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HERITAGE PHARMA
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23155000110

hydralazine 10 mg tablet

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Uses

Hypertension

Hydralazine is used in the management of moderate to severe hypertension. Although other antihypertensive drug classes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics) are preferred for the initial management of hypertension in adults, direct vasodilators such as hydralazine may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs.

Hydralazine generally is used in conjunction with a diuretic and another hypotensive agent. The use of a diuretic may prevent tolerance to hydralazine and also the sodium retention and increased plasma volume that may occur after prolonged hydralazine therapy. Use of hydralazine in conjunction with other hypotensive agents also may permit a reduction in the dosage of each drug and minimizes adverse effects while maintaining blood pressure control. (See Drug Interactions: Diuretics and Hypotensive Agents.) Adverse effects such as tachycardia and precipitation of angina may be minimized by administering the drug in conjunction with a β-adrenergic blocking agent (β-blocker).

For additional information on overall principles and expert recommendations for treatment of hypertension,

Hypertensive Crises

Parenteral hydralazine may be used for the management of severe hypertension when the drug cannot be given orally or when blood pressure must be lowered immediately. Because hydralazine has a less predictable hypotensive effect and greater cardiac stimulating effects, other agents (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside) usually are preferred for the management of severe hypertension or hypertensive emergencies when a parenteral hypotensive agent is employed. In addition, because of potential adverse effects on cerebrovascular circulation, hydralazine generally is not recommended for the management of severe hypertension or hypertensive emergencies associated with cerebrovascular accidents or in patients with cerebral edema and encephalopathy. However, IV or IM hydralazine has been used effectively and historically has been considered the parenteral hypotensive agent of choice for the management of hypertensive emergencies associated with pregnancy (e.g., preeclampsia, eclampsia).(See Hypertension During Pregnancy under Uses: Hypertension.) Excessive falls in blood pressure should be avoided in any hypertensive crisis since they may precipitate renal, cerebral, or coronary ischemia.

Hypertension during Pregnancy

Hydralazine has been used parenterally in the hospital setting for urgent lowering of blood pressure in severely hypertensive pregnant women, including those with preeclampsia. Recommendations for the management of such patients are based principally on experience in women with preeclampsia or gestational hypertension in the third trimester. Delivery is the preferred method of management for women with severe preeclampsia; however, use of antihypertensive drugs is recommended in such women who have severely elevated blood pressures (sustained systolic blood pressure of at least 160 mm Hg or diastolic blood pressure of at least 110 mm Hg) to prevent potentially life-threatening cardiovascular, renal, and cerebrovascular complications. Results of several randomized clinical trials evaluating antihypertensive therapy in women with severe hypertension during pregnancy suggest that IV hydralazine, IV labetalol, or oral nifedipine are appropriate antihypertensives for urgently lowering blood pressure in such patients; choice of therapy should be based on clinician experience and preference as well as patient-specific-factors (e.g., concomitant medical conditions or therapies) and drug-related factors (e.g., route of administration, adverse effects, contraindications, local availability, cost). Although hydralazine historically has been considered the agent of choice for management of hypertensive emergencies associated with pregnancy, some clinicians now prefer IV labetalol for its more rapid onset, shorter duration of action, and more predictable hypotensive effect. If antihypertensive therapy is considered for the management of preeclampsia, it should be recognized that such therapy is employed solely for maternal benefit; it does not improve perinatal outcomes and may adversely affect uteroplacental flow.

Heart Failure

Hydralazine is used in fixed combination with isosorbide dinitrate (BiDil) as an adjunct to standard therapy for the treatment of heart failure in self-identified black patients to improve survival, decrease rate of hospitalization for worsened heart failure, and improve patient-reported functional status. Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. ( and .) The combination of hydralazine and isosorbide dinitrate is recommended by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) for self-identified black patients with New York Heart Association (NYHA) functional class III or IV heart failure and reduced ejection fraction who are receiving optimal therapy with ACE inhibitors and β-blockers (unless contraindicated). The ACCF and AHA also state that combined therapy with hydralazine and isosorbide dinitrate may be considered in patients with current or prior symptomatic heart failure with reduced ejection fraction who cannot receive an ACE inhibitor or angiotensin II receptor antagonist because of drug intolerance, hypotension, or renal insufficiency.

Efficacy of the hydralazine/isosorbide dinitrate fixed-combination preparation was evaluated in a multicenter, randomized, placebo-controlled, double-blind trial (the African-American Heart Failure Trial; A-HeFT trial) in 1050 self-identified black adults (mean age: 57 years) with stable moderate-to-severe heart failure (NYHA functional class III in over 95% of patients) secondary to left ventricular dysfunction (ejection fraction 35% or less). Patients were randomized to receive the fixed-combination preparation containing hydralazine and isosorbide dinitrate (initially, 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate 3 times daily and titrated [as tolerated] to a target dosage of 75 mg of hydralazine hydrochloride and 40 mg of isosorbide dinitrate 3 times daily) or placebo for up to 18 months. Patients also received standard therapy (e.g., diuretics [mainly loop diuretics], β-blockers, ACE inhibitors, angiotensin II receptor antagonists, cardiac glycosides, and/or aldosterone antagonists).

The A-HeFT trial was terminated early (after a mean follow-up period of 10-12 months) primarily because of a significant reduction (43%) in all-cause mortality in patients receiving the fixed-combination preparation containing hydralazine and isosorbide dinitrate; mortality rate was about 10.2 or 6.2% in patients receiving placebo or the fixed combination, respectively.

The primary end point of the study (a mean primary composite score consisting of all-cause mortality, first hospitalization for worsening of heart failure, and improvement of quality of life [as assessed by responses to the Minnesota Living with Heart Failure questionnaire]) also showed substantial differences between drug therapy and placebo. Patients receiving the fixed combination containing hydralazine and isosorbide dinitrate experienced a significant reduction (33%) in the rate of first hospitalization for heart failure (16.4 or 24.4% for those receiving the drug or placebo, respectively) and a significant improvement in response to the Minnesota Living with Heart Failure questionnaire (a self-report of functional status). Factors of age, gender, baseline disease, or concomitant medications appeared to have no effect on survival or rate of hospitalization. The fixed combination containing hydralazine and isosorbide dinitrate had a slight but significant blood pressure-lowering effect; a mean decrease of 1.9 and 2.4 mm Hg from baseline in systolic and diastolic blood pressure, respectively, was observed in patients receiving the drugs, while an increase of 1.2 and 0.8 mm Hg from baseline in systolic and diastolic blood pressure, respectively, was observed in patients receiving placebo. However, the role of reduced blood pressure in the improved outcome of patients receiving the study medications has not been evaluated. The manufacturer states that there is no adequate clinical experience with hydralazine hydrochloride or isosorbide dinitrate as separate agents† or with dosages of the drugs other than those used in the A-HeFT trial for the treatment of heart failure.

In another randomized, placebo-controlled, comparative, long-term (median 2.3 years; range: 6-68 months) study (Vasodilator Heart Failure Trial [V-HeFT I]) in patients with chronic congestive heart failure (associated with ischemic or nonischemic cardiomyopathy) who were receiving conventional therapy (cardiac glycosides and diuretics, without an ACE inhibitor), addition of hydralazine hydrochloride (up to 300 mg daily) given concomitantly with isosorbide dinitrate (up to 160 mg daily) resulted in a 25-30% decrease in overall mortality rates after 2 years when compared with conventional therapy and placebo or prazosin (up to 20 mg daily). However, despite substantial increases in ejection fraction, the combination of the 2 vasodilators was not associated with decreased hospitalizations and many patients discontinued therapy during follow-up, although retrospective analysis of such data indicate that there was a trend favoring the administration of the 2 vasodilators, which was attributed to an effect observed in black patients.

