ADVERSE REACTIONS SECTION.


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)] 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)] 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 Pfizer at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Postmarketing Experience The following adverse reactions have been identified during post approval use of HEPARIN SODIUM INJECTION. Because these reactions are reported voluntarily from 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)]. 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 including: Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases.-Ovarian (corpus luteum) hemorrhage developed in 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 have occurred following deep subcutaneous (intrafat) injection of heparin sodium. Because such reactions occur more frequently after intramuscular administration, the IM route is not recommended.Histamine-like reactions Such reactions have been observed at the site of injection. 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; asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occur less frequently. Itching and burning, especially on the plantar site of the feet, may occur. 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 been reported.. Hemorrhage 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 including: Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases.-Ovarian (corpus luteum) hemorrhage developed in number of women of reproductive age receiving short- or long-term heparin therapy.-Retroperitoneal hemorrhage. - Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases.. -Ovarian (corpus luteum) hemorrhage developed in 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 have occurred following deep subcutaneous (intrafat) injection of heparin sodium. Because such reactions occur more frequently after intramuscular administration, the IM route is not recommended.. Histamine-like reactions Such reactions have been observed at the site of injection. 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; asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occur less frequently. Itching and burning, especially on the plantar site of the feet, may occur.. 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 been reported.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. No studies in animals have been performed addressing mutagenesis or impairment of fertility.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce 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 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. AbsorptionHeparin 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.. DistributionHeparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg.. Elimination. MetabolismHeparin does not undergo enzymatic degradation.. ExcretionHeparin 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 h.. Specific Populations. Geriatric patientsPatients 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)].

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. The use of HEPARIN SODIUM INJECTION is contraindicated in patients:History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosisHistory of thrombocytopenia with pentosan polysulfateKnown 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 heparinAn uncontrollable bleeding state [see Warnings and Precautions (5.2)], except when this is due to disseminated intravascular coagulation. 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). 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).

DESCRIPTION SECTION.


