^
Rx only
EXCEL is a registered trademark of B. Braun Medical Inc.
B. Braun Medical Inc. Bethlehem, PA 18018-3524 USA1-800-227-2862
Y36-003-101 LD-787-2
^ Other Medications That May Interfere With Heparin
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) – 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).
^ Pharmacodynamics
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.
^ 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.
^ 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) ]. 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:
^ Converting To Oralanticoagulants Other Than Warfarin
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.
^ Patient Counseling Information
Hemorrhage
Inform patients that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they are treated with heparin, and that they should report any unusual bleeding or bruising to their physician. Hemorrhage can occur at virtually any site in patients receiving heparin. Fatal hemorrhages have occurred [ see Warnings and Precautions (5.2) ] .
Prior to Surgery
Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is scheduled [ see Warnings and Precautions (5.2) ] .
Heparin-Induced Thrombocytopenia
Inform patients of the risk of heparin-induced thrombocytopenia (HIT). HIT may progress to the development of venous and arterial thromboses, a condition known as heparin-induced thrombocytopenia and thrombosis (HITT). HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy [ see Warnings and Precautions (5.3 and 5.4) ].
Hypersensitivity
Inform patients that generalized hypersensitivity reactions have been reported. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [ see Warnings and Precautions (5.7), Adverse Reactions (6) ] .
Other Medications
Because of the risk of hemorrhage, advise patients to inform their physicians and dentists of all medications they are taking, including non-prescription medications, and before starting any new medication [see Drug Interactions (7.2)].
^ Coagulation Testing And Monitoring
When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly [ see Overdosage (10) ]. Periodic platelet counts, hematocrits are recommended during the entire course of heparin therapy [ see Dosage and Administration (2.2) ].
^ Heparinresistance
Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients, and patients with antithrombin III deficiency.
Consider measurement of anti-thrombin levels if heparin resistance is suspected. Monitor coagulation tests frequently in such patients. It may be necessary to adjust the dose of heparin based on coagulation test monitoring, such as anti-Factor Xa levels and/or partial thromboplastin time.
^ Description
Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties. It is composed of polymers of alternating derivations of alpha-L-iduronic acid 2-sulfate (1), 2-deoxy-2-sulfamino- alpha-D-glucose 6-sulfate (2), beta-D-glucuronic acid (3), 2-acetamido-2- deoxy-alpha-D-glucose (4), and alpha-L-iduronic acid (5).
Structure of Heparin Sodium (representative subunits):
Heparin Sodium in 0.45% Sodium Chloride Injection is a sterile, single-dose, clear, nonpyrogenic solution prepared from Heparin Sodium USP (derived from porcine intestinal mucosa and standardized for use as an anticoagulant) in 0.45% Sodium Chloride Injection. It is to be administered by intravenous injection. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.
The pH range is 7.0 (6.8-7.2) and the osmolarity mOsmol/L (calc.) is 206. The concentration of electrolytes is 109 mEq/L Sodium, 77 mEq/L Chloride, 32 mEq/L Phosphate, and 6 mEq/L Citrate.
50 USP units/mL: Each 100 mL of the 25,000 USP units per 500 mL preparation contains: 5,000 USP units of heparin sodium, 0.45 g Sodium Chloride USP, 0.43 g Dibasic Sodium Phosphate USP, 0.037 g Citric Acid Anhydrous USP, and Water for Injection USP until quantity sufficient.
100 USP units/mL: Each 100 mL of the 25,000 USP units per 250 mL preparation contains: 10,000 USP units of heparin sodium, 0.45 g Sodium Chloride USP, 0.43 g Dibasic Sodium Phosphate USP, 0.037 g Citric Acid Anhydrous USP, and Water for Injection USP until quantity sufficient.
The plastic container is made from a multilayered film specifically developed for parenteral drugs. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary.
The plastic container is not made with natural rubber latex, PVC or DEHP.
The closure system has two ports; the one for the administration set has a tamper evident plastic protector.
^ laboratory Monitoring For Efficacy And Safety
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.
^ 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 should be administered, very slowly, in any 10 minute period. Each mg of protamine sulfate neutralizes approximately 100 USP Heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 30 minutes after intravenous injection.
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.
^ Cardiovascular Surgery
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.
^ Platelet Inhibitors
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.
^3 Dosage Forms And Strengths
HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION is a sterile, single-dose, clear, nonpyrogenic solution available as:
^ 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.
^ 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 plasma 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.
^ Pediatric Use
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) ].
^ Converting To Warfarin
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) ].