In a subsequent randomized, comparative, long-term (median 2.5 years; range: 6-68 months) study (V-HeFT II) in patients with ischemic or nonischemic cardiomyopathy and mild to moderate heart failure (NYHA functional class II and III) who were receiving conventional therapy (cardiac glycosides and diuretics), addition of enalapril maleate (up to 20 mg daily) resulted in a 28% decrease in overall mortality rates after 2 years when compared with conventional therapy and concomitant use of hydralazine hydrochloride (up to 300 mg daily) with isosorbide dinitrate (up to 160 mg daily). Retrospective analysis of the data indicates that such decreases in mortality rates in patients receiving enalapril in conjunction with conventional therapy were not observed in black patients. In addition, concomitant therapy with the 2 vasodilators had more favorable effects on ventricular ejection fraction and exercise tolerance than those associated with enalapril.

Other Uses

Hydralazine has produced hemodynamic and clinical improvement in some patients with unexplained pulmonary hypertension; however, the drug does not produce consistent results and may cause serious adverse reactions (e.g., symptomatic hypotension, severe dyspnea) in patients with this condition. Further studies are needed to determine the safety, efficacy, and role of hydralazine in the treatment of unexplained pulmonary hypertension. The drug should be used for the treatment of this condition only with careful hemodynamic monitoring and clinical evaluation.

Dosage and Administration

Administration

Hydralazine hydrochloride usually is administered orally. In patients who are unable to take the drug orally or when a rapid decrease in blood pressure is required, the drug may be given IM or IV. Oral therapy with hydralazine should replace parenteral therapy as soon as possible.

Dosage

When hydralazine therapy is discontinued in patients with a marked reduction in blood pressure, withdrawal should be gradual to avoid a possible sudden increase in blood pressure. One study found 20-25 mg of IV hydralazine hydrochloride approximately equal to 75-100 mg of oral hydralazine hydrochloride.

Hypertension

Dosage of hydralazine must be adjusted according to the patient's blood pressure response and tolerance. Generally, dosage of hydralazine required for satisfactory blood pressure control is higher in rapid acetylators than in slow acetylators.

Adult Dosage

For the management of hypertension, an initial adult oral dosage of hydralazine hydrochloride of 10 mg 4 times daily for 2-4 days has been suggested. Dosage then can be increased to 25 mg 4 times daily for the remainder of the week. If necessary, dosage can be increased for the second and subsequent weeks to 50 mg 4 times daily. In a few patients, 300-400 mg daily may be required. Generally, slow acetylators should not receive more than 200 mg daily of oral hydralazine hydrochloride. For maintenance therapy, dosage is adjusted to the lowest effective level. Studies have shown hydralazine may be administered twice daily in many patients for maintenance therapy. Some experts recommend a usual dosage range of 12.5-50 mg twice daily; the rationale for this reduced dosage is that it usually is preferable to add another antihypertensive agent to the regimen than to increase maximum hydralazine hydrochloride dosage beyond 100 mg daily because of poor patient tolerance of increasing dosages of the drug.

Pediatric Dosage

Although the manufacturers have not established pediatric dosage recommendations, some clinicians have suggested an initial oral dosage of hydralazine hydrochloride of 0.75 mg/kg daily or 25 mg/m daily, given in 4 divided doses. An initial oral dose should not exceed 25 mg. If necessary, dosage may be increased gradually over a period of 3-4 weeks up to 7.5 mg/kg (maximum 200 mg) daily. For parenteral hydralazine therapy in children, some clinicians have suggested 1.7-3.5 mg/kg daily or 50-100 mg/m daily divided in 4-6 doses. An initial parenteral dose should not exceed 20 mg. If parenteral hydralazine is given with reserpine, dosage of hydralazine may be reduced to 0.15 mg/kg or 4 mg/m every 12-24 hours. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of hydralazine hydrochloride is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting hydralazine hydrochloride dosage in the management of hypertension,

Hypertensive Crises

For the management of severe hypertension or hypertensive emergencies, the usual adult IM dose of hydralazine hydrochloride is 10-40 mg and the usual IV dose is 10-20 mg, using low doses in these ranges initially; the parenteral doses are repeated as necessary and may be increased within these ranges according to the blood pressure response.

