HEPARIN SODIUM

Heparin is a heterogenous 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-glucuronic acid). Structure of heparin sodium (representative subunits): HEPARIN SODIUM INJECTION is a sterile preparation of heparin sodium derived from porcine intestinal tissue, standardized for anticoagulant activity, in water for injection. It is intended for intravenous or deep subcutaneous administration. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. For formulations preserved with benzyl alcohol, each mL of the 1,000 UPS units and 5,000 USP units per mL preparations contains: heparin sodium 1,000 UPS units or 5,000 USP units; 9 mg sodium chloride; 9.45 mg benzyl alcohol added as preservative. Each mL of the 10,000 USP units per mL preparations contains: heparin sodium 10,000 USP units; 9.45 mg benzyl alcohol added as preservative. The preservative-free product contains (per mL): 1,000 USP units of heparin sodium and 9 mg sodium chloride. When necessary, the pH of HEPARIN SODIUM INJECTION is adjusted with hydrochloric acid and/or sodium hydroxide. The pH range is 5.0 to 7.5. Chemical Structure

HEPARIN SODIUM 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 INJECTION is an anticoagulant indicated for ( 1 ): • Prophylaxis and treatment of venous thrombosis and pulmonary embolism • Prophylaxis and treatment of the thromboembolic complications associated with atrial fibrillation • Treatment of acute and chronic consumption coagulopathies • Prevention of clotting in arterial and cardiac surgery • Prophylaxis and treatment of peripheral arterial embolism • Anticoagulant use in transfusion, extracorporeal circulation, and dialysis procedures

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 333 units/kg subcutaneously Every 12 hours 250 units/kg subcutaneously 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/24 hours to 40,000 units/24 hours * Based on 68 kg patient. Adjust dose based on laboratory monitoring. • Cardiovascular Surgery ( 2.5 ) Intravascular via Total Body Perfusion Initial Dose not less than 150 units/kg; adjust for longer procedures • Low-dose Prophylaxis of Postoperative Thromboembolism ( 2.6 ) Deep Subcutaneous (Intrafat) Injection Initial Dose 5,000 units 2 hours before surgery Every 8 to 12 hours 5,000 units • Extracorporeal dialysis ( 2.9 ) Intravascular via Extracorporeal Dialysis 25 units/kg to 30 units/kg followed by infusion rate of 1,500 units/hour to 2,000 units/hour if 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 [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 SODIUM INJECTION is added to an infusion solution for continuous intravenous (IV) administration, invert the container at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Storage of prepared infusion solution should not exceed 4 hours at room temperature or 24 hours at 2° to 8°C (36° to 46°F). HEPARIN SODIUM INJECTION is incompatible with certain substances in solution (e.g., alteplase, amikacin sulfate, atracurium besylate, ciprofloxacin, cytarabine, daunorubicin, droperidol, erythromycin lactobionate, gentamicin sulfate, idarubicin, kanamycin sulfate, mitoxantrone HCl, polymyxin B sulfate, promethazine HCl, streptomycin sulfate, tobramycin sulfate). Consult specialized references to verify with which substances incompatibilities have been noted, as compatibility may depend on concentration, temperature, time, and other variables. 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. HEPARIN SODIUM INJECTION is not intended for intramuscular (IM) use [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 initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injections. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of HEPARIN SODIUM INJECTION 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 Use a different site for each injection to prevent the development of hematoma Initial Dose 333 units/kg subcutaneously Every 12 hours 250 units/kg subcutaneously Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USP 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 Continuous Intravenous Infusion Initial Dose 5,000 units by intravenous injection Continuous 20,000 units to 40,000 units per 24 hours in 1,000 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 units/kg to 100 units/kg ( intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 units/kg/hour to 30 units/kg/hour; 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; 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 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) ] . 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.

The use of HEPARIN SODIUM INJECTION is contraindicated in patients: • History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis • History of thrombocytopenia with pentosan polysulfate • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.1) ] • In whom suitable blood coagulation tests (e.g., whole-blood clotting time, partial thromboplastin time) cannot be performed at appropriate intervals. This contraindication refers to full-dose heparin regimens only; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin • An uncontrollable 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 ) • History of thrombocytopenia with pentosan polysulfate ( 4 ) • Known hypersensitivity to heparin or pork products ( 4 ) • In whom suitable blood coagulation tests cannot be performed at appropriate intervals ( 4 ) • An uncontrollable bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

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 (5.6) ] • Heparin Resistance [see Warnings and Precautions (5.8) ] • Hypersensitivity [see Warnings and Precautions (5.9) ] • Hyperkalemia [see Warnings and Precautions (5.10) ] 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 Pfizer 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 INJECTION. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. • Hemorrhage – Hemorrhage is the chief complication that may result from heparin therapy [see Warnings and Precautions (5.2) ] . Gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect 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 have occurred following deep subcutaneous (intrafat) injection of heparin sodium. Because such reactions occur more frequently after intramuscular administration, the IM route is not recommended. • Histamine-like reactions – Such reactions have been observed at the site of injection. 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; asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occur less frequently. Itching and burning, especially on the plantar site of the feet, may occur. • Metabolism and Nutrition Disorders – Hyperkalemia. • Elevations of serum aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. • Others – Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have been reported.

• Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding ( 7.2 ) • 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 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. 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 (5.5) ] . 7.4 Other Interactions Digitalis, tetracyclines, nicotine, or antihistamines, or intravenous (IV) nitroglycerin may partially counteract the anticoagulant action of heparin sodium. 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).

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate.