Heparin Sodium: Package Insert and Label Information (Page 2 of 3)

7 DRUG INTERACTIONS

7.1 Oral Anticoagulants

Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained.

7.2 Platelet Inhibitors

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.

7.3 Other Interactions

Digitalis, tetracyclines, nicotine, or antihistamines, or intravenous (IV) nitroglycerin may partially counteract the anticoagulant action of heparin sodium.

7.4 Drug/Laboratory Test Interactions

Prothrombin time – Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with warfarin, allow a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose of heparin to elapse before blood is drawn to obtain a valid prothrombin time.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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 up to 10,000 units/kg/day, approximately 10 times the maximum recommended human dose (MRHD) of 40,000 units/24 hours infusion [see Data ]. In pregnant animals, doses up to10 times higher than the maximum human daily dose based on body weight resulted in increased resorptions. Consider the benefits and risks of HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION to a pregnant woman and possible risks to the fetus when prescribing HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION.

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.

Data

Human Data

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.

Animal Data

In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 units/kg/day, approximately 10 times the maximum human daily dose based on body weight. The number of early resorptions increased in both species. There was no evidence of teratogenic effects.

8.2 Lactation

Risk Summary

There is no information regarding the presence of HEPARIN SODIUM IN 0.45% 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 0.45% SODIUM CHLORIDE INJECTION and any potential adverse effects on the breastfed infant from HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION or from the underlying maternal condition [see Use in Specific Populations (8.4) ].

8.4 Pediatric Use

There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience [see Dosage and Administration (2.4)].

8.5 Geriatric Use

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) ]. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

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 ½ hour after intravenous injection.

Because fatal reactions often resembling anaphylaxis have been reported, the drug 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.

11 DESCRIPTION

Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans possessing anticoagulant properties. It is composed of polymers of alternating derivations of α-D-glucosamido (N -Sulfated O -Sulfated or N -acetylated) and O -sulfated uronic acid (α-L-iduronic acid or β-D-glucoronic acid).

Structure of Heparin Sodium (representative subunits):

structural formula for heparin
(click image for full-size original)

HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION is a sterile preparation of heparin sodium (derived from porcine intestinal mucosa) for intravenous administration. It contains no bacteriostatic or antimicrobial agent or added buffer. The solution may contain sodium hydroxide and/or hydrochloric acid for pH adjustment. The pH range is 6.1 (5.0 – 7.5) and the osmolarity mOsmol/L (calc.) is 155. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.

Each mL of the 50 USP units per mL preparations contains: 50 USP units of heparin sodium, 4.5 mg sodium chloride and 0.1 mg edetate disodium, anhydrous added as a stabilizer.

Each mL of the 100 USP units per mL preparations contains: 100 USP units of heparin sodium, 4.5 mg sodium chloride and 0.1 mg edetate disodium, anhydrous added as a stabilizer

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. 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.

Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age [see Use in Specific Populations (8.5) ].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals to evaluate the carcinogenic potential, reproduction studies in animals to determine effects on fertility of males and females, and studies to determine mutagenic potential have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING

Intravenous solutions with heparin sodium are supplied in single-dose flexible plastic containers in varied sizes and concentrations as shown in the accompanying Table.

Unit of Sale

Concentration

Each

NDC 0409-7650-62

Case containing 24

25,000 USP units/250 mL

(100 USP units/mL)

0409-7650-52

250 mL flexible plastic container

NDC 0409-7651-62

Case containing 24

12,500 USP units/250 mL

(50 USP units/mL)

0409-7651-52

250 mL flexible plastic container

NDC 0409-7651-03

Case containing 24

25,000 USP units/500 mL

(50 USP units/mL)

0409-7651-13

500 mL flexible plastic container

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

17 PATIENT COUNSELING INFORMATION

Hemorrhage

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)].

Heparin-Induced Thrombocytopenia

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. 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)].

Hypersensitivity

Inform patients that generalized hypersensitivity reactions have been reported. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions (5.7), Adverse Reactions (6)].

Other Medications

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 (7.2) ].
EN-4244

Hospira logo

Hospira, Inc., Lake Forest, IL 60045 USA

PRINCIPAL DISPLAY PANEL — 250 mL Bag Label — 7650

250 mL
NDC 0409-7650-52

HEPARIN SODIUM

25,000 USP Units
per 250 mL
(100 USP Units/mL)
in 0.45% Sodium Chloride Injection

EACH 100 mL CONTAINS HEPARIN
SODIUM 10,000 USP UNITS (PORCINE
INTESTINAL MUCOSA); SODIUM
CHLORIDE 0.45 g; EDETATE DISODIUM,
ANHYDROUS 10 mg ADDED AS STABILIZER.
MAY CONTAIN SODIUM HYDROXIDE
AND/OR HYDROCHLORIC ACID FOR pH
ADJUSTMENT. STERILE. NOT MADE WITH
NATURAL RUBBER LATEX.
USUAL DOSAGE: SEE INSERT.

ADDITIVES SHOULD NOT
BE MADE TO THIS SOLUTION.

SINGLE DOSE CONTAINER. DISCARD
UNUSED PORTION. FOR INTRAVENOUS
USE ONLY.

Rx only

3
VCONTAINS DEHP

IM-3954

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Hospira

PRINCIPAL DISPLAY PANEL -- 250 mL Bag Label -- 7650
(click image for full-size original)

PRINCIPAL DISPLAY PANEL — 250 mL Bag Overwrap — 7650

2 HDPE

TO OPEN TEAR AT NOTCH

DO NOT REMOVE FROM OVERWRAP UNTIL READY FOR USE. AFTER REMOVING
THE OVERWRAP, CHECK FOR MINUTE LEAKS BY SQUEEZING CONTAINER FIRMLY.
IF LEAKS ARE FOUND, DISCARD SOLUTION AS STERILITY MAY BE IMPAIRED.
RECOMMENDED STORAGE: ROOM TEMPERATURE (25°C). AVOID EXCESSIVEHEAT. PROTECT FROM FREEZING. SEE INSERT.

98-4321-R14-3/98

PRINCIPAL DISPLAY PANEL -- 250 mL Bag Overwrap -- 7650
(click image for full-size original)

PRINCIPAL DISPLAY PANEL — 250 mL Bag Label — 7651

250 mL
NDC 0409-7651-52

12,500 USP Units / 250 mL
(50 USP Units / mL)

Heparin Sodium in
0.45% Sodium Chloride Injection

EACH 100 mL CONTAINS HEPARIN SODIUM
5,000 USP UNITS (PORCINE INTESTINAL
MUCOSA); SODIUM CHLORIDE 0.45 g;
EDETATE DISODIUM, ANHYDROUS
10 mg ADDED AS STABILIZER. MAY
CONTAIN SODIUM HYDROXIDE AND/OR
HYDROCHLORIC ACID FOR pH ADJUSTMENT.
STERILE. NOT MADE WITH NATURAL
RUBBER LATEX. USUAL DOSAGE: SEE INSERT.

ADDITIVES SHOULD NOT BE MADE
TO THIS SOLUTION.

SINGLE DOSE CONTAINER. DISCARD
UNUSED PORTION. FOR INTRAVENOUS USE
ONLY.

Rx ONLY

3
VCONTAINS DEHP

Hospira

IM-3959

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

PRINCIPAL DISPLAY PANEL -- 250 mL Bag Label -- 7651
(click image for full-size original)

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