Heparin Sodium in Sodium Chloride

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Fatal Medication Errors [ see Warnings and Precautions (5.1) ] Hemorrhage [ see Warnings and Precautions (5.2) ] Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) [ see Warnings and Precautions (5.3) ] Thrombocytopenia [ see Warnings and Precautions (5.4) ] Hypersensitivity [ see Warnings and Precautions (5.5) ] 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 B. Braun Medical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Postmarketing Experience 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. Hemorrhage - Hemorrhage is the chief complication that may result from heparin therapy [ see Warnings and Precautions (5.2) ]. Gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect: Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. Retroperitoneal hemorrhage. Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Thrombocytopenia : [ see Warnings and Precautions (5.3 and 5.4) ] Hypersensitivity - Generalized hypersensitivity reactions have been reported with chills, fever, and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar site of the feet, may occur [ see Warnings and Precautions (5.5) ]. Elevations of serum aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Others - Osteoporosis following long-term administration of high-doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported.

4 CONTRAINDICATIONS The use of HEPARIN SODIUM is contraindicated in patients: • With a history of heparin-induced thrombocytopenia (HIT) (With or Without Thrombosis) [ see Warnings and Precautions (5.3) ] • With a known hypersensitivity to heparin or pork products ( e.g. , anaphylactoid reactions) [ see Adverse Reactions (6.1) ] • History of Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) (4) • Known hypersensitivity to heparin or pork products (4)

11 DESCRIPTION Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties. It is composed of polymers of alternating derivations of alpha-L-iduronic acid 2-sulfate (1), 2-deoxy-2-sulfamino-alpha-D-glucose 6-sulfate (2), beta-D-glucuronic acid (3), 2-acetamido-2-deoxy-alpha-D-glucose (4), and alpha-L-iduronic acid (5). Structure of Heparin Sodium (representative subunits): Heparin Sodium 1,000 USP units per 500 mL (2 USP units per mL) in 0.9% Sodium Chloride Injection is a sterile, nonpyrogenic solution prepared from Heparin Sodium USP (derived from porcine intestinal mucosa and standardized for use as an anticoagulant) in 0.9% Sodium Chloride Injection. It is to be administered by intravenous injection. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Each 100 mL contains 0.43 g Dibasic Sodium Phosphate•7H 2 O USP and 0.037 g Citric Acid Anhydrous USP as a buffer system, 0.9 g Sodium Chloride USP, and Water for Injection USP qs. pH: 7.0 (6.8-7.2); Calculated Osmolarity: 360 mOsmol/liter Concentration of Electrolytes (mEq/liter): Sodium 186; Chloride 154; Phosphate (HPO ) 32; Citrate 6 The plastic container is made from a multilayered film specifically developed for parenteral drugs. It contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary. The plastic container is not made with natural rubber latex, PVC or DEHP. The closure system has two ports; the one for the administration set has a tamper evident plastic protector. heparin sodium chemical formula Symbol

2 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) 2.1 Preparation for Administration 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. This product should not be infused under pressure. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Maintenance of Catheter Patency 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.

1 INDICATIONS AND USAGE 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. HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION at the concentration of 2 USP units/mL is an anticoagulant indicated for: • Maintenance of catheter patency. (1)

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 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.

7 DRUG INTERACTIONS • Drugs that interfere with platelet aggregation may induce bleeding. (7) 7.1 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.

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. 12.2 Pharmacodynamics Bleeding time is usually unaffected by heparin. 12.3 Pharmacokinetics 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 (t ½ = 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.

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.

12.3 Pharmacokinetics 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 (t ½ = 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.

20160520

20

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium 1,000 USP units per 500 mL (2 USP units per mL) in 0.9% Sodium Chloride Injection. Heparin Sodium 1,000 USP units per 500 mL (2 USP units per mL) in 0.9% Sodium Chloride Injection (3)

Heparin Sodium in Sodium Chloride Heparin Sodium in Sodium Chloride HEPARIN SODIUM HEPARIN WATER SODIUM CHLORIDE SODIUM PHOSPHATE, DIBASIC ANHYDROUS CITRIC ACID

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.

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.

NDA019953

Heparin Sodium in Sodium Chloride

Heparin Sodium in Sodium Chloride

0264-9872

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL HEPARIN SODIUM 1,000 USP units per 500 mL (2 USP units per mL) in 0.9% Sodium Chloride Injection NDC 0264-9872-10 500 mL EXCEL® CONTAINER 1,000 USP units per 500 mL (2 USP units per mL) HEPARIN LD-312-6 Y94-003-292 Each 100 mL contains: Heparin Sodium USP (porcine intestinal mucosa) 200 USP Heparin units Sodium Chloride USP 0.9 g Dibasic Sodium Phosphate•7H 2 O USP 0.43 g Citric Acid Anhydrous USP 0.037g Water for Injection USP qs Electrolytes (mEq/liter): Sodium 186 Chloride 154 Phosphate (HPO ) 32 Citrate 6 WARNING: CONTAINS SULFITES. Do not admix with other drugs. Sterile. Single dose container. For intravenous use only. Recommended Storage: Room temperature (25°C). Avoid excessive heat. Protect from freezing. See Package Insert. Do not remove overwrap until ready for use. REF P8721 Not made with natural rubber latex, PVC or DEHP. Rx only B. Braun Medical Inc. Bethlehem, PA 18018-3524 USA API from Spain LD-311-5 Y94-003-291 EXP LOT =4 Recycle 7 500 mL Container Label P8721

Rx only EXCEL is a registered trademark of B. Braun Medical Inc. B. Braun Medical Inc. Bethlehem, PA 18018-3524 USA 1-800-227-2862 Y36-002-901 LD-240-8

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 (HITT). HIT (With or Without Thrombosis) can occur up to several weeks after the discontinuation of heparin therapy [ see Warnings and Precautions (5.3) ]. Hypersensitivity Inform patients that generalized hypersensitivity reactions have been reported. 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 (7.1) ].

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) ].

8.2 Lactation Risk Summary 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) ].

8.4 Pediatric Use There are no adequate and well controlled studies on heparin use in pediatric patients.

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, approximately 2777 times the recommended human dose (MRHD) for maintenance of catheter patency of heparin [ see Data ]. In pregnant animals, doses up to 2777 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. 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 USP units/kg/day, approximately 2777 times the human daily dose. The number of early resorptions increased in both species. There was no evidence of teratogenic effects.

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, approximately 2777 times the recommended human dose (MRHD) for maintenance of catheter patency of heparin [ see Data ]. In pregnant animals, doses up to 2777 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. 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 USP units/kg/day, approximately 2777 times the human daily dose. 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 0.9% 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) ]. 8.4 Pediatric Use There are no adequate and well controlled studies on heparin use in pediatric patients. 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) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium in 0.9% Sodium Chloride Injection is supplied sterile and nonpyrogenic in Full Fill 500 mL EXCEL® Containers packaged 24 per case. NDC REF Concentration Size 0264-9872-10 P8721 Heparin Sodium 1,000 USP units per 500 mL (2 USP units per mL) in 0.9% Sodium Chloride Injection 500 mL Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely affect the product. Storage in automated dispensing machines: Brief exposure up to 2 weeks to ultraviolet or fluorescent light does not adversely affect the product labeling legibility; prolonged exposure can cause fading of the red label. Rotate stock frequently.