Heparin Sodium

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Fatal Medication Errors [see Warnings and Precautions (5.1) ] • Hemorrhage [see Warnings and Precautions (5.2) ] • Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) [see Warnings and Precautions (5.3) ] • Thrombocytopenia [see Warnings and Precautions (5.4) ] • Heparin Resistance [see Warnings and Precautions (5.6) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.7) ] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT (With or Without Thrombosis), local irritation, hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Postmarketing Experience The following adverse reactions have been identified during post-approval use of heparin sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hemorrhage Hemorrhage is the chief complication that may result from heparin therapy [see Warnings and Precautions (5.2) ]. 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: a. Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient's death. b. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication if unrecognized may be fatal. c. Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis) : [see Warnings and Precautions ( 5.3 , 5.4 )] Local Irritation Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. Hypersensitivity Generalized hypersensitivity reactions have been reported with chills, fever, and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar site of the feet, may occur [see Warnings and Precautions (5.7) ] . Episodes of painful, ischemic, and cyanosed limbs have been reported with heparin use. Elevations of Serum Aminotransferases Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in a high percentage of patients(and healthy subjects) who have received heparin. Others Osteoporosis following long-term administration of high-doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia.

4 CONTRAINDICATIONS The use of heparin sodium is contraindicated in patients: • With history of heparin-induced thrombocytopenia (HIT) (With or Without Thrombosis) [see Warnings and Precautions (5.3) ] • With a known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.1) ] • In whom suitable blood coagulation tests — e.g., the whole blood clotting time, partial thromboplastin time, etc., — cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin) [see Warnings and Precautions (5.5) ] • With an uncontrollable active bleeding state [see Warnings and Precautions (5.5) ] , except when treating disseminated intravascular coagulation • History of Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) ( 4 ) • Known hypersensitivity to heparin or pork products ( 4 ) • In whom suitable blood coagulation tests cannot be performed at appropriate intervals ( 4 ) • With an uncontrollable active bleeding state, except when treating disseminated intravascular coagulation ( 4 )

11 DESCRIPTION Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans possessing anticoagulant properties. It is composed of polymers of alternating derivations of α-D-glucosamido ( N -Sulfated O -Sulfated or N -acetylated) and O -sulfated uronic acid (α-L-iduronic acid or β-D-glucoronic acid). Structure of Heparin Sodium (representative subunits): HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION is a sterile preparation of heparin sodium (derived from porcine intestinal mucosa) for intravenous administration. It contains no bacteriostatic or antimicrobial agent or added buffer. The solution may contain sodium hydroxide and/or hydrochloric acid for pH adjustment. The pH range is 6.1 (5.0 – 7.5) and the osmolarity mOsmol/L (calc.) is 155. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Each mL of the 50 USP units per mL preparations contains: 50 USP units of heparin sodium, 4.5 mg sodium chloride and 0.1 mg edetate disodium, anhydrous added as a stabilizer. Each mL of the 100 USP units per mL preparations contains: 100 USP units of heparin sodium, 4.5 mg sodium chloride and 0.1 mg edetate disodium, anhydrous added as a stabilizer. structural formula for heparin