If IV hydralazine is used in the management of a hypertensive emergency in adults, the initial goal of such therapy is to reduce mean arterial blood pressure by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia. If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours. Patients with aortic dissection should have their systolic pressure reduced to less than 100 mm Hg if tolerated.

Hydralazine hydrochloride also has been administered IM for the management of hypertensive crises, but the onset of hypotensive effect is delayed compared with IV administration.

Although the manufacturers have not established pediatric dosage recommendations, some clinicians have suggested an IV or IM hydralazine hydrochloride dose of 0.2-0.6 mg/kg for rapid reduction of blood pressure in pediatric patients (1-17 years of age) with severe hypertension. The drug should be administered every 4 hours when given by injection (''IV bolus'').

Hypertension during Pregnancy

For the urgent lowering of blood pressure in severely hypertensive pregnant women, the usual initial adult IV dose of hydralazine hydrochloride is 5 mg, followed by IV doses of 5-10 mg every 20-40 minutes as necessary to achieve an adequate reduction in blood pressure; maximum total doses of 20 or 25 mg have been recommended. Alternatively, hydralazine hydrochloride has been infused IV at a rate of 0.5-10 mg/hour for the management of severe hypertension during pregnancy. Blood pressure should be closely monitored when parenteral hydralazine is employed.

Heart Failure

For the adjunctive treatment of heart failure in self-identified black patients, the recommended initial dosage of the fixed-combination preparation is 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate (1 tablet of BiDil) 3 times daily. The dosage may be titrated to a maximum tolerated dosage, not to exceed 2 tablets (a total of 75 mg of hydralazine hydrochloride and 40 mg of isosorbide dinitrate) 3 times daily. Although rapid titration (over 3-5 days) of dosage can be undertaken, slower titration may be needed in some patients who experience adverse effects. In patients who experience intolerable adverse effects, the dosage may be decreased to as little as one-half of the fixed-combination tablet 3 times daily; however, an attempt should be made to titrate the dosage up once the adverse effects subside.

If the drugs are administered separately in the treatment of heart failure, an initial dosage of hydralazine hydrochloride 25-50 mg 3 or 4 times daily, given concomitantly with isosorbide dinitrate 20-30 mg 3 or 4 times daily, is recommended by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA). Dosages of the drugs should be titrated to levels similar to those recommended for the fixed-combination preparation and administered at least 3 times daily. The maximum recommended dosages are hydralazine hydrochloride 300 mg daily and isosorbide dinitrate 120 mg daily.

Dosage in Renal Impairment

Patients with severe renal failure may require a lower dosage of hydralazine.

Cautions

The most frequently occurring adverse effects of hydralazine are headache, palpitation, and tachycardia; these adverse effects can be minimized by starting with small doses and increasing dosage gradually to effective levels and by concomitant administration with other antihypertensive drugs such as propranolol. Patients should be instructed to consult a clinician if headache continues with repeated dosing. Generally, adverse effects of hydralazine are reversible when dosage is reduced, but in some cases it may be necessary to discontinue the drug.

GI Effects

Adverse GI disturbances such as anorexia, nausea, vomiting, and diarrhea may occur, especially with large doses. Constipation and adynamic ileus also have been reported. Cholecystitis has been reported occasionally in patients receiving fixed-combination therapy with hydralazine and isosorbide dinitrate.

Cardiovascular Effects

Hydralazine-induced tachycardia may precipitate angina pectoris and ECG effects characteristic of myocardial ischemia. The drug may accentuate specific cardiovascular abnormalities and has been implicated in the production of myocardial infarction. Orthostatic hypotension and dizziness may occur rarely, but are less pronounced with hydralazine than with guanethidine or ganglionic blockers. A paradoxical pressor response, edema, and palpitations also have been reported. IV administration of hydralazine in patients with preexisting increased intracranial pressure may produce increased cerebral ischemia.

Sodium retention resulting in edema and weight gain has been reported in patients receiving hydralazine and can usually be controlled by concomitant administration with a thiazide diuretic.

In clinical trials in patients receiving hydralazine hydrochloride (37.5 mg) in fixed combination with isosorbide dinitrate (20 mg), chest pain and ventricular tachycardia have been reported.

Sensitivity Reactions

Hydralazine has produced a syndrome resembling systemic lupus erythematosus (SLE) or rheumatoid arthritis, characterized by fever, arthralgia, splenomegaly, glomerulonephritis, lymphadenopathy, asthenia, myalgia, malaise, pleuritic chest pain, edema, and the presence of antinuclear antibodies (ANA) and LE cells in the blood. Rash or maculopapular facial rash characteristic of SLE also has occurred. Patients with hydralazine-induced SLE may have a positive direct Coombs' test; Coombs'-positive hemolytic anemia without SLE has occurred rarely. One case of hydralazine-induced SLE associated with pericarditis and pericardial tamponade has been reported. Hydralazine-induced SLE syndrome probably represents a hypersensitivity reaction in which hydralazine antibodies and anti-DNA antibodies are formed. The incidence of hydralazine-induced SLE syndrome is greatest in patients receiving more than 200 mg of the drug daily for prolonged periods, but cases have occurred rarely in patients receiving 100 mg daily.

Other hypersensitivity reactions including urticaria, pruritus, chills, vascular collapse, and eosinophilia have occurred rarely. Hepatitis, including granulomatous hepatitis, has been reported rarely in patients receiving hydralazine. In clinical trials in patients receiving hydralazine hydrochloride (37.5 mg) in fixed combination with isosorbide dinitrate (20 mg), angioedema has been reported occasionally.

Hematologic Effects

Blood dyscrasias consisting of reduction in hemoglobin concentration and erythrocyte count, leukopenia, agranulocytosis, lymphadenopathy, thrombocytopenia with or without purpura, and splenomegaly have been reported rarely; if these abnormalities occur, hydralazine should be discontinued.

Nervous System Effects

Peripheral neuritis characterized by paresthesia, numbness, and tingling has been reported rarely. These symptoms of peripheral neuritis may be caused by pyridoxine deficiency, and pyridoxine should be administered concomitantly with hydralazine if these symptoms occur. Headache, dizziness, and tremors have been reported with hydralazine.

In clinical trials in patients receiving hydralazine hydrochloride (37.5 mg) in fixed combination with isosorbide dinitrate (20 mg), somnolence, malaise, and sweating have been reported.

Other Adverse Effects

Nasal congestion, flushing, lacrimation, and conjunctivitis have occurred occasionally. Muscle cramps, weakness, asthenia, dyspnea, difficulty in micturition, and tremors also have been reported. In patients with severe hypertension and uremia, rapid increase in hydralazine dosage may produce a marked decrease in blood pressure, resulting in psychotic reactions such as anxiety, disorientation or depression, and coma. Impotence has been reported very rarely.

In clinical trials in patients receiving hydralazine and hydrochloride (37.5 mg) in fixed combination with isosorbide dinitrate (20 mg), bronchitis, sinusitis, rhinitis, hyperlipidemia, hypercholesterolemia, hyperglycemia, amblyopia, myalgia, tendon disorder, and alopecia have been reported.

Precautions and Contraindications

When hydralazine is used in fixed combination with isosorbide dinitrate, the cautions, precautions, and contraindications associated with nitrates should be considered in addition to those associated with hydralazine.

Hydralazine generally is considered to be safe for use in patients with renal impairment, but the manufacturers state the drug should be used with caution in patients with severe renal impairment.

Patients who are slow acetylators of hydralazine may have a higher risk of developing drug-induced SLE than rapid acetylators; decreased renal function also increases risk. Patients receiving hydralazine should be instructed to report abnormalities such as joint or chest pain or fever to their physicians. If arthralgia, fever, chest pain, continued malaise, or other unexplained signs and symptoms occur during hydralazine therapy, appropriate laboratory studies such as complete blood counts and ANA titer determinations should be performed. Hydralazine should be discontinued in patients who develop this syndrome unless the potential benefit of antihypertensive therapy with the drug outweighs the potential risk. Signs and symptoms of hydralazine-induced SLE usually regress when the drug is discontinued, but residual effects have been detected years later; long-term treatment with corticosteroids may be necessary if symptoms do not regress.

Complete blood counts and ANA titer determinations should be performed before and periodically during prolonged hydralazine therapy, even in asymptomatic patients. The manufacturers state that a positive ANA titer requires that the implications of the test result be weighed against the benefits from therapy with the drug, but some experts state that an increase in ANA titer requires immediate discontinuance of the drug.

Some commercially available formulations of hydralazine may contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Patients who engage in potentially hazardous activities such as operating machinery or driving motor vehicles should be warned about possible faintness, dizziness, or weakness.

Hydralazine should be used with caution in patients with cerebrovascular accidents or with severe renal damage. Because of the risk of orthostatic hypotension, preparations containing hydralazine should be used with caution in patients who may be volume depleted, those with preexisting hypotension, or those receiving other hypotensive agents. In addition, patients receiving hydralazine in fixed combination with isosorbide dinitrate should be advised that inadequate fluid intake or excessive fluid loss due to diarrhea, vomiting, or perspiration may result in excessive hypotension, possibly leading to lightheadedness or even syncope. If syncope occurs, the fixed-combination therapy with hydralazine and isosorbide dinitrate should be discontinued and the patient's clinician should be notified as soon as possible. Because of the risk of developing hypotension and tachycardia, careful clinical and hemodynamic monitoring is recommended when preparations containing hydralazine are used in patients with acute myocardial infarction. Patients receiving hydralazine in fixed-dose combination with isosorbide dinitrate should be cautioned against concomitant use of phosphodiesterase type 5 (PDE type 5) inhibitors (e.g., sildenafil [Viagra, Revatio], tadalafil [Cialis]), vardenafil [Levitra].

Hydralazine also should be used with caution, if at all, in patients with known or suspected coronary artery disease and is contraindicated in patients with mitral valve rheumatic heart disease or hypersensitivity to the drug.

Pediatric Precautions

Safety and efficacy of hydralazine alone or in fixed combination with isosorbide dinitrate in children have not been established. However, there is some experience with use of hydralazine in children. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Geriatric Precautions

Clinical studies of hydralazine in fixed combination with isosorbide dinitrate did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Although other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic and/or renal function and of concomitant disease and drug therapy observed in the elderly also should be considered. Hydralazine may be eliminated more slowly in geriatric patients.

Mutagenicity and Carcinogenicity

Hydralazine has been shown to be mutagenic in bacterial systems. In addition, hydralazine was positive for mutagenicity in the in vitro rat and rabbit hepatocyte DNA repair assays. However, there was no evidence of mutagenicity or clastogenicity when hydralazine was tested with additional in vivo and in vitro studies, including mouse fibroblasts and lymphoma or germinal cells, Chinese hamster bone marrow cells, and human cell line fibroblasts.

In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) in female and male mice receiving hydralazine hydrochloride 250 mg/kg daily (approximately 6 or 80 times the maximum recommended human dosage daily, given as hydralazine hydrochloride in fixed combination with isosorbide dinitrate [on a body surface area basis] or alone, respectively). In addition, in a 2-year carcinogenicity study in rats that used hydralazine hydrochloride oral gavage dosages of 15, 30, and 60 mg/kg daily (up to 3 or 5-20 times, the maximum recommended human dosage daily, given as hydralazine hydrochloride in fixed combination with isosorbide dinitrate [on a body surface area basis] or alone, respectively), there was a small but statistically significant increase in benign neoplastic nodules in male (high-dosage group) and female (high- and intermediate-dosage groups) rats. A statistically significant increase in benign interstitial cell tumors of the testes also was observed in the high-dosage group.

