HEPARIN SODIUM- heparin sodium injection, solution
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION safely and effectively. See full prescribing information for HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION.
HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION, for intravenous use
Initial U.S. Approval: 1984
INDICATIONS AND USAGE
HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION at the concentration of 2 USP units/mL is an anticoagulant indicated for:
DOSAGE AND ADMINISTRATION
Although the rate of infusion of the 2 USP units/mL formulation is dependent upon the age, weight, clinical condition of the patient, and the procedure being employed, an infusion rate of 3 mL/hour has been found to be satisfactory. (2.2)
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
Most common adverse reactions are: hemorrhage, thrombocytopenia, HIT (with or without thrombosis), hypersensitivity reactions, and elevations of aminotransferase levels. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
Heparin Sodium Injection in 0.9% Sodium Chloride at the concentration of 2 USP units/mL is indicated as an anticoagulant to maintain catheter patency.
Confirm the selection of the correct formulation and strength prior to administration of the drug.
This product should be administered by intravenous infusion.
Do not use Heparin Sodium in 0.9% Sodium Chloride Injection as a "catheter lock flush" product.
Do not admix with other drugs.
Do not use plastic containers in series connection.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Use only if solution is clear and container and seals are intact.
Although the rate of infusion of the 2 USP units/mL formulation is dependent upon the age, weight, clinical condition of the patient, and the procedure being employed, an infusion rate of 3 mL/hour has been found to be satisfactory.
Preparation for Administration
(Use aseptic technique)
The use of HEPARIN SODIUM is contraindicated in patients:
Do not use this product as a "catheter lock flush" product. Heparin is supplied in various strengths. Fatal hemorrhages have occurred due to medication errors. Carefully examine all heparin products to confirm the correct container choice prior to administration of the drug.
Hemorrhage, including fatal events, has occurred in patients receiving HEPARIN SODIUM. Avoid using heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the potential risks.
Hemorrhage can occur at virtually any site in patients receiving heparin. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.1)]. A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical Pharmacology (12.3)]. An unexplained fall in hematocrit or fall in blood pressure should lead to serious consideration of a hemorrhagic event.
Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage, including:
HIT is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition known as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Monitor thrombocytopenia of any degree closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT, and, if necessary, administer an alternative anticoagulant.
HIT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT.
Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Obtain platelet counts before and periodically during heparin therapy. Monitor thrombocytopenia of any degree closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3)].
Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations [see Adverse Reactions (6.1)].
Because Heparin Sodium in 0.9% Sodium Chloride Injection is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy.
The following serious adverse reactions are described elsewhere in the labeling:
The following adverse reactions have been identified during post-approval use of heparin sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium.
In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. No teratogenicity was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses, approximately 2,777 times the maximum recommended human dose (MRHD) for maintenance of catheter patency of heparin [see Data]. In pregnant animals, doses up to 2,777 times higher than the human daily dose of heparin resulted in increased resorptions. Consider the benefits and risks of HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION to a pregnant woman and possible risks to the fetus when prescribing HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
The maternal and fetal outcomes associated with uses of heparin via various dosing methods and administration routes during pregnancy have been investigated in numerous studies. These studies generally reported normal deliveries with no maternal or fetal bleeding and no other complications.
In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 USP units/kg/day, approximately 2,777 times the human daily dose. The number of early resorptions increased in both species. There was no evidence of teratogenic effects.
There is no information regarding the presence of HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION in human milk, the effects on the breastfed infant, or the effects on milk production. Due to its large molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk would not be orally absorbed by a nursing infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION and any potential adverse effects on the breastfed infant from HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION or from the underlying maternal condition [see Use in Specific Populations (8.4)].
There are no adequate and well-controlled studies on heparin use in pediatric patients.
There are limited adequate and well-controlled studies in patients 65 years and older. However, a higher incidence of bleeding has been reported in patients over 60 years of age, especially women [see Warnings and Precautions (5.2)].
Bleeding is the chief sign of heparin overdosage.
Neutralization of heparin effect:
When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10 minute period. Each mg of protamine sulfate neutralizes approximately 100 USP Heparin Units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection.
Because fatal reactions often resembling anaphylaxis have been reported, protamine sulfate should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.
For additional information, consult the prescribing information for Protamine Sulfate Injection, USP.
Intravenous solutions with heparin sodium (derived from porcine intestinal mucosa) are sterile, nonpyrogenic fluids for intravenous administration. Each 100 mL contains heparin sodium 200 USP Units; sodium chloride, 0.9 g; citric acid, monohydrate, 40 mg and dibasic sodium phosphate, heptahydrate, 434 mg added as buffers. Osmolar concentration, 378 mOsmol/liter (calc.); pH 7.0 (5.0 – 7.5).
Heparin Sodium, USP is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose-6-sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose, and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2) > (1) > (4) > (3) > (5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.
Structure of Heparin Sodium (representative subunits):
Sodium Chloride, USP is chemically designated NaCl, a white crystalline compound freely soluble in water.
Dibasic Sodium Phosphate, USP (Heptahydrate), is chemically designated (Na2HPO4 ∙ 7H2O), colorless or white granular salt freely soluble in water.
Citric Acid, USP, hydrous (monohydrate) is chemically designated C6H8O7 ∙ H2O, colorless, translucent crystals or white crystalline powder very soluble in water. It has the following structural formula:
Water for Injection, USP is chemically designated H2O.
The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out certain of its chemical components in very small amounts before the expiration period is attained. However, the safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers.
Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor.
Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases it is not measurably affected by low doses of heparin.
Loglinear plots of heparin plasma concentrations with time for a wide range of dose levels are linear which suggests the absence of zero order processes. Liver and the reticuloendothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t½ = 10 minutes) and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin.
Intravenous solutions with heparin sodium are available in single-dose containers as follows:
|Unit of Sale||Product||Container Size (mL)||Each|
Carton of 18
|Heparin Sodium 1,000 USP Units/500 mL (2 USP Units/mL) in 0.9% Sodium Chloride||500||NDC 0409-7620-13|
500 mL single-dose flexible plastic container
Carton of 12
|Heparin Sodium 2,000 USP Units/1,000 mL (2 USP Units/mL) in 0.9% Sodium Chloride||1,000||NDC 0409-7620-49|
1,000 mL single-dose flexible plastic container
Inform patients that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they are treated with heparin, and that they should report any unusual bleeding or bruising to their physician. Hemorrhage can occur at virtually any site in patients receiving heparin. Fatal hemorrhages have occurred [see Warnings and Precautions (5.2)].
Prior to Surgery
Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is scheduled [see Warnings and Precautions (5.2)].
Inform patients of the risk of heparin-induced thrombocytopenia (HIT). HIT may progress to the development of venous and arterial thromboses, a condition known as heparin-induced thrombocytopenia and thrombosis (HITT). HIT (With or Without Thrombosis) can occur up to several weeks after the discontinuation of heparin therapy [see Warnings and Precautions (5.3 and 5.4)].
Because of the risk of hemorrhage, advise patients to inform their physicians and dentists of all medications they are taking, including non-prescription medications, and before starting any new medication [see Drug Interactions (7.1)].