HEPARIN SODIUM IN SODIUM CHLORIDE- heparin sodium in sodium chloride_injection

Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the closing sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). 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. Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, they are not measurably affected by low doses of heparin. Bleeding time is usually unaffected by heparin. Absorption Heparin is not absorbed through the 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. 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 macrophages) and b) slower first order elimination. Low doses of heparin are cleared mostly by a saturable, rapid, zero-order process. Slower first order elimination usually occurs with very high doses of heparin and is dependent on renal function. The plasma half-life is dose-dependent, and it ranges from 0. 5 to 2 hours. 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 ) Renal and Hepatic Impairment The rate of clearance of unfractionated heparin may be decreased in patients with renal or hepatic impairment. Patients with renal or hepatic impairment, following similar doses of heparin may have higher plasma levels of heparin compared with patient with normal renal and hepatic function [see Warnings and Precautions (5.

Heparin Sodium in 0. 45% 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 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.

Recommended Adult Dosages: Therapeutic Anticoagulant Effect with Full-Dose Heparin* (2. 3) Intermittent Intravenous Injection Initial Dose 10,000 Units Subsequent Doses 5,000 Units to 10,000 Units every 4 to 6 hours Continuous Intravenous Infusion Initial Dose 5,000 Units by intravenous injection Continuous 20,000 Units to 40,000 Units every 24 hours *Based on 150 lb. (68 kg) patient. Cardiovascular Surgery (2. 5) Intravascular via Total Body Perfusion Initial Dose Greater than or equal to 150 units/kg; adjust for longer procedures Extracorporeal Dialysis (2. 8) Intravascular via Extracorporeal Dialysis Follow equipment manufacturer’s operating directions carefully. For pediatric dosing, see section 2. 4 Confirm the selection of the correct formulation and strength prior to administration of the drug. This product should be administered by intravenous infusion only. Do not use Heparin Sodium in 0. 45% Sodium Chloride Injection as a “catheter lock flush” product. Do not admix with other drugs. Discard unused portion. Do not use plastic containers in series connection. 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. Use only if solution is clear and container and seals are intact. Adjust the dosage of heparin sodium according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, determine the coagulation time approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, perform coagulation tests 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 the 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. 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* Intermittent Intravenous Injection Initial Dose 10,000 Units Subsequent Doses 5,000 Units to 10,000 Units every 4 to 6 hours Continuous Initial Dose 5,000 Units by intravenous injection Continuous 20,000 Units to 40,000 Units every 24 hours * Based on 150 lb. 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/kg 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 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0. 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. 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. 1) ] 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. Follow equipment manufacturer’s operating directions carefully. A dose of 25 units to 30 units/kg followed by an infusion rate of 1,500 units to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

The following serious 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) ] Thrombocytopenia [ see Warnings and Precautions (5. 4) ] Heparin Resistance [ see Warnings and Precautions (5. 6) ] Hypersensitivity [ see Warnings and Precautions (5. 7) ] Hyperkalemia [see Warnings and Precautions (5. 8) Elevations of Serum Aminotransferases [see Warnings and Precautions (5. 9) Most common adverse reactions are: hemorrhage, thrombocytopenia, HIT or HITT, hypersensitivity reactions, heparin resistance, hyperkalemia, and elevations of aminotransferase levels. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. Hemorrhage en dash [ see Warnings and Precautions (5. 2) ] [see Overdosage (10)] 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 anticoagulant therapy. Retroperitoneal hemorrhage. Vascular Disorders en dash HIT and HITT, including delayed onset cases, and Thrombocytopenia en dash [ see Warnings and Precautions (5. 4) ] Histamine-like reactions en dash Hypersensitivity en dash [ see Warnings and Precautions (5. 7) ] Musculoskeletal, Connective Tissue and Bone Disorders en dash Metabolism and Nutrition Disorders en dash General Disorders and Administration Site Conditions en dash Elevations of serum aminotransferases en dash Others en dash.

The use of HEPARIN SODIUM in 0. 45% SODIUM CHLORIDE INJECTION is contraindicated in patients with the following conditions: History of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITT) [ see Warnings and Precautions (5. 3) ] Known hypersensitivity to heparin or pork products (e. , anaphylactoid reactions) [ see Warnings and Precautions (5. 7) Adverse Reactions (6. 1) ] In whom suitable blood coagulation tests em dash e. , the whole blood clotting time, partial thromboplastin time, etc. , em dash 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) Uncontrollable active bleeding state except when this is due to disseminated intravascular coagulation [see Warnings and Precautions (5. 2) History of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITT) (5. 3) Known hypersensitivity to heparin or pork products (5. 7) In whom suitable blood coagulation tests cannot be performed at appropriate intervals (5. 5) Uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation (5.

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 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 ] The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 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. 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. There is no information regarding the presence of HEPARIN SODIUM IN 0. 45% SODIUM CHLORIDE INJECTION in human milk, the effects on the breastfed infant, 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 infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HEPARIN SODIUM IN 0. 45% SODIUM CHLORIDE INJECTION and any potential adverse effects on the breastfed infant from HEPARIN SODIUM IN 0. 45% SODIUM CHLORIDE INJECTION or from the underlying maternal condition [ see Use in Specific Populations (8. 4) ] 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) ] There are limited adequate and well-controlled studies in patients 65 years and older. However, a higher incidence of bleeding has been reported in patients over 60 years of age, especially women [ see Warnings and Precautions (5. 2) ] [ see Clinical Pharmacology (12.

Drugs that interfere with coagulation, platelet aggregation or drugs that counteract coagulation may induce bleeding. (7) 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. Drugs such as NSAIDS (including acetylsalicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIv/IIa 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. To reduce the risk of bleeding, a reduction in the dose of antiplatelet agent or heparin is recommended. Digitalis, tetracyclines, nicotine, 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. Antithrombin III (human) en dash 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).

OVERDOSAGE
An overdose requires immediate medical attention and treatment. Symptoms Bleeding is the chief sign of heparin overdosage. Easy bruising, petechial formations, nosebleeds, blood in urine or tarry stools may be the first signs or symptoms of a heparin overdose. In the event of symptomatic heparin overdose, consider stopping heparin infusion. 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 very slowly, Ideally, the dose required to neutralize the action of heparin should be guided by blood coagulation tests or calculated from a protamine neutralization test. Because fatal reactions often resembling anaphylaxis have been reported, protamine sulfate should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information, consult the prescribing information for Protamine Sulfate Injection, USP. Blood or plasma transfusions may be necessary; these dilute but do not neutralize heparin.
NONCLINICAL TOXICOLOGY
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.

B. Braun Medical Inc.

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