking Agents (Systemic) monograph; and/or
   • Charcoal, Activated (Oral-Local) monograph; and/or
   • Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Headache
    
hypotension
    
myocardial ischemia and subsequent myocardial infarction{01} (anxiety; cough; dizziness, lightheadedness, or fainting; nausea; prolonged abdominal, back, or chest pain that may radiate to the arms, shoulders, neck, chest, back, teeth, or jaw; shortness of breath, sudden; sweating, unusual; vomiting)
    
flushing of skin
    
shock, severe
    
tachycardia (fast heartbeat)


Note: Myocardial ischemia with marked ST segment depression has been reported {26}.


Treatment of overdose


To decrease absorption:
Evacuation of gastric contents {01}. If conditions permit, activated charcoal may be administered {01} {26}.



Specific treatment:
For shock: Plasma expanders {01}. If a vasopressor is required, care should be taken not to precipitate or aggravate cardiac arrhythmia {01}.

For tachycardia: Beta-adrenergic blocking agents {01}.



Monitoring:
Fluid and electrolyte status and renal function should be monitored {01}.



Supportive care:
Support of cardiovascular system is most important {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Hydralazine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to hydralazine

Pregnancy—Blood problems and fetal distress reported in infants of mothers who took hydralazine orally; high doses have caused birth defects in animals





Use in children—Aspartame-containing oral solution must be used with caution in children with phenylketonuria

Other medications, especially diazoxide
Other medical problems, especially acute aortic dissection, coronary artery disease, or mitral valvular disease, such as that associated with rheumatic heart disease

Proper use of this medication
Compliance with therapy; taking medication at the same times each day to maintain the therapeutic effect

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For use as an antihypertensive
Possible need for control of weight and diet, especially sodium intake {03}

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure, but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing medication; serious consequences of untreated hypertension

For oral solution dosage form
May be mixed with fruit juice or applesauce just prior to administration {39}

Precautions while using this medication
Making regular visits to physician to check progress

» Caution when driving or doing things requiring alertness because of possible headache or dizziness

Phenylketonuric patients
The oral solution dosage form contains phenylalanine 1.4 mg per teaspoonful {39}

For use as an antihypertensive
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician


Side/adverse effects
Signs of potential side effects, especially allergic reaction, angina pectoris, cutaneous vasculitis, lymphadenopathy, peripheral neuritis, sodium and water retention, edema, SLE-like syndrome, and blood dyscrasias


General Dosing Information
In response to hydralazine-induced vasodilation, reflex tachycardia and fluid retention can occur when hydralazine is administered alone long-term {01} {42}. Concurrent administration of hydralazine with a diuretic and a beta-adrenergic blocking or other appropriate sympatholytic agent may prevent fluid retention and excessive sympathetic stimulation of the heart {01} {42} {44}.

Incidence and severity of some of the side effects of hydralazine can be minimized if the dosage is increased slowly to its therapeutic level.

Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery is not necessary, but that the anesthesiologist must be made aware of such therapy.

Peripheral neuritis has been observed in some patients on hydralazine therapy {01}. Evidence suggests that this may be due to an antipyridoxine effect. Discontinuation of hydralazine or continuation of hydralazine with supplemental vitamin B 6 (pyridoxine) 100 to 200 mg per day usually results in remission of the neuritis over a period of 4 to 6 weeks.

Due to differences in oral bioavailability between acetylator phenotypes, rapid acetylators may require a larger oral dose than slow acetylators require for the control of blood pressure {45}.

To avoid a sudden increase in blood pressure, patients on hydralazine who have shown a significant decrease in blood pressure should have the medication withdrawn gradually at cessation of therapy.
For oral dosage forms
Food may enhance the bioavailability of hydralazine by reducing first-pass metabolism in the gastrointestinal wall {01}. Consistent administration in relation to meals is recommended.

The oral solution of hydralazine may be mixed with fruit juice or applesauce just prior to administration {39}.

