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NDA 17-037/S-158 

Page 3 


Heparin Sodium Injection, USP 

Rx only 


Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called 

glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars 

occurring in heparin are: (1) 

α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6-

sulfate, (3) 

β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose and (5) α-L-iduronic acid. 

These sugars are present in decreasing amounts, usually in the order (2)

>(1)>(4)>(3)>(5), and are 

joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of 

its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic 

protons of the sulfate units are partially replaced by sodium ions. 

Structural formula of Heparin Sodium (representative sub-units): 


Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal 

mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep 

subcutaneous routes. The potency is determined by a biological assay using a USP reference standard 

based on units of heparin activity per milligram. 

Heparin Sodium Injection, USP is available in the following concentrations/mL: 

Heparin Sodium 

Sodium Chloride Benzyl 


1000 USP units 

8.6 mg 

0.01 mL 

5000 USP units 

7 mg 

0.01 mL 

10,000 USP units 

5 mg 

0.01 mL 


pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. 



Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in 

vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of 

heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating 

activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis 

has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and 

preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin 

clot by inhibiting the activation of the fibrin stabilizing factor. 

Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of 

heparin; in most cases, it is not measurably affected by low doses of heparin. 

NDA 17-037/S-158 

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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. 

Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, 

although there are considerable individual variations. Loglinear plots of heparin plasma concentrations 

with time, for a wide range of dose levels, are linear, which suggests the absence of zero order 

processes. Liver and the reticuloendothelial system are the sites of biotransformation. The biphasic 

elimination curve, a rapidly declining alpha phase (t



=10 min.) and after the age of 40 a slower beta 

phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and 

concentration half-life may reflect factors such as protein binding of heparin. 

Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. 




Heparin Sodium Injection is indicated for: 


Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension; 


Low-dose regimen for prevention of postoperative deep venous thrombosis and pulmonary embolism 

in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of 

developing thromboembolic disease (see DOSAGE AND ADMINISTRATION); 


Prophylaxis and treatment of pulmonary embolism; 

Atrial fibrillation with embolization; 

Diagnosