HEPARIN SODIUM IN SODIUM CHLORIDE

Dosage and Administration Preparation of Administration ( 2.1 ) 01/2022 Warnings and Precautions ( 5.2 , 5.6 , 5.7 ) 01/2022

1 INDICATIONS & USAGE Heparin sodium is indicated for: Prophylaxis and treatment of venous thromboembolism and 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; Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures.

2 DOSAGE & ADMINISTRATION 2.1 Preparation for Administration Confirm the selection of the correct formulation and strength prior to administration of the drug. INSTRUCTIONS FOR USE for the freeflex® 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. Do not admix with other drugs. Do not use flexible container in series connections. 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 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 * 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 to 100 units/kg (intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants 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 …

3 DOSAGE FORM & STRENGTHS Heparin Sodium in 0.45% Sodium Chloride Injection is available as: Injection: 50 USP units per mL in 0.45% Sodium Chloride clear solution (25,000 USP units per 500 mL) in single-dose freeflex® bag Injection: 100 USP units per mL in 0.45% Sodium Chloride clear solution (25,000 USP units per 250 mL) in single-dose freeflex® bag Heparin Sodium in 5% Dextrose Injection is available as: Injection: 50 USP units per mL in 5% Dextrose clear solution (25,000 USP units per 500 mL) in single-dose freeflex® bag Injection: 100 USP units per mL in 5% Dextrose clear solution (25,000 USP units per 250 mL) in single-dose freeflex® bag

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 , 5.3) ] • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.1) ] Heparin Sodium in Sodium Chloride Injection is contraindicated in patients with the following conditions: ( 4 ) • With an uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation ( 5.1 ) • With a history of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia with thrombosis (HITT) ( 5.2 ) • With severe thrombocytopenia ( 5.2 , 5.3 ) • Known hypersensitivity to heparin or pork products ( 5.5 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [see Warnings and Precautions (5.1) ] • Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia with Thrombosis [see Warnings and Precautions (5.2) ] • Thrombocytopenia [see Warnings and Precautions (5.3) ] • Heparin Resistance [see Warnings and Precautions (5.4) ] • Hypersensitivity [see Warnings and Precautions (5.5) ] • Hyperkalemia [see Warnings and Precautions (5.6) ] • Elevations of Serum Aminotransferases [see Warnings and Precautions (5.7) ] Most common adverse reactions are: hemorrhage, thrombocytopenia, HIT and HITT, hypersensitivity, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 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 the 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 (5.1) ]. 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 cases, Thrombocytopenia [see Warnings and Precautions (5.2 , 5.3) ]. 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 : General 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) ]. 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 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 ( 7.2 ) 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 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 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 POPULATONS 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 40,000 units/24 hours infusion (see Data). Consider the benefits and risks of Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection to a pregnant woman and possible risks to the fetus when prescribing Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection to a pregnant woman. 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 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 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 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose 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 in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection and any potential adverse effects on the breastfed infant from Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose 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 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 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 )].

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 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.

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. Heparin Sodium in Sodium Chloride Injection is a buffered, sterile, nonpyrogenic solution of Heparin Sodium, USP derived from porcine intestinal mucosa, standardized for anticoagulant activity supplied in single dose containers for vascular administration. It contains no antimicrobial agents. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Table 1. Composition, Osmolarity, pH, and Ionic Concentration of Heparin in 0.9% Sodium Chloride Injection Product Description and Size 1,000 USP Heparin Units in 0.9% Sodium Chloride Injection, 500 mL 1,000 USP Heparin Units in 0.9% Sodium Chloride Injection, 500 mL 2,000 USP Heparin Units in 0.9% Sodium Chloride Injection, 1,000 mL 2,000 USP Heparin Units in 0.9% Sodium Chloride Injection, 1,000 mL NDC# 0338-0431-03 0338-0424-18 0338-0433-04 0338-0428-12 Manufacturing Location Jayuya, PR Toongabbie, AUS Jayuya, PR Toongabbie, AUS Heparin Sodium, USP (units/mL) 2 2 2 2 Sodium Chloride, USP (NaCl) (g/L) 9 9 9 9 Dibasic Sodium Phosphate Heptahydrate, USP (Na 2 HPO 4 *7H 2 O) (g/L) 4.34 ---- 4.34 ---- Dibasic Sodium Phosphate Dodecahydrate, USP (Na 2 HPO 4 *12H 2 O) (g/L) ---- 5.80 ---- 5.80 Citric Acid Hydrous, USP (C 6 H 8 O 7 *H 2 O) (g/L) 0.4 0.4 0.4 0.4 Osmolarity Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. (mOsmol/L) 322 322 322 322 pH 7.0 (6.0 to 8.0) 7.0 (6.0 to 8.0) 7.0 (6.0 to 8.0) 7.0 (6.0 to 8.0) Sodium (mEq/L) 186 186 186 186 Chloride (mEq/L) 154 154 154 154 Phosphate (as HPO 4 = ) (mEq/L) 32 (16 mmol/L) 32 (16 mmol/L) 32 (16 mmol/L) 32 (16 mmol/L) Citrate (mEq/L) 6 6 6 6 This VIAFLEX PLUS plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). VIAFLEX PLUS on the container indicates the presence of a drug additive in a drug vehicle. The VIAFLEX PLUS plastic container system utilizes the same container as the VIAFLEX plastic container system. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g ., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. Heparin Sodium Structural Formula

10 OVERDOSAGE An overdose requires immediate medical attention and treatment. 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. 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 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. Blood or plasma transfusions may be necessary; these dilute but do not neutralize heparin.

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium in Sodium Chloride Injection in VIAFLEX PLUS plastic container is supplied as follows: Product Description Size Code NDC 1,000 USP Heparin Units in Sodium Chloride Injection 500 mL 2B0953 0338-0431-03 1,000 USP Heparin Units in Sodium Chloride Injection 500 mL AHB0953U 0338-0424-18 2,000 USP Heparin Units in Sodium Chloride Injection 1,000 mL 2B0944 0338-0433-04 2,000 USP Heparin Units in Sodium Chloride Injection 1,000 mL AHB0944U 0338-0428-12 Store at 25°C (77°F). Brief exposure up to 40°C (104°F) does not adversely affect the product. Avoid excessive heat.