Sandoz Hydralazine

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 Sandoz Hydralazinee (hydralazine).

In a few resistant patients, up to 300 mg of Sandoz Hydralazinee (hydralazine) daily may be required for a significant antihypertensive effect. In such cases, a lower dosage of Sandoz Hydralazinee (hydralazine) 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.

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

WARNINGS

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.)

PRECAUTIONS

General

Myocardial stimulation produced by Sandoz Hydralazinee (hydralazine) 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 Sandoz Hydralazinee (hydralazine) may accentuate specific cardiovascular inadequacies. For example, Sandoz Hydralazinee (hydralazine) 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 Sandoz Hydralazinee (hydralazine) 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 Sandoz Hydralazinee (hydralazine) , 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 Sandoz Hydralazinee (hydralazine). However, as with any antihypertensive agent, Sandoz Hydralazinee (hydralazine) 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 Sandoz Hydralazinee (hydralazine) 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 Sandoz Hydralazinee (hydralazine) 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 Sandoz Hydralazinee (hydralazine) 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.

Adverse reactions with Sandoz Hydralazinee (hydralazine) 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.

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.