HEPARIN SODIUM

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, anhydrous, 37 mg and dibasic sodium phosphate, heptahydrate, 430 mg added as buffers. Each liter contains the following electrolytes: Sodium 186.1 mEq; phosphate (as HPO 4 =) 32.1 mEq; citrate 5.8 mEq; and chloride 153.9 mEq. Osmolar concentration, 358 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, anhydrous is chemically designated C 6 H 8 O 7, 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 free flex ® container closure system is not made from natural rubber latex, is Non-PVC and Non-DEHP. 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. Heparin Sodium Structural Formula Citric Acid Structural Formula

Heparin Sodium Injection in Sodium Chloride at a concentration of 2 units/mL is indicated as an anticoagulant to maintain catheter patency. HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION at a concentration of 2 units/mL is indicated as an anticoagulant to maintain catheter patency. ( 1 )

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. INSTRUCTIONS FOR USE for the free flex ® Bag Leave bag in the overwrap until time of use. The intact port cap provides visual tamper evidence. Do not use if port cap is prematurely removed. Maintain strict aseptic technique during handling. To Open: Always inspect the bag before and after removal from the overwrap. Place the bag on a clean, flat surface. Starting in the bottom corner, peel the overwrap open and remove the bag. Check the bag for leaks by squeezing firmly. If leaks are found, discard the bag. Do not use if the solution is cloudy or a precipitate is present. To Prepare for Administration: Immediately before connecting the infusion set, firmly grasp the BLUE infusion port cap with the arrow pointing away from the bag between index finger and thumb. Gently break off the port cap. The membrane of the infusion port is sterile, and disinfection before initial use is not necessary if proper aseptic handling technique is followed. Use a non-vented infusion set or close the air-inlet on a vented set. The BLUE infusion port is compatible with spike systems produced according to ISO 8536-4, with an external spike diameter of 5.5 to 5.7 mm. Close the roller clamp of the infusion set. Hold the base of the BLUE infusion port and insert the spike by rotating your wrist slightly until the spike is fully inserted. The port membrane contains a self-sealing septum that helps prevent leakage after removing the spike. The infusion port is not intended to be spiked more than once. Hang from the hole at the top of the bag. For Single Use Only. Discard unused portion. 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.

The use of HEPARIN SODIUM IN SODIUM CHLORIDE is contraindicated in patients with the following conditions: Uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation [see Warnings and Precautions ( 5.1 )] History of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) [see Warnings and Precautions ( 5.2 )] Severe thrombocytopenia [see Warnings and Precautions ( 5.3 )] Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6.1 )] Heparin Sodium in Sodium Chloride Injection is contraindicated in patients with the following conditions: ( 4 ) Uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation ( 5.1 ) History of heparin-induced thrombocytopenia (HIT) and heparin induced thrombocytopenia with thrombosis ( 5.2 ) Severe thrombocytopenia ( 5.3 ) Known hypersensitivity to heparin or pork products ( 5.5 , 6.1 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.1 )] Heparin-Induced Thrombocytopenia and Heparin-Induced thrombocytopenia with Thrombosis [see Warnings and Precautions ( 5.2 )] Thrombocytopenia [see Warnings and Precautions ( 5.3 )] Heparin Resistance [see Warnings and Precautions ( 5.4 )] Hypersensitivity [see Warnings and Precautions ( 5.5 )] Increased Risk of Bleeding in Older Patients, Especially Women [see Warnings and Precautions ( 5.6 )] Most common adverse reactions are: hemorrhage, thrombocytopenia, HIT and HITT, hypersensitivity, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hemorrhage - Hemorrhage is the chief complication that may result from heparin therapy [see Warnings and Precautions ( 5.1 )] . An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug [see Overdosage ( 10 )]. Gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect: - Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy, including fatal cases. - Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. - Retroperitoneal hemorrhage. HIT and HITT, including delayed onset [see Warnings and Precautions ( 5.2 )] Histamine-like reactions: Such reactions have been observed at the site of injections. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin, occasionally requiring skin grafting. Hypersensitivity - Generalized hypersensitivity reactions have been reported with chills, fever, and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar site of the feet, may occur [see Warnings and Precautions ( 5.5 )]. Elevations of serum aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Others - Osteoporosis following long-term administration of high-doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported.

Drugs that interfere with platelet aggregation or drugs that counteract coagulation may induce bleeding. ( 7 ) 7.1 Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained. 7.2 Platelet Inhibitors Drugs such as NSAIDS (including acetylsalicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIv/IIa antagonists (including abciximab, eptifobatide, and tirofiban), and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. To reduce the risk of bleeding, a reduction in the dose of the antiplatelet agent or heparin is recommended. 7.3 Other Medications that May Interfere with Heparin Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin. Antithrombin III (human) – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage of heparin is recommended during treatment with antithrombin III (human).