Heparin Sodium

Warnings and Precautions, Unresponsiveness to Heparin with Concomitant Use with Andexanet Alfa ( 5.5 ) 9/2025

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. 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 an …

3 DOSAGE FORMS AND STRENGTHS Heparin Sodium Injection, USP preserved with benzyl alcohol is available as follows: 1,000 USP units per mL single-dose vials 5,000 USP units per mL single-dose vials 10,000 USP units per mL single-dose vials 1,000 USP units per mL multiple-dose vials 5,000 USP units per mL multiple-dose vials 10,000 USP units per mL multiple-dose vials 10,000 USP units per 10 mL (1,000 USP units per mL) multiple-dose vials 30,000 USP units per 30 mL (1,000 USP units per mL) multiple-dose vials 50,000 USP units per 10 mL (5,000 USP units per mL) multiple-dose vials 40,000 USP units per 4 mL (10,000 USP units per mL) multiple-dose vials Injection (preserved with Benzyl Alcohol) ( 3 ) Single-dose Vials 1,000 USP units per mL 5,000 USP units per mL 10,000 USP units per mL Multiple-dose Vials 1,000 USP units per mL 5,000 USP units per mL 10,000 USP units per mL 10,000 USP units per 10 mL (1,000 USP units per mL) 30,000 USP units per 30 mL (1,000 USP units per mL) 50,000 USP units per 10 mL (5,000 USP units per mL) 40,000 USP units per 4 mL (10,000 USP units per mL)

4 CONTRAINDICATIONS 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 )

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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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. • Metabolism and Nutrition Disorders – Hyperkalemia.

7 DRUG INTERACTIONS • 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).

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 infor 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 reproductive 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 USP units/24 hours infusion (see Data ) . Consider the benefits and risks of HEPARIN SODIUM INJECTION to a pregnant woman 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 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, and any heparin in milk would not be orally absorbed by a breastfed 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. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant [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 [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 low-birth weight infants in the neonatal intensive care un …

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.

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

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 30 minutes 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 prescribing information for protamine sulfate injection. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium Injection preserved with benzyl alcohol is available in the following strengths and package sizes: NDC Heparin Sodium Injection, USP (1,000 USP units per mL) Package Factor 71288- 402 -02 1,000 USP units per mL, Single-Dose Vial* 25 vials per carton 71288- 449 -02 1,000 USP units per mL, Multi-Dose Vial 25 vials per carton 71288- 402 -11 10,000 USP units per 10 mL, Multi-Dose Vial 25 vials per carton 71288- 402 -31 30,000 USP units per 30 mL, Multi-Dose Vial 25 vials per carton NDC Heparin Sodium Injection, USP (5,000 USP units per mL) Package Factor 71288- 403 -02 5,000 USP units per mL, Single-Dose Vial* 25 vials per carton 71288- 450 -02 5,000 USP units per mL, Multi-Dose Vial 25 vials per carton 71288- 403 -11 50,000 USP units per 10 mL, Multi-Dose Vial 25 vials per carton NDC Heparin Sodium Injection, USP (10,000 USP units per mL) Package Factor 71288- 404 -02 10,000 USP units per mL, Single-Dose Vial* 25 vials per carton 71288- 451 -02 10,000 USP units per mL, Multi-Dose Vial 25 vials per carton 71288- 404 -05 40,000 USP units per 4 mL, Multi-Dose Vial 25 vials per carton *Discard unused portion. Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex.