Heparin Sodium

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

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/24 hours to 40,000 Units/24 hours 2.4 Pediatric Use There are no adequate and well-controlled studies on heparin use in pediatric …

5 WARNINGS AND PRECAUTIONS • Fatal Medication Errors: Confirm choice of correct strength prior to administration ( 5.1 ) • Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage ( 5.2 ) • HIT (With or Without Thrombosis): Monitor for signs and symptoms and discontinue if indicative of HIT (With or Without Thrombosis) ( 5.3 ) • Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Monitor platelet count and hematocrit in all patients receiving heparin ( 5.6 ) • Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients ( 5.9 ) 5.1 Fatal Medication Errors Do not use this product as a "catheter lock flush" product. Heparin is supplied in various strengths. Fatal hemorrhages have occurred due to medication errors. Carefully examine all heparin products to confirm the correct container choice prior to administration of the drug. 5.2 Hemorrhage Hemorrhage, including fatal events, has occurred in patients receiving heparin sodium. Avoid using heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the potential risks. 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) ] . A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical Pharmacology (12.3) ] . These patients may require a lower dose . An unexplained fall in hematocrit or fall in blood pressure should lead to serious consideration of a 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 tap 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 and continuous tube drainage of the stomach or small intestine. • Other — Menstruation, liver disease with impaired hemostasis. 5.3 Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) HIT is a serious immune-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition known as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and fatal outcomes. Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used. Future use of heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/m…

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 (5.6) ] • With an uncontrollable active bleeding state [see Warnings and Precautions (5.6) ] , 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 )

7 DRUG INTERACTIONS • Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding ( 7 ) • Andexanet alfa may reduce the efficacy of heparin when used concomitantly ( 7.3 ) 7.1 Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained. 7.2 Platelet Inhibitors Drugs such as 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 Unresponsiveness to Heparin With Concomitant Use With Andexanet Alfa Andexanet binds to heparin-bound antithrombin III (ATIII) and may reduce the anticoagulant effect of heparin. Unresponsiveness to unfractionated heparin may lead to serious and life-threatening thrombotic events. Use of andexanet alfa as an antidote for heparin has not been established. Avoid use of heparin after use of andexanet alfa for the reversal of direct Factor Xa inhibitors (apixaban and rivaroxaban). If anticoagulation is needed, use an alternative anticoagulant to heparin [see Warnings and Precautions (5.4) ] . 7.4 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. 7.5 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.

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.

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 (5.5) ] • Heparin Resistance [see Warnings and Precautions (5.7) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] • Hyperkalemia [see Warnings and Precautions (5.9) ] 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 , 5.5 )] 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 (5.8) ] . Episodes of painful, ischemic, and cyanosed limbs have been reported with heparin use. Metabolism and Nutrition Disorders – Hyperkalemia. 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 inje…