HEPARIN SODIUM IN SODIUM CHLORIDE

Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties. It is composed of polymers of alternating derivations of alpha-L-iduronic acid 2-sulfate (1), 2-deoxy-2-sulfamino- alpha-D-glucose 6-sulfate (2), beta-D-glucuronic acid (3), 2-acetamido-2- deoxy-alpha-D-glucose (4), and alpha-L-iduronic acid (5). Structure of Heparin Sodium (representative subunits): Heparin Sodium in 0.45% Sodium Chloride Injection is a sterile, single-dose, clear, nonpyrogenic solution prepared from Heparin Sodium USP (derived from porcine intestinal mucosa and standardized for use as an anticoagulant) in 0.45% Sodium Chloride Injection. It is to be administered by intravenous injection. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. The pH range is 7.0 (6.8-7.2) and the osmolarity mOsmol/L (calc.) is 206. The concentration of electrolytes is 109 mEq/L Sodium, 77 mEq/L Chloride, 32 mEq/L Phosphate, and 6 mEq/L Citrate. 50 USP units/mL: Each 100 mL of the 25,000 USP units per 500 mL preparation contains: 5,000 USP units of heparin sodium, 0.45 g Sodium Chloride USP, 0.43 g Dibasic Sodium Phosphate USP, 0.037 g Citric Acid Anhydrous USP, and Water for Injection USP until quantity sufficient. 100 USP units/mL: Each 100 mL of the 25,000 USP units per 250 mL preparation contains: 10,000 USP units of heparin sodium, 0.45 g Sodium Chloride USP, 0.43 g Dibasic Sodium Phosphate USP, 0.037 g Citric Acid Anhydrous USP, and Water for Injection USP until quantity sufficient. The plastic container is made from a multilayered film specifically developed for parenteral drugs. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary. The plastic container is not made with natural rubber latex, PVC or DEHP. The closure system has two ports; the one for the administration set has a tamper evident plastic protector. heparin sodium chemical formula

Heparin Sodium in 0.45% 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 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.

Recommended Adult Dosages: Therapeutic Anticoagulant Effect with Full-Dose Heparin* (2.3) Intermittent Intravenous Injection Initial Dose 10,000 Units Subsequent Doses 5,000 Units to 10,000 Units every 4 to 6 hours Continuous Intravenous Infusion Initial Dose 5,000 Units by intravenous injection Continuous 20,000 Units to 40,000 Units every 24 hours *Based on 150 lb. (68 kg) patient. Cardiovascular Surgery (2.5) Intravascular via Total Body Perfusion Initial Dose Greater than or equal to 150 units/kg; adjust for longer procedures Extracorporeal Dialysis (2.8) Intravascular via Extracorporeal Dialysis Follow equipment manufacturer’s operating directions carefully. For pediatric dosing, see section 2.4 of full prescribing information. 2.1 Preparation for Administration Confirm the selection of the correct formulation and strength prior to administration of the drug. This product should be administered by intravenous infusion only. Do not use Heparin Sodium in 0.45% Sodium Chloride Injection as a “catheter lock flush” product. Do not admix with other drugs. Discard unused portion. Do not use plastic containers in series connection. This product should not be infused under pressure. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and container and seals are intact. 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of heparin sodium according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, determine the coagulation time approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, perform coagulation tests 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 the 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. 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* Intermittent Intravenous Injection Initial Dose 10,000 Units Subsequent Doses 5,000 Units to 10,000 Units every 4 to 6 hours Continuous Intravenous Infusion Initial Dose 5,000 Units by intravenous injection Continuous 20,000 Units to 40,000 Units every 24 hours * Based on 150 lb. (68 kg) patient. 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; 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 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 (7.1) ] . 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 to 30 units/kg followed by an infusion rate of 1,500 units to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

The use of HEPARIN SODIUM in 0.45% SODIUM CHLORIDE INJECTION is contraindicated in patients with the following conditions: History of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITT) [ see Warnings and Precautions (5.3) ] Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [ see Warnings and Precautions (5.7) and 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 (5.5) ] Uncontrollable active bleeding state except when this is due to disseminated intravascular coagulation [see Warnings and Precautions (5.2) ] History of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITT) (5.3) Known hypersensitivity to heparin or pork products (5.7) In whom suitable blood coagulation tests cannot be performed at appropriate intervals (5.5) Uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation (5.2)

The following serious 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) ] 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 or HITT, hypersensitivity reactions, heparin resistance, hyperkalemia, and elevations of aminotransferase levels. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Postmarketing Experience The following adverse reactions have been identified during post-approval use of heparin sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. Hemorrhage – Hemorrhage is the chief complication that may result from heparin therapy [ see Warnings and Precautions (5.2) ] . 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 with heparin therapy, including fatal cases. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. Retroperitoneal hemorrhage. Vascular Disorders – Contusion, Vasospastic reactions (including episodes of painful, ischemic, and cyanosed limbs). HIT and HITT, including delayed onset cases, and Thrombocytopenia – [ see Warnings and Precautions (5.3 and 5.4) ] 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 (5.7) ] . 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. 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.

Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding. (7) 7.1 Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained. 7.2 Platelet Inhibitors Drugs such as NSAIDS (including acetylsalicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIv/IIa antagonists (including abciximab, 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 Medications that May Interfere with Heparin Digitalis, tetracyclines, nicotine, 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. 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).