For parenteral dosage forms
Most patients can be transferred to the oral dosage form of hydralazine within 24 to 48 hours after initiation of parenteral therapy {22}.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

HYDRALAZINE HYDROCHLORIDE ORAL SOLUTION

Usual adult dose
Hypertension
Oral, initially 40 mg per day {01}, divided into two or four doses {01} {49} {51}, for the first two to four days {01}, followed by 100 mg per day {01}, divided into two or four doses {01} {49} {51}, for the balance of the first week {01}. For the second and subsequent weeks, 200 mg per day {01}, divided into two or four doses {01} {49} {51}. Maintenance dosage should be adjusted to the lowest effective dose {01}.

Note: Hydralazine conventionally has been administered in four divided doses per day {01}, the basis for this convention being the short plasma half-life of hydralazine {49}. However, a study of the blood pressure–lowering effects of hydralazine in hypertensive patients found that there was no significant difference in efficacy when two-, three-, or four-dose regimens were used {49}. A possible explanation for the lack of a difference may be that hydralazine is readily taken up by arterial blood vessels and released very slowly, prolonging the hypotensive effect {49}.


[Congestive heart failure]1
Oral, initially, when administered concurrently with isosorbide dinitrate, 40 to 150 mg per day {09} {10} {43} {52}, divided into two, three, or four doses {09} {10} {43} {49} {52}. If tolerated, the dose may be increased to up to 300 mg per day {09} {10} {43}, divided into two, three, or four doses {09} {10} {43} {49} {52}. Patients with low blood pressure, severe heart failure, or advanced age may be started at 30 mg per day in divided doses {43} {52}.


Usual adult prescribing limits
300 mg daily {01}.

Usual pediatric dose
Hypertension
Oral, 750 mcg (0.75 mg) per kg of body weight a day {01} divided into two or four doses {01} {49} {51}, the dosage being increased gradually over three or four weeks as needed, up to a maximum of 7.5 mg per kg of body weight or 200 mg a day {01}.


Strength(s) usually available
U.S.—
Not commercially available. Compounding required for prescriptions.

Canada—
Not commercially available. Compounding required for prescriptions.

Packaging and storage:
Package in a light-resistant glass or plastic 120-mL bottle, with a child-resistant cap {39}. Store at refrigerator temperature, 2 to 8 °C (36 to 46 °F) {39}.

Preparation of dosage form:


For a 0.1% oral solution (5 mg per 5 mL)—Hydralazine Hydrochloride USP  100  mg 
For a 1% oral solution (50 mg per 5 mL)—Hydralazine Hydrochloride USP  gram 
Remaining ingredients: 
Sorbitol solution USP (70%)  40  grams 
Methylparaben NF  65  mg 
Propylparaben NF  35  mg 
Propylene Glycol USP  10  grams 
Aspartame NF  50  mg 
Purified Water, a sufficient quantity to make  100  mL 
Dissolve the appropriate amount of hydralazine hydrochloride in 30 mL of purified water {39}. Add aspartame and shake or stir until dissolved {39}. Add sorbitol solution {39}. In a separate container, dissolve the methylparaben and propylparaben in the propylene glycol and, while stirring, add this mixture to the solution containing the hydralazine hydrochloride {39}. Add purified water to make 100 mL and mix {39}.

Note: Contains 1.4 mg of phenylalanine per teaspoonful (5 mL) {39}.



Stability:
Preparation is stable for 30 days after the day on which it was compounded {39}.

Auxiliary labeling:
   • Store in refrigerator {39}.
   • Expiration date.
   • Do not take other medicines without your doctor's advice.


HYDRALAZINE HYDROCHLORIDE TABLETS USP

Usual adult dose
Hypertension
Oral, initially 40 mg per day {01}, divided into two or four doses {01} {49} {51}, for the first two to four days, followed by 100 mg per day {01}, divided into two or four doses {01} {49} {51}, for the balance of the first week {01}. For the second and subsequent weeks, 200 mg per day {01}, divided into two or four doses {01} {49} {51}. Maintenance dosage should be adjusted to the lowest effective dose {01}.

Note: Hydralazine conventionally has been administered in four divided doses per day {01}, the basis for this convention being the short plasma half-life of hydralazine {49}. However, a study of the blood pressure–lowering effects of hydralazine in hypertensive patients found that there was no significant difference in efficacy when two-, three-, or four-dose regimens were used {49}. A possible explanation for the lack of a difference may be that hydralazine is readily taken up by arterial blood vessels and released very slowly, prolonging the hypotensive effect {49}.


[Congestive heart failure]1
Oral, initially, when administered concurrently with isosorbide dinitrate, 40 to 150 mg per day {09} {10} {43} {52}, divided into two, three, or four doses {09} {10} {43} {49} {52}. If tolerated, the dose may be increased to up to 300 mg per day {09} {10} {43}, divided into two, three, or four doses {09} {10} {43} {49} {52}. Patients with low blood pressure, severe heart failure, or advanced age may be started at 30 mg per day {52}, divided into two or three doses {43} {49}.


Usual adult prescribing limits
300 mg daily {01}.

Usual pediatric dose
Hypertension
Oral, 750 mcg (0.75 mg) per kg of body weight a day {01} divided into two or four doses {01} {49} {51}, the dosage being increased gradually over three or four weeks as needed, up to a maximum of 7.5 mg per kg of body weight or 200 mg a day {01}.


Strength(s) usually available
U.S.—


10 mg (Rx)[Generic]


25 mg (Rx)[Generic]


50 mg (Rx)[Generic]


100 mg (Rx)[Generic]

Canada—


10 mg (Rx) [Apo-Hydral] [Apresoline (scored) (tartrazine)] [Novo-Hylazin]{42}[Generic]


25 mg (Rx) [Apo-Hydralazine{35}] [Apresoline (lactose)] [Novo-Hylazin][Generic]


50 mg (Rx) [Apo-Hydralazine{35}] [Apresoline (lactose)] [Novo-Hylazin][Generic]

Note: The Apresoline brand name product is no longer commercially available in the U.S.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.



Parenteral Dosage Forms

HYDRALAZINE HYDROCHLORIDE INJECTION USP

Usual adult dose
Hypertension
Intramuscular or intravenous, 5 to 40 mg, repeated as needed {22} {23} {24} {25} {28} {29}.

Pre-eclampsia or eclampsia: Intravenous, 5 mg every fifteen to twenty minutes {25} {31}. If a therapeutic response is not achieved after a total dose of 20 mg, another agent should be considered {31}. Continuous intravenous infusion of hydralazine should be avoided because a rapid uncontrolled decline in blood pressure could increase the risk for development of fetal distress, necessitating cesarean delivery {41}.


Usual pediatric dose
Hypertension
Intramuscular or intravenous, 1.7 to 3.5 mg per kg of body weight a day, divided into four to six daily doses {22}.


Strength(s) usually available
U.S.—


20 mg per mL (Rx)[Generic]

Canada—


20 mg per mL (Rx) [Apresoline Injection]

Note: The Apresoline brand name product is no longer commercially available in the U.S.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Hydralazine hydrochloride injection should be used immediately after the ampul is opened. {22}

Incompatibilities:
Hydralazine hydrochloride injection may undergo color changes when added to infusion fluids {22}. It is recommended that hydralazine hydrochloride injection not be added to infusion solutions {22}.



Revised: 08/24/1998



References
  1. Apresoline hydrochloride tablets package insert (Ciba—US), Rev 8/89, Rec 11/91; Rev 4/92, Rec 3/94; Rev 5/95, Rec 2/98.
  1. Leier CV, Desch CE, Magorien RD. Positive inotropic effects of hydralazine in human subjects: comparison with prazosin in the setting of congestive heart failure. Am J Cardiol 1980; 46: 1039-43.
  1. Cardiovascular and Renal Drugs Advisory Panel Meeting, 2/25/92.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1996. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1995: 345.
  1. Apresoline hydrochloride parenteral package insert (Ciba—US), Rev 4/86, Rec 11/91.
  1. Panel comment, 8/97
  1. Chatterjee K, Ports TA, Brundage BH, et al. Oral hydralazine in chronic heart failure: sustained beneficial hemodynamic effects. Ann Intern Med 1980; 92: 600-4.
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