Heparin Sodium 1000 [USP'U]/mL Injection

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 ( 5.6 , 5.7 ) • Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients ( 5.10 )

5.1Fatal Medication Errors Do not use HEPARIN SODIUM INJECTION as a "catheter lock flush" product. HEPARIN SODIUM INJECTION is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 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] ) . A 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 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 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 a 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 a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a 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 t…

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 (5.6) ] • Heparin Resistance [see Warnings and Precautions (5.8) ] • Hypersensitivity [see Warnings and Precautions (5.9) ] • Hyperkalemia [see Warnings and Precautions (5.10) ] 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 a 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 a number of women of reproductive age receiving short- or long-term heparin therapy. - Retroperitoneal hemorrhage. • HIT and HITT, including delayed onset cases [see Warnings and Precautions (5.3) ] . • Local irritation – Local irritation, erythema, mild pain, hematoma, or ulceration 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. • Metabolism and Nutrition Disorders – Hyperkalemia. • 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.

7 DRUG INTERACTIONS • Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding ( 7.2 ) • Andexanet alfa may reduce the efficacy of heparin when used concomitantly ( 7.3 )

7.1Oral 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.

7.2Platelet 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.

7.3Unresponsiveness to Heparin with Concomitant Use with Andexanet Alfa Andexanet binds to heparin-bound antithrombin III (ATIII) and may reduce the anticoagulant effect of heparin. Unresponsiveness to unfractionated heparin may lead to serious and life-threatening thrombotic events. Use of andexanet alfa as an antidote for heparin has not been established.

Avoid use of heparin after use of andexanet alfa for the reversal of direct Factor Xa inhibitors (apixaban and rivaroxaban). If anticoagulation is needed, use an alternative anticoagulant to heparin [see Warnings and Precautions (5.5) ] .

7.4Other Interactions Digitalis, tetracyclines, nicotine, or antihistamines, or intravenous (IV) nitroglycerin may partially counteract the anticoagulant action of heparin sodium. Antithrombin III (human) – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage of heparin is recommended during treatment with antithrombin III (human).