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1 INDICATIONS AND USAGE Heparin Sodium Injection is indicated for: • Prophylaxis and treatment of venous thrombosis and pulmonary embolism; • Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease; • Atrial fibrillation with embolization; • Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); • Prevention of clotting in arterial and cardiac surgery; • Prophylaxis and treatment of peripheral arterial embolism. • Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures. HEPARIN SODIUM INJECTION is an anticoagulant indicated for ( 1 ) • Prophylaxis and treatment of venous thrombosis and pulmonary embolism • Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease • Atrial fibrillation with embolization • Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) • Prevention of clotting in arterial and cardiac surgery • Prophylaxis and treatment of peripheral arterial embolism • Use as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: • Therapeutic Anticoagulant Effect with Full-Dose Heparin† ( 2.3 ) Deep Subcutaneous (Intrafat) Injection Use a different site for each injection Initial Dose 5,000 units by intravenous injection followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion † Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial to ensure that the 1 mL vial is not confused with a “catheter lock flush” vial or other 1 mL vial of incorrect strength [ s ee Warnings and Precautions ( 5.1 )]. Confirm the selection of the correct formulation and strength prior to administration of the drug. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site [see Adverse Reactions ( 6.1 )] . 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient's coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience.

urs after the injection. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect *Based on 68 kg patient METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE Deep Subcutaneous (Intrafat) Injection Use a different site for each injection to prevent the development of hematoma Initial Dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or 8,000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Continuous Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.4 Pediatric Dosing Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants [see Warnings and Precautions ( 5.4 )]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Recommended Pediatric Use Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.7 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )] .

to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )] . 2.8 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.9 Extracorporeal Dialysis Follow equipment manufacturers' operating directions carefully. A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers' recommendations are not available.

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium Injection, USP is available as: Heparin Sodium Injection, USP, preservative free , is available as follows: • 2,000 USP units per 2 mL, single-dose vial • 5,000 USP units per 0.5 mL, single-dose vial Heparin Sodium Injection, USP contains benzyl alcohol and is available as follows: • 50,000 USP units per 10 mL, multiple-dose vial • 40,000 USP units per 4 mL, multiple-dose vial Heparin Sodium Injection, USP contains parabens and is available as follows: • 1,000 USP units per mL, multiple-dose vial • 10,000 USP units per 10 mL, multiple-dose vial • 30,000 USP units per 30 mL, multiple-dose vial • 5,000 USP units per mL, multiple-dose vial • 10,000 USP units per mL, multiple-dose vial • 50,000 USP units per 5 mL, multiple-dose vial • 20,000 USP units per mL, multiple-dose vial Heparin Sodium Injection, USP (porcine), preservative free Heparin Sodium Injection, USP (porcine) contains benzyl alcohol Heparin Sodium Injection, USP (porcine) contains parabens 2 mL single-dose vial contains 2,000 USP units 10 mL multiple-dose vial contains 50,000 USP units 1 mL multiple-dose vial contains 1,000 USP units 0.5 mL single-dose vial contains 5,000 USP units 4 mL multiple-dose vial contains 40,000 USP units 10 mL multiple-dose vial contains 10,000 USP units 30 mL multiple-dose vial contains 30,000 USP units 1 mL multiple-dose vial contains 5,000 USP units 1 mL multiple-dose vial contains 10,000 USP units 5 mL multiple-dose vial contains 50,000 USP units 1 mL multiple-dose vial contains 20,000 USP units

<table styleCode="Noautorules" width="100%"><col width="36%"/><col width="27%"/><col width="37%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Heparin Sodium Injection, USP (porcine), <content styleCode="bold">preservative free</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Heparin Sodium Injection, USP (porcine) contains <content styleCode="bold">benzyl alcohol</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Heparin Sodium Injection, USP (porcine) contains <content styleCode="bold">parabens</content></paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 mL single-dose vial contains 2,000 USP units</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 mL multiple-dose vial contains 50,000 USP units </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 mL multiple-dose vial contains 1,000 USP units</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5 mL single-dose vial contains 5,000 USP units</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4 mL multiple-dose vial contains 40,000 USP units </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 mL multiple-dose vial contains 10,000 USP units</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30 mL multiple-dose vial contains 30,000 USP units </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 mL multiple-dose vial contains 5,000 USP units </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 mL multiple-dose vial contains 10,000 USP units </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5 mL multiple-dose vial contains 50,000 USP units </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1 mL multiple-dose vial contains 20,000 USP units </paragraph></td></tr></tbody></table>

4 CONTRAINDICATIONS The use of Heparin Sodium Injection is contraindicated in patients with the following conditions: • History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions ( 5.3 )] ; • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions ( 6.1 )]; • In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); • An uncontrolled active bleeding state [see Warnings and Precautions ( 5.4 )] , except when this is due to disseminated intravascular coagulation. • History of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITTS) ( 4 ) • Known hypersensitivity to heparin or pork products ( 4 ) • In whom suitable blood coagulation tests cannot be performed at appropriate intervals ( 4 ) • An uncontrolled bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS • Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) • Hemorrhage: Hemorrhage, including fatal events, has occurred in patients receiving heparin. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) • HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS ( 5.3 ) • Benzyl Alcohol Toxicity: Use preservative-free formulation in neonates and infants • Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Periodically monitor platelet count, hematocrit, and occult blood in stool in all patients receiving heparin ( 5.5 , 5.6 ) 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. 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, fall in blood pressure or any other unexplained symptom 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: • Cardiovascular - Subacute bacterial endocarditis, severe hypertension. • Surgical - During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. • Hematologic - Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. • Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy - 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). • Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine. • Other - Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation.

ed Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing Heparin Sodium Injection multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Heparin Sodium Injection multiple-dose vials and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations ( 8.4 )] . 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions ( 5.3 )]. 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage ( 10 )] . Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration ( 2.2 )] . 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity 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 Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [see Warnings and Precautions ( 5.2 )] • Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions ( 5.3 )] • Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions ( 5.4 )] • Thrombocytopenia [see Warnings and Precautions ( 5.5 )] • Heparin Resistance [see Warnings and Precautions ( 5.7 )] • Hypersensitivity [see Warnings and Precautions ( 5.8 )] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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 Injection. 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 ( 5.2 )] . 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 including: o Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases. o Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term heparin therapy. o Retroperitoneal hemorrhage • HIT and HITT, including delayed onset cases [see Warnings and Precautions ( 5.3 )]. • Local Irritation – Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. • 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 [see Warnings and Precautions ( 5.3 )]. • 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur. [see Warnings and Precautions ( 5.8 )] • Elevations of 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.

7 DRUG INTERACTIONS Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding ( 7.2 ) 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 salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, 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 antiplatelet agent or heparin is recommended. 7.3 Other Interactions 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).

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Preservative-free formulation recommended. ( 8.1 ) • Lactation: Preservative-free formulation recommended. ( 8.2 ) • Pediatric Use: Use preservative-free formulation in neonates and infants. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no available data on heparin sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day ( see Data ). Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Use in Specific Populations ( 8.4 )]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 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 If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a breastfed infant. There is no information regarding the presence of Heparin Sodium 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 breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Heparin Sodium Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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.

inical need for Heparin Sodium Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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 )] . Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions ( 5.1 )] . Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary There are no available data on heparin sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day ( see Data ). Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Use in Specific Populations ( 8.4 )]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 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.

8.4 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 )] . Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions ( 5.1 )] . Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. 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 the heparin effect, 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 with protamine, it should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection.

11 DESCRIPTION Heparin 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. Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is to be administered by intravenous or deep subcutaneous routes. 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): Heparin Sodium Injection, USP (porcine), preservative free, is available as follows: Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 9 mg sodium chloride; Water for Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Each 0.5 mL of the 5,000 units per 0.5 mL preparation contains: 5,000 USP Heparin units (porcine); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available as follows: Each mL of the 5,000 units per mL preparation contains: 5,000 USP Heparin units (porcine); 6 mg sodium chloride; 15 mg benzyl alcohol (as a preservative); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Each mL of the 10,000 units per mL preparation contains: 10,000 USP Heparin units (porcine); 5 mg sodium chloride; 10.42 mg benzyl alcohol (as a preservative); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Heparin Sodium Injection, USP (porcine), preserved with parabens, is available as follows: Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 9 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Each mL of the 5,000 units per mL preparation contains: 5,000 USP Heparin units (porcine); 5 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Each mL of the 10,000 units per mL preparation contains: 10,000 USP Heparin units (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

m hydroxide may have been added for pH adjustment (5.0 to 7.5). Each mL of the 10,000 units per mL preparation contains: 10,000 USP Heparin units (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Each mL of the 20,000 units per mL preparation contains: 20,000 USP Heparin units (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). hepar-struc-01.jpg

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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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. The 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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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. The 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 )] .

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.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection, USP (porcine), preservative free , is available as follows: Product Code Unit of Sale Strength Each 27602 NDC 63323-276-02 Unit of 25 2,000 USP units per 2 mL (1,000 USP units per mL) NDC 63323-276-01 2 mL single-dose, flip-top vial 504313 NDC 63323-543-13 Unit of 25 5,000 USP units per 0.5 mL NDC 63323-543-03 0.5 mL fill in a 2 mL single-dose, flip-top vial Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made with natural rubber latex. Discard unused portion. Heparin Sodium Injection, USP (porcine) contains benzyl alcohol and is available as follows: Product Code Unit of Sale Strength Each 4710 NDC 63323-047-10 Unit of 25 50,000 USP units per 10 mL (5,000 USP units per mL) NDC 63323-047-01 10 mL multiple-dose, flip-top vial 504514 NDC 63323-459-14 Unit of 25 40,000 USP units per 4 mL (10,000 USP units per mL) NDC 63323-459-04 4 mL fill in a 5 mL multiple-dose, flip-top vial Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made with natural rubber latex. Heparin Sodium Injection, USP (porcine) contains parabens and is available as follows: Product Code Unit of Sale Strength Each 504013 NDC 63323-540-13 Unit of 25 1,000 USP units per mL NDC 63323-540-03 1 mL fill in a 2 mL multiple-dose, flip-top vial 504015 NDC 63323-540-15 Unit of 25 10,000 USP units per 10 mL (1,000 USP units per mL) NDC 63323-540-05 10 mL multiple-dose, flip-top vial RF504015 NDC 65219-066-10 Unit of 25 10,000 USP units per 10 mL (1,000 USP units per mL) NDC 65219-066-01 10 mL multiple-dose, flip-top vial This product contains an RFID 504036 NDC 63323-540-36 Unit of 25 30,000 USP units per 30 mL (1,000 USP units per mL) NDC 63323-540-33 30 mL multiple-dose, flip-top vial 926206 NDC 63323-262-06 Unit of 25 5,000 USP units per mL NDC 63323-262-03 1 mL fill in a 2 mL multiple-dose, flip-top vial 504213 NDC 63323-542-13 Unit of 25 10,000 USP units per mL NDC 63323-542-09 1 mL fill in a 2 mL multiple-dose, flip-top vial 504214 NDC 63323-542-14 Unit of 25 50,000 USP units per 5 mL (10,000 USP units per mL) NDC 63323-542-04 5 mL fill in a 10 mL multiple-dose, flip-top vial 915513 NDC 63323-915-13 Unit of 25 20,000 USP units per mL NDC 63323-915-03 1 mL fill in a 2 mL multiple-dose, flip-top vial Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made with natural rubber latex. STORAGE: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

<table styleCode="Noautorules" width="100%"><col width="11%"/><col width="22%"/><col width="29%"/><col width="38%"/><tbody><tr><td align="justify" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Product</content> <content styleCode="bold">Code</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Each</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27602 </paragraph></td><td align="justify" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-276-02 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2,000 USP units per 2 mL (1,000 USP units per mL) </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-276-01 2 mL single-dose, flip-top vial </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>504313 </paragraph></td><td align="justify" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 63323-543-13 Unit of 25 </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5,000 USP units per 0.5 mL </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 63323-543-03 0.5 mL fill in a 2 mL single-dose, flip-top vial </paragraph></td></tr></tbody></table>

43-13 Unit of 25 </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5,000 USP units per 0.5 mL </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 63323-543-03 0.5 mL fill in a 2 mL single-dose, flip-top vial </paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="11%"/><col width="23%"/><col width="29%"/><col width="37%"/><tbody><tr><td align="justify" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Product</content> <content styleCode="bold">Code</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Each</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4710 </paragraph></td><td align="justify" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-047-10 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>50,000 USP units per 10 mL (5,000 USP units per mL) </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-047-01 10 mL multiple-dose, flip-top vial </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>504514 </paragraph></td><td align="justify" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 63323-459-14 Unit of 25 </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>40,000 USP units per 4 mL (10,000 USP units per mL) </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 63323-459-04 4 mL fill in a 5 mL multiple-dose, flip-top vial </paragraph></td></tr></tbody></table>

aph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>40,000 USP units per 4 mL (10,000 USP units per mL) </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 63323-459-04 4 mL fill in a 5 mL multiple-dose, flip-top vial </paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="12%"/><col width="22%"/><col width="29%"/><col width="37%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Product</content> <content styleCode="bold">Code</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Each</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>504013 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-540-13 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1,000 USP units per mL </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-540-03 1 mL fill in a 2 mL multiple-dose, flip-top vial </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>504015 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-540-15 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10,000 USP units per 10 mL (1,000 USP units per mL) </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-540-05 10 mL multiple-dose, flip-top vial </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>RF504015 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 65219-066-10 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10,000 USP units per 10 mL (1,000 USP units per mL) </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 65219-066-01 10 mL multiple-dose, flip-top vial This product contains an RFID </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>504036 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-540-36 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30,000 USP units per 30 mL (1,000 USP units per mL) </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-540-33 30 mL multiple-dose, flip-top vial </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>926206 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-262-06 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5,000 USP units per mL </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-262-03 1 mL fill in a 2 mL multiple-dose, flip-top vial </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>504213 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-542-13 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10,000 USP units per mL </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><parag

ragraph>504213 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-542-13 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10,000 USP units per mL </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><parag raph>NDC 63323-542-09 1 mL fill in a 2 mL multiple-dose, flip-top vial </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>504214 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-542-14 Unit of 25 </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>50,000 USP units per 5 mL (10,000 USP units per mL) </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NDC 63323-542-04 5 mL fill in a 10 mL multiple-dose, flip-top vial </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>915513 </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 63323-915-13 Unit of 25 </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>20,000 USP units per mL </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 63323-915-03 1 mL fill in a 2 mL multiple-dose, flip-top vial </paragraph></td></tr></tbody></table>

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions ( 5.8 ), 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 ( 7.1 )] . Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451645B hepar-img-01.jpg

1 INDICATIONS AND USAGE Heparin Sodium Injection is indicated for: Prophylaxis and treatment of venous thrombosis and pulmonary embolism; Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease; Atrial fibrillation with embolization; Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and cardiac surgery; Prophylaxis and treatment of peripheral arterial embolism. Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures. HEPARIN SODIUM INJECTION is an anticoagulant indicated for ( 1 ) Prophylaxis and treatment of venous thrombosis and pulmonary embolism Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease Atrial fibrillation with embolization Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) Prevention of clotting in arterial and cardiac surgery Prophylaxis and treatment of peripheral arterial embolism Use as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: Therapeutic Anticoagulant Effect with Full-Dose Heparin † ( 2.3 ) † Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. Deep Subcutaneous (Intrafat) Injection Use a different site for each injection Initial Dose 5,000 units by intravenous injection followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.1 Preparation for Administration Confirm the choice of the correct heparin sodium injection vial to ensure that the 1 mL vial is not confused with a “catheter lock flush” vial or other 1 mL vial of incorrect strength [see Warnings and Precautions ( 5.1 )] . Confirm the selection of the correct formulation and strength prior to administration of the drug. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Administer heparin sodium by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site [see Adverse Reactions ( 6.1 )] . 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of heparin sodium injection according to the patient's coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with heparin sodium injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience.

urs after the injection. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect *Based on 68 kg patient METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE Deep Subcutaneous (Intrafat) Injection Use a different site for each injection to prevent the development of hematoma Initial Dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or 8,000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Continuous Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.4 Pediatric Dosing Use preservative-free heparin sodium injection in neonates and infants [see Warnings and Precautions ( 5.4 )] . There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Recommended Pediatric Use Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.7 Converting to Warfarin To ensure continuous anticoagulation when converting from heparin sodium to warfarin, continue full heparin sodium injection therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin sodium injection therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )] .

ontinuous anticoagulation when converting from heparin sodium to warfarin, continue full heparin sodium injection therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin sodium injection therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )] . 2.8 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.9 Extracorporeal Dialysis Follow equipment manufacturers' operating directions carefully. A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers' recommendations are not available.

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium Injection, USP is available as: Heparin Sodium Injection, USP contains benzyl alcohol and is available as follows: 20,000 USP units per 1 mL, multi-dose vial Heparin Sodium Injection, USP (porcine) contains benzyl alcohol: 1 mL multi-dose vial contains 20,000 USP units

4 CONTRAINDICATIONS The use of heparin sodium injection is contraindicated in patients with the following conditions: History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions ( 5.3 )] ; Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions ( 6.1 )]; In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); An uncontrolled active bleeding state [see Warnings and Precautions ( 5.4 )] , except when this is due to disseminated intravascular coagulation. History of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITTS) ( 4 ) Known hypersensitivity to heparin or pork products ( 4 ) In whom suitable blood coagulation tests cannot be performed at appropriate intervals ( 4 ) An uncontrolled bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) Hemorrhage: Hemorrhage, including fatal events, has occurred in patients receiving heparin. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS ( 5.3 ) Benzyl Alcohol Toxicity: Use preservative-free formulation in neonates and infants Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Periodically monitor platelet count, hematocrit, and occult blood in stool in all patients receiving heparin ( 5.5 , 5.6 ) Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients. ( 5.9 ) 5.1 Fatal Medication Errors Do not use heparin sodium injection as a “catheter lock flush” product. Heparin sodium injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL heparin sodium injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all heparin sodium injection vials to confirm the correct vial choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. 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, fall in blood pressure or any other unexplained symptom 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: Cardiovascular - Subacute bacterial endocarditis, severe hypertension. Surgical - During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic - Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy - 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other - Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation.

ed Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing Heparin Sodium Injection multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Heparin Sodium Injection multiple-dose vials and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations ( 8.4 )] . 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions ( 5.3 )] . 5.6 Coagulation Testing and Monitoring When using a full dose heparin sodium regimen, adjust the heparin sodium dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin sodium promptly [see Overdosage ( 10 )] . Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration ( 2.2 )] . 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity 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 Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

arranted. 5.8 Hypersensitivity 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 Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy. 5.9 Hyperkalemia Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin. Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.2 )] Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions ( 5.3 )] Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions ( 5.4 )] Thrombocytopenia [see Warnings and Precautions ( 5.5 )] Heparin Resistance [see Warnings and Precautions ( 5.7 )] Hypersensitivity [see Warnings and Precautions ( 5.8 )] Hyperkalemia [see Warnings and Precautions ( 5.9 )] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 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 Injection. 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 ( 5.2 )] . 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 including: 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 heparin therapy. Retroperitoneal hemorrhage HIT and HITT, including delayed onset cases [see Warnings and Precautions ( 5.3 )] . Local Irritation - Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. 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 [see Warnings and Precautions ( 5.3 )] . 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur. [see Warnings and Precautions ( 5.8 )] Elevations of 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. Metabolism and Nutrition Disorders – Hyperkalemia.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Preservative-free formulation recommended. ( 8.1 ) Lactation: Preservative-free formulation recommended. ( 8.2 ) Pediatric Use: Use preservative-free formulation in neonates and infants. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no available data on heparin sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day ( see Data ). Consider the benefits and risks of heparin sodium for the mother and possible risks to the fetus when prescribing heparin sodium injection to a pregnant woman. If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Use in Specific Populations ( 8.4 )] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 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 If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a breastfed infant. There is no information regarding the presence of Heparin Sodium 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 breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for heparin sodium and any potential adverse effects on the breastfed infant from heparin sodium 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.

with the mother's clinical need for heparin sodium and any potential adverse effects on the breastfed infant from heparin sodium 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 )] . Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin sodium injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions ( 5.1 )] . Benzyl Alcohol Toxicity Use preservative-free heparin sodium injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary There are no available data on heparin sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day ( see Data ). Consider the benefits and risks of heparin sodium for the mother and possible risks to the fetus when prescribing heparin sodium injection to a pregnant woman. If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Use in Specific Populations ( 8.4 )] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 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.

8.4 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 )] . Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin sodium injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions ( 5.1 )] . Benzyl Alcohol Toxicity Use preservative-free heparin sodium injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

11 DESCRIPTION Heparin 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. Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is to be administered by intravenous or deep subcutaneous routes. 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): Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available as follows: Each mL of the 20,000 units per mL preparation contains: 20,000 USP heparin units (porcine); 10.42 mg benzyl alcohol (as a preservative); water for injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5 to 7.5). Structural Formula

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection, USP (porcine) contains benzyl alcohol and is available as follows: NDC Heparin Sodium Injection, USP Package Factor 72603- 224 -25 20,000 USP units per mL, 1 mL Multi-Dose Vial 25 vials per carton Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex. STORAGE: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

<table width="100%" styleCode="Noautorules"><colgroup><col width="22.733%" align="left"/><col width="38.633%" align="left"/><col width="38.633%" align="left"/></colgroup><tbody><tr><td align="left" valign="top"><content styleCode="bold">NDC</content></td><td align="left" valign="top"><content styleCode="bold">Heparin Sodium Injection, USP</content></td><td align="left" valign="top"><content styleCode="bold">Package Factor</content></td></tr><tr><td align="justify" valign="top">72603-<content styleCode="bold">224</content>-25</td><td align="justify" valign="top">20,000 USP units per mL, 1 mL Multi-Dose Vial</td><td align="justify" valign="top">25 vials per carton</td></tr></tbody></table>

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions ( 5.8 ), 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 ( 7.1 )] . Manufactured for Northstar Rx LLC, Memphis, TN 38141. Manufactured by Nanjing King-Friend Biochemical Pharmaceutical Co., Ltd. Nanjing, China 210061 Revised: March 2025 8A6FDN9-01

1 INDICATIONS AND USAGE Heparin sodium injection is indicated for: Prophylaxis and treatment of venous thrombosis and pulmonary embolism Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease Atrial fibrillation with embolization Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) Prevention of clotting in arterial and cardiac surgery Prophylaxis and treatment of peripheral arterial embolism Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures HEPARIN SODIUM INJECTION is an anticoagulant indicated for ( 1 ) Prophylaxis and treatment of venous thrombosis and pulmonary embolism Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease Atrial fibrillation with embolization Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) Prevention of clotting in arterial and cardiac surgery Prophylaxis and treatment of peripheral arterial embolism Use as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: Therapeutic Anticoagulant Effect with Full-Dose Heparin † ( 2.3 ) Deep Subcutaneous (Intrafat) Injection Use a different site for each injection Initial Dose 5,000 units by intravenous injection, followed by 10,000 units to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 units to 10,000 units of a concentrated solution 15,000 units to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP by intravenous injection Every 4 to 6 hours 5,000 units to 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 units/24hours to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion † Based on 68 kg patient. Adjust dose based on laboratory monitoring. 2.1 Preparation for Administration Confirm the selection of the correct formulation and strength prior to administration of the drug. Confirm the choice of the correct heparin sodium injection vial prior to administration of the drug to a patient [see Warnings and Precaution ( 5.1 )]. The 1 mL vial must not be confused with a “catheter lock flush” vial or other 1 mL vial of inappropriate strength. Confirm that you have selected the correct medication and strength prior to administration of the drug. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site . Converting to Oral Anticoagulant When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time. In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering. Low-Dose Prophylaxis of Postoperative Thromboembolism A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism.

oembolism A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or plateletactive drugs (see WARNINGS ). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters. Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. Blood Transfusion Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood. Laboratory Samples Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of heparin sodium injection according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with heparin sodium injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter.

elet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodically monitor platelet counts and hematocrits during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect Method of Administration Frequency Recommended Dose (Based on 68 kg patient) Deep Subcutaneous (Intrafat) Injection A different site should be used for each injection to prevent development of massive hematoma Initial Dose 5,000 units by intravenous injection, followed by 10,000 units to 20,000 units of a concentrated solution, subcutaneously Every 8 hours Or Every 12 hours 8,000 units to 10,000 units of a concentrated solution 15,000 units to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP by intravenous injection Every 4 to 6 hours 5,000 units to 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 units/24 hours to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.4 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.5 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.6 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.7 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )].

g to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )]. 2.8 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.9 Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

3 DOSAGE FORMS AND STRENGTHS Heparin sodium injection, USP (porcine), contains parabens and is available as follows: Strength Fill Volume 1,000 USP Heparin units/10 mL 1 mL fill in a 2 mL vial, Pack of 25 vials 10,000 USP Heparin units/10 mL(1,000 USP Heparin units/mL) 10 mL fill in a 10 mL vial, Pack of 25 vials 30,000 USP Heparin units/30 mL(1,000 USP Heparin units/mL) 30 mL fill in a 30 mL vial, Pack of 25 vials 5,000 USP Heparin units/mL 1 mL fill in a 2 mL vial, Pack of 10 vials 1 mL fill in a 2 mL vial, Pack of 25 vials 10,000 USP Heparin units/mL 1 mL fill in a 2 mL vial, Pack of 25 vials Heparin sodium is available as: ( 3 ) Heparin Sodium Injection (parabens): Injection: 1,000 USP Heparin units/mL Injection: 10,000 USP Heparin units/10 mL (1,000 USP Heparin units/mL) Injection: 30,000 USP Heparin units/30 mL (1,000 USP Heparin units/mL) Injection: 5,000 USP Heparin units/mL Injection: 10,000 USP Heparin units/mL

<table width="100%"><col width="36%"/><col width="64%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Fill Volume</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1,000 USP Heparin units/10 mL</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1 mL fill in a 2 mL vial, Pack of 25 vials</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>10,000 USP Heparin units/10 mL(1,000 USP Heparin units/mL)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>10 mL fill in a 10 mL vial, Pack of 25 vials</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>30,000 USP Heparin units/30 mL(1,000 USP Heparin units/mL)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>30 mL fill in a 30 mL vial, Pack of 25 vials</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>5,000 USP Heparin units/mL</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1 mL fill in a 2 mL vial, Pack of 10 vials</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1 mL fill in a 2 mL vial, Pack of 25 vials</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>10,000 USP Heparin units/mL</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1 mL fill in a 2 mL vial, Pack of 25 vials</paragraph></td></tr></tbody></table>

4 CONTRAINDICATIONS The use of heparin sodium injection is contraindicated in patients with the following conditions: History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions ( 5.3 )] Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions ( 6.1 )] In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin) An uncontrolled active bleeding state [see Warnings and Precautions ( 5.4 )] , except when this is due to disseminated intravascular coagulation. Severe thrombocytopenia ( 4 ) When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals ( 4 ) An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) HIT and HITT: Monitor for signs and symptoms and discontinue if indicative of HIT and HITT ( 5.3 ) Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Monitor platelet count and hematocrit in all patients receiving heparin ( 5.5 , 5.6 ) 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in syringes containing a highly concentrated solution of 10,000 units in 1 mL (5,000 units per 0.5 mL). Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection syringes to confirm the correct syringe choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. 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, fall in blood pressure or any other unexplained symptom 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: Cardiovascular - Subacute bacterial endocarditis, severe hypertension. Surgical -During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic - Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy - 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other - Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT.

pment of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions ( 5.3 )]. 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage ( 10 )]. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration ( 2.2 )]. 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations. Because heparin sodium injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.2 )] Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions ( 5.3 )] Thrombocytopenia [see Warnings and Precautions ( 5.4 )] Heparin Resistance [see Warnings and Precautions ( 5.6 )] Hypersensitivity [see Warnings and Precautions ( 5.7 )] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITT, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Plano Pharmaceuticals Inc. at 773-726-1154 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Post-Marketing Experience The following adverse reactions have been identified during post approval use of Heparin Sodium Injection. 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 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 heparin therapy. Retroperitoneal hemorrhage HIT and HITT, including delayed onset cases [see Warnings and Precautions ( 5.3 )]. Local Irritation – Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. 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 [see Warnings and Precautions ( 5.3 )]. 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur [see Warnings and Precautions ( 5.8 )]. Elevations of aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin [see Drug Interactions ( 7.4 )]. Miscellaneous - 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.

7 DRUG INTERACTIONS Drugs that interfere with platelet aggregation: May induce bleeding ( 7.2 ) 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 five 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 salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, 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 antiplatelet agent or heparin is recommended. 7.3 Other Interactions 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).

8 USE IN SPECIFIC POPULATIONS Pregnancy: Limited human data in pregnant women. ( 8.1 ) Lactation: Advise females not to breastfeed. ( 8.2 ) Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. ( 8.5 ) 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day (see Data) . Consider the benefits and risks of heparin sodium injection for the mother and possible risks to the fetus when prescribing heparin sodium Injection to a pregnant woman. If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during pregnancy. The 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 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 injection 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, and any heparin in milk would not be orally absorbed by a nursing child. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for heparin sodium injection and any potential adverse effects on the breastfed child from heparin sodium injection or from the underlying maternal condition [see Use in Specific Populations ( 8.4 )]. If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Exercise caution when administering heparin sodium injection to a nursing mother (see Use in Specific Populations ( 8.4 )). 8.4 Pediatric Use Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug.

nd may be orally absorbed by a nursing infant. Exercise caution when administering heparin sodium injection to a nursing mother (see Use in Specific Populations ( 8.4 )). 8.4 Pediatric Use Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin sodium injection vials have been confused with "catheter lock flush” vials [see Warnings and Precaution ( 5.1 )]. 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )]. Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology ( 12.3 )].

8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day (see Data) . Consider the benefits and risks of heparin sodium injection for the mother and possible risks to the fetus when prescribing heparin sodium Injection to a pregnant woman. If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during pregnancy. The 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 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.

8.4 Pediatric Use Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin sodium injection vials have been confused with "catheter lock flush” vials [see Warnings and Precaution ( 5.1 )].

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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )]. Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology ( 12.3 )].

11 DESCRIPTION Heparin 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. Heparin sodium injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is to be administered by intravenous or deep subcutaneous routes. 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 sub-units): Heparin sodium injection, USP (porcine), preserved with parabens, is available as follows: Each 1,000 Units/mL contains: 1,000 USP Heparin Units; 9 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5 to 7.5). Each 5,000 Units/mL contains: 5,000 USP Heparin Units; 5 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5 to 7.5). Each 10,000 Units/mL contains: 10,000 USP Heparin Units; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5 to 7.5). Heparin Sodium Chemical Structure

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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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. The 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 )].

12.3 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 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin sodium injection, USP (porcine), contains parabens and is available as follows: Strength NDC Fill Volume 1,000 USP Heparin units/mL 87188-101-90 1 mL fill in a 2 mL vial, Pack of 25 vials 10,000 USP Heparin units/10 mL (1,000 USP Heparin units/mL) 87188-101-80 10 mL fill in a 10 mL vial, Pack of 25 vials 30,000 USP Heparin units/30 mL (1,000 USP Heparin units/mL) 87188-101-70 30 mL fill in a 30 mL vial Pack of 25 vials 5,000 USP Heparin units/mL 87188-102-90 1 mL fill in a 2 mL vial, Pack of 25 vials 10,000 USP Heparin units/mL 87188-103-90 1 mL fill in a 2 mL vial, Pack of 25 vials The above products are available in multiple dose, flip-top vials. Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Avoid excessive heat. Do not freeze.

<table border="0" width="100%"><tbody><tr><td><paragraph>Strength</paragraph></td><td>NDC</td><td>Fill Volume</td></tr><tr><td>1,000 USP Heparin units/mL</td><td>87188-101-90</td><td>1 mL fill in a 2 mL vial, Pack of 25 vials </td></tr><tr><td>10,000 USP Heparin units/10 mL (1,000 USP Heparin units/mL) </td><td>87188-101-80</td><td>10 mL fill in a 10 mL vial, Pack of 25 vials </td></tr><tr><td>30,000 USP Heparin units/30 mL (1,000 USP Heparin units/mL) </td><td>87188-101-70</td><td>30 mL fill in a 30 mL vial Pack of 25 vials </td></tr><tr><td>5,000 USP Heparin units/mL</td><td>87188-102-90</td><td>1 mL fill in a 2 mL vial, Pack of 25 vials </td></tr><tr><td>10,000 USP Heparin units/mL</td><td>87188-103-90</td><td>1 mL fill in a 2 mL vial, Pack of 25 vials </td></tr></tbody></table>

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions ( 5.8 ), 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 ( 7.1 )]. Revised: January 2019 Distributed by Plano Pharmaceuticals Inc. 125 S Wilke Rd. suite 353, Arlington Heights, IL 60005

1 INDICATIONS AND USAGE Heparin Sodium Injection is indicated for: • Prophylaxis and treatment of venous thrombosis and pulmonary embolism; • Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease; • Atrial fibrillation with embolization; • Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); • Prevention of clotting in arterial and cardiac surgery; • Prophylaxis and treatment of peripheral arterial embolism; • Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures. Heparin Sodium Injection is an anticoagulant indicated for ( 1 ): • Prophylaxis and treatment of venous thrombosis and pulmonary embolism • Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease • Atrial fibrillation with embolization • Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) • Prevention of clotting in arterial and cardiac surgery • Prophylaxis and treatment of peripheral arterial embolism • Use as an anticoagulant in blood transfusions, extracorporeal circulation and dialysis procedures

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: • Therapeutic Anticoagulant Effect with Full-Dose Heparin* ( 2.3 ) * Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. Deep, Subcutaneous (Intrafat) Injection Initial dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Use a different site for each injection. Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial or cartridge prior to administration of the drug to a patient [see Warnings and Precautions (5.1) ] . Heparin Sodium Injection products must not be confused with “catheter lock flush” products. To lessen this risk for a cartridge, a red cautionary statement has been added to the cartridge and box/bin. Read the cautionary statement and confirm that you have selected the correct medication and strength. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [see Adverse Reactions (6) ] . 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts, and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration.

priate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts, and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE [based on 150 lb (68 kg) patient] Deep, Subcutaneous (Intrafat) Injection Initial dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.4 Pediatric Use Do not use benzyl alcohol-preserved drugs in neonates and infants. Use preservative-free Heparin Sodium Injection in neonates and infants [see Warnings and Precautions (5.4) ]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (Intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous injection (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) with a fine (25- to 26-gauge) needle to minimize tissue trauma. 2.7 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood.

odium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.8 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1) ] . 2.9 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.10 Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturer’s recommendations are not available.

3 DOSAGE FORMS AND STRENGTHS • Heparin Sodium: 5,000 USP units/0.5 mL, Carpuject™ single-dose cartridge, preservative-free • Heparin Sodium: 5,000 USP units/1 mL, Carpuject™ single-dose cartridge, preserved with benzyl alcohol Carpuject TM Single-dose cartridge • Heparin Sodium: 5,000 USP units/0.5 mL, Preservative-free ( 3 ) • Heparin Sodium: 5,000 USP units/1 mL, Preserved with benzyl alcohol ( 3 )

4 CONTRAINDICATIONS The use of Heparin Sodium Injection is contraindicated in patients with the following conditions: • History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions (5.3) ] • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.2) ] • In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin) • An uncontrolled active bleeding state [see Warnings and Precautions (5.2) ] , except when this is due to disseminated intravascular coagulation • Severe thrombocytopenia ( 4 ) • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) ( 4 ) • When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals ( 4 ) • An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS • Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) • Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) • HIT and HITT: Monitor for signs and symptoms and discontinue if indicative of HIT and HITT ( 5.3 ) • Benzyl Alcohol Toxicity: Do not use benzyl alcohol-preserved drugs in neonates and infants ( 5.4 ) • Monitoring: Blood coagulation tests guide therapy for full-dose heparin ( 5.6 ) • Monitor platelet count and hematocrit in all patients receiving heparin ( 5.5 , 5.6 ) • Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients ( 5.9 ) 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials and sterile cartridges containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection vials and cartridges to confirm the correct product choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.2) ] . 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, fall in blood pressure or any other unexplained symptom 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: • Cardiovascular — Subacute bacterial endocarditis, severe hypertension. • Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. • Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia, and some vascular purpuras. • Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy — 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). • Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine. • Other — Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation.

ed Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection vials and cartridges. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing Heparin Sodium Injection cartridges in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Heparin Sodium Injection cartridges (Heparin Sodium Injection 5,000 USP units/1 mL single-dose cartridge contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations (8.4) ] . 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3) ] . 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage (10) ] . Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2) ]. 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. Because Heparin Sodium Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. Because Heparin Sodium Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy. 5.9 Hyperkalemia Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin. Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [see Warnings and Precautions (5.2) ] • Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions (5.3) ] • Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.4) ] • Thrombocytopenia [see Warnings and Precautions (5.5) ] • Heparin Resistance [see Warnings and Precautions (5.7) ] • Hypersensitivity [see Warnings and Precautions (5.8) ] • Hyperkalemia [see Warnings and Precautions (5.9) ] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITT, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.2 ) 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 . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Heparin Sodium Injection. 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 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 heparin therapy. • Retroperitoneal hemorrhage. • HIT and HITT, including delayed onset cases [see Warnings and Precautions (5.3) ]. • Local irritation - Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. • 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 [see Warnings and Precautions (5.3) ] . • 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur [see Warnings and Precautions (5.8) ] . • Elevations of aminotransferases - Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. • Miscellaneous - 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. • Metabolism and nutrition disorders - Hyperkalemia.

7 DRUG INTERACTIONS Drugs that interfere with platelet aggregation: May induce bleeding. ( 7.2 ) 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 salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, 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 antiplatelet agent or heparin is recommended. 7.3 Other Interactions 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).

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Preservative-free formulation recommended. Limited human data in pregnant women ( 8.1 ) • Lactation: Advise females not to breastfeed ( 8.2 ) • Pediatric Use: Use preservative-free formulation in neonates and infants ( 8.4 ) • Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age ( 8.5 ) 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day [see Data ] . Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Warnings and Precautions (5.4) ] . The 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 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 If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. There is no information regarding the presence of Heparin Sodium 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 Injection and any potential adverse effects on the breastfed infant from Heparin Sodium Injection or from the underlying maternal condition [see Use in Specific Populations (8.4) ] .

ant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Heparin Sodium Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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) ] . Carefully examine all Heparin Sodium Injection vials and cartridges to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions (5.1) ] . Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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, particularly women, over 60 years of age [see Warnings and Precautions (5.2) ] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day [see Data ] . Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Warnings and Precautions (5.4) ] . The 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 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.

8.4 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) ] . Carefully examine all Heparin Sodium Injection vials and cartridges to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions (5.1) ] . Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

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, particularly women, over 60 years of age [see Warnings and Precautions (5.2) ] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology (12.3) ] .

11 DESCRIPTION Heparin 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. Structural formula of heparin sodium (representative subunits): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Carpuject™ sterile cartridge unit contain a sterile solution of Heparin Sodium Injection, USP. Heparin Sodium Injection 5,000 USP units/1 mL, single-dose cartridge, preserved with benzyl alcohol Each mL contains 5,000 USP units of heparin sodium and benzyl alcohol 1% as a preservative, in Water for Injection. The pH is adjusted between 5.0 to 7.5 with hydrochloric acid or sodium hydroxide. Heparin Sodium Injection 5,000 USP units/0.5 mL, single-dose cartridge, preservative-free Each 0.5 mL of preservative-free Heparin Sodium Injection contains 5,000 USP units in Water for Injection. The pH is adjusted between 5.0 to 7.5 with hydrochloric acid or sodium hydroxide as required. Chemical Structure

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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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. The 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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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.

12.3 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) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection is supplied in the following strengths and package configurations: Unit of Sale Concentration (per total volume) NDC 55154-2380-5 5,000 USP units/0.5 mL Preservative-free Overbagged with 5 x 0.5 mL fill in 2.5 mL Carpuject™ Single-dose cartridge with Luer Lock for the Carpuject™ Syringe System in each bag WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Do not freeze. Discard unused portion after initial use.

<table width="75%"><col width="46%"/><col width="39%"/><thead><tr><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Unit of Sale</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Concentration</content> <content styleCode="bold">(per total volume)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC 55154-2380-5</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"><paragraph>5,000 USP units/0.5 mL</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Preservative-free</content></content></paragraph></td><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Overbagged with 5 x 0.5 mL fill in 2.5 mL Carpuject&#x2122; Single-dose cartridge with Luer Lock for the Carpuject&#x2122; Syringe System in each bag</paragraph></td><td styleCode="Rrule Botrule " valign="top"/></tr></tbody></table>

Carpuject™ Single-dose cartridges with Luer Lock are packaged in a Slim-Pak™ tamper detection package. Note that a needle is not included. Instructions for Use of the Syringe Systems • Instructions for using the Carpuject™ Syringe are available with the reusable Carpuject™ Holder, List 2049-02. • Carpuject™ Single-dose cartridges are to be used ONLY with Carpuject™ Holders, List 2049-02. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . For medical information about Heparin Sodium Injection, please visit www.pfizermedinfo.com or call 1-800-438-1985. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Distributed By: Cardinal Health Dublin, OH 43017 L35626590424 LAB-0844-6.0 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 (5.2) ] . 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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions (5.8) , Adverse Reactions (6.2) ] . 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) ] .

DESCRIPTION Heparin 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. Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is to be administered by intravenous or deep subcutaneous routes. 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): Heparin Sodium Injection, USP (porcine), preserved with parabens, is available as follows: Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 9 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5). Each mL of the 5,000 units per mL preparation contains: 5,000 USP Heparin units (porcine); 5 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5). Each mL of the 10,000 units per mL preparation contains: 10,000 USP Heparin units (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5). Each mL of the 20,000 units per mL preparation contains: 20,000 USP Heparin units (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5). STRUCTURE

CLINICAL PHARMACOLOGY 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. 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. Peak plasma levels of heparin are achieved two to four 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 (t1⁄2 = 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. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

INDICATIONS & USAGE Heparin Sodium Injection, USP is indicated for: Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension; Low-dose regimen for prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease (see DOSAGE AND ADMINISTRATION) ; Prophylaxis and treatment of pulmonary embolism; Atrial fibrillation with embolization; Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and cardiac surgery; Prophylaxis and treatment of peripheral arterial embolism. Heparin may also be employed as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures.

CONTRAINDCATIONS Heparin sodium should NOT be used in patients with the following conditions: Severe thrombocytopenia; When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); An uncontrollable active bleeding state (see WARNINGS ), except when this is due to disseminated intravascular coagulation.

WARNINGS Heparin is not intended for intramuscular use. Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of the drug. Benzyl Alcohol Toxicity Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity (see PRECAUTIONS , Pediatric Use). Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations (see ADVERSE REACTIONS , Hypersensitivity). Hemorrhage Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Heparin sodium should be used with extreme caution in disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: Cardiovascular—Subacute bacterial endocarditis, severe hypertension. Surgical—During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic—Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Gastrointestinal—Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other—Menstruation, liver disease with impaired hemostasis. Coagulation Testing When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be promptly discontinued (see OVERDOSAGE ). Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered. Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets.

uct should be discontinued, and, if necessary, an alternative anticoagulant administered. Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) Heparin-induced Thrombocytopenia (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 referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered, if patients require continued anticoagulation. Delayed Onset of HIT and HITT Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis 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 and HITT.

PRECAUTIONS General Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) See WARNINGS. Heparin Resistance Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. Increased Risk to Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. 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 (see DOSAGE AND ADMINISTRATION ). Drug Interactions 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 five 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. 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. Other Interactions 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. Drug/Laboratory Test Interactions Hyperaminotransferasemia Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases that might be caused by drugs (like heparin) should be interpreted with caution. 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. Pregnancy Pregnancy Category C There are no adequate and well-controlled studies on heparin use in pregnant women. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. Heparin sodium does not cross the placenta, based on human and animal studies. Administration of heparin to pregnant animals at doses higher than the maximum human daily dose based on body weight resulted in increased resorptions. Use heparin sodium during pregnancy only if the potential benefit justifies the potential risk to the fetus. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy.

than the maximum human daily dose based on body weight resulted in increased resorptions. Use heparin sodium during pregnancy only if the potential benefit justifies the potential risk to the fetus. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants (see PRECAUTIONS , Pediatric Use). 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. Nursing Mothers If available, preservative-free HEPARIN SODIUM INJECTION is recommended when heparin therapy is needed during lactation. 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. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Exercise caution when administering HEPARIN SODIUM INJECTION to a nursing mother (see PRECAUTIONS , Pediatric Use). 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 , Pediatric Use). Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which HEPARIN SODIUM INJECTION vials have been confused with “catheter lock flush” vials (see WARNINGS , Fatal Medication Errors). Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS , General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS Hemorrhage Hemorrhage is the chief complication that may result from heparin therapy (see WARNINGS ). An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (see OVERDOSAGE ). It should be appreciated that 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: (a) Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient’s death. (b) Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, may be fatal. (c) Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT See WARNINGS. Local Irritation Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. 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 side of the feet, may occur (see WARNINGS and PRECAUTIONS ). Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications, remains to be determined. Miscellaneous 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. Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin.

OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment 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. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. 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 labeling of Protamine Sulfate Injection, USP products.

DOSAGE & ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Confirm the choice of the correct Heparin Sodium Injection vial prior to administration of the drug to a patient (see WARNINGS , Fatal Medication Errors). The 1 mL vial must not be confused with a “catheter lock flush” vial or other 1 mL vial of inappropriate strength. Confirm that you have selected the correct medication and strength prior to administration of the drug. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site. The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every four hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn four to six hours after the injection. 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. Converting to Oral Anticoagulant When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time. In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering. Therapeutic Anticoagulant Effect with Full-Dose Heparin Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Pediatric Use Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants (see WARNINGS , Benzyl Alcohol Toxicity and PRECAUTIONS , Pediatric Use).

sage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Pediatric Use Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants (see WARNINGS , Benzyl Alcohol Toxicity and PRECAUTIONS , Pediatric Use). There are no adequate and well-controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70. Geriatric Use Patients over 60 years of age may require lower doses of heparin. Surgery of the Heart and Blood Vessels Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. Low-Dose Prophylaxis of Postoperative Thromboembolism A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS ). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters. Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. Blood Transfusion Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation.

no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters. Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. Blood Transfusion Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood. Laboratory Samples Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts. DOSAGE

HOW SUPPLIED HEPARIN SODIUM INJECTION, USP is supplied in the following dosage forms. NDC 51662-1434-1 HEPARIN SODIUM INJECTION, USP 10,000 USP UNITS/mL 1mL VIAL HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Heparin Sodium Injection, USP (porcine) contains parabens and is available as follows: Sterile, Nonpyrogenic Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made from natural rubber latex. STORAGE Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] HOW SUPPLIED

REFERENCES Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg. 1992;40(3):110-111. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215. Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin-Induced Thrombosis.” Chest 98(1524-26). Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency Medicine, 2005;45(4):417-419. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post-Angiography Pulmonary Embolism. Blood. 2003;102(11):127b. Code: TS/DRUGS/13/2010 Manufactured by: Aurobindo Pharma Limited IDA, Pashamylaram – 502307, TS., India. Distributed by: McKesson Corporation dba SKY Packaging 4971 Southridge Blvd, Suite 101 Memphis, TN 38141 Toll Free: 1-888-243-4363 Revised: July 2018

1 INDICATIONS & USAGE Heparin sodium injection is indicated for: • Prophylaxis and treatment of venous thrombosis and pulmonary embolism; • Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease; • Atrial fibrillation with embolization; • Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); • Prevention of clotting in arterial and cardiac surgery; • Prophylaxis and treatment of peripheral arterial embolism. • Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures. Heparin sodium injection is an anticoagulant indicated for ( 1 ) • Prophylaxis and treatment of venous thrombosis and pulmonary embolism • Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease • Atrial fibrillation with embolization • Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) • Prevention of clotting in arterial and cardiac surgery • Prophylaxis and treatment of peripheral arterial embolism • Use as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures

2 DOSAGE & ADMINISTRATION Recommended Adult Dosages: • Therapeutic Anticoagulant Effect with Full-Dose Heparin† ( 2.3 ) Deep Subcutaneous (Intrafat) Injection Use a different site for each injection Initial Dose 5,000 units by intravenous injection followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 ml of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion † Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. 2.1 Preparation for Administration Confirm the choice of the correct heparin sodium injection vial to ensure that the 1 mL vial is not confused with a “catheter lock flush” vial or other 1 mL vial of incorrect strength [see Warnings and Precautions ( 5.1 )] . Confirm the selection of the correct formulation and strength prior to administration of the drug. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Administer heparin sodium injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site [see Adverse Reactions ( 6.1 )] . 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of heparin sodium injection according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with heparin sodium injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience.

urs after the injection. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE Deep Subcutaneous (Intrafat) Injection Use a different site for each injection to prevent the development of hematoma Initial Dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or 8,000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Continuous Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion *Based on 68 kg patient 2.4 Pediatric Dosing Use preservative-free heparin sodium injection in neonates and infants. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Recommended Pediatric Use Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.7 Converting to Warfarin To ensure continuous anticoagulation when converting from heparin sodium injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )] .

to Warfarin To ensure continuous anticoagulation when converting from heparin sodium injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )] . 2.8 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.9 Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

3 DOSAGE FORMS & STRENGTHS Heparin Sodium Injection, USP, preservative free , is available as follows: • 5,000 USP units per 0.5 mL, single-dose vial Heparin Sodium Injection, USP (porcine), preservative free • 0.5 mL single-dose vial contains 5,000 USP units

