HEPARIN SODIUM 10000 [USP'U]/100mL Injection, Solution

5.1Fatal 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.

5.2Hemorrhage 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.

5.3Heparin-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/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation.

Delayed Onset of HIT (With or Without Thrombosis): Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) 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 (With or Without Thrombosis).

5.4Unresponsiveness to Heparin with Concomitant Use With Andexanet Alfa Unresponsiveness to unfractionated heparin leading to non-prolongation of activated…

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)]

6.1Postmarketing 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 injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia.

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 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.

7.3Unresponsiveness 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 (5.4)].

7.4Other 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.

7.5Drug/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.