Heparin Sodium

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [ see Warnings and Precautions (5.1) ] • Heparin-Induced Thrombocytopenia and Heparin-Induced thrombocytopenia with Thrombosis [see Warnings and Precautions (5.2) ] • Thrombocytopenia [see Warnings and Precautions (5.3) ] • Heparin Resistance [see Warnings and Precautions (5.4) ] • Hypersensitivity [see Warnings and Precautions (5.5) ] • Increased Risk of Bleeding in Older Patients, Especially Women [see Warnings and Precautions (5.6) ] Most common adverse reactions are: hemorrhage, thrombocytopenia, HIT and HITT, hypersensitivity, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Postmarketing Experience The following adverse reactions have been identified during postapproval 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 or establish a causal relationship to drug exposure. Hemorrhage - Hemorrhage is the chief complication that may result from heparin therapy [see Warnings and Precautions (5.1) ] . An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug [see Overdosage (10) ] . 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 during anticoagulant 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. HIT and HITT, including delayed onset [see Warnings and Precautions (5.2) ] Histamine-like reactions: Such reactions have been observed at the site of injections. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin, occasionally requiring skin grafting. 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 IN SODIUM CHLORIDE is contraindicated in patients with the following conditions: • Uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation [see Warnings and Precautions (5.1) ] • History of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) [see Warnings and Precautions (5.2) ] • Severe thrombocytopenia [see Warnings and Precautions (5.3) ] • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Warnings and Precautions (5.5) , Adverse Reactions (6.1) ] Heparin Sodium in Sodium Chloride Injection is contraindicated in patients with the following conditions: ( 4 ) • Uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation ( 5.1 ) • History of heparin-induced thrombocytopenia (HIT) and heparin induced thrombocytopenia with thrombosis ( 5.2 ) • Severe thrombocytopenia ( 5.3 ) • Known hypersensitivity to heparin or pork products ( 5.5 , 6.1 )

11 DESCRIPTION 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. Each liter contains the following electrolytes: Sodium 186.4 mEq; phosphate (as HPO 4 =) 32.4 mEq, citrate 5.7 mEq and chloride 154 mEq. 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 (Na 2 HPO 4 ∙ 7H 2 O), colorless or white granular salt freely soluble in water. Citric Acid, USP, hydrous (monohydrate) is chemically designated C 6 H 8 O 7 ∙ H 2 O, colorless, translucent crystals or white crystalline powder very soluble in water. It has the following structural formula: Water for Injection, USP is chemically designated H 2 O. The flexible plastic container is fabricated from either polyvinylchloride or polyolefin plastic. 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. Chemical Structure Chemical Structure

2 DOSAGE AND ADMINISTRATION Infuse through intravenous catheter at a rate of 6 units per hour. ( 2.2 ) 2.1 Preparation for Administration Do not administer unless solution is clear and seal is intact.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Warning: Do not use plastic containers in series connection. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Do not use Heparin Sodium in Sodium Chloride Injection as a “catheter lock flush” product. Do not admix with other drugs. Discard unused portion. To Open Tear outer wrap and remove solution container. Preparation for Administration (Use aseptic technique) 1. Close flow control clamp of administration set. 2. Remove cover from outlet port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: When using a vented administration set, replace bacterial retentive air filter with piercing pin cover. Insert piercing pin with twisting motion until shoulder of air filter housing rests against the outlet port flange. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Attach venipuncture device to set. 7. Open clamp to expel air from set and venipuncture device. Close clamp. 8. Perform venipuncture. 9. Regulate rate of administration with flow control clamp. 2.2 Recommended Dosage for Maintenance of Catheter Patency The recommended starting dose is 6 units per hour by intravenous infusion through an intravenous catheter to maintain catheter patency.

1 INDICATIONS AND USAGE Heparin Sodium Injection in Sodium Chloride at a concentration of 2 units/mL is indicated as an anticoagulant to maintain catheter patency. HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION at a concentration of 2 units/mL is indicated as an anticoagulant to maintain 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 or drugs that counteract coagulation may induce bleeding. ( 7 ) 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 NSAIDS (including acetylsalicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIv/IIa antagonists (including abciximab, eptifobatide, and tirofiban), 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. To reduce the risk of bleeding, a reduction in the dose of the antiplatelet agent or heparin is recommended. 7.3 Other Medications that May Interfere with Heparin Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin. Antithrombin III (human) – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage of heparin is recommended during treatment with antithrombin III (human).

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin II, thereby inhibiting the activated coagulation factors involved in the closing sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). 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 Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, they are not measurably affected by low doses of heparin. Bleeding time is usually unaffected by heparin. 12.3 Pharmacokinetics Absorption Heparin is not absorbed through the gastrointestinal tract and therefore administered via parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration. Distribution Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg. Elimination Metabolism Heparin does not undergo enzymatic degradation. Excretion Heparin is mainly cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero order process due to binding to proteins, endothelial cells and macrophage) and b) slower first order elimination. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h. Specific Populations Geriatric Patients 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) ] .

12.1 Mechanism of Action Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin II, thereby inhibiting the activated coagulation factors involved in the closing sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). 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 Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, they are not measurably affected by low doses of heparin. Bleeding time is usually unaffected by heparin.

12.3 Pharmacokinetics Absorption Heparin is not absorbed through the gastrointestinal tract and therefore administered via parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration. Distribution Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg. Elimination Metabolism Heparin does not undergo enzymatic degradation. Excretion Heparin is mainly cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero order process due to binding to proteins, endothelial cells and macrophage) and b) slower first order elimination. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h. Specific Populations Geriatric Patients 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) ] .

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3 DOSAGE FORMS AND STRENGTHS • Injection: 1,000 USP units per 500 mL (2 units per mL) clear solution in a single-dose infusion bag • Injection: 2,000 USP units per 1,000 mL (2 units per mL) clear solution in a single-dose infusion bag • Injection: 1,000 USP units in Sodium Chloride per 500 mL single-dose infusion bag (2 units per mL) ( 3 ) • Injection: 2,000 USP units in Sodium Chloride per 1,000 mL single-dose infusion bag (2 units per mL) ( 3 )

Heparin Sodium HEPARIN SODIUM HEPARIN SODIUM HEPARIN SODIUM CHLORIDE CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE WATER Heparin Sodium HEPARIN SODIUM HEPARIN SODIUM HEPARIN SODIUM CHLORIDE CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE WATER Heparin Sodium HEPARIN SODIUM HEPARIN SODIUM HEPARIN SODIUM CHLORIDE CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

NDA018916

Heparin Sodium

HEPARIN SODIUM

0409-1005

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

5.7 Laboratory Tests Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration.

PRINCIPAL DISPLAY PANEL - 500 mL Bag 1,000 USP Units/500 mL (2 USP Units/mL) 500 mL NDC 0409-7620-13 HEPARIN SODIUM 1,000 USP Units/500 mL (2 USP Units/mL) in 0.9% Sodium Chloride Injection EACH 100 mL CONTAINS HEPARIN SODIUM 200 USP UNITS (PORCINE INTESTINAL MUCOSA); SODIUM CHLORIDE 0.9 g; CITRIC ACID, MONOHYDRATE 40 mg AND DIBASIC SODIUM PHOSPHATE, HEPTAHYDRATE 434 mg ADDED AS BUFFERS. 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. 3 V CONTAINS DEHP Rx only DISTRIBUTED BY HOSPIRA, INC., LAKE FOREST, IL 60045 USA Hospira 14478901 IM-4470 PRINCIPAL DISPLAY PANEL - 500 mL Bag

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-0807-4.0 Logo

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 (5.1) ]. Prior to Surgery Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is scheduled [see Warnings and Precautions (5.1) ]. 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 can occur up to several weeks after the discontinuation of heparin therapy [see Warnings and Precautions (5.2) ]. 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 (5.5) , Adverse Reactions (6.1) ] . 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) ] .

8.5 Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women [see Warnings and Precautions (5.1) ].

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium in Sodium Chloride Injection use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans (see Error! Hyperlink reference not valid. ) . Consider the benefits and risks of HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION for the mother and possible risks to the fetus when prescribing HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 >50 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 Geriatric Use: A higher incidence of bleeding has been reported in patients over 60 years of age, especially women ( 5.6 , 8.5 ) 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium in Sodium Chloride Injection use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans (see Error! Hyperlink reference not valid. ) . Consider the benefits and risks of HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION for the mother and possible risks to the fetus when prescribing HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 >50 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 in human milk, the effects on the breastfed child, or the effects on milk production. Due to its large molecular weight, heparin is not likely to be excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION and any potential adverse effects on the breastfed child from HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION or from the underlying maternal condition [see Use in Specific Populations (8.4) ] . 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women [see Warnings and Precautions (5.1) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Intravenous solutions with heparin sodium are available in single-dose containers as follows: Unit of Sale Concentration NDC 0409-7620-03 Case of 18 Single-dose flexible plastic containers 1,000 USP Units/500 mL (2 USP Units/mL) NDC 0409-1005-20 Case of 20 Single-dose flexible plastic containers 1,000 USP Units/500 mL (2 USP Units/mL) NDC 0409-7620-59 Case of 12 Single-dose flexible plastic containers 2,000 USP Units/1,000 mL (2 USP Units/mL) NDC 0409-2222-12 Case of 12 Single-dose flexible plastic containers 2,000 USP Units/1,000 mL (2 USP Units/mL) Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing.

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