11 DESCRIPTION. Heparin is heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, possessing anticoagulant properties. It is composed of polymers of alternating derivations of -D-glucosamido (N-sulfated O-sulfated or N-acetylated) and O-sulfated uronic acid (-L-iduronic acid or -D-glucuronic acid).Structure of heparin sodium (representative subunits):HEPARIN SODIUM INJECTION is sterile preparation of heparin sodium derived from porcine intestinal tissue, standardized for anticoagulant activity, in water for injection. It is intended for intravenous or deep subcutaneous administration. The potency is determined by biological assay using USP reference standard based on units of heparin activity per milligram.For formulations preserved with benzyl alcohol, each mL of the 1,000 UPS units and 5,000 USP units per mL preparations contains: heparin sodium 1,000 UPS units or 5,000 USP units; mg sodium chloride; 9.45 mg benzyl alcohol added as preservative. Each mL of the 10,000 USP units per mL preparations contains: heparin sodium 10,000 USP units; 9.45 mg benzyl alcohol added as preservative.The preservative-free product contains (per mL): 1,000 USP units of heparin sodium and mg sodium chloride.When necessary, the pH of HEPARIN SODIUM INJECTION is adjusted with hydrochloric acid and/or sodium hydroxide. The pH range is 5.0 to 7.5.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Recommended Adult Dosages:Therapeutic Anticoagulant Effect with Full-Dose Heparin Based on 68 kg patient. Adjust dose based on laboratory monitoring. (2.3)Deep Subcutaneous (Intrafat) Injection Use different site for each injection Initial Dose333 units/kg subcutaneouslyEvery 12 hours250 units/kg subcutaneouslyIntermittentIntravenous InjectionInitial Dose10,000 unitsEvery to hours5,000 units to 10,000 unitsContinuousIntravenous InfusionInitial Dose5,000 unitsContinuous20,000 units/24 hours to 40,000 units/24 hoursCardiovascular Surgery (2.5)Intravascular via Total Body PerfusionInitial Dosenot less than 150 units/kg;adjust for longer proceduresLow-dose Prophylaxis of Postoperative Thromboembolism (2.6)Deep Subcutaneous (Intrafat) InjectionInitial Dose5,000 units hours before surgeryEvery to 12 hours5,000 unitsExtracorporeal dialysis (2.9) Intravascular via Extracorporeal Dialysis25 units/kg to 30 units/kg followed by infusion rate of 1,500 units/hour to 2,000 units/hour if manufacturers recommendations are not available. Therapeutic Anticoagulant Effect with Full-Dose Heparin Based on 68 kg patient. Adjust dose based on laboratory monitoring. (2.3). Cardiovascular Surgery (2.5). Low-dose Prophylaxis of Postoperative Thromboembolism (2.6). Extracorporeal dialysis (2.9) 2.1Preparation for Administration. Confirm the choice of the correct HEPARIN SODIUM INJECTION vial to ensure that the mL vial is not confused with catheter lock flush vial or other mL vial of incorrect strength [see Warnings and Precautions (5.1)]. Confirm the selection of the correct formulation and strength prior to administration of the drug.Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains precipitate.When HEPARIN SODIUM INJECTION is added to an infusion solution for continuous intravenous (IV) administration, invert the container at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Storage of prepared infusion solution should not exceed hours at room temperature or 24 hours at to 8C (36 to 46F). HEPARIN SODIUM INJECTION is incompatible with certain substances in solution (e.g., alteplase, amikacin sulfate, atracurium besylate, ciprofloxacin, cytarabine, daunorubicin, droperidol, erythromycin lactobionate, gentamicin sulfate, idarubicin, kanamycin sulfate, mitoxantrone HCl, polymyxin sulfate, promethazine HCl, streptomycin sulfate, tobramycin sulfate). Consult specialized references to verify with which substances incompatibilities have been noted, as compatibility may depend on concentration, temperature, time, and other variables.Administer HEPARIN SODIUM INJECTION by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. HEPARIN SODIUM INJECTION is not intended for intramuscular (IM) use [see Adverse Reactions (6.1)].. 2.2Laboratory Monitoring for Efficacy and Safety. Adjust the dosage of HEPARIN SODIUM INJECTION according to the patients coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to times normal or when the whole blood clotting time is elevated approximately 2.5 to times the control value. When initiating treatment with HEPARIN SODIUM INJECTION by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous injections, tests for adequacy of dosage are best performed on samples drawn to hours after the injections.Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of HEPARIN SODIUM INJECTION therapy, regardless of the route of administration.. 2.3Therapeutic Anticoagulant Effect with Full-Dose Heparin. The dosing recommendations in Table are based on clinical experience. Although dosages 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 EffectMETHOD OF ADMINISTRATIONFREQUENCYRECOMMENDED DOSEBased on 68 kg patient Deep Subcutaneous (Intrafat) Injection Use different site for each injection to prevent the development of hematomaInitial Dose333 units/kg subcutaneouslyEvery 12 hours250 units/kg subcutaneouslyIntermittent Intravenous InjectionInitial Dose10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USPEvery to hours5,000 units to 10,000 units, either undiluted or in 50 mL to 100 mL of 0.9% Sodium Chloride Injection, USPContinuous Intravenous InfusionInitial Dose 5,000 units by intravenous injectionContinuous20,000 units to 40,000 units per 24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion. 2.4Pediatric Use. Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants.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 guideline in pediatric patients:Initial Dose75 units/kg to 100 units/kg intravenous bolus over 10 minutes)Maintenance DoseInfants: 25 units/kg/hour to 30 units/kg/hour; Infants less than months have the highest requirements (average 28 units/kg/hour)Children greater than year of age: 18 units/kg/hour to 20 units/kg/hour;Older children may require less heparin, similar to weight-adjusted adult dosageMonitoring Adjust heparin to maintain aPTT of 60 seconds to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70. 2.5Cardiovascular 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, 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.. 2.6Low-Dose Prophylaxis of Postoperative Thromboembolism. The most widely used dosage has been 5,000 units hours before surgery and 5,000 units every to 12 hours thereafter for days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with fine (25 to 26-gauge) needle to minimize tissue trauma.. 2.7Converting to Warfarin. To ensure continuous anticoagulation when converting from HEPARIN SODIUM INJECTION to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1)]. 2.8Converting 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 to hours before the time that the next dose of heparin was to have been administered.. 2.9Extracorporeal Dialysis Follow equipment manufacturers operating directions carefully. dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers recommendations are not available.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. HEPARIN SODIUM INJECTION is available as:1,000 USP units/mL preservative-free, single-dose Vial: 2,000 USP units/2 mL 1,000 USP units/mL preserved with benzyl alcohol, multiple-dose Vial: 10,000 USP units/10 mL Vial: 30,000 USP units/30 mL 5,000 USP units/mL preserved with benzyl alcohol, multiple-dose Vial: 50,000 USP units/10 mL Vial: 5,000 USP units/1 mL10,000 USP units/mL preserved with benzyl alcohol, multiple-dose Vial: 10,000 USP units/1 mL. 1,000 USP units/mL preservative-free, single-dose Vial: 2,000 USP units/2 mL. 1,000 USP units/mL preserved with benzyl alcohol, multiple-dose Vial: 10,000 USP units/10 mL Vial: 30,000 USP units/30 mL. 5,000 USP units/mL preserved with benzyl alcohol, multiple-dose Vial: 50,000 USP units/10 mL Vial: 5,000 USP units/1 mL. 10,000 USP units/mL preserved with benzyl alcohol, multiple-dose Vial: 10,000 USP units/1 mL. Preservative-free, single-dosePreserved with Benzyl Alcohol, multiple-dose1,000 USP units/mL Vial: 2,000 USP units/2 mL1,000 USP units/mL Vial: 10,000 USP units/10 mL Vial: 30,000 USP units/30 mL5,000 USP units/mL Vial: 50,000 USP units/10 mL Vial: 5,000 USP units/1 mL10,000 USP units/mL Vial: 10,000 USP units/1 mL.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding (7.2). 7.1Oral Anticoagulants. Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, period of at least hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if valid prothrombin time is to be obtained.. 7.2Platelet 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.. 7.3Other 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, reduced dosage of heparin is recommended during treatment with antithrombin III (human).

GERIATRIC USE SECTION.


8.5 Geriatric Use. There are limited adequate and well-controlled studies in patients 65 years and older, however 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)].

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. HEPARIN SODIUM INJECTION preservative-free is available in the following strengths and package sizes:DESCRIPTIONNDC1,000 USP units/mL Preservative-free, 25 vials: 2,000 USP units/2 mL, single-doseDiscard unused portion 0069-0043-01HEPARIN SODIUM INJECTION preserved with benzyl alcohol is available in the following strengths and package sizes:DESCRIPTIONNDC1,000 USP units/mL 25 vials: 10,000 USP units/10 mL, multiple-dose0069-0058-01 10 vials: 30,000 USP units/30 mL, multiple-dose0069-0137-035,000 USP units/mL 25 vials: 50,000 USP units/10 mL, multiple-dose0069-0059-01 25 vials: 5,000 USP units/1 mL, multiple-dose0069-0059-0310,000 USP units/mL 25 vials: 10,000 USP units/1 mL, multiple-dose0069-0062-01. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains precipitate.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. HEPARIN SODIUM 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.. 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 INJECTION is an anticoagulant indicated for (1):Prophylaxis and treatment of venous thrombosis and pulmonary embolismProphylaxis and treatment of the thromboembolic complications associated with atrial fibrillation Treatment of acute and chronic consumption coagulopathies Prevention of clotting in arterial and cardiac surgery Prophylaxis and treatment of peripheral arterial embolism Anticoagulant use in transfusion, extracorporeal circulation, and dialysis procedures Prophylaxis and treatment of venous thrombosis and pulmonary embolism. Prophylaxis and treatment of the thromboembolic complications associated with atrial fibrillation Treatment of acute and chronic consumption coagulopathies Prevention of clotting in arterial and cardiac surgery Prophylaxis and treatment of peripheral arterial embolism Anticoagulant use in transfusion, extracorporeal circulation, and dialysis procedures.

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. HemorrhageInform 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 SurgeryAdvise patients to inform physicians and dentists that they are receiving heparin before any surgery is scheduled [see Warnings and Precautions (5.2)].. Heparin-Induced ThrombocytopeniaInform patients of the risk of heparin-induced thrombocytopenia (HIT). HIT may progress to the development of venous and arterial thromboses, 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)].. HypersensitivityInform 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 MedicationsBecause 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)].

LACTATION SECTION.


8.2Lactation. Risk SummaryThere 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 breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mothers 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 nursing infant [see Use in Specific Populations (8.4)].

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce 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 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.

NONCLINICAL TOXICOLOGY SECTION.


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. No studies in animals have been performed addressing mutagenesis or impairment of fertility.

OVERDOSAGE SECTION.


10 OVERDOSAGE. Bleeding is the chief sign of heparin overdosage.. Neutralization of Heparin EffectWhen 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 protamine dose, be assumed to have 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 10,000 USP units/10 mL Multidose Vial Label. NDC 0069-0058-02Multidose VialHeparinSodium Injection, USP10,000 USP units /10 mL(1,000 USP units/mL)Warning: ContainsBenzyl AlcoholRx only. PRINCIPAL DISPLAY PANEL 10,000 USP units/10 mL Multidose Vial Label.

PEDIATRIC USE SECTION.


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 result of medication errors [see Warnings and Precautions (5.1)].. Benzyl Alcohol ToxicityUse 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 unit who received benzyl alcohol as preservative in infusion solutions. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.When prescribing HEPARIN SODIUM INJECTION in infants consider the combined daily metabolic load of benzyl alcohol from all sources including HEPARIN SODIUM INJECTION (HEPARIN SODIUM INJECTION contains 9.45 mg of benzyl alcohol) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions (5.4)].

PHARMACODYNULLMICS SECTION.


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.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. AbsorptionHeparin 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.. DistributionHeparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg.. Elimination. MetabolismHeparin does not undergo enzymatic degradation.. ExcretionHeparin 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 h.. Specific Populations. Geriatric patientsPatients 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)].

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk SummaryThere are no available data on heparin sodium use in pregnant women to infor 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 pregnant woman and possible risks to the fetus when prescribing HEPARIN SODIUM INJECTION to 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 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 DataThe 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 DataIn published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at 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.

RECENT MAJOR CHANGES SECTION.


Contraindications (4)9/2019Warnings and Precautions (5)9/2019.

SPL UNCLASSIFIED SECTION.


2.1Preparation for Administration. Confirm the choice of the correct HEPARIN SODIUM INJECTION vial to ensure that the mL vial is not confused with catheter lock flush vial or other mL vial of incorrect strength [see Warnings and Precautions (5.1)]. Confirm the selection of the correct formulation and strength prior to administration of the drug.Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains precipitate.When HEPARIN SODIUM INJECTION is added to an infusion solution for continuous intravenous (IV) administration, invert the container at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Storage of prepared infusion solution should not exceed hours at room temperature or 24 hours at to 8C (36 to 46F). HEPARIN SODIUM INJECTION is incompatible with certain substances in solution (e.g., alteplase, amikacin sulfate, atracurium besylate, ciprofloxacin, cytarabine, daunorubicin, droperidol, erythromycin lactobionate, gentamicin sulfate, idarubicin, kanamycin sulfate, mitoxantrone HCl, polymyxin sulfate, promethazine HCl, streptomycin sulfate, tobramycin sulfate). Consult specialized references to verify with which substances incompatibilities have been noted, as compatibility may depend on concentration, temperature, time, and other variables.Administer HEPARIN SODIUM INJECTION by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. HEPARIN SODIUM INJECTION is not intended for intramuscular (IM) use [see Adverse Reactions (6.1)].

STORAGE AND HANDLING SECTION.


Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains precipitate.

USE IN SPECIFIC POPULATIONS SECTION.


