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Hydralazine Hydrochloride: Package Insert and Label Information

HYDRALAZINE HYDROCHLORIDE — hydralazine hydrochloride tablet
Ascend Laboratories, LLC

DESCRIPTION

HydrALAZINE hydrochloride, USP, is an antihypertensive, for oral administration. Its chemical name is 1-hydrazinophthalazine monohydrochloride, and its structural formula is:

structure

C8 H8 N4 • HCl

CLINICAL PHARMACOLOGY

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.

INDICATIONS & USAGE

Essential hypertension, alone or as an adjunct.

CONTRAINDICATIONS

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 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 HydrALAZINE may accentuate specific cardiovascular inadequacies. For example, 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 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 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 HydrALAZINE . However, as with any antihypertensive agent, 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.

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 .

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 2-year carcinogenicity study of rats given HydrALAZINE by gavage 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 rats and one rabbit hepatocyte in vitro DNA repair studies. Additional in vivo 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 .

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 to15 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

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when HydrALAZINE is administered to a nursing woman.

Pediatric Use

ADVERSE REACTIONS

Adverse reactions with 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.

OVERDOSAGE

Acute Toxicity

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

Signs and Symptoms

Signs and symptoms of overdosage include hypotension, tachycardia, headache, 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.

DOSAGE & ADMINISTRATION

Initiate therapy in gradually increasing dosages; adjust according to individual response. Start with 10 mg four times daily for the first 2 to 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.

HOW SUPPLIED

HydrALAZINE Hydrochloride Tablets, USP:

10 mgOrange colored, slightly mosaic, circular, biconvex uncoated tablets debossed with ‘293’ on one side and plain on other sideBottles of 100 Tablets NDC 67877-293-01Bottles of 500 Tablets NDC 67877-293-05Bottles of 1000 Tablets NDC 67877-293-10
25 mgOrange colored, slightly mosaic, circular, biconvex uncoated tablets debossed with ‘292’ on one side and plain on other sideBottles of 100 Tablets NDC 67877-292-01Bottles of 500 Tablets NDC 67877-292-05Bottles of 1000 Tablets NDC 67877-292-10
50 mgOrange colored, slightly mosaic, circular, biconvex uncoated tablets debossed with ‘291’ on one side and plain on other sideBottles of 100 Tablets NDC 67877-291-01Bottles of 500 Tablets NDC 67877-291-05Bottles of 1000 Tablets NDC 67877-291-10
100 mgOrange colored, slightly mosaic, circular, biconvex uncoated tablets debossed with ‘290’ on one side and plain on other sideBottles of 100 Tablets NDC 67877-290-01 Bottles of 500 Tablets NDC 67877-290-05

Dispense in a tight, light-resistant container.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Manufactured by:

ALKEM LABORATORIES LIMITED

H.O.: ALKEM HOUSE,

Senapati Bapat Marg, Lower Parel,

Mumbai — 400 013, INDIA

Distributed by:

Ascend Laboratories, LLC

Montvale, NJ 07645

December, 2012

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

HydrALAZINE Hydrochloride Tablets, USP 10 mg — Container Label

NDC 67877-293-01

HydrALAZINE

Hydrochloride

Tablets, USP

10 mg

Rx Only

100 Tablets

Hydralazine HCl Tabs. 10 mg 100's
(click image for full-size original)

HydrALAZINE Hydrochloride Tablets, USP 25 mg — Container Label

NDC 67877-292-05

HydrALAZINE

Hydrochloride

Tablets, USP

25 mg

Rx Only

500 Tablets

Hydralazine HCl Tabs. 25 mg 500's
(click image for full-size original)

HydrALAZINE Hydrochloride Tablets, USP 50 mg — Container Label

NDC 67877-291-10

HydrALAZINE

Hydrochloride

Tablets, USP

50 mg

Rx Only

1000 Tablets

Hydralazine HCl Tabs. 50 mg 1000's
(click image for full-size original)

HydrALAZINE Hydrochloride Tablets, USP 100 mg — Container Label

NDC 67877-290-01

HydrALAZINE

Hydrochloride

Tablets, USP

100 mg

Rx Only

100 Tablets

Hydralazine HCl Tabs. 100 mg 100's
(click image for full-size original)
HYDRALAZINE HYDROCHLORIDE hydralazine hydrochloride tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67877-293
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
HYDRALAZINE HYDROCHLORIDE (Hydralazine) HYDRALAZINE HYDROCHLORIDE 10 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE
SODIUM STARCH GLYCOLATE TYPE A POTATO
FD&C YELLOW NO. 6
SILICON DIOXIDE
STEARIC ACID
MANNITOL
POVIDONE K30
Product Characteristics
Color ORANGE (Light Orange) Score no score
Shape ROUND (Circular biconvex) Size 6mm
Flavor Imprint Code 293
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:67877-293-01 100 TABLET (100 TABLET) in 1 BOTTLE None
2 NDC:67877-293-05 500 TABLET (500 TABLET) in 1 BOTTLE None
3 NDC:67877-293-10 1000 TABLET (1000 TABLET) in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200737 05/24/2010
HYDRALAZINE HYDROCHLORIDE hydralazine hydrochloride tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67877-292
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
HYDRALAZINE HYDROCHLORIDE (Hydralazine) HYDRALAZINE HYDROCHLORIDE 25 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE
SODIUM STARCH GLYCOLATE TYPE A POTATO
FD&C YELLOW NO. 6
POVIDONE K30
SILICON DIOXIDE
STEARIC ACID
MANNITOL
Product Characteristics
Color ORANGE (Light Orange) Score no score
Shape ROUND (Circular biconvex) Size 8mm
Flavor Imprint Code 292
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:67877-292-01 100 TABLET (100 TABLET) in 1 BOTTLE None
2 NDC:67877-292-05 500 TABLET (500 TABLET) in 1 BOTTLE None
3 NDC:67877-292-10 1000 TABLET (1000 TABLET) in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200737 05/24/2010
HYDRALAZINE HYDROCHLORIDE hydralazine hydrochloride tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67877-291
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
HYDRALAZINE HYDROCHLORIDE ( Hydralazine) HYDRALAZINE HYDROCHLORIDE 50 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE
SODIUM STARCH GLYCOLATE TYPE A POTATO
FD&C YELLOW NO. 6
POVIDONE K30
SILICON DIOXIDE
STEARIC ACID
MANNITOL
Product Characteristics
Color ORANGE (Light Orange) Score no score
Shape ROUND (Circular biconvex) Size 10mm
Flavor Imprint Code 291
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:67877-291-01 100 TABLET (100 TABLET) in 1 BOTTLE None
2 NDC:67877-291-05 500 TABLET (500 TABLET) in 1 BOTTLE None
3 NDC:67877-291-10 1000 TABLET (1000 TABLET) in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200737 11/24/2009
HYDRALAZINE HYDROCHLORIDE hydralazine hydrochloride tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67877-290
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
HYDRALAZINE HYDROCHLORIDE (Hydralazine) HYDRALAZINE HYDROCHLORIDE 100 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE
SODIUM STARCH GLYCOLATE TYPE A POTATO
FD&C YELLOW NO. 6
POVIDONE K30
SILICON DIOXIDE
STEARIC ACID
MANNITOL
Product Characteristics
Color ORANGE (Light Orange) Score no score
Shape ROUND (Circular biconvex) Size 12mm
Flavor Imprint Code 290
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:67877-290-01 100 TABLET (100 TABLET) in 1 BOTTLE None
2 NDC:67877-290-05 500 TABLET (500 TABLET) in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200737 05/24/2010
Labeler — Ascend Laboratories, LLC (141250469)
Establishment
Name Address ID/FEI Operations
Alkem Laboratories Limited, Daman 915628612 MANUFACTURE (67877-293), MANUFACTURE (67877-292), MANUFACTURE (67877-291), MANUFACTURE (67877-290)

Revised: 03/2013 Ascend Laboratories, LLC