Heparin Sodium

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 Hepalink USA Inc. at 1-888-355-1375 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

History of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITTS) ( 4 ) Known hypersensitivity to heparin or pork products ( 4 ) In whom suitable blood coagulation tests cannot be performed at appropriate intervals ( 4 ) An uncontrolled bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

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 subunits): Heparin sodium injection, USP (porcine), preservative free, is available as follows: Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 9 mg sodium chloride; Water for Injection q.s. made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Heparin sodium injection, USP (porcine), preserved with benzyl alcohol, is available as follows: Each mL of the 5,000 units per mL preparation contains: 5,000 USP Heparin units (porcine); 6 mg sodium chloride; 15 mg benzyl alcohol (as a preservative); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5). Heparin Sodium Injection, USP (porcine), preserved with parabens, is available as follows: Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 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 (5.0 to 7.5). Each mL of the 5,000 units per mL preparation contains: 5,000 USP Heparin units (porcine); 5 mg sodium chloride; 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 (5.0 to 7.5). Each mL of the 10,000 units per mL preparation contains: 10,000 USP Heparin units (porcine); 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 (5.0 to 7.5). Each mL of the 20,000 units per mL preparation contains: 20,000 USP Heparin units (porcine); 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 (5.0 to 7.5). Heparin Chemical Structure

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 to 20,000 units of a concentrated solution, subcutaneously Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 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 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring.

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

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 1/2 hour 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 labeling of Protamine Sulfate Injection.

Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding ( 7.2 )

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, they are not measurably affected by low doses of heparin. The bleeding time is usually unaffected by heparin. 12.3 Pharmacokinetics Absorption Heparin is not absorbed through the gastrointestinal tract and therefore administered via parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration. Distribution Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg. Elimination Metabolism Heparin does not undergo enzymatic degradation. Excretion Heparin is mainly cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero order process due to binding to proteins, endothelial cells and macrophage) and b) slower first order elimination. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h. Specific Populations Geriatric patients Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (aPTTs) compared with patients under 60 years of age [see Use in Specific Populations ( 8.5 )] .

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Heparin Sodium Injection, USP (porcine), preservative free 2 mL single-dose vial contains 2,000 USP units Heparin sodium injection, USP contains benzyl alcohol: 10 mL multiple-dose vial contains 50,000 USP units Heparin sodium injection, USP contains parabens: 1 mL multiple-dose vial contains 1,000 USP units 10 mL multiple-dose vial contains 10,000 USP units 30 mL multiple-dose vial contains 30,000 USP units 1 mL multiple-dose vial contains 5,000 USP units 1 mL multiple-dose vial contains 10,000 USP units 5 mL multiple-dose vial contains 50,000 USP units 1 mL multiple-dose vial contains 20,000 USP units

Heparin Sodium Heparin Sodium HYDROCHLORIC ACID SODIUM HYDROXIDE HEPARIN SODIUM HEPARIN METHYLPARABEN PROPYLPARABEN WATER Heparin Sodium Heparin Sodium METHYLPARABEN PROPYLPARABEN WATER HYDROCHLORIC ACID SODIUM HYDROXIDE HEPARIN SODIUM HEPARIN Heparin Sodium Heparin Sodium SODIUM CHLORIDE METHYLPARABEN PROPYLPARABEN WATER HYDROCHLORIC ACID SODIUM HYDROXIDE HEPARIN SODIUM HEPARIN Heparin Sodium Heparin Sodium SODIUM CHLORIDE METHYLPARABEN PROPYLPARABEN WATER HYDROCHLORIC ACID SODIUM HYDROXIDE HEPARIN SODIUM HEPARIN Heparin Sodium Heparin Sodium SODIUM HYDROXIDE HYDROCHLORIC ACID WATER SODIUM CHLORIDE HEPARIN SODIUM HEPARIN Heparin Sodium Heparin Sodium SODIUM HYDROXIDE HYDROCHLORIC ACID WATER SODIUM CHLORIDE HEPARIN SODIUM HEPARIN BENZYL ALCOHOL

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

ANDA202957

Heparin Sodium

Heparin Sodium

81952-111

HUMAN PRESCRIPTION DRUG

INTRAVENOUS,SUBCUTANEOUS

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 5,000 USP Units/mL - 1 mL Container Label NDC 81952-111-01 Rx only HEPARIN SODIUM INJECTION, USP 5,000 USP Units/mL NOT FOR LOCK FLUSH For IV or SC use Multiple Dose Vial 1 mL heparin-fig1

17 PATIENT COUNSELING INFORMATION Hemorrhage Inform patients that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they are treated with heparin, and that they should report any unusual bleeding or bruising to their physician. Hemorrhage can occur at virtually any site in patients receiving heparin. Fatal hemorrhages have occurred [see Warnings and Precautions ( 5.2 )] . Prior to Surgery Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is scheduled [see Warnings and Precautions ( 5.2 )] . Heparin-Induced Thrombocytopenia Inform patients of the risk of heparin-induced thrombocytopenia (HIT). HIT may progress to the development of venous and arterial thromboses, a condition known as heparin-induced thrombocytopenia and thrombosis (HITT). HIT and HITT can occur up to several weeks after the discontinuation of heparin therapy [see Warnings and Precautions ( 5.3 )] . Hypersensitivity Inform patients that generalized hypersensitivity reactions have been reported. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions ( 5.8 ), Adverse Reactions ( 6.1 )] . Other Medications Because of the risk of hemorrhage, advise patients to inform their physicians and dentists of all medications they are taking, including non-prescription medications, and before starting any new medication [see Drug Interactions ( 7.1 )] . Manufactured by: Shenzhen Techdow Pharmaceutical Co., Ltd. 19 Gaoxinzhongyi Road, Nanshan District, Shenzhen, P.R. China, 518057 Distributed by: Hepalink USA Inc. Langhorne, PA19047-1885 Toll Free: 1-888-355-1375

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 ) See 17 for PATIENT COUNSELING INFORMATION

16 HOW SUPPLIED Heparin sodium injection, USP (porcine), preservative free , is available as follows: NDC Number Concentration Vial Fill Volume Vial Type Pack Size 81952-115-07 1,000 USP Heparin Units/mL 2 mL Single-Dose Vial Carton of 25 vials Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made with natural rubber latex. Discard unused portion. Heparin Sodium Injection, USP (porcine) contains benzyl alcohol and is available as follows: NDC Number Concentration Vial Fill Volume Vial Type Pack Size 81952-114-09 5,000 USP Heparin Units/mL 10 mL Multiple-Dose Vial Carton of 25 vials Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made with natural rubber latex. Heparin Sodium Injection, USP (porcine) contains parabens and is available as follows: NDC Number Concentration Vial Fill Volume Vial Type Pack Size 81952-112-06 1,000 USP Heparin Units/mL 1 mL Multiple-Dose Vial Carton of 25 vials 81952-112-09 1,000 USP Heparin Units/mL 10 mL Multiple-Dose Vial Carton of 25 vials 81952-112-10 1,000 USP Heparin Units/mL 30 mL Multiple-Dose Vial Carton of 25 vials 81952-111-06 5,000 USP Heparin Units/mL 1 mL Multiple-Dose Vial Carton of 25 vials 81952-113-06 10,000 USP Heparin Units/mL 1 mL Multiple-Dose Vial Carton of 25 vials 81952-113-08 10,000 USP Heparin Units/mL 5 mL Multiple-Dose Vial Carton of 25 vials 81952-116-06 20,000 USP Heparin Units/mL 1 mL Multiple-Dose Vial Carton of 25 vials Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made with natural rubber latex. STORAGE: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].