^Principal Display Panel - Ml Container Label
NDC 0264-3301-10
HEPARIN SODIUM in 0.45% Sodium Chloride Injection 25,000 USP units per 500 mL (50 USP units per mL)
LD-789-2 Y94-003-515
For Intravenous Use Only
Each 100 mL contains: Heparin Sodium USP (porcine intestinal mucosa) 5,000 USP Heparin units; Sodium Chloride USP 0.45 g; Dibasic Sodium Phosphate•7H2O USP 0.43 g; Citric Acid Anhydrous USP 0.037 g;Water for Injection USP qs
Electrolytes (mEq/liter): Sodium 109; Phosphate (HPO ) 32;
Citrate 6; Chloride 77
WARNING: Do not admix with other drugs.
Sterile. Single dose container. Discard unused portion.
Store at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Avoid excessive heat. Protect from freezing. Recommended Dosage: see Prescribing Information. Do not remove overwrap until ready for use.
Not made with natural rubber latex, PVC or DEHP.
500 mL EXCEL® CONTAINER
Rx only
REF P3301
EXCEL is a registered trademark of B. Braun Medical Inc.
B. Braun Medical Inc. Bethlehem, PA 18018-3524 USA1-800-227-2862
Prepared in USA. API from Spain.
Y94-003-514 LD-788-2
EXP
LOT
^4 Contraindications
The use of HEPARIN SODIUM in 0.45% SODIUM CHLORIDE INJECTION is contraindicated in patients with the following conditions:
^ Therapeutic Anticoagulant Effectwith 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
* Based on 150 lb. (68 kg) patient.
^ Extracorporeal Dialysis
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.
^ How Supplied/storage And Handling
Heparin Sodium in 0.45% Sodium Chloride Injection is a clear solution and is supplied sterile and nonpyrogenic in single-dose EXCEL® Containers packaged 24 per case.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing.
Store at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]
^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.
^ Geriatric Use
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) ]. Lower doses of heparin may be indicated in these patients [ see Clinical Pharmacology (12.3) ].
^Risk Summary
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) ].
^ 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.
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
^ Pediatric Use
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:
^ Elevations Of Serum Aminotransferases
Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Elevation of these enzymes in patients receiving heparin should be interpreted with caution. These elevations typically resolve upon heparin discontinuation.
^ Hypersensitivity Reactions
Hypersensitivity reactions with chills, fever and urticaria as the most usual manifestations and also asthma, rhinitis, lacrimation, and anaphylactoid reactions have been reported. Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations [ see Adverse Reactions (6.1) ].
Because Heparin Sodium in 0.45% Sodium Chloride Injection is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy to pork products.
^ Preparation For Administration
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.
^ Heparin-induced Thrombocytopenia (hit) Andheparin-induced Thrombocytopenia And Thrombosis (hitt)
HIT is a serious immune-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 HITT. 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 possibly death.
Once HIT or HITT is diagnosed or strongly suspected, discontinue all heparin sources (including heparin flushes) and use an alternative anticoagulant.
Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin, or platelet activation induced by heparin. Obtain platelet counts at baseline and periodically during heparin administration. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin in heparin–naive individuals and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin initiation), especially in patients with a recent exposure to heparin (i.e., previous 3 months).
Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT.
Monitor thrombocytopenia of any degree closely. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, 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 therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT or HITT.
^ Thrombocytopenia
Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Obtain platelet counts before and periodically during heparin therapy. Monitor thrombocytopenia of any degree closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT, and, if necessary, administer an alternative anticoagulant [ see Warnings and Precautions (5.3) ].
^6 Adverse Reactions
The following serious adverse reactions are described elsewhere in the labeling:
^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.
^ Pharmacokinetics
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 0.07 L/kg.
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 (5.2)].
^Principal Display Panel - Ml Container Label
NDC 0264-3462-20
HEPARIN SODIUM in 0.45% Sodium Chloride Injection 25,000 USP units per 250 mL (100 USP units per mL)
LD-791-1 Y94-003-502
For Intravenous Use Only
Each 100 mL contains: Heparin Sodium USP (porcine intestinal mucosa) 10,000 USP Heparin units; Sodium Chloride USP 0.45 g; Dibasic Sodium Phosphate•7H2O USP 0.43 g; Citric Acid Anhydrous USP 0.037 g;Water for Injection USP qs
Electrolytes (mEq/liter): Sodium 109; Phosphate (HPO ) 32; Citrate 6; Chloride 77
WARNING: Do not admix with other drugs.
Sterile. Single dose container. Discard unused portion.
Store at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Avoid excessive heat. Protect from freezing. Recommended Dosage: see Prescribing Information. Do not remove overwrap until ready for use.
Not made with natural rubber latex, PVC or DEHP.
Rx only
EXCEL is a registered trademark of B. Braun Medical Inc.
250 mL EXCEL® CONTAINER
REF P3462
B. Braun Medical Inc. Bethlehem, PA 18018-3524 USA1-800-227-2862
Prepared in USA. API from Spain.
Y94-003-501 LD-790-1
EXP
LOT
^1 Indications And Usage
Heparin Sodium in 0.45% Sodium Chloride Injection is indicated for:
^ Mechanism Of Action
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.