Heparin Sodium

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 and HITT: Monitor for signs and symptoms and discontinue if indicative of HIT and HITT ( 5.3 ) Monitoring: Blood coagulation tests guide therapy for full-dose heparin sodium Monitor platelet count and hematocrit in all patients receiving heparin sodium ( 5.5 , 5.6 ) Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients ( 5.8 ) 5.1 Fatal Medication Errors Do not use heparin sodium injection as a “catheter lock flush” product. Heparin sodium injection is supplied in syringes containing a highly concentrated solution of 10,000 units in 1 mL (5,000 units per 0.5 mL). Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL heparin sodium injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all heparin sodium injection syringes to confirm the correct syringe choice prior to administration of the drug. 5.2 Hemorrhage Avoid using heparin sodium in the presence of major bleeding, except when the benefits of heparin sodium therapy outweigh the potential risks. Hemorrhage can occur at virtually any site in patients receiving heparin sodium. Fatal hemorrhages have occurred. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin sodium [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, fall in blood pressure or any other unexplained symptom 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 sodium 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 sodium 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 Sodium-Induced Thrombocytopenia and Heparin Sodium-Induced Thrombocytopenia and Thrombosis Heparin sodium-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction. HIT occurs in patients treated with heparin sodium 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 referred to as heparin sodium-induced thrombocytopenia with 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. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin sodium, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin sodium therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.4 Thrombocytopenia Thrombocytopenia in patients receiving heparin sodium has been reported at frequencies up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin sodium therapy. Obtain platelet counts before and periodically during heparin sodium therapy. Monitor thrombocytopenia of any degree closely. If the count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin sodium, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions ( 5.3 )]. 5.5 Coagulation Testing and Monitoring When using a full dose heparin sodium regimen, adjust the heparin sodium dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin sodium promptly [see Overdosage ( 10 )] . Periodic platelet counts and hematocrits are recommended during the entire course of heparin sodium therapy, regardless of the route of administration [see Dosage and Administration ( 2.2 )] . 5.6 Heparin Sodium Resistance Resistance to heparin sodium 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 sodium doses based on anti-Factor Xa levels may be warranted. 5.7 Hypersensitivity Patients with documented hypersensitivity to heparin sodium should be given the drug only in clearly life- threatening situations. Because heparin sodium is derived from animal tissue, it should be used with caution in patients with a history of allergy. 5.8 Hyperkalemia Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin. Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.2 )] Heparin Sodium-Induced Thrombocytopenia and Heparin Sodium-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions ( 5.3 )] Thrombocytopenia [see Warnings and Precautions ( 5.4 )] Heparin Sodium Resistance [see Warnings and Precautions ( 5.6 )] Hypersensitivity [see Warnings and Precautions ( 5.7 )] Hyperkalemia [see Warnings and Precautions ( 5.8 )] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITT, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 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 injection. 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 is the chief complication that may result from heparin sodium 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: Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin sodium therapy, including fatal cases. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term heparin sodium 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 may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. Histamine-like reactions – Such reactions have been observed at the site of injections. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin sodium, 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, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring less frequently. Itching and burning, especially on the plantar side of the feet, may occur [see Warnings and Precautions ( 5.7 )]. Elevations of aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin sodium. Miscellaneous - Osteoporosis following long-term administration of high doses of heparin sodium, 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. Metabolism and Nutrition Disorders – Hyperkalemia.