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosages: • Therapeutic Anticoagulant Effect with Full-Dose Heparin* ( 2.3 ) Intermittent Intravenous Injection Initial Dose 10,000 Units Every 4 to 6 hours 5,000 Units to 10,000 Units Continuous Intravenous Infusion Initial Dose 5,000 Units Continuous 20,000 Units to 40,000 Units/24 hours *Based on 150 lb (68 kg) patient. • Cardiovascular Surgery ( 2.5 ) Intravascular via Total Body Perfusion Initial Dose Not less than 150 units/kg; adjust for longer procedures • Extracorporeal Dialysis ( 2.8 ) For pediatric dosing see section 2.4 of full prescribing information. Intravascular via Extracorporeal Dialysis Follow equipment manufacturer's operating directions carefully. 2.1 Preparation for Administration Confirm the selection of the correct formulation and strength prior to administration of the drug. Do not use HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION as a "catheter lock flush" product. Administer this product by intravenous infusion. Do not admix with other drugs. This product should not be infused under pressure. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless the solution is clear and container is undamaged. Discard unused portion To Open Tear outer wrap and remove solution container. For PVC bags, some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. (Use aseptic technique) 1. Close flow control clamp of administration set. 2. Remove cover from outlet port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: See full directions on administration set carton. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Open flow control clamp and clear air from set. Close clamp. 7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. 8. Regulate rate of administration with flow control clamp. Warning: Do not use flexible container in series connections. 2.2 Laboratory Monitoring for Efficacy and Safety The dosage of heparin sodium should be adjusted according to the patient's coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed 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 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 Method of Administration Frequency Recommended Dose Based on 150 lb. (68 kg) patient. Intermittent Intravenous Injection Initial Dose 10,000 Units Every 4 to 6 hours 5,000 Units to 10,000 Units Continuous Intravenous Infusion Initial Dose 5,000 Units by intravenous injection Continuous 20,000 Units to 40,000 Units/24 hours 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 units to 100 units/kg (intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 units/kg/hour to 30 units/kg/hour; Infants less than 2 months have the highest requirements (average 28 units/kg/hour) Children greater than 1 year of age: 18 units/kg/hour 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 seconds 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 an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a 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. 2.6 Converting to Warfarin To ensure continuous anticoagulation when converting from heparin sodium to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.4) ] . 2.7 Converting 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 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.8 Extracorporeal Dialysis Follow equipment manufacturer's operating directions carefully. A 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.

1 INDICATIONS AND USAGE HEPARIN SODIUM IN SODIUM CHLORIDE 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. HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION is indicated for: ( 1 ) • 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

10 OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment 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 ½ hour after intravenous injection. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information, the labeling of Protamine Sulfate Injection, USP products should be consulted.

7 DRUG INTERACTIONS Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding. ( 7 ) 7.1 Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained. 7.2 Platelet Inhibitors Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine 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 Other Interactions Digitalis, tetracyclines, nicotine, or antihistamines, or intravenous nitroglycerin 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. 7.4 Drug/Laboratory Tests Interactions Prothrombin time – Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with warfarin, allow a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose of heparin to elapse before blood is drawn to obtain a valid prothrombin time. Hyperaminotransferasemia Significant elevations of aminotransferase AST (SGOT) and ALT (SGPT) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, rises that might be caused by drugs (like heparin) should be interpreted with caution.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo . Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. 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 Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases it is not measurably affected by low doses of heparin. 12.3 Pharmacokinetics Absorption Heparin is not absorbed through 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) ].

12.1 Mechanism of Action Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo . Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. 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 Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases it is not measurably affected by low doses of heparin.

12.3 Pharmacokinetics Absorption Heparin is not absorbed through 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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3 DOSAGE FORMS AND STRENGTHS HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION is available as: • Injection: 100 USP Units/mL in Sodium Chloride clear solution (25,000 USP Units/250 mL) in single-dose flexible plastic container • Injection: 50 USP Units/mL in Sodium Chloride clear solution (12,500 USP Units/250 mL) in single-dose flexible plastic container • Injection: 50 USP Units/mL in Sodium Chloride clear solution (25,000 USP Units/500 mL) in single-dose flexible plastic container Heparin sodium is available as: ( 3 ) • Injection: 100 USP Units/mL in Sodium Chloride clear solution (25,000 USP Units/250 mL) in single-dose flexible plastic container • Injection: 50 USP Units/mL in Sodium Chloride clear solution (12,500 USP Units/250 mL) in single-dose flexible plastic container • Injection: 50 USP Units/mL in Sodium Chloride clear solution (25,000 USP Units/500 mL) in single-dose flexible plastic container

Heparin Sodium HEPARIN SODIUM HEPARIN SODIUM HEPARIN SODIUM CHLORIDE EDETATE DISODIUM ANHYDROUS SODIUM HYDROXIDE HYDROCHLORIC ACID WATER Heparin Sodium HEPARIN SODIUM HEPARIN SODIUM HEPARIN SODIUM CHLORIDE EDETATE DISODIUM ANHYDROUS SODIUM HYDROXIDE HYDROCHLORIC ACID WATER Heparin Sodium HEPARIN SODIUM HEPARIN SODIUM HEPARIN SODIUM CHLORIDE EDETATE DISODIUM ANHYDROUS SODIUM HYDROXIDE HYDROCHLORIC ACID WATER Heparin Sodium HEPARIN SODIUM HEPARIN SODIUM HEPARIN SODIUM CHLORIDE EDETATE DISODIUM ANHYDROUS SODIUM HYDROXIDE HYDROCHLORIC ACID WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies in animals to evaluate the carcinogenic potential, reproduction studies in animals to determine effects on fertility of males and females, and the studies to determine mutagenic potential have not been conducted.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies in animals to evaluate the carcinogenic potential, reproduction studies in animals to determine effects on fertility of males and females, and the studies to determine mutagenic potential have not been conducted.

NDA018916

Heparin Sodium

HEPARIN SODIUM

0409-7650

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 250 mL Bag Label - 7650 250 mL NDC 0409-7650-52 HEPARIN SODIUM 25,000 USP Units per 250 mL (100 USP Units/mL) in 0.45% Sodium Chloride Injection EACH 100 mL CONTAINS HEPARIN SODIUM 10,000 USP UNITS (PORCINE INTESTINAL MUCOSA); SODIUM CHLORIDE 0.45 g; EDETATE DISODIUM, ANHYDROUS 10 mg ADDED AS STABILIZER. MAY CONTAIN SODIUM HYDROXIDE AND/OR HYDROCHLORIC ACID FOR pH ADJUSTMENT. STERILE. NOT MADE WITH NATURAL RUBBER LATEX. USUAL DOSAGE: SEE INSERT. ADDITIVES SHOULD NOT BE MADE TO THIS SOLUTION. SINGLE DOSE CONTAINER. DISCARD UNUSED PORTION. FOR INTRAVENOUS USE ONLY. Rx only 3 V CONTAINS DEHP IM-3954 HOSPIRA, INC., LAKE FOREST, IL 60045 USA Hospira PRINCIPAL DISPLAY PANEL - 250 mL Bag Label - 7650

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 (With or Without Thrombosis) can occur up to several weeks after the discontinuation of heparin therapy [see Warnings and Precautions ( 5.3 , 5.4 )] . 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 (5.7) , 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 (7.2) ] . This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1392-3.0 Hospira logo

8.5 Geriatric Use 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) ] .

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 units to 100 units/kg (intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 units/kg/hour to 30 units/kg/hour; Infants less than 2 months have the highest requirements (average 28 units/kg/hour) Children greater than 1 year of age: 18 units/kg/hour 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 seconds to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70.

8.1 Pregnancy Risk Summary There are no available data on HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION 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 up to 10,000 USP units/kg/day, 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 IN SODIUM CHLORIDE INJECTION to a pregnant woman and possible risks to the fetus when prescribing HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION. 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 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION 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 up to 10,000 USP units/kg/day, 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 IN SODIUM CHLORIDE INJECTION to a pregnant woman and possible risks to the fetus when prescribing HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION. 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 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 SODIUM CHLORIDE INJECTION 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 nursing child. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION and any potential adverse effects on the breastfed child from HEPARIN SODIUM IN SODIUM CHLORIDE 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 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) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Intravenous solutions with HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION are supplied in single-dose flexible plastic containers in varied sizes and concentrations as shown in the accompanying Table. Unit of Sale Concentration NDC 0409-7650-62 Case of 24 Single-dose flexible plastic containers 25,000 USP units/250 mL (100 USP units/mL) NDC 0409-7650-30 Case of 30 Single-dose flexible plastic containers 25,000 USP units/250 mL (100 USP units/mL) NDC 0409-7651-62 Case of 24 Single-dose flexible plastic containers 12,500 USP units/250 mL (50 USP units/mL) NDC 0409-0012-30 Case of 30 Single-dose flexible plastic containers 12,500 USP units/250 mL (50 USP units/mL) NDC 0409-7651-03 Case of 24 Single-dose flexible plastic containers 25,000 USP units/500 mL (50 USP units/mL) NDC 0409-3150-20 Case of 20 Single-dose flexible plastic containers 25,000 USP units/500 mL (50 USP units/mL) Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Protect from freezing.