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). 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 SummaryThere are no available data on heparin sodium use in pregnant women to infor 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 pregnant woman and possible risks to the fetus when prescribing HEPARIN SODIUM INJECTION to 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 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 DataThe 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 DataIn published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at 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.. 8.2Lactation. Risk SummaryThere 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 breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mothers 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 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 result of medication errors [see Warnings and Precautions (5.1)].. Benzyl Alcohol ToxicityUse 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 unit who received benzyl alcohol as preservative in infusion solutions. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.When prescribing HEPARIN SODIUM INJECTION in infants consider the combined daily metabolic load of benzyl alcohol from all sources including HEPARIN SODIUM INJECTION (HEPARIN SODIUM INJECTION contains 9.45 mg of benzyl alcohol) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions (5.4)].. 8.5 Geriatric Use. There are limited adequate and well-controlled studies in patients 65 years and older, however 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)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Fatal Medication Errors: Confirm choice of correct strength prior to administration (5.1)Hemorrhage: Hemorrhage, including fatal events, has occurred in patients receiving heparin. Use caution in conditions with increased risk of hemorrhage (5.2)HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS (5.3)Benzyl Alcohol Toxicity: Use preservative-free formulation in neonates and infants (5.4) Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Periodically monitor platelet count, hematocrit, and occult blood in stool in all patients receiving heparin (5.5, 5.6). Fatal Medication Errors: Confirm choice of correct strength prior to administration (5.1). Hemorrhage: Hemorrhage, including fatal events, has occurred in patients receiving heparin. Use caution in conditions with increased risk of hemorrhage (5.2). HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS (5.3). Benzyl Alcohol Toxicity: Use preservative-free formulation in neonates and infants (5.4). Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Periodically monitor platelet count, hematocrit, and occult blood in stool in all patients receiving heparin (5.5, 5.6). 5.1Fatal Medication Errors. Do not use HEPARIN SODIUM INJECTION as catheter lock flush product. HEPARIN SODIUM INJECTION is supplied in vials containing various strengths of heparin, including vials that contain highly concentrated solution of 10,000 units in mL. Fatal hemorrhages have occurred due to medication errors. Carefully examine all HEPARIN SODIUM INJECTION vials to confirm the correct vial choice prior to administration of the drug.. 5.2Hemorrhage. Avoid using heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the potential risks.Hemorrhage, including fatal events, has occurred in patients receiving heparin. Hemorrhage can occur at virtually any site in patients receiving heparin. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.1]). higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical Pharmacology (12.3)]. An unexplained fall in hematocrit or fall in blood pressure should lead to serious consideration of hemorrhagic event.Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage, including: Cardiovascular Subacute bacterial endocarditis, severe hypertension. Surgical During and immediately following: (a) spinal puncture or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia, and some vascular purpuras. Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy 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, reduce the heparin dose during concomitant treatment with antithrombin III (human). Gastrointestinal Ulcerative lesions, continuous tube drainage of the stomach or small intestine, and clinical settings in which stress-induced gastrointestinal hemorrhage is possible. Other Menstruation, liver disease with impaired hemostasis, severe renal disease, or in patients with indwelling catheters.. Cardiovascular Subacute bacterial endocarditis, severe hypertension.. Surgical During and immediately following: (a) spinal puncture or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye.. Hematologic Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia, and some vascular purpuras.. Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy 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, reduce the heparin dose during concomitant treatment with antithrombin III (human).. Gastrointestinal Ulcerative lesions, continuous tube drainage of the stomach or small intestine, and clinical settings in which stress-induced gastrointestinal hemorrhage is possible.. Other Menstruation, liver disease with impaired hemostasis, severe renal disease, or in patients with indwelling catheters.. 5.3Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis. Heparin-induced thrombocytopenia (HIT) is serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT occurs in patients treated with heparin and is due to the development of antibodies to platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, condition known as heparin-induced thrombocytopenia and thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Monitor thrombocytopenia of any degree closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT and HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.. 5.4Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative. Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants.Serious and fatal adverse reactions including gasping syndrome can occur in neonates and low-birth weight infants treated with benzyl alcohol-preserved formulation in infusion solutions, including HEPARIN SODIUM INJECTION. The gasping syndrome is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.When prescribing HEPARIN SODIUM INJECTION in infants consider the combined daily metabolic load of benzyl alcohol from all sources including HEPARIN SODIUM INJECTION (HEPARIN SODIUM INJECTION contains 9.45 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations (8.4)]. 5.5Thrombocytopenia. Thrombocytopenia in patients receiving heparin has been reported at frequencies up to 30%. It can occur to 20 days (average to 9) following the onset of heparin therapy. Obtain platelet counts before and periodically during heparin therapy. Monitor thrombocytopenia of any degree closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3)].. 5.6Coagulation Testing and Monitoring. When using full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage (10)]. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2)].. 5.7Heparin Resistance. Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted.. 5.8Hypersensitivity. Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations.Because HEPARIN SODIUM INJECTION is derived from animal tissue, it should be used with caution in patients with history of allergy.