Apresoline, hydralazine hydrochloride USP, is an antihypertensive, available as 10-, 25-, 50-, and 100-mg tablets for oral administration. Its chemical name is 1-hydrazinophthalazine monohydrochloride, and its structural formula is:

Hydralazine hydrochloride, USP is a white to off-white, odorless crystalline powder. It is soluble in water, slightly soluble in alcohol, and very slightly soluble in ether. It melts at about 275°C, with decomposition, and has a molecular weight of 196.84.

Inactive Ingredients. Acacia, D&C Yellow No. 10 (10-mg tablets), FD&C Blue No. 1 (25-mg and 50-mg tablets), FD&C Yellow No. 5 and FD&C Yellow No. 6 (100-mg tablets), lactose, magnesium stearate, mannitol, polyethylene glycol, sodium starch glycolate, starch, and stearic acid.

Last updated on RxList: 12/8/2004

Essential hypertension, alone or as an adjunct.

Initiate therapy in gradually increasing dosages; adjust according to individual response. Start with 10 mg four times daily for the first 2-4 days, increase to 25 mg four times daily for the balance of the first week. For the second and subsequent weeks, increase dosage to 50 mg four times daily. For maintenance, adjust dosage to the lowest effective levels.

The incidence of toxic reactions, particularly the L.E. cell syndrome, is high in the group of patients receiving large doses of Apresoline.

In a few resistant patients, up to 300 mg of Apresoline daily may be required for a significant antihypertensive effect. In such cases, a lower dosage of Apresoline combined with a thiazide and/or reserpine or a beta blocker may be considered. However, when combining therapy, individual titration is essential to ensure the lowest possible therapeutic dose of each drug.

Tablets 10 mg – round, pale yellow, dry-coated (imprinted CIBA 37)
   Bottles of 100 ........................... NDC 0083-0037-30
Tablets 25 mg – round, deep blue, dry-coated (imprinted CIBA 39)
    Bottles of 100 ........................... NDC 0083-0039-30
Tablets 50 mg – round, light blue, dry-coated (imprinted CIBA 73)
    Bottles of 100 ........................... NDC 0083-0073-30
Tablets 100 mg – round, peach, dry-coated (imprinted CIBA 101)
   Bottles of 100 ........................... NDC 0083-0101-30

Samples, when available, are identified by the word SAMPLE appearing on each tablet.

Do not store above 86°F (30 C).

Dispense in tight, light-resistant container (USP).

666692     C95-14 (Rev. 5-95)

CIBA
Ciba-Geigy Corporaton
Pharmaceuticals Division
Summit, New Jersey 07901

Last updated on RxList: 12/8/2004

Adverse reactions with Apresoline are usually reversible when dosage is reduced. However, in some cases it may be necessary to discontinue the drug. The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency.

Common

Headache, anorexia, nausea, vomiting, diarrhea, palpitations, tachycardia, angina pectoris.

Less Frequent

Digestive: constipation, paralytic ileus.

Cardiovascular: hypotension, paradoxical pressor response, edema.

Respiratory: dyspnea.

Neurologic: peripheral neuritis evidenced by paresthesia, numbness, and tingling, dizziness: tremors; muscle cramps; psychotic reactions characterized by depression, disorientation, or anxiety.

Genitourinary: difficulty in urination.

Hematologic: blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, purpura, lymphadenopathy; splenomegaly.

Hypersensitive Reactions: rash, urticaria, pruritus, fever, chills, arthralgia, eosinophilia, and, rarely, hepatitis.

Other: nasal congestion, flushing, lacrimation, conjunctivitis.

MAO inhibitors should be used with caution in patients receiving hydralazine.

When other potent parenteral antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide injection and Apresoline are used concomitantly.

Last updated on RxList: 12/8/2004

In a few patients hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residua have been detected many years later. Long-term treatment with steroids may be necessary. (See PRECAUTIONS, Laboratory Tests.)

General

Myocardial stimulation produced by Apresoline can cause anginal attacks and ECG changes of myocardial ischemia. The drug has been implicated in the production of myocardial infarction. It must, therefore, be used with caution in patients with suspected coronary artery disease.

The “hyperdynamic" circulation caused by Apresoline may accentuate specific cardiovascular inadequacies. For example, Apresoline may increase pulmonary artery pressure in patients with mitral valvular disease. The drug may reduce the pressor responses to epinephrine. Postural hypotension may result from Apresoline but is less common than with ganglionic blocking agents. It should be used with caution in patients with cerebral vascular accidents.

In hypertensive patients with normal kidneys who are treated with Apresoline, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances where control values were below normal, improved renal function has been noted after administration of Apresoline. However, as with any antihypertensive agent, Apresoline should be used with caution in patients with advanced renal damage.

Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Published evidence suggests an antipyridoxine effect, and that pyridoxine should be added to the regimen if symptoms develop. The Apresoline tablets (100 mg) contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who are also hypersensitive to aspirin.

Information for Patients

Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed.

Laboratory Tests

Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydralazine even though the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise, or other unexplained signs or symptoms.

A positive antinuclear antibody titer requires that the physician carefully weigh the implications of the test results against the benefits to be derived from antihypertensive therapy with hydralazine.

Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, and purpura, have been reported. If such abnormalities develop, therapy should be discontinued.

Drug/Drug Interactions

MAO inhibitors should be used with caution in patients receiving hydralazine.

When other potent parental antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide infection and Apresoline are used concomitantly.

Drug/Food Interactions

Administration of hydralazine with food results in higher plasma levels.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) of both male and female mice given hydralazine continuously in their drinking water at a dosage of about 250 mg/kg per day (about 80 times the maximum recommended human dose). In a P-year carcinogenicity study of rats given hydralazine by lavage at dose levels of 15, 30, and 60 mg/kg/day (approximately 5 to 20 times the recommended human daily dosage), microscopic examination of the liver revealed a small, but statistically significant, increase in benign neoplastic nodules in male and female rats from the high-dose group and in female rats from the intermediate-dose group. Benign interstitial cell tumors of the testes were also significantly increased in male rats from the high-dose group. The tumors observed are common in aged rats and a significantly increased incidence was not observed until 18 months of treatment. Hydralazine was shown to be mutagenic in bacterial systems (Gene Mutation and DNA Repair) and in one of two rat and one rabbit hepatocyte in vitro DNA repair studies. Additional in vim and in vitro studies using lymphoma cells, germinal cells, and fibroblasts from mice, bone marrow cells from Chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic potential for hydralazine.

The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observation has not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusions.

Pregnancy Category C

Animal studies indicate that hydralazine is teratogenic in mice at 20 to 30 times the maximum daily human dose of 200 to 300 mg and possibly in rabbits at 10 to 15 times the maximum daily human dose, but that it is nonteratogenic in rats. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones.

There are no adequate and well-controlled studies in pregnant women. Although clinical experience does not include any positive evidence of adverse effects on the human fetus, hydralazine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.

Nursing Mothers

Hydralazine has been shown to be excreted in breast milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established in controlled clinical trials, although there is experience with the use of Apresoline in these patients. The usual recommended oral starting dosage is 0.75 mg/kg of body weight daily in four divided doses. Dosage may be increased gradually over the next 3-4 weeks to a maximum of 7.5 mg/kg or 200 mg daily.

Last updated on RxList: 12/8/2004

Acute Toxicity

No deaths due to acute poisoning have been reported.
   Highest known dose survived: adults, 10g orally.
   Oral LD50 in rats: 173 and 187 mg/kg.

Signs and Symptoms

Signs and symptoms of overdosage include hypotension, tachycardia, head- ache, and generalized skin flushing.
   Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia, and profound shock.

Treatment

There is no specific antidote.
   The gastric contents should be evacuated, taking adequate precautions against aspiration and for protection of the airway. An activated charcoal slurry may be instilled if conditions permit. These manipulations may have to be omitted or carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock.
   Support of the cardiovascular system is of primary importance. Shock should be treated with plasma expanders. If possible, vasopressors should not be given, but if a vasopressor is required, care should be taken not to precipitate or aggravate cardiac arrhythmia. Tachycardia responds to beta blockers. Digitalization may be necessary, and renal function should be monitored and supported as required.
   No experience has been reported with extracorporeal or peritoneal dialysis.

Hypersensitivity to hydralazine; coronary artery disease; mitral valvular rheumatic heart disease.

Last updated on RxList: 12/8/2004

Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state.

The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Hydralazine also maintains or increases renal and cerebral blood flow.

Hydralazine is rapidly absorbed after oral administration, and peak plasma levels are reached at 1-2 hours. Plasma levels of apparent hydralazine decline with a half-life of 3-7 hours. Binding to human plasma protein is 87% Plasma levels of hydralazine vary widely among individuals. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine.

Last updated on RxList: 12/8/2004

Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed.

Report flu-like symptoms, rise slowly from sitting/lying position; take with meals.

Last updated on RxList: 12/8/2004

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

HYDRALAZINE - ORAL

(hye-DRAL-a-zeen)

COMMON BRAND NAME(S): Apresoline

USES: Hydralazine is used with or without other medications to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Hydralazine is called a vasodilator. It works by relaxing blood vessels so blood can flow through the body more easily.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Hydralazine may also be used with other medications to treat heart failure.

HOW TO USE: Take this medication by mouth with or without food, usually 2 to 4 times daily or as directed by your doctor. The dosage is based on your medical condition and response to treatment. Your doctor may start you at a low dose and gradually increase your dose. Follow your doctor's instructions carefully.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick. It may take up to several weeks before you get the full benefit of this drug.

Do not stop taking this medication without consulting your doctor. Some conditions may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.

Tell your doctor if your condition worsens (for example, your routine blood pressure readings increase).

SIDE EFFECTS: Headache, pounding/fast heartbeat, loss of appetite, nausea, vomiting, diarrhea, or dizziness may occur as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To reduce the risk of dizziness, get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may infrequently cause nerve problems. Tell your doctor promptly if you experience numbness or tingling. Your doctor may recommend a vitamin B6 supplement (pyridoxine).

Tell your doctor immediately if any of these unlikely but serious side effects occur: severe tiredness, aching/swollen joints, rash on nose and cheeks, swollen glands, change in the amount of urine, bloody/pink urine, signs of infection (such as fever, chills, persistent sore throat), easy bruising/bleeding.

Seek immediate medical attention if this rare but serious side effect occurs: chest/jaw/left arm pain.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking hydralazine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a certain heart condition (coronary artery disease), a certain heart valve problem (rheumatic heart disease of the mitral valve).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood vessel problems, previous stroke, kidney problems.

This drug may make you dizzy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are taking this medication.

Older adults may be more sensitive to the side effects of this medication, especially dizziness.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether hydralazine passes into breast milk. However, it is unlikely to harm a nursing infant. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: MAO inhibitors (isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine).

Check the labels on all your medicines (such as cough-and-cold products, diet aids, pain relievers) because they may contain ingredients that could increase your blood pressure or heart rate. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call their local poison control center directly. Symptoms of overdose may include: severe dizziness, fainting, flushing, chest/jaw/left arm pain, irregular heartbeat.

NOTES: Do not share this medication with others.

Lifestyle changes such as stress reduction programs, exercise, and dietary changes may help this medication work better. Talk to your doctor or pharmacist about lifestyle changes that might benefit you.

Laboratory and/or medical tests (such as complete blood count) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Have your blood pressure checked regularly while taking this medication. Learn how to monitor your own blood pressure, and share the readings with your doctor.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised August 2008 Copyright(c) 2008 First DataBank, Inc.