4 CONTRAINDICATIONS The use of heparin sodium injection is contraindicated in patients with the following conditions: • History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions ( 5.3 )] ; • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions ( 6.1 )] ; • In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); • An uncontrolled active bleeding state [see Warnings and Precautions ( 5.2 )] , except when this is due to disseminated intravascular coagulation. • History of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITTS) ( 4 ) • Known hypersensitivity to heparin or pork products ( 4 ) • In whom suitable blood coagulation tests cannot be performed at appropriate intervals ( 4 ) • An uncontrolled bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS • Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) • Hemorrhage: Hemorrhage, including fatal events, has occurred in patients receiving heparin. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) • HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS ( 5.3 ) • Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Periodically monitor platelet count, hematocrit, and occult blood in stool in all patients receiving heparin ( 5.5 , 5.6 ) • Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients. ( 5.9 ) 5.1 Fatal Medication Errors Do not use heparin sodium injection as a “catheter lock flush” product. Heparin sodium injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL heparin sodium injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all heparin sodium injection vials to confirm the correct vial choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. 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, fall in blood pressure or any other unexplained symptom 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: • Cardiovascular -Subacute bacterial endocarditis, severe hypertension. • Surgical -During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. • Hematologic -Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. • Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy -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, reduce the heparin dose during concomitant treatment with antithrombin III (human). • Gastrointestinal -Ulcerative lesions and continuous tube drainage of the stomach or small intestine. • Other -Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation.

ed Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions ( 5.3 )] . 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage ( 10 )] . Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration ( 2.2 )] . 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity 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 injection is derived from animal tissue, it should be used with caution in patients with a history of allergy. 5.9 Hyperkalemia Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin. Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [see Warnings and Precautions ( 5.2 )] • Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions ( 5.3 )] • Thrombocytopenia [see Warnings and Precautions ( 5.5 )] • Heparin Resistance [see Warnings and Precautions ( 5.7 )] • Hypersensitivity [see Warnings and Precautions ( 5.8 )] • Hyperkalemia [see Warnings and Precautions ( 5.9 )] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BE Pharmaceuticals Inc. at 1-877-648-9517 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 injection. 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 ( 5.2 )] . 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 including: • 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 heparin therapy. • Retroperitoneal hemorrhage • HIT and HITT, including delayed onset cases [see Warnings and Precautions ( 5.3 )] . • Local Irritation – Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. • 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 [see Warnings and Precautions ( 5.3 )] . • 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur. [see Warnings and Precautions ( 5.8 )] • Elevations of 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. • Metabolism and Nutrition Disorders – Hyperkalemia.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Preservative-free formulation recommended. ( 8.1 ) • Lactation: Preservative-free formulation recommended. ( 8.2 ) • Pediatric Use: Use preservative-free formulation in neonates and infants. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no available data on heparin sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day (see Data) . Consider the benefits and risks of heparin sodium injection for the mother and possible risks to the fetus when prescribing heparin sodium injection to a pregnant woman. If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 to 4% and 15 to 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 If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during lactation. There is no information regarding the presence of heparin sodium 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 breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for heparin sodium injection and any potential adverse effects on the breastfed infant from heparin sodium 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 )] . Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug.

re 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 )] . Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin sodium injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions ( 5.1 )] . 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary There are no available data on heparin sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day (see Data) . Consider the benefits and risks of heparin sodium injection for the mother and possible risks to the fetus when prescribing heparin sodium injection to a pregnant woman. If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 to 4% and 15 to 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.

8.4 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 )] . Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin sodium injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions ( 5.1 )] .

11 DESCRIPTION Heparin 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) ß-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. Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is to be administered by intravenous or deep subcutaneous routes. 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): Heparin Sodium Injection, USP (porcine), preservative free, is available as follows: Each 0.5 mL of the 5,000 units per 0.5 mL preparation contains: 5,000 USP Heparin units (porcine); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). hepstr

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.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection, USP (porcine), preservative free , is available as follows: Unit of Sale Strength Each NDC 71839-118-25 Unit of 25 5,000 USP units per 0.5 mL NDC 71839-118-01 0.5 mL fill in a 2 mL single-dose, flip-top vial Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made with natural rubber latex. Discard unused portion STORAGE: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="25%"/><col width="34%"/><col width="40%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom"><content styleCode="bold">Unit of Sale </content> </td><td styleCode="Rrule" valign="bottom"><content styleCode="bold">Strength </content> </td><td styleCode="Rrule" valign="bottom"><content styleCode="bold">Each </content> </td></tr><tr><td styleCode="Lrule Rrule" valign="top">NDC 71839-118-25 Unit of 25 </td><td styleCode="Rrule" valign="top">5,000 USP units per 0.5 mL </td><td styleCode="Rrule" valign="top">NDC 71839-118-01 0.5 mL fill in a 2 mL single-dose, flip-top vial </td></tr></tbody></table>

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions ( 5.8 ), 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 ( 7.1 )] . Distributed by: 20003992 BE Pharmaceuticals Inc. 203 New Edition Court Cary, NC 27511 Manufactured by: Biological E. Limited Plot No. 4, Survey no. 542/P, Biotech Park Phase-II, Kolthur Village, Shameerpet Mandal, Medchal, Telangana 500078, India. heparinlogo

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use HEPARIN SODIUM INJECTION safely and effectively. See full prescribing information for HEPARIN SODIUM INJECTION. HEPARIN SODIUM INJECTION, USP for intravenous or subcutaneous use Initial U.S. Approval: 2009 INDICATIONS AND USAGE Heparin Sodium Injection, USP is an anticoagulant indicated for ( 1 ) Prophylaxis and treatment of venous thrombosis and pulmonary embolism Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease Atrial fibrillation with embolization Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) Prevention of clotting in arterial and cardiac surgery Prophylaxis and treatment of peripheral arterial embolism Use as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures DOSAGE AND ADMINISTRATION Recommended Adult Dosages: Therapeutic Anticoagulant Effect with Full-Dose Heparin† ( 2- 2.3) DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS Severe thrombocytopenia ( 4 ) Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) ( 4 ) When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals ( 4 ) An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation ( 4 ) WARNINGS AND PRECAUTIONS Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5- 5.1) Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5- 5.2) HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS 5- (5.3) Benzyl Alcohol Toxicity: Do not use this product in neonates and infants ( 5- 5.4) Monitoring: Blood coagulation tests guide therapy for full-dose heparin ( 5- 5.6) Monitor platelet count and hematocrit in all patients receiving heparin ( 5- 5.5, 5- 5.6) ADVERSE REACTIONS Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6- 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or https://www.fda.gov/medwatch. DRUG INTERACTIONS Drugs that interfere with platelet aggregation: May induce bleeding ( 7- 7.2) USE IN SPECIFIC POPULATIONS Pregnancy: Preservative-free formulation recommended. Limited human data in pregnant women. ( 8- 8.1) Lactation: Advise females not to breastfeed. ( 8- 8.2) Pediatric Use: Use preservative-free formulation in neonates and infants. ( 8- 8.4) Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. ( 8- 8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2017 HIGHLIGHT 1 HIGHLIGHT 2

les not to breastfeed. ( 8- 8.2) Pediatric Use: Use preservative-free formulation in neonates and infants. ( 8- 8.4) Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. ( 8- 8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2017 HIGHLIGHT 1 HIGHLIGHT 2 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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions (5.8), Adverse Reactions (6.2)]. 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)]. SPL UNCLASSIFIED Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1193-1.0 LOGO

TABLE OF CONTENTS FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration 2.2 Laboratory Monitoring for Efficacy and Safety 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin 2.4 Pediatric Use 2.5 Cardiovascular Surgery 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism 2.7 Blood Transfusion 2.8 Converting to Warfarin 2.9 Converting to Oral Anticoagulants other than Warfarin 2.10 Extracorporeal Dialysis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Fatal Medication Errors 5.2 Hemorrhage 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative 5.5 Thrombocytopenia 5.6 Coagulation Testing and Monitoring 5.7 Heparin Resistance 5.8 Hypersensitivity 6 ADVERSE REACTIONS 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Oral Anticoagulants 7.2 Platelet Inhibitors 7.3 Other Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION PRINCIPAL DISPLAY PANEL - 50,000 USP Units/10 mL Vial Label PRINCIPAL DISPLAY PANEL - 50,000 USP Units/10 mL Vial Tray * Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS & USAGE Heparin Sodium Injection, USP is indicated for: Prophylaxis and treatment of venous thrombosis and pulmonary embolism; Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease; Atrial fibrillation with embolization; Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and cardiac surgery; Prophylaxis and treatment of peripheral arterial embolism; Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures.

2 DOSAGE & ADMINISTRATION 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection, USP vial to ensure that the 1 mL vial is not confused with a "catheter lock flush" vial or other 1 mL vial of incorrect strength [see Warnings and Precautions (5.1)]. Confirm the selection of the correct formulation and strength prior to administration of the drug. To lessen this risk, the 1 mL vial includes a red cautionary label that extends above the main label. Read the cautionary statement and confirm that you have selected the correct medication and strength. Then locate the "Tear Here" point on the label, and remove this red cautionary label prior to removing the flip-off cap. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection, USP by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection, USP by intramuscular injection because of the risk of hematoma at the injection site [see Adverse Reactions (6)]. 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection, USP according to the patient's coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection, USP by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect 2.4 Pediatric Use Do not use this product in neonates and infants. Use preservative-free Heparin Sodium Injection, USP in neonates and infants [see Warnings and Precautions (5.4)]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience.

se Do not use this product in neonates and infants. Use preservative-free Heparin Sodium Injection, USP in neonates and infants [see Warnings and Precautions (5.4)]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.7 Blood Transfusion Add 450 to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood. 2.8 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection, USP to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1)]. 2.9 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.10 Extracorporeal Dialysis Follow equipment manufacturers' operating directions carefully. A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers' recommendations are not available. DOSAGE 1 DOSAGE 2

3 DOSAGE FORMS & STRENGTHS Heparin Sodium Injection, USP is available as: Injection: 1,000 USP units/mL preserved with benzyl alcohol clear solution in 1 mL single-dose and 10 mL, 30 mL multiple-dose vials Injection: 5,000 USP units/mL preserved with benzyl alcohol clear solution in 1 mL single-dose and 10 mL multiple-dose vials Injection: 10,000 USP units/mL preserved with benzyl alcohol clear solution in 1 mL single-dose vial

4 CONTRAINDICATIONS The use of Heparin Sodium Injection is contraindicated in patients with the following conditions: History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions (5.3)]; Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.2)]; In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); An uncontrolled active bleeding state [see Warnings and Precautions (5.4)], except when this is due to disseminated intravascular coagulation.

5 WARNINGS AND PRECAUTIONS 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a "catheter lock flush" product. Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL "catheter lock flush" vials. Carefully examine all Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.2)]. 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, fall in blood pressure or any other unexplained symptom 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: Cardiovascular — Subacute bacterial endocarditis, severe hypertension. Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other — Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant.

, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection multiple-dose vials. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing Heparin Sodium Injection multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Heparin Sodium Injection multiple-dose vials (contains 10.42 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations (8.4)]. 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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 HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3)]. 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage (10)]. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2)]. 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. Because Heparin Sodium Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions (5.2)] Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions (5.3)] Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.4)] Thrombocytopenia [see Warnings and Precautions (5.5)] Heparin Resistance [see Warnings and Precautions (5.7)] Hypersensitivity [see Warnings and Precautions (5.8)] 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Heparin Sodium Injection. 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 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 heparin therapy. Retroperitoneal hemorrhage. HIT and HITT, including delayed onset cases [see Warnings and Precautions (5.3)]. Local irritation-Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. 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 [see Warnings and Precautions (5.3)]. 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur [see Warnings and Precautions (5.8)]. Elevations of aminotransferases-Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin . Miscellaneous-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.

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 NSAIDS (including salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, 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 antiplatelet agent or heparin is recommended. 7.3 Other Interactions 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).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day [see Data]. Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Warnings and Precautions (5.4)]. The 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 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 If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. There is no information regarding the presence of Heparin Sodium 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 Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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)]. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug.

e 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)]. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection, USP vials have been confused with "catheter lock flush" vials [see Warnings and Precautions (5.1)]. Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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, particularly women, over 60 years of age [see Warnings and Precautions (5.2)]. Patients over 60 years of age may require lower doses of heparin. 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 the heparin effect, 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 with protamine, it should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection.

11 DESCRIPTION Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans possessing 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. Structure of Heparin Sodium (representative subunits): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Heparin Sodium Injection, USP is available in the following concentrations/mL: pH 5.0–7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. STRUCTURE DESCRIPTION

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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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. The 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)].

16 HOW SUPPLIED/STORAGE AND HANDELING (derived from porcine intestinal mucosa) HEPARIN SODIUM INJECTION, USP is supplied in the following dosage forms. NDC 51662-1486-1 HEPARIN SODIUM INJECTION, USP 10,000 USP UNITS/mL 1mL VIAL HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]. how supplied

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium Injection, USP, preservative free , is available as follows: 2,000 USP units per 2 mL, single-dose vial Heparin Sodium Injection, USP (porcine), preservative free: 2 mL single-dose vial contains 2,000 USP units

ed Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including heparin sodium injection multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing heparin sodium injection multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including heparin sodium injection multiple-dose vials and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations ( 8.4 )] . 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions ( 5.3 )] . 5.6 Coagulation Testing and Monitoring When using a full dose heparin sodium regimen, adjust the heparin sodium dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin sodium promptly [see Overdosage ( 10 )] . Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration ( 2.2 )] . 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity 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 Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.2 )] Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions ( 5.3 )] Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions ( 5.4 )] Thrombocytopenia [see Warnings and Precautions ( 5.5 )] Heparin Resistance [see Warnings and Precautions ( 5.7 )] Hypersensitivity [see Warnings and Precautions ( 5.8 )] Hyperkalemia [see Warnings and Precautions ( 5.9 )] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 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 Injection. 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 ( 5.2 )] . 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 including: o Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases. o Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term heparin therapy. o Retroperitoneal hemorrhage HIT and HITT, including delayed onset cases [see Warnings and Precautions ( 5.3 )] . Local Irritation – Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. 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 [see Warnings and Precautions ( 5.3 )] . 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur. [see Warnings and Precautions ( 5.8 )] Elevations of 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. Metabolism and Nutrition Disorders – Hyperkalemia.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Preservative-free formulation recommended. ( 8.1 ) Lactation: Preservative-free formulation recommended. ( 8.2 ) Pediatric Use: Use preservative-free formulation in neonates and infants. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no available data on heparin sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day ( see Data ). Consider the benefits and risks of heparin sodium for the mother and possible risks to the fetus when prescribing heparin sodium injection to a pregnant woman. If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Use in Specific Populations ( 8.4 )] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 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 If available, preservative-free heparin sodium injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a breastfed infant. There is no information regarding the presence of heparin sodium 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 breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for heparin sodium and any potential adverse effects on the breastfed infant from heparin sodium 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.

with the mother's clinical need for heparin sodium and any potential adverse effects on the breastfed infant from heparin sodium 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 )] . Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin sodium injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions ( 5.1 )]. Benzyl Alcohol Toxicity Use preservative-free heparin sodium injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology ( 12.3 )] .

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 )] . Carefully examine all heparin sodium injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin sodium injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions ( 5.1 )]. Benzyl Alcohol Toxicity Use preservative-free heparin sodium injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

11 DESCRIPTION Heparin 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) ß-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. Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is to be administered by intravenous or deep subcutaneous routes. 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): Heparin Sodium Injection, USP (porcine), preservative free, is available as follows: Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 9 mg sodium chloride; Water for Injection q.s. made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Structure

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection, USP (porcine), preservative free , is available as follows: NDC Heparin Sodium Injection, USP (1,000 USP units per mL) Package Factor 72603- 336 -25 2,000 USP units per 2 mL Single-Dose Vial 25 vials per carton Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. Discard unused portion. STORAGE: Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

<table width="100%" styleCode="Noautorules"><colgroup><col width="24.033%" align="left"/><col width="55.967%" align="left"/><col width="20.000%" align="left"/></colgroup><tbody><tr><td align="justify" valign="top"><content styleCode="bold">NDC</content></td><td align="justify" valign="top"><content styleCode="bold">Heparin Sodium Injection, USP (1,000 USP units per mL)</content></td><td align="justify" valign="top"><content styleCode="bold">Package Factor</content></td></tr><tr><td align="justify" valign="top">72603-<content styleCode="bold">336</content>-25</td><td align="justify" valign="top">2,000 USP units per 2 mL Single-Dose Vial</td><td align="justify" valign="top">25 vials per carton</td></tr></tbody></table>

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions ( 5.8 ), 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 ( 7.1 )] . Manufactured for Northstar Rx LLC, Memphis, TN 38141. Manufactured by Nanjing King-Friend Biochemical Pharmaceutical Co., Ltd. Nanjing, China 210061 Revised: March 2025 8A6ECN9-01

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: Therapeutic Anticoagulant Effect with Full-Dose Heparin † ( 2.4 ) Deep Subcutaneous (Intrafat) Injection Use a different site for each injection Initial Dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion † Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial to ensure that the 1 mL vial is not confused with a “catheter lock flush” vial or other 1 mL vial of incorrect strength [s ee Warnings and Precautions (5.1) ] . Confirm the selection of the correct formulation and strength prior to administration of the drug. To lessen this risk, the 1 mL vial includes a red cautionary label that extends above the main label. Read the cautionary statement and confirm that you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this red cautionary label prior to removing the flip-off cap. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [ see Adverse Reactions (6) ]. 2.3 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection.

inistered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.4 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE [based on 150 lb (68 kg) patient] Deep Subcutaneous (Intrafat) Injection Initial dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or 8,000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.5 Pediatric Use Do not use benzyl alcohol-preserved drugs in neonates and infants. Use preservative-free Heparin Sodium Injection in neonates and infants [ see Warnings and Precautions (5.4) ]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (Intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.6 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.7 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.8 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation.

Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.8 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.9 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1) ] . 2.10 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.11 Extracorporeal Dialysis Follow equipment manufacturer's operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

en administered. 2.11 Extracorporeal Dialysis Follow equipment manufacturer's operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available. 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial to ensure that the 1 mL vial is not confused with a “catheter lock flush” vial or other 1 mL vial of incorrect strength [s ee Warnings and Precautions (5.1) ] . Confirm the selection of the correct formulation and strength prior to administration of the drug. To lessen this risk, the 1 mL vial includes a red cautionary label that extends above the main label. Read the cautionary statement and confirm that you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this red cautionary label prior to removing the flip-off cap. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [ see Adverse Reactions (6) ].

Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [ see Adverse Reactions (6) ]. 2.3 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration.

opriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.4 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE [based on 150 lb (68 kg) patient] Deep Subcutaneous (Intrafat) Injection Initial dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or 8,000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.5 Pediatric Use Do not use benzyl alcohol-preserved drugs in neonates and infants. Use preservative-free Heparin Sodium Injection in neonates and infants [ see Warnings and Precautions (5.4) ]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (Intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.6 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.7 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma.

gery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.8 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.9 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1) ] . 2.10 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.11 Extracorporeal Dialysis Follow equipment manufacturer's operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium Injection, USP preserved with benzyl alcohol is available as follows: 1,000 USP units/mL single-dose vials 5,000 USP units/mL single-dose vials Injection (preserved with Benzyl Alcohol) Single-dose Vials 1,000 USP units per mL 5,000 USP units per mL

4 CONTRAINDICATIONS The use of Heparin Sodium Injection is contraindicated in patients with the following conditions: History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions (5.3) ] ; Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.1) ] ; In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); An uncontrolled active bleeding state [ see Warnings and Precautions (5.2) ], except when this is due to disseminated intravascular coagulation. Severe thrombocytopenia ( 4 ) When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals ( 4 ) An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS ( 5.3 ) Benzyl Alcohol Toxicity: Do not use benzyl alcohol-preserved drugs in neonates and infants. ( 5.4 ) Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Monitor platelet count and hematocrit in all patients receiving heparin ( 5.5 , 5.6 ) 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. 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, fall in blood pressure or any other unexplained symptom 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: Cardiovascular - Subacute bacterial endocarditis, severe hypertension. Surgical - During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic - Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy - 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other - Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT.

pment of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing Heparin Sodium Injection vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Heparin Sodium Injection vials (contains 10.42 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations (8.4) ] . 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3) ]. 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [ see Overdosage (10) ]. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [ see Dosage and Administration (2) ]. 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. Because Heparin Sodium Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [ see Warnings and Precautions (5.2) ] Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [ see Warnings and Precautions (5.3) ] Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [ see Warnings and Precautions (5.4) ] Thrombocytopenia [ see Warnings and Precautions (5.5) ] Heparin Resistance [ see Warnings and Precautions (5.7) ] Hypersensitivity [ see Warnings and Precautions (5.8) ] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 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 Injection. 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 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 heparin therapy. Retroperitoneal hemorrhage HIT and HITT, including delayed onset cases [ see Warnings and Precautions (5.3) ]. Local Irritation – Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. 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 [ see Warnings and Precautions (5.3) ]. 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur [ see Warnings and Precautions (5.8) ]. Elevations of aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Miscellaneous - 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.

7 DRUG INTERACTIONS Drugs that interfere with platelet aggregation: May induce bleeding ( 7.2 ) 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 salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, 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 antiplatelet agent or heparin is recommended. 7.3 Other Interactions 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).

8 USE IN SPECIFIC POPULATIONS Pregnancy: Preservative-free formulation recommended. Limited human data in pregnant women. ( 8.1 ) Lactation: Advise females not to breastfeed. ( 8.2 ) Pediatric Use: Use preservative-free formulation in neonates and infants. ( 8.4 ) Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. ( 8.5 ) 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day [ see Data ]. Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [ see Warnings and Precautions (5.4) ] The 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 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 If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. There is no information regarding the presence of Heparin Sodium 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 Injection and any potential adverse effects on the breastfed infant from Heparin Sodium Injection or from the underlying maternal condition [ see Use in Specific Populations (8.4) ].

ant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Heparin Sodium Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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 (2.5) ]. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [ see Warnings and Precautions (5.1) ]. Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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, particularly women, over 60 years of age [ see Warnings and Precautions (5.2) ]. Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [ see Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day [ see Data ]. Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [ see Warnings and Precautions (5.4) ] The 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 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 If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. There is no information regarding the presence of Heparin Sodium 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 Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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 (2.5) ]. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [ see Warnings and Precautions (5.1) ]. Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

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, particularly women, over 60 years of age [ see Warnings and Precautions (5.2) ]. Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [ see Clinical Pharmacology (12.3) ].

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): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Heparin Sodium Injection, USP preserved with Benzyl Alcohol is available in the following concentrations/mL: Heparin Sodium Sodium Chloride Benzyl Alcohol 1,000 USP units 8.6 mg 10.42 mg 5,000 USP units 7 mg 10.42 mg pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. chemical structure

<table><col/><col/><col/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule">Heparin Sodium</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">Sodium Chloride</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">Benzyl Alcohol</td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule">1,000 USP units</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">8.6 mg</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">10.42 mg</td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule">5,000 USP units</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">7 mg</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">10.42 mg</td></tr></tbody></table>

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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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. The 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) ].

12.3 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) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection preserved with benzyl alcohol is available in the following strengths and package sizes in single-dose vials: DESCRIPTION NDC 1,000 USP units/mL 1 vial: 1,000 USP units/mL, single-dose* 72572-250-01 25 vials: 1,000 USP units/mL, single-dose* 72572-250-25 5,000 USP units/mL 1 vial: 5,000 USP units/mL, single-dose* 72572-255-01 25 vials: 5,000 USP units/mL, single-dose* 72572-255-25 *Discard unused portion Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature].

<table><col/><col/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">DESCRIPTION</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">NDC</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">1,000 USP units/mL</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> 1 vial: 1,000 USP units/mL, single-dose*</td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>72572-250-01</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph> 25 vials: 1,000 USP units/mL, single-dose*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>72572-250-25</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">5,000 USP units/mL</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> 1 vial: 5,000 USP units/mL, single-dose* </td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>72572-255-01</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph> 25 vials: 5,000 USP units/mL, single-dose*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>72572-255-25</paragraph></td></tr></tbody></table>

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [ see Warnings and Precautions (5.8) , 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 (7.1) ]. Distributed by: Civica, Inc. Lehi, Utah 84048 Manufactured by: Hikma Pharmaceuticals USA Inc. Cherry Hill, New Jersey 08003 Revised July 2025 462-807-01

Warnings and Precautions, Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia with Thrombosis ( 5.2) 11/2024 Warnings and Precautions, Unresponsiveness to Heparin with Concomitant Use with Andexanet Alfa ( 5.3 ) 11/2025 Warnings and Precautions, Heparin Resistance ( 5.5 ) 11/2024 Warnings and Precautions, Hypersensitivity Reactions ( 5.6 ) 11/2024 Warnings and Precautions, Elevations of Serum Aminotransferases ( 5.9 ) 11/2024

<table styleCode="Noautorules" width="100%"><col width="77%"/><col width="23%"/><tbody><tr><td valign="top"><paragraph>Warnings and Precautions, Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia with Thrombosis (<linkHtml href="#S5.2">5.2)</linkHtml></paragraph></td><td align="right" valign="top"><paragraph>11/2024</paragraph></td></tr><tr><td valign="top"><paragraph>Warnings and Precautions, Unresponsiveness to Heparin with Concomitant Use with Andexanet Alfa (<linkHtml href="#ID_71394f78-f2b7-4573-8cf0-e10f91014559">5.3</linkHtml>)</paragraph></td><td align="right" valign="top"><paragraph>11/2025</paragraph></td></tr><tr><td valign="top"><paragraph>Warnings and Precautions, Heparin Resistance (<linkHtml href="#S5.4">5.5</linkHtml>)</paragraph></td><td align="right" valign="top"><paragraph>11/2024</paragraph></td></tr><tr><td valign="top"><paragraph>Warnings and Precautions, Hypersensitivity Reactions (<linkHtml href="#S5.5">5.6</linkHtml>)</paragraph></td><td align="right" valign="top"><paragraph>11/2024</paragraph></td></tr><tr><td valign="top"><paragraph>Warnings and Precautions, Elevations of Serum Aminotransferases (<linkHtml href="#ID_7264bc42-1a0e-40b9-8e64-4e7a1c53ba48">5.9</linkHtml>)</paragraph></td><td align="right" valign="top"><paragraph>11/2024</paragraph></td></tr></tbody></table>

1 INDICATIONS AND USAGE Heparin Sodium in Sodium Chloride Injection 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 )

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.

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium in 0.9% Sodium Chloride Injection is available as: • Injection: 1,000 USP Units/500 mL (2 USP Units/mL) clear solution in a single-dose flexible plastic container • Injection: 2,000 USP Units/1,000 mL (2 USP Units/mL) clear solution in a single-dose flexible plastic container Heparin Sodium in 0.9% Sodium Chloride Injection is available as: ( 3 ) • Injection: 1,000 USP Units/500 mL (2 USP Units/mL) clear solution in a single-dose flexible plastic container. • Injection: 2,000 USP Units/1,000 mL (2 USP Units/mL) clear solution in a single-dose flexible plastic container.

4 CONTRAINDICATIONS The use of Heparin Sodium in Sodium Chloride Injection 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 (5.2 , 5.4) ] • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Warnings and Precautions (5.6) , 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 (HITT). ( 5.2 ) • Severe thrombocytopenia. ( 5.2 , 5.4 ) • Known hypersensitivity to heparin or pork products. ( 5.6 , 6.1 )

5 WARNINGS AND PRECAUTIONS • Hemorrhage: Fatal hemorrhages have occurred. Monitor for signs of bleeding and manage promptly. ( 5.1 ) • HIT and HITT: Monitor for signs and symptoms and discontinue if indicative of HIT or HITT. ( 5.2 ) • Thrombocytopenia: Monitor platelet count during therapy; discontinue heparin if HIT or HITT is suspected. ( 5.4 ) • Heparin Resistance: Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. ( 5.5 ) • Hypersensitivity Reactions: Use in patients with prior reactions only in life-threatening situations. ( 5.6 ) • Increased Risk of Bleeding in Older Patients, Especially Women: A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. ( 5.7 ) • Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients. ( 5.8 ) • Elevations of Serum Aminotransferases: Interpret elevation of these enzymes with caution. ( 5.9 ) • 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. ( 5.10 ) 5.1 Hemorrhage 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. Fatal hemorrhages have occurred. An unexplained fall in hematocrit or fall in blood pressure, or any other unexplained symptom 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: • Cardiovascular — Subacute bacterial endocarditis. Severe hypertension. • Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye. • Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. • Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine. • Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). • Other — Menstruation, liver disease with impaired hemostasis. 5.2 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia With Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious immune-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor-4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT.

pment of antibodies to a platelet Factor-4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, thrombus formation on a prosthetic cardiac valve, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Once HIT or HITT is diagnosed or strongly suspected, discontinue all heparin sources (including heparin flushes) and use an alternative anticoagulant. Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin, or platelet activation induced by heparin. Obtain platelet counts at baseline and periodically during heparin administration. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin in heparin–naive individuals and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin initiation), especially in patients with a recent exposure to heparin (i.e., previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.3 Unresponsiveness to Heparin with Concomitant Use With Andexanet Alfa Unresponsiveness to unfractionated heparin leading to non-prolongation of activated clotting times and serious thrombotic events has occurred when unfractionated heparin was administered after use of andexanet alfa for the reversal of direct Factor Xa inhibitors (apixaban and rivaroxaban). Avoid use of heparin after use of andexanet alfa. Use an alternative anticoagulant to heparin [see Drug Interactions (7.3) ] . 5.4 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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. If the count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.2) ]. 5.5 Heparin Resistance Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients , and patients with antithrombin deficiency . Consider measurement of antithrombin levels if heparin resistance is suspected. Monitor coagulation tests frequently in such patients. It may be necessary to adjust the dose of heparin based on coagulation test monitoring, such as anti-Factor Xa levels and/or partial thromboplastin time. 5.6 Hypersensitivity Reactions Hypersensitivity reactions with chills, fever, and urticaria as the most usual manifestations and also asthma, rhinitis, lacrimation, and anaphylactoid reactions have been reported.

rin based on coagulation test monitoring, such as anti-Factor Xa levels and/or partial thromboplastin time. 5.6 Hypersensitivity Reactions Hypersensitivity reactions with chills, fever, and urticaria as the most usual manifestations and also asthma, rhinitis, lacrimation, and anaphylactoid reactions have been reported. Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. Because Heparin Sodium in Sodium Chloride Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy to pork products. 5.7 Increased Risk of Bleeding in Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Use in Specific Populations (8.5) ] . 5.8 Hyperkalemia Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin. Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician. 5.9 Elevations of Serum Aminotransferases Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Elevation of these enzymes in patients receiving heparin should be interpreted with caution. These elevations typically resolve upon heparin discontinuation. 5.10 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.

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 (5.4) ] • Heparin Resistance [see Warnings and Precautions (5.5) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.6) ] • Increased Risk of Bleeding in Older Patients, Especially Women [see Warnings and Precautions (5.7) ] • Hyperkalemia [see Warnings and Precautions (5.8) ] • Elevations of Serum Aminotransferases [see Warnings and Precautions (5.9) ] Most common adverse reactions are: hemorrhage, thrombocytopenia, HIT and HITT, hypersensitivity reactions, heparin resistance, hyperkalemia, and elevations of aminotransferase levels. ( 6 ) 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. Vascular disorders – Contusion, vasospastic reactions (including episodes of painful, ischemic, and cyanosed limbs). 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 (5.6) ] . Musculoskeletal, connective tissue and bone disorders – Osteoporosis with long-term administration of heparin. Metabolism and nutrition disorders – Hyperkalemia. General disorders and administration site conditions – Erythema, mild pain, ulceration. Elevations of serum aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin.

nd nutrition disorders – Hyperkalemia. General disorders and administration site conditions – Erythema, mild pain, ulceration. Elevations of serum aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Others – Cutaneous necrosis after systemic administration, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported.

7 DRUG INTERACTIONS • Drugs that interfere with platelet aggregation or drugs that counteract coagulation may induce bleeding. ( 7 ) • Andexanet alfa may reduce the efficacy of heparin when used concomitantly. ( 7.3 ) 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 Unresponsiveness to Heparin with Concomitant Use With Andexanet Alfa Andexanet binds to heparin-bound antithrombin III (ATIII) and may reduce the anticoagulant effect of heparin. Unresponsiveness to unfractionated heparin may lead to serious and life-threatening thrombotic events. Use of andexanet alfa as an antidote for heparin has not been established. Avoid use of heparin after use of andexanet alfa for the reversal of direct Factor Xa inhibitors (apixaban and rivaroxaban). If anticoagulation is needed, use an alternative anticoagulant to heparin [see Warnings and Precautions (5.3) ] . 7.4 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).

8 USE IN SPECIFIC POPULATIONS Geriatric Use: A higher incidence of bleeding has been reported in patients over 60 years of age, especially women. ( 5.7 , 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 Data ) . 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 (5.7) ].

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 Data ) . 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.

10 OVERDOSAGE An overdose requires immediate medical attention and treatment. Symptoms Bleeding is the chief sign of heparin overdosage. Easy bruising, petechial formations, nosebleeds, blood in urine or tarry stools may be the first signs or symptoms of a heparin overdose. In the event of symptomatic heparin overdose, consider stopping heparin infusion. Treatment 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 30 minutes after intravenous injection. Ideally, the dose required to neutralize the action of heparin should be guided by blood coagulation tests or calculated from a protamine neutralization test. 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. Blood or plasma transfusions may be necessary; these dilute but do not neutralize heparin. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

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

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 macrophages) and b) slower first order elimination. Low doses of heparin are cleared mostly by a saturable, rapid, zero-order process. Slower first order elimination usually occurs with very high doses of heparin and is dependent on renal function. 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) ] . Patients with Renal and Hepatic Impairment The rate of clearance of unfractionated heparin may be decreased in patients with renal or hepatic impairment. Patients with renal or hepatic impairment, following similar doses of heparin may have higher plasma levels of heparin compared with patients with normal renal and hepatic function [see Warnings and Precautions (5.1) ] .

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 macrophages) and b) slower first order elimination. Low doses of heparin are cleared mostly by a saturable, rapid, zero-order process. Slower first order elimination usually occurs with very high doses of heparin and is dependent on renal function. 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) ] . Patients with Renal and Hepatic Impairment The rate of clearance of unfractionated heparin may be decreased in patients with renal or hepatic impairment. Patients with renal or hepatic impairment, following similar doses of heparin may have higher plasma levels of heparin compared with patients with normal renal and hepatic function [see Warnings and Precautions (5.1) ] .

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.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium in 0.9% Sodium Chloride Injection is a clear solution and is 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°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Protect from freezing.

<table styleCode="Noautorules" width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-7620-03</content></paragraph><paragraph>Case of 18 Single-dose flexible plastic containers</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1,000 USP Units/500 mL</paragraph><paragraph>(2 USP Units/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-1005-20</content></paragraph><paragraph>Case of 20 Single-dose flexible plastic containers</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1,000 USP Units/500 mL</paragraph><paragraph>(2 USP Units/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-7620-59</content></paragraph><paragraph>Case of 12 Single-dose flexible plastic containers</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2,000 USP Units/1,000 mL</paragraph><paragraph>(2 USP Units/mL)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC 0409-2222-12</content></paragraph><paragraph>Case of 12 Single-dose flexible plastic containers</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2,000 USP Units/1,000 mL</paragraph><paragraph>(2 USP Units/mL)</paragraph></td></tr></tbody></table>

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 or HITT 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 (5.6) , 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) ] . This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . For medical information about Heparin Sodium in Sodium Chloride Injection, please visit www.pfizermedinfo.com or call 1-800-438‑1985.

<table styleCode="Noautorules" width="100%"><col width="90%"/><col width="10%"/><tbody><tr><td valign="top"><paragraph>Warnings and Precautions, Unresponsiveness to Heparin with </paragraph><paragraph>Concomitant Use with Andexanet Alfa (<linkHtml href="#ID_babefc93-8da4-4eb3-ab5e-5350c0e2cb6b">5.4</linkHtml>)</paragraph></td><td valign="top"><paragraph>11/2025</paragraph></td></tr></tbody></table>

1 INDICATIONS AND USAGE HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION is indicated for: • Prophylaxis and treatment of venous thrombosis and pulmonary embolism; • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation; • Treatment of acute and chronic consumption coagulopathies (disseminated intravascular coagulation); • Prevention of clotting in arterial and cardiac surgery; • Prophylaxis and treatment of peripheral arterial embolism; • Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures. HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION is indicated for: ( 1 ) • Prophylaxis and treatment of venous thrombosis and pulmonary embolism • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation • Treatment of acute and chronic consumption coagulopathies (disseminated intravascular coagulation) • Prevention of clotting in arterial and cardiac surgery • Prophylaxis and treatment of peripheral arterial embolism • Anticoagulant use in blood transfusions, extracorporeal circulation and dialysis procedures

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: • Therapeutic Anticoagulant Effect with Full-Dose Heparin* ( 2.3 ) Intermittent Intravenous Injection Initial Dose 10,000 Units Every 4 to 6 hours 5,000 Units to 10,000 Units Continuous Intravenous Infusion Initial Dose 5,000 Units Continuous 20,000 Units to 40,000 Units/24 hours *Based on 150 lb (68 kg) patient. • Cardiovascular Surgery ( 2.5 ) Intravascular via Total Body Perfusion Initial Dose Not less than 150 units/kg; adjust for longer procedures • Extracorporeal Dialysis ( 2.8 ) For pediatric dosing see section 2.4 of full prescribing information. Intravascular via Extracorporeal Dialysis Follow equipment manufacturer's operating directions carefully. 2.1 Preparation for Administration Confirm the selection of the correct formulation and strength prior to administration of the drug. Do not use HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION as a "catheter lock flush" product. Administer this product by intravenous infusion. Do not admix with other drugs. 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. Do not administer unless the solution is clear and container is undamaged. Discard unused portion. To Open Tear outer wrap and remove solution container. For PVC bags, some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. (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: See full directions on administration set carton. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Open flow control clamp and clear air from set. Close clamp. 7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. 8. Regulate rate of administration with flow control clamp. Warning: Do not use flexible container in series connections. 2.2 Laboratory Monitoring for Efficacy and Safety The dosage of heparin sodium should be adjusted according to the patient's coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy. 2.3 Therapeutic Anticoagulant Effect With Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience.

ated approximately 2.5 to 3 times the control value. Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy. 2.3 Therapeutic Anticoagulant Effect With Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect Method of Administration Frequency Recommended Dose Based on 150 lb. (68 kg) patient. Intermittent Intravenous Injection Initial Dose 10,000 Units Every 4 to 6 hours 5,000 Units to 10,000 Units Continuous Intravenous Infusion Initial Dose 5,000 Units by intravenous injection Continuous 20,000 Units/24 hours to 40,000 Units/24 hours 2.4 Pediatric Use There are no adequate and well-controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 units/kg to 100 units/kg (intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 units/kg/hour to 30 units/kg/hour (continuous intravenous infusion); Infants less than 2 months have the highest requirements (average 28 units/kg/hour) Children greater than 1 year of age: 18 units/kg/hour to 20 units/kg/hour (continuous intravenous infusion); Older children may require less heparin, similar to weight-adjusted adult dosage. Monitoring Adjust heparin to maintain APTT of 60 seconds to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70. 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Converting to Warfarin To ensure continuous anticoagulation when converting from heparin sodium to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.5) ] . 2.7 Converting to Oral Anticoagulants Other Than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.8 Extracorporeal Dialysis Follow equipment manufacturer's operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers' recommendations are not available.

2.4 Pediatric Use There are no adequate and well-controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 units/kg to 100 units/kg (intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 units/kg/hour to 30 units/kg/hour (continuous intravenous infusion); Infants less than 2 months have the highest requirements (average 28 units/kg/hour) Children greater than 1 year of age: 18 units/kg/hour to 20 units/kg/hour (continuous intravenous infusion); Older children may require less heparin, similar to weight-adjusted adult dosage. Monitoring Adjust heparin to maintain APTT of 60 seconds to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70. 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) ] .

<table styleCode="Noautorules" width="80%"><col width="28%"/><col width="63%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Initial Dose</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>75 units/kg to 100 units/kg (intravenous bolus over 10 minutes)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Maintenance Dose</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Infants: 25 units/kg/hour to 30 units/kg/hour (continuous intravenous infusion); Infants less than 2 months have the highest requirements (average 28 units/kg/hour) Children greater than 1 year of age: 18 units/kg/hour to 20 units/kg/hour (continuous intravenous infusion); Older children may require less heparin, similar to weight-adjusted adult dosage.</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Monitoring </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Adjust heparin to maintain APTT of 60 seconds to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70.</paragraph></td></tr></tbody></table>

3 DOSAGE FORMS AND STRENGTHS HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION is available as: • Injection: 25,000 USP Units/250 mL (100 USP Units/mL) in clear solution in single-dose flexible plastic container • Injection: 12,500 USP Units/250 mL (50 USP Units/mL) in clear solution in single-dose flexible plastic container • Injection: 25,000 USP Units/500 mL (50 USP Units/mL) in clear solution in single-dose flexible plastic container HEPARIN SODIUM in 0.45% Sodium Chloride Injection is available as: ( 3 ) • Injection: 25,000 USP Units/250 mL (100 USP Units/mL) in clear solution in single-dose flexible plastic container • Injection: 12,500 USP Units/250 mL (50 USP Units/mL) in clear solution in single-dose flexible plastic container • Injection: 25,000 USP Units/500 mL (50 USP Units/mL) in clear solution in single-dose flexible plastic container

4 CONTRAINDICATIONS The use of heparin sodium is contraindicated in patients: • With 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) ] • In whom suitable blood coagulation tests (e.g., the whole blood clotting time, partial thromboplastin time, etc.) cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin) [see Warnings and Precautions (5.6) ] • With an uncontrollable active bleeding state [see Warnings and Precautions (5.6) ] , except when treating disseminated intravascular coagulation • History of Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) ( 4 ) • Known hypersensitivity to heparin or pork products ( 4 ) • In whom suitable blood coagulation tests cannot be performed at appropriate intervals ( 4 ) • With an uncontrollable active bleeding state, except when treating disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS • Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) • Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) • HIT (With or Without Thrombosis): Monitor for signs and symptoms and discontinue if indicative of HIT (With or Without Thrombosis) ( 5.3 ) • Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Monitor platelet count and hematocrit in all patients receiving heparin ( 5.6 ) • Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients ( 5.9 ) 5.1 Fatal Medication Errors 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. 5.2 Hemorrhage 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) ] . These patients may require a lower dose . 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: • Cardiovascular — Subacute bacterial endocarditis. Severe hypertension. • Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye. • Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. • Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). • Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine. • Other — Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) HIT is a serious immune-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.

mbocytopenia (HIT) (With or Without Thrombosis) HIT is a serious immune-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 fatal outcomes. Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used. Future use of heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation. Delayed Onset of HIT (With or Without Thrombosis): Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) 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 (With or Without Thrombosis). 5.4 Unresponsiveness to Heparin with Concomitant Use With Andexanet Alfa Unresponsiveness to unfractionated heparin leading to non-prolongation of activated clotting times and serious thrombotic events has occurred when unfractionated heparin was administered after use of andexanet alfa for the reversal of direct Factor Xa inhibitors (apixaban and rivaroxaban). Avoid use of heparin after use of andexanet alfa. Use an alternative anticoagulant to heparin [see Drug Interactions (7.3) ] . 5.5 Thrombocytopenia 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. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm 3 ) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm 3 or if recurrent thrombosis develops, the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered [see Warnings and Precautions (5.3) ] . 5.6 Coagulation Testing and Monitoring When heparin sodium is administered in therapeutic amounts, its dosage should be monitored by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly [see Overdosage (10) ] . Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy [see Dosage and Administration (2.2) ] . 5.7 Heparin Resistance Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted.

rombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Reactions 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 is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy. 5.9 Hyperkalemia Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin. Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.

6 ADVERSE REACTIONS The following clinically significant 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 (5.5) ] • Heparin Resistance [see Warnings and Precautions (5.7) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] • Hyperkalemia [see Warnings and Precautions (5.9) ] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT (With or Without Thrombosis), local irritation, hypersensitivity reactions, 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 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 or establish a causal relationship to drug exposure. Hemorrhage Hemorrhage is the chief complication that may result from heparin therapy [see Warnings and Precautions (5.2) ]. 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: a. Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient's death. b. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication if unrecognized may be fatal. c. Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis): [see Warnings and Precautions (5.3 , 5.5 )] Local Irritation Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. 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 (5.8) ] . Episodes of painful, ischemic, and cyanosed limbs have been reported with heparin use. Metabolism and Nutrition Disorders – Hyperkalemia.

nd anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar site of the feet, may occur [see Warnings and Precautions (5.8) ] . Episodes of painful, ischemic, and cyanosed limbs have been reported with heparin use. Metabolism and Nutrition Disorders – Hyperkalemia. Elevations of Serum Aminotransferases Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in a high percentage of patients (and healthy subjects) 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. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia.

7 DRUG INTERACTIONS • Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding ( 7 ) • Andexanet alfa may reduce the efficacy of heparin when used concomitantly ( 7.3 ) 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 Unresponsiveness to Heparin With Concomitant Use With Andexanet Alfa Andexanet binds to heparin-bound antithrombin III (ATIII) and may reduce the anticoagulant effect of heparin. Unresponsiveness to unfractionated heparin may lead to serious and life-threatening thrombotic events. Use of andexanet alfa as an antidote for heparin has not been established. Avoid use of heparin after use of andexanet alfa for the reversal of direct Factor Xa inhibitors (apixaban and rivaroxaban). If anticoagulation is needed, use an alternative anticoagulant to heparin [see Warnings and Precautions (5.4) ] . 7.4 Other Interactions Digitalis, tetracyclines, nicotine, or antihistamines, or intravenous nitroglycerin 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. 7.5 Drug/Laboratory Tests 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. Hyperaminotransferasemia Significant elevations of aminotransferase AST (SGOT) and ALT (SGPT) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, rises that might be caused by drugs (like heparin) should be interpreted with caution.

8 USE IN SPECIFIC POPULATIONS 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses up to 10,000 USP Units/kg/day, approximately 10 times the maximum recommended human dose (MRHD) of 40,000 USP Units/24 hours infusion (see Data ) . Consider the benefits and risks of HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION to a pregnant woman 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 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 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 SODIUM CHLORIDE INJECTION 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, and any heparin in milk would not be orally absorbed by a nursing child. 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 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 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) ] .

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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses up to 10,000 USP Units/kg/day, approximately 10 times the maximum recommended human dose (MRHD) of 40,000 USP Units/24 hours infusion (see Data ) . Consider the benefits and risks of HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION to a pregnant woman 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 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 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.

8.5 Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women [see Warnings and Precautions (5.2) ] . Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology (12.3) ] .

10 OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment 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. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. 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, the labeling of Protamine Sulfate Injection, USP products should be consulted. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

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): HEPARIN SODIUM IN 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. structural formula for heparin

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 Absorption Heparin is not absorbed through 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 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 Absorption Heparin is not absorbed through 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) ].

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 the studies to determine mutagenic potential have not been conducted.

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 the studies to determine mutagenic potential have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION is a clear solution and is supplied in single-dose flexible plastic containers in varied sizes and concentrations as shown in the accompanying Table. Unit of Sale Concentration NDC 0409-7650-62 Case of 24 Single-dose flexible plastic containers 25,000 USP Units/250 mL (100 USP Units/mL) NDC 0409-7650-30 Case of 30 Single-dose flexible plastic containers 25,000 USP Units/250 mL (100 USP Units/mL) NDC 0409-7651-62 Case of 24 Single-dose flexible plastic containers 12,500 USP Units/250 mL (50 USP Units/mL) NDC 0409-0012-30 Case of 30 Single-dose flexible plastic containers 12,500 USP Units/250 mL (50 USP Units/mL) NDC 0409-7651-03 Case of 24 Single-dose flexible plastic containers 25,000 USP Units/500 mL (50 USP Units/mL) NDC 0409-3150-20 Case of 20 Single-dose flexible plastic containers 25,000 USP Units/500 mL (50 USP Units/mL) Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Protect from freezing.

<table styleCode="Noautorules" width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-7650-62</content></paragraph><paragraph>Case of 24 Single-dose flexible plastic containers</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25,000 USP Units/250 mL</paragraph><paragraph>(100 USP Units/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-7650-30</content></paragraph><paragraph>Case of 30 Single-dose flexible plastic containers</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25,000 USP Units/250 mL</paragraph><paragraph>(100 USP Units/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-7651-62</content></paragraph><paragraph>Case of 24 Single-dose flexible plastic containers</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12,500 USP Units/250 mL</paragraph><paragraph>(50 USP Units/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-0012-30</content></paragraph><paragraph>Case of 30 Single-dose flexible plastic containers</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12,500 USP Units/250 mL</paragraph><paragraph>(50 USP Units/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-7651-03</content></paragraph><paragraph>Case of 24 Single-dose flexible plastic containers</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25,000 USP Units/500 mL</paragraph><paragraph>(50 USP Units/mL)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC 0409-3150-20</content></paragraph><paragraph>Case of 20 Single-dose flexible plastic containers</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>25,000 USP Units/500 mL</paragraph><paragraph>(50 USP Units/mL)</paragraph></td></tr></tbody></table>

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 , 5.5 )] . 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 (5.8) , 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 (7.2) ] . This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . For medical information about HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION, please visit www.pfizermedinfo.com or call 1-800-438-1985. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1392-6.0 Hospira logo

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use HEPARIN SODIUM INJECTION safely and effectively. See full prescribing information for HEPARIN SODIUM INJECTION. HEPARIN SODIUM INJECTION, for intravenous or subcutaneous use Initial U.S. Approval: 1984 INDICATIONS AND USAGE Heparin Sodium Injection is an anticoagulant indicated for ( 1 ): Prophylaxis and treatment of venous thrombosis and pulmonary embolism Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdomino-thoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease Atrial fibrillation with embolization Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) Prevention of clotting in arterial and cardiac surgery Prophylaxis and treatment of peripheral arterial embolism Use as an anticoagulant in blood transfusions, extracorporeal circulation and dialysis procedures DOSAGE AND ADMINISTRATION Recommended Adult Dosages: Therapeutic Anticoagulant Effect with Full-Dose Heparin* (2.3) DOSAGE FORMS AND STRENGTHS Heparin Sodium: 5,000 USP Units/0.5 mL, Preservative free ( 3 ) Heparin Sodium: 5,000 USP Units/1 mL ( 3 ) CONTRAINDICATIONS Severe thrombocytopenia ( 4 ) When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals ( 4 ) An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation ( 4 ) WARNINGS AND PRECAUTIONS Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5- 5.1) Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5- 5.2) HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS ( 5- 5.3) Benzyl Alcohol Toxicity: Do not use this product in neonates and infants ( 5- 5.4) Monitoring: Blood coagulation tests guide therapy for full-dose heparin ( 5- 5.6) Monitor platelet count and hematocrit in all patients receiving heparin ( 5- 5.5, 5- 5.6) ADVERSE REACTIONS Most common adverse reactions are: hemorrhage, thrombocytopenia, HIT and HITTS, local irritation, hypersensitivity reactions, and elevations of aminotransferase levels. ( 6- 6.2) 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. DRUG INTERACTIONS Drugs that interfere with platelet aggregation: May induce bleeding. ( 7- 7.2) USE IN SPECIFIC POPULATIONS Pregnancy: Preservative-free formulation recommended. Limited human data in pregnant women ( 8- 8.1) Lactation: Advise females not to breastfeed ( 8- 8.2) Pediatric Use: Use preservative-free formulation in neonates and infants ( 8- 8.4) Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age ( 8- 8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: 4/2019 HIGHLIGHTS

tion: Advise females not to breastfeed ( 8- 8.2) Pediatric Use: Use preservative-free formulation in neonates and infants ( 8- 8.4) Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age ( 8- 8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: 4/2019 HIGHLIGHTS SPL UNCLASSIFIED Carpuject™ Single-dose cartridges with Luer Lock are packaged in a Slim-Pak™ tamper detection package. Note that a needle is not included. 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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions (5.8), Adverse Reactions (6.2)]. 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)]. SPL UNCLASSIFIED Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-0844-3.0 LOGO

TABLE OF CONTENTS FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration 2.2 Laboratory Monitoring for Efficacy and Safety 2.3 Therapeutic Anticoagulant Effect With Full-Dose Heparin 2.4 Pediatric Use 2.5 Cardiovascular Surgery 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism 2.7 Blood Transfusion 2.8 Converting to Warfarin 2.9 Converting to Oral Anticoagulants other than Warfarin 2.10 Extracorporeal Dialysis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Fatal Medication Errors 5.2 Hemorrhage 5.3 Heparin-induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative 5.5 Thrombocytopenia 5.6 Coagulation Testing and Monitoring 5.7 Heparin Resistance 5.8 Hypersensitivity 6 ADVERSE REACTIONS 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Oral Anticoagulants 7.2 Platelet Inhibitors 7.3 Other Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS & USAGE Heparin Sodium Injection is indicated for: Prophylaxis and treatment of venous thrombosis and, pulmonary embolism; Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdomino-thoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease; Atrial fibrillation with embolization; Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and cardiac surgery; Prophylaxis and treatment of peripheral arterial embolism; Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures.

2 DOSAGE & ADMINISTRATION 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial or cartridge prior to administration of the drug to a patient [see Warnings and Precautions (5.1)]. Heparin Sodium Injection, products must not be confused with "catheter lock flush" products. To lessen this risk for a cartridge, a red cautionary statement has been added to the cartridge and box/bin. Read the cautionary statement and confirm that you have selected the correct medication and strength. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [see Adverse Reactions (6)]. 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient's coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts, and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect With Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: 2.4 Pediatric Use Use preservative-free Heparin Sodium Injection in neonates and infants [see Warnings and Precautions (5.4)]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight.

re based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous injection (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.7 Blood Transfusion Add 450 to 600 USP units of Heparin Sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.8 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1)]. 2.9 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of Heparin Sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.10 Extracorporeal Dialysis Follow equipment manufacturers' operating directions carefully. A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturer's recommendations are not available. DOSAGE 1 DOSAGE 2

4 CONTRAINDICATIONS The use of Heparin Sodium Injection is contraindicated in patients with the following conditions: History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions (5.3)] Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.2)] In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low dose heparin) An uncontrolled active bleeding state [see Warnings and Precautions (5.4)], except when this is due to disseminated intravascular coagulation

5 WARNINGS AND PRECAUTIONS 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a "catheter lock flush" product. Heparin Sodium Injection is supplied in vials and sterile cartridges containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL "catheter lock flush" vials. Carefully examine all Heparin Sodium Injection vials and cartridges to confirm the correct product choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.2)]. 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, fall in blood pressure or any other unexplained symptom 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: Cardiovascular — Subacute bacterial endocarditis, severe hypertension. Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia, and some vascular purpuras. Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy — 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other — Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-Induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant.

, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of Heparin Sodium should be evaluated for HIT or HITT. 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection multiple-dose vials. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which toxicity may occur is not known[see Use in Specific Populations (8.4)]. 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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 HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3)]. 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage (10)]. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2)]. 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. Because Heparin Sodium Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.2)] Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions ( 5.3)] Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.4)] Thrombocytopenia [see Warnings and Precautions (5.5)] Heparin Resistance [see Warnings and Precautions (5.7)] Hypersensitivity [see Warnings and Precautions (5.8)] 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Heparin Sodium Injection. 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 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 heparin therapy Retroperitoneal hemorrhage. HIT and HITT, including delayed onset cases [see Warnings and Precautions (5.3)]. Local Irritation- Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of Heparin Sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. 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 [see Warnings and Precautions (5.3)]. 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur [see Warnings and Precautions (5.8)]. Elevations of aminotransferases- Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin [see Drug Interactions (7.4)]. Miscellaneous- 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.

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 NSAIDS (including salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, 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 antiplatelet agent or heparin is recommended. 7.3 Other Interactions 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).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of Heparin Sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/day [see Data]. Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Warnings and Precautions (5.4)]. The 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 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 If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. There is no information regarding the presence of Heparin Sodium 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 Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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)]. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug.

e 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)]. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with "catheter lock flush" vials [see Warnings and Precautions (5.1)]. Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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, particularly women, over 60 years of age [see Warnings and Precautions (5.2)]. Patients over 60 years of age may require lower doses of heparin. 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 the heparin effect, 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 with protamine, it should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection.

11 DESCRIPTION Heparin is a heterogenous 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. Structural formula of Heparin Sodium (representative subunits): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Carpuject™ sterile cartridge unit contain a sterile solution of Heparin Sodium Injection, USP. Each mL contains 5,000 USP Units of heparin sodium and benzyl alcohol 1% as a preservative, in Water for Injection. The pH is adjusted between 5.0 to 7.5 with hydrochloric acid or sodium hydroxide. Each mL of Preservative-Free Heparin Sodium Injection contains 10,000 USP Units in Water for Injection. The pH is adjusted between 5.0 to 7.5 with hydrochloric acid or sodium hydroxide as required. STRUCTURE

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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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. The 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)].

16 HOW SUPPLIED/STORAGE AND HANDLING HEPARIN SODIUM INJ, USP is supplied in the following dosage forms. NDC 51662-1460-1 HEPARIN SODIUM INJ, USP 5,000 USP UNITS/mL 1mL CARPUJECT HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Heparin Sodium is supplied in the following strengths and package configurations: Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Do not freeze. Discard unused portion after initial use. HOW SUPPLIED

SPL UNCLASSIFIED Instructions for Use of the Syringe Systems Instructions for using the Carpuject™ Syringe are available with the reusable Carpuject™ Holder, List 2049-02. Carpuject™ Single-dose cartridges are to be used ONLY with Carpuject™ Holders, List 2049-02.

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: Therapeutic Anticoagulant Effect with Full-Dose Heparin † ( 2.4 ) Deep Subcutaneous (Intrafat) Injection Use a different site for each injection Initial Dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion † Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial to ensure that the 1 mL vial is not confused with a “catheter lock flush” vial or other 1 mL vial of incorrect strength [s ee Warnings and Precautions (5.1) ] . Confirm the selection of the correct formulation and strength prior to administration of the drug. To lessen this risk, the 1 mL vial includes a red cautionary label that extends above the main label. Read the cautionary statement and confirm that you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this red cautionary label prior to removing the flip-off cap. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [ see Adverse Reactions (6) ]. 2.2 Instructions for Use of Prefilled Syringe CAUTION: Certain glass syringes may malfunction, break or clog when connected to some Needleless Luer Access Devices (NLADs) and needles. This syringe has a larger internal syringe tip and an external collar (luer collar). The external collar must remain attached to the syringe. Data show that the syringe achieves acceptable connections with the BD Eclipse™ Needle and the Terumo SurGuard2™ Safety Needle and with the following non-center post NLADs: Alaris SMARTSITE™, B-Braun ULTRASITE™, BD-Q SYTE™, Maximum MAX PLUS™, and B-Braun SAFSITE™. The data also show acceptable connections are achieved to the center post ICU Medical CLAVE™. However, spontaneous disconnection of this glass syringe from needles and NLADs with leakage of drug product may occur. Assure that the needle or NLAD is securely attached before beginning the injection. Visually inspect the glass syringe-needle or glass syringe-NLAD connection before and during drug administration.

™. However, spontaneous disconnection of this glass syringe from needles and NLADs with leakage of drug product may occur. Assure that the needle or NLAD is securely attached before beginning the injection. Visually inspect the glass syringe-needle or glass syringe-NLAD connection before and during drug administration. Refer to Figure 1 for syringe diagram. Figure 1 1. Inspect the outer packaging (plastic tube) by verifying: - plastic tube integrity - drug name - drug strength - dose volume - route of administration - expiration date to be sure that the drug has not expired - sterile field applicability Do not use if package has been damaged. 2. Remove the plastic tube cap of the outer packaging to access the syringe. 3. Remove the syringe from the plastic tube. 4. Perform visual inspection on the syringe by verifying: - absence of syringe damage - absence of external particles - absence of internal particles - proper drug color - expiration date to be sure that the drug has not expired - drug name - drug strength - dose volume - route of administration - sterile field applicability 5. Push plunger rod slightly to break the stopper loose while tip cap is still on. 6. Remove tip cap by twisting it off. (See Figure 2) Figure 2 7. Discard the tip cap. 8. Expel air bubble. 9. Adjust dose by expelling extra volume (where applicable) from the syringe into sterile material prior to administration. 10. Connect the syringe to appropriate injection connection depending on route of administration. Before injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD). 11. Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration. 12. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle. To prevent needle-stick injuries, needles should not be recapped. NOTES: - All steps must be done sequentially - Do not autoclave syringe - Do not use this product on a sterile field - Do not introduce any other fluid into the syringe at any time - This product is for single dose only; discard unused portion CSFW 2 - corrected smaller from Word Figure 2 2.3 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.4 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience.

les drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.4 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE [based on 150 lb (68 kg) patient] Deep Subcutaneous (Intrafat) Injection Initial dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or 8,000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.5 Pediatric Use Do not use benzyl alcohol-preserved drugs in neonates and infants. Use preservative-free Heparin Sodium Injection in neonates and infants [ see Warnings and Precautions (5.4) ]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (Intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.6 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.7 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25- to 26-gauge) needle to minimize tissue trauma. 2.8 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood.

sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.9 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1) ] . 2.10 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.11 Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

en administered. 2.11 Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available. 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial to ensure that the 1 mL vial is not confused with a “catheter lock flush” vial or other 1 mL vial of incorrect strength [s ee Warnings and Precautions (5.1) ] . Confirm the selection of the correct formulation and strength prior to administration of the drug. To lessen this risk, the 1 mL vial includes a red cautionary label that extends above the main label. Read the cautionary statement and confirm that you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this red cautionary label prior to removing the flip-off cap. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [ see Adverse Reactions (6) ].

Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [ see Adverse Reactions (6) ]. 2.2 Instructions for Use of Prefilled Syringe CAUTION: Certain glass syringes may malfunction, break or clog when connected to some Needleless Luer Access Devices (NLADs) and needles. This syringe has a larger internal syringe tip and an external collar (luer collar). The external collar must remain attached to the syringe. Data show that the syringe achieves acceptable connections with the BD Eclipse™ Needle and the Terumo SurGuard2™ Safety Needle and with the following non-center post NLADs: Alaris SMARTSITE™, B-Braun ULTRASITE™, BD-Q SYTE™, Maximum MAX PLUS™, and B-Braun SAFSITE™. The data also show acceptable connections are achieved to the center post ICU Medical CLAVE™. However, spontaneous disconnection of this glass syringe from needles and NLADs with leakage of drug product may occur. Assure that the needle or NLAD is securely attached before beginning the injection. Visually inspect the glass syringe-needle or glass syringe-NLAD connection before and during drug administration. Refer to Figure 1 for syringe diagram. Figure 1 1. Inspect the outer packaging (plastic tube) by verifying: - plastic tube integrity - drug name - drug strength - dose volume - route of administration - expiration date to be sure that the drug has not expired - sterile field applicability Do not use if package has been damaged. 2. Remove the plastic tube cap of the outer packaging to access the syringe. 3. Remove the syringe from the plastic tube. 4. Perform visual inspection on the syringe by verifying: - absence of syringe damage - absence of external particles - absence of internal particles - proper drug color - expiration date to be sure that the drug has not expired - drug name - drug strength - dose volume - route of administration - sterile field applicability 5. Push plunger rod slightly to break the stopper loose while tip cap is still on. 6. Remove tip cap by twisting it off. (See Figure 2) Figure 2 7. Discard the tip cap. 8. Expel air bubble. 9. Adjust dose by expelling extra volume (where applicable) from the syringe into sterile material prior to administration. 10. Connect the syringe to appropriate injection connection depending on route of administration. Before injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD). 11. Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration. 12. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle. To prevent needle-stick injuries, needles should not be recapped. NOTES: - All steps must be done sequentially - Do not autoclave syringe - Do not use this product on a sterile field - Do not introduce any other fluid into the syringe at any time - This product is for single dose only; discard unused portion CSFW 2 - corrected smaller from Word Figure 2

eedles should not be recapped. NOTES: - All steps must be done sequentially - Do not autoclave syringe - Do not use this product on a sterile field - Do not introduce any other fluid into the syringe at any time - This product is for single dose only; discard unused portion CSFW 2 - corrected smaller from Word Figure 2 2.3 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration.

4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.5 Pediatric Use Do not use benzyl alcohol-preserved drugs in neonates and infants. Use preservative-free Heparin Sodium Injection in neonates and infants [ see Warnings and Precautions (5.4) ]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (Intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.6 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.7 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25- to 26-gauge) needle to minimize tissue trauma.

ery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25- to 26-gauge) needle to minimize tissue trauma. 2.8 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.9 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1) ] . 2.10 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.11 Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium Injection, USP preserved with benzyl alcohol is available as follows: 5,000 USP units/mL single-dose vials Injection (preserved with Benzyl Alcohol) Single-dose Vials 5,000 USP units per mL

5 WARNINGS AND PRECAUTIONS Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS ( 5.3 ) Benzyl Alcohol Toxicity: Do not use benzyl alcohol-preserved drugs in neonates and infants. ( 5.4 ) Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Monitor platelet count and hematocrit in all patients receiving heparin ( 5.5 , 5.6 ) 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials and syringes containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection vials and syringes to confirm the correct vial or syringe choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. 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, fall in blood pressure or any other unexplained symptom 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: Cardiovascular - Subacute bacterial endocarditis, severe hypertension. Surgical - During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic - Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy - 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other - Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT).

occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing Heparin Sodium Injection vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Heparin Sodium Injection vials (contains 10.42 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations (8.4) ] . 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3) ]. 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [ see Overdosage (10) ]. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [ see Dosage and Administration (2.3) ]. 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. Because Heparin Sodium Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [ see Warnings and Precautions (5.2) ] Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [ see Warnings and Precautions (5.3) ] Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [ see Warnings and Precautions (5.4) ] Thrombocytopenia [ see Warnings and Precautions (5.5) ] Heparin Resistance [ see Warnings and Precautions (5.7) ] Hypersensitivity [ see Warnings and Precautions (5.8) ] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 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 Injection. 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 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 heparin therapy. Retroperitoneal hemorrhage HIT and HITT, including delayed onset cases [ see Warnings and Precautions (5.3) ]. Local Irritation – Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. 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 [ see Warnings and Precautions (5.3) ]. 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur [ see Warnings and Precautions (5.8) ]. Elevations of aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Miscellaneous - 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.

ant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Heparin Sodium Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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 (2.5) ]. Carefully examine all Heparin Sodium Injection vials and syringes to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [ see Warnings and Precautions (5.1) ]. Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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, particularly women, over 60 years of age [ see Warnings and Precautions (5.2) ]. Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [ see Clinical Pharmacology (12.3) ].