The relevance of these findings to humans currently is not fully known. The manufacturer states that although long-term clinical observation has not suggested an association between carcinogenicity in humans and administration of hydralazine, there is insufficient experience from epidemiologic studies to draw definitive conclusions.

Pregnancy, Fertility, and Lactation

Pregnancy

Safe use of hydralazine in pregnancy has not been established. Hydralazine is teratogenic in mice and possibly in rabbits but not in rats. Teratogenic effects in animals have included cleft palate and malformation of facial and cranial bones.

A meta-analysis of randomized, controlled trials comparing hydralazine with other antihypertensive agents for the treatment of severe hypertension during pregnancy showed that hydralazine was associated with a higher incidence of maternal hypotension, placental abruption, cesarean sections, and oliguria, as well as a higher incidence of lower Apgar scores and adverse effects on fetal heart rate than the other hypotensive drugs. In one study in 13 pregnant women with long-standing hypertension during 15 pregnancies who received combination therapy with hydralazine and propranolol, 14 live births and one unexplained stillbirth were reported. The only neonatal complications observed were 2 cases of mild hypoglycemia. In patients receiving hydralazine during pregnancy, the drug and its metabolites have been detected in maternal and umbilical plasma using a nonselective assay. The manufacturers state that although clinical experience with the drug does not indicate any positive evidence of adverse effect on the human fetus to date, hydralazine should not be used during pregnancy unless the possible benefits outweigh the potential risks to the fetus.

Lactation

It is not known whether hydralazine is distributed into breast milk. Because many drugs are distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Diuretics and Hypotensive Agents

When hydralazine is administered with diuretics or other hypotensive agents, the hypotensive effect of hydralazine may be increased. This effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly. When parenteral hydralazine and parenteral diazoxide (parenteral formulation no longer commercially available in the US) are used concomitantly, profound hypotensive episodes may occur. When other potent parenteral hypotensive agents are used in combination with hydralazine, patients should be continually observed for several hours for any excessive reduction in blood pressure.

Other Drugs

The manufacturers state that monoamine oxidase (MAO) inhibitors should be used with caution in patients receiving hydralazine, since these drugs have a synergistic effect resulting in a marked decrease in blood pressure.

Hydralazine may reduce the pressor response to epinephrine.

The fixed-combination preparation containing hydralazine should not be used concomitantly with phosphodiesterase type 5 (PDE type 5) inhibitors (e.g., sildenafil, vardenafil, tadalafil).

Pharmacokinetics

Because assay methods used in many published pharmacokinetic studies were nonspecific and measured inactive metabolites, the accuracy of the reported values for various pharmacokinetic parameters (e.g., bioavailability) of hydralazine has been questioned.

It is not known whether impaired renal or hepatic function has an effect on the pharmacokinetics of hydralazine.

Absorption

Hydralazine hydrochloride is rapidly absorbed from the GI tract and is extensively metabolized in the GI mucosa during absorption and on first pass through the liver. Following oral administration of a single 50-mg dose of C-hydralazine to patients with hypertension, about 66% of the dose was absorbed. With fixed dosage, there are large interindividual variations in the plasma concentrations of hydralazine; however, with a given dosage, plasma concentrations generally remain constant in individual patients. Acetylation phenotype is an important determinant of the plasma concentration of hydralazine; slow acetylators have been shown to have higher plasma concentrations of the drug than rapid acetylators when the same dose of hydralazine is administered orally. A mean absolute bioavailability of 10-26% has been reported in patients with heart failure receiving a single 75-mg oral hydralazine dose; the higher bioavailability values were observed in slow acetylators.

Following oral administration of 100 mg of C-hydralazine to healthy adults in one study, peak plasma concentrations of the drug and metabolites occurred in 2 hours and plasma concentrations of the unchanged drug ranged from 1.6-3.2 mcg/mL. When escalating doses of hydralazine (75 mg to 1 g) were administered 3 times daily in patients with congestive heart failure, up to a ninefold increase in dose-normalized area under the plasma-concentration time curve (AUC) values was observed; this nonlinear pharmacokinetic pattern is likely to be associated with saturable first-pass metabolism. After oral administration of a single dose of hydralazine, the antihypertensive effect begins in 20-30 minutes and lasts 2-4 hours. In one study, plasma hydralazine concentrations were similar after IV administration in both slow and rapid acetylator phenotype adults; the plasma concentrations of hydralazine in these patients 3 hours after IV administration of 20-25 mg of the drug ranged from 0.11-0.33 mcg/mL. Following IV administration of hydralazine, the hypotensive effect begins within 5-20 minutes, is maximum in 10-80 minutes, and lasts 2-6 hours. After IM administration of 20 mg of the drug to healthy individuals, peak plasma concentrations of 0.16-0.61 mcg/mL occur within 1 hour. The hypotensive effect begins within 10-30 minutes and lasts 2-6 hours after IM administration.

Following oral administration of a single 75-mg dose of hydralazine hydrochloride given in fixed combination with 40 mg of isosorbide dinitrate (2 tablets of BiDil) in 19 healthy adults, peak plasma hydralazine concentrations of 88 ng/mL per 65 kg were reached in 1 hour.

Administration of hydralazine with food has been reported to result in higher plasma concentrations of the drug. The effect of food on the bioavailability of hydralazine administered in fixed combination with isosorbide dinitrate is not known.

Distribution

Animal studies indicate that hydralazine is widely distributed into body tissues. In rats, highest concentrations of the drug are found in the kidneys, plasma, and liver; lower concentrations are present in the brain, lungs, muscle, heart, and fat. Radioisotope studies indicate hydralazine has a high affinity for arterial walls. A steady-state volume of distribution of 2.2 L/kg has been reported in patients with congestive heart failure receiving a 0.3-mg/kg IV hydralazine dose.

Hydralazine appears to readily cross the placenta. In patients receiving hydralazine during pregnancy, the drug and its metabolites have been detected in maternal and umbilical plasma using a nonselective assay. The drug appears to be distributed into milk; limited data suggest that milk concentrations of the drug would be clinically unimportant.

Approximately 85-87% of hydralazine in the blood is bound to plasma proteins following administration of usual doses.

Elimination

The plasma half-life of hydralazine generally is 2-4 hours, but may be up to 8 hours in some patients. Plasma concentrations are increased and possibly prolonged in patients with impaired renal function. In one study, the plasma half-life was the same in both rapid and slow acetylators.

Hydralazine is metabolized extensively in the GI mucosa during absorption and in the liver by acetylation, hydroxylation, and conjugation with glucuronic acid. Four metabolites have been identified, and they apparently have no therapeutic activity. A small amount of hydralazine is reportedly converted to a hydrazone, which may be responsible for some toxic effects. Following oral administration of the drug, the main circulating metabolites of hydralazine are hydralazine pyruvate hydrazone and methyltriazolophthalazine. First-pass acetylation in the GI mucosa and liver is related to genetic acetylator phenotype. The rate of acetylation is genetically determined and varies among individuals; however, it is constant for each person. Slow acetylation is an autosomal recessive trait and results from a relative deficiency of the hepatic enzyme N-acetyl transferase. About 50% of American blacks and whites and the majority of American Indians, Native Alaskans, and Asians are rapid acetylators of hydralazine. The metabolism of hydralazine appears to be similar in healthy individuals and in patients with systemic lupus erythematosus (SLE); however, patients with hydralazine-induced SLE are usually slow acetylators.

Hydralazine is rapidly excreted in urine, mainly as metabolites. The major identified metabolite of hydralazine present in the urine is acetylhydrazinophthalazinone. Negligible amounts of unchanged drug are excreted in the urine. Approximately 10% of an oral dose is excreted in feces. The rate of excretion of the drug is apparently unrelated to acetylator phenotype. It is not known whether hydralazine is dialyzable.

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