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 (2.5) ]. Carefully examine all Heparin Sodium Injection vials and syringes to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [ see Warnings and Precautions (5.1) ]. Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

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): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Heparin Sodium Injection, USP preserved with Benzyl Alcohol is available in the following concentrations/mL: Heparin Sodium Sodium Chloride Benzyl Alcohol 1,000 USP units 8.6 mg 10.42 mg 5,000 USP units 7 mg 10.42 mg 10,000 USP units 5 mg 10.42 mg pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. Heparin Sodium Injection, USP, preservative-free is available in the following concentrations: Heparin Sodium Sodium Chloride 5,000 USP units/1 mL 7 mg 5,000 USP units/0.5 mL 5 mg pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. chemical structure

<table width="400px"><col/><col/><col/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule">Heparin Sodium</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">Sodium Chloride</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">Benzyl Alcohol</td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule">1,000 USP units</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">8.6 mg</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">10.42 mg</td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule">5,000 USP units</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">7 mg</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">10.42 mg</td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 10,000 USP units</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">5 mg</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">10.42 mg</td></tr></tbody></table> <table width="350px" cellspacing="0" cellpadding="0" border="0"><col width="92.7pt"/><col width="77.55pt"/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Heparin Sodium</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sodium Chloride</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5,000 USP units/1 mL</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7 mg</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 5,000 USP units/0.5 mL</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 5 mg</td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection preserved with benzyl alcohol is available in the following strengths and package sizes in single-dose vials: 25 vials: 5,000 USP units/mL, single-dose* *Discard unused portion NDC: 70518-4547-00 NDC: 70518-4547-01 PACKAGING: 25 in 1 PACKAGE PACKAGING: 1 mL VIAL, TYPE 0 Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [ see Warnings and Precautions (5.8) , 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 (7.1) ]. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: • Therapeutic Anticoagulant Effect with Full-Dose Heparin † ( 2.4 ) † Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. Deep Subcutaneous (Intrafat) Injection Use a different site for each injection Initial Dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial to ensure that the 1 mL vial is not confused with a “catheter lock flush” vial or other 1 mL vial of incorrect strength [s ee Warnings and Precautions ( 5.1 )]. Confirm the selection of the correct formulation and strength prior to administration of the drug. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [ see Adverse Reactions ( 6 ) ]. 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient's coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience.

les drawn 4 to 6 hours after the injection. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE [based on 150 lb (68 kg) patient] Deep Subcutaneous (Intrafat) Injection Initial dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or 8,000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose Every 4 to 6 hours 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose Continuous 5,000 units by intravenous injection 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.4 Pediatric Use Use preservative-free Heparin Sodium Injection in neonates and infants. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (Intravenous bolus over 10 minutes) Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Maintenance Dose Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.7 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.8 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range.

from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.8 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )] . 2.9 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.10 Extracorporeal Dialysis Follow equipment manufacturers' operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers' recommendations are not available.

2.4 Pediatric Use Use preservative-free Heparin Sodium Injection in neonates and infants. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (Intravenous bolus over 10 minutes) Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Maintenance Dose Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 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 ( 2.5 ) ]. Carefully examine all Heparin Sodium Injection syringes to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [ see Warnings and Precautions ( 5.1 ) ]. Use preservative-free Heparin Sodium Injection in neonates and infants.

<table styleCode="Noautorules" width="100%"><col width="25%"/><col width="75%"/><tbody><tr><td valign="top"><paragraph>Initial Dose </paragraph></td><td valign="top"><paragraph>75 to 100 units/kg (Intravenous bolus over 10 minutes) Infants: 25 to 30 units/kg/hour; Infants &lt; 2 months have the highest requirements (average 28 units/kg/hour) </paragraph></td></tr><tr><td valign="top"><paragraph>Maintenance Dose </paragraph></td><td valign="top"><paragraph>Children &gt; 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage </paragraph></td></tr><tr><td valign="top"><paragraph>Monitoring </paragraph></td><td valign="top"><paragraph>Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 </paragraph></td></tr></tbody></table>

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium Injection, USP preservative-free is available as follows: • 5,000 USP units/mL single-dose prefilled syringes Injection (Preservative-Free) Single-Dose Prefilled Syringe • 5,000 USP units per mL

4 CONTRAINDICATIONS The use of Heparin Sodium Injection is contraindicated in patients with the following conditions: • History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions ( 5.3 )] ; • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions ( 6.1 )]. • In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); • An uncontrolled active bleeding state [ see Warnings and Precautions ( 5.2 ) ], except when this is due to disseminated intravascular coagulation. • Severe thrombocytopenia ( 4 ) • When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals ( 4 ) • An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS • Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) • Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) • HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS ( 5.3 ) • Monitoring: Blood coagulation tests guide therapy for full-dose heparin. • Monitor platelet count and hematocrit in all patients receiving heparin ( 5.5 , 5.6 ) 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in syringes containing 5,000 units in 1 mL of heparin. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection syringes to confirm the correct syringe choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. 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, fall in blood pressure or any other unexplained symptom 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: • Cardiovascular - Subacute bacterial endocarditis, severe hypertension. • Surgical - During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. • Hematologic - Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. • Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy - 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). • Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine. • Other - Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT.

pment of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.5 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions ( 5.3 )]. 5.6 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [ see Overdosage ( 10 ) ]. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [ see Dosage and Administration ( 2.3 ) ]. 5.7 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.8 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations. Because Heparin Sodium Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [ see Warnings and Precautions ( 5.2 ) ] • Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [ see Warnings and Precautions ( 5.3 ) ] • Thrombocytopenia [ see Warnings and Precautions ( 5.5 ) ] • Heparin Resistance [ see Warnings and Precautions ( 5.7 ) ] • Hypersensitivity [ see Warnings and Precautions ( 5.8 ) ] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA Inc. at, LLC 1-800-551-7176 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 Injection. 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 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: o Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases. o Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term heparin therapy. o Retroperitoneal hemorrhage • HIT and HITT, including delayed onset cases [see Warnings and Precautions ( 5.3 )]. • Local Irritation – Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. • 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 [ see Warnings and Precautions ( 5.3 ) ]. • 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur. [ see Warnings and Precautions ( 5.8 ) ] • Elevations of aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. • Miscellaneous - 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.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Preservative-free formulation recommended. Limited human data in pregnant women. ( 8.1 ) • Lactation: Advise females not to breastfeed. ( 8.2 ) • Pediatric Use: Use preservative-free formulation in neonates and infants. ( 8.4 ) • Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. ( 8.5 ) 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day [ see Data ]. Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. The 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 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 If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. There is no information regarding the presence of Heparin Sodium 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 Injection and any potential adverse effects on the breastfed infant from Heparin Sodium 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 ( 2.5 ) ]. Carefully examine all Heparin Sodium Injection syringes to confirm choice of the correct strength prior to administration of the drug.

o adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience [ see Dosage and Administration ( 2.5 ) ]. Carefully examine all Heparin Sodium Injection syringes to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [ see Warnings and Precautions ( 5.1 ) ]. Use preservative-free Heparin Sodium Injection in neonates and infants. 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [ see Clinical Pharmacology ( 12.3 ) ].

8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day [ see Data ]. Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. The 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 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.

8.5 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [ see Clinical Pharmacology ( 12.3 ) ].

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): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Heparin Sodium Injection, USP, preservative-free is available in the following concentration: Heparin Sodium Sodium Chloride 5,000 USP units / 1 mL 7 mg pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. hepar-struc-01.jpg

<table width="100%"><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr styleCode="Toprule"><td valign="top"/><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph>Heparin Sodium </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph>Sodium Chloride 5,000 </paragraph></td><td valign="top"/></tr><tr styleCode="Botrule"><td valign="top"/><td align="center" valign="top"><paragraph>USP units / 1 mL </paragraph></td><td align="center" valign="top"><paragraph>7 mg </paragraph></td><td valign="top"/></tr></tbody></table>

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 III, thereby inhibiting the activated coagulation factors involved in the clotting 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. The 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 ) ].

12.3 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 ) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection, USP preservative-free is available as: Product Code Unit of Sale Strength Each 757810 NDC 76045-108-10 Unit of 24 5,000 USP units per 1 mL NDC 76045-108-00 1 mL pre-filled single-dose syringe Discard unused portion Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature]. Protect from freezing. Do not place syringe on a sterile field.

<table width="100%"><col width="15%"/><col width="22%"/><col width="28%"/><col width="35%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Product Code</content></paragraph></td><td styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Each</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>757810 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>NDC 76045-108-10 Unit of 24 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>5,000 USP units per 1 mL </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>NDC 76045-108-00 1 mL pre-filled single-dose syringe </paragraph></td></tr></tbody></table>

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [ see Warnings and Precautions ( 5.8 ), 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 ( 7.1 ) ].

INSTRUCTIONS FOR USE Figure 1: Outer Packaging and Prefilled Syringe NOTES: • Do not introduce any other fluid into the syringe at any time. • Do not dilute for IV push. • Do not re-sterilize the syringe. • Do not use this product on a sterile field. • This product is for single-dose only. 1. Inspect the outer packaging (blister pack) to confirm the integrity of the packaging. Do not use if the blister pack or the prefilled syringe has been damaged. 2. Remove the syringe from the outer packaging. (See Figure 2 ) Figure 2 3. Visually inspect the syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 4. Twist off the syringe tip cap. Do not remove the label around the luer lock collar. (See Figure 3 ) Figure 3 5. Expel air bubble(s). Adjust the dose (if applicable). 6. Administer the dose ensuring that pressure is maintained on the plunger rod during the entire administration. 7. Discard the used syringe into an appropriate receptacle. For more information concerning this drug, please call Fresenius Kabi USA, LLC at 1-800-551-7176. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The brand names mentioned in this document are the trademarks of their respective owners. This “Instructions for Use” has been approved by the U.S. Food and Drug Administration. Revised: November 2020 Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451593 hepar-img-01.jpg hepar-img-02.jpg hepar-img-03.jpg hepar-img-04.jpg

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: • Therapeutic Anticoagulant Effect with Full-Dose Heparin † ( 2.3 ) † Based on 68 kg patient. Adjust dose based on laboratory monitoring. Deep Subcutaneous (Intrafat) Injection Use a different site for each injection Initial Dose 5,000 units by intravenous injection, followed by 10,000 units to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 units to 10,000 units of a concentrated solution 15,000 units to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP by intravenous injection Every 4 to 6 hours 5,000 units to 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 units/24 hours to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection syringe to ensure that the 1 mL syringe is not confused with a “catheter lock flush” syringe or other 1 mL syringe of incorrect strength [ s ee Warnings and Precautions ( 5.1 )]. Confirm the selection of the correct formulation and strength prior to administration of the drug. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [see Adverse Reactions ( 6 )] . 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient's coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodically monitor platelet counts and hematocrits during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience.

samples drawn 4 to 6 hours after the injection. Periodically monitor platelet counts and hematocrits during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE [based on 68 kg patient] Deep Subcutaneous (Intrafat) Injection A different site should be used for each injection to prevent development of massive hematoma Initial Dose 5,000 units by intravenous injection, followed by 10,000 units to 20,000 units of a concentrated solution, subcutaneously Every 8 hours Or Every 12 hours 8,000 units to 10,000 units of a concentrated solution 15,000 units to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP by intravenous injection Every 4 to 6 hours 5,000 units to 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 units/24 hours to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.4 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.5 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma. 2.6 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.7 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions ( 7.1 )] . 2.8 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.9 Extracorporeal Dialysis Follow equipment manufacturers' operating directions carefully.

nistering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.9 Extracorporeal Dialysis Follow equipment manufacturers' operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers' recommendations are not available. 2.10 Administration Technique Figure 1: Outer Packaging and Prefilled Syringe NOTES: - Do not introduce any other fluid into the syringe at any time. - Do not dilute for intravenous push. - Do not re-sterilize the syringe. - Do not use this product on a sterile field. - This product is for single dose only. 1. Inspect the outer packaging (blister pack) to confirm the integrity of the packaging. Do not use if the blister pack or the prefilled syringe has been damaged. 2. Remove the syringe from the outer packaging. (See Figure 2) Figure 2 3. Visually inspect the syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 4. Twist off the syringe tip cap. Do not remove the label around the luer lock collar. (See Figure 3) Figure 3 5. Expel air bubble(s). Adjust the dose (if applicable). 6. Administer the dose ensuring that pressure is maintained on the plunger rod during the entire administration. 7. Discard the syringe into the appropriate receptacle. hepar-img-01.jpg hepar-img-02.jpg hepar-img-03.jpg

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium Injection, USP is available as: • Injection: 5,000 USP units per 0.5 mL (10,000 USP units/mL) preservative-free clear solution in a prefilled single-dose syringe. Injection: 5,000 USP units per 0.5 mL (10,000 USP units/mL) preservative-free clear solution in prefilled single-dose syringe

<table width="100%"><col width="100%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Injection:</content> 5,000 USP units per 0.5 mL (10,000 USP units/mL) preservative-free clear solution in prefilled single-dose syringe </paragraph></td></tr></tbody></table>

4 CONTRAINDICATIONS The use of Heparin Sodium Injection is contraindicated in patients with the following conditions: • History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions ( 5.3 )] ; • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions ( 6.1 )] • In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); • An uncontrolled active bleeding state [see Warnings and Precautions ( 5.4 )] , except when this is due to disseminated intravascular coagulation. • Severe thrombocytopenia ( 4 ) • When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals ( 4 ) • An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

5 WARNINGS AND PRECAUTIONS • Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) • Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) • HIT and HITT: Monitor for signs and symptoms and discontinue if indicative of HIT and HITT ( 5.3 ) • Monitoring: Blood coagulation tests guide therapy for full-dose heparin. • Monitor platelet count and hematocrit in all patients receiving heparin ( 5.5 , 5.6 ) 5.1 Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in syringes containing a highly concentrated solution of 10,000 units in 1 mL (5,000 units per 0.5 mL). Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection syringes to confirm the correct syringe choice prior to administration of the drug. 5.2 Hemorrhage 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. Fatal hemorrhages have occurred. 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, fall in blood pressure or any other unexplained symptom 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: • Cardiovascular - Subacute bacterial endocarditis, severe hypertension. • Surgical - During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. • Hematologic - Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. • Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy o 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). • Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine. • Other - Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT.

pment of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies 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/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions ( 5.3 )]. 5.5 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage ( 10 )] . Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration ( 2.2 )] . 5.6 Heparin Resistance Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted. 5.7 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations. Because Heparin Sodium Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [see Warnings and Precautions ( 5.2 )] • Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions ( 5.3 )] • Thrombocytopenia [see Warnings and Precautions ( 5.4 )] • Heparin Resistance [see Warnings and Precautions ( 5.6 )] • Hypersensitivity [see Warnings and Precautions ( 5.7 )] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITT, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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 Injection. 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 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: o Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases. o Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term heparin therapy. o Retroperitoneal hemorrhage • HIT and HITT, including delayed onset cases [see Warnings and Precautions ( 5.3 )]. • Local Irritation – Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. • 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 [see Warnings and Precautions ( 5.3 )] . • 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 less frequently. Itching and burning, especially on the plantar side of the feet, may occur. [see Warnings and Precautions (5.8)] • Elevations of aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin [see Drug Interactions (7.4)] . • Miscellaneous - 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.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Limited human data in pregnant women. ( 8.1 ) • Lactation: Advise females not to breastfeed. ( 8.2 ) • Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. ( 8.5 ) 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day ( see Data ). Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. The 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 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 Injection 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, and any heparin in milk would not be orally absorbed by a nursing child. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Heparin Sodium Injection and any potential adverse effects on the breastfed child from Heparin Sodium Injection or from the underlying maternal condition [see Use in Specific Populations ( 8.4 )] . 8.4 Pediatric Use Pediatric dosing is not achievable with the prefilled syringe presentation. Use another heparin product presentation when dosing 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology ( 12.3 )].

8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium 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. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 45,000 units/ day ( see Data ). Consider the benefits and risks of Heparin Sodium Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium Injection to a pregnant woman. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. The 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 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.

8.5 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, particularly women, over 60 years of age [see Warnings and Precautions ( 5.2 )] . Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology ( 12.3 )].

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 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): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Each 0.5 mL of Heparin Sodium Injection, USP contains: Heparin Sodium Sodium Chloride 5,000 USP units 2.5 mg pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. hepar-struc-01.jpg

<table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Heparin Sodium </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Sodium Chloride </paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5,000 USP units </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.5 mg </paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection, USP is a preservative-free clear solution available as: Product Code Unit of Sale Strength Each 761805 NDC 63323-118-05 Unit of 24 5,000 USP units per 0.5 mL (10,000 USP units per mL) NDC 63323-118-01 0.5 mL fill in 1 mL prefilled single dose syringe Discard unused portion Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature]. Protect from freezing. Do not place syringe on a sterile field.

<table width="100%"><col width="16%"/><col width="23%"/><col width="30%"/><col width="31%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Product Code</content></paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Each</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>761805 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>NDC 63323-118-05 Unit of 24 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>5,000 USP units per 0.5 mL (10,000 USP units per mL) </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC 63323-118-01 0.5 mL fill in 1 mL prefilled single dose syringe </paragraph></td></tr></tbody></table>

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 and HITT 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. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [ see Warnings and Precautions (5.8), 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 ( 7.1 ) ]. For more information concerning this drug, please call Fresenius Kabi USA, LLC at 1-800-551-7176. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The brand names mentioned in this document are the trademarks of their respective owners. Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451614 hepar-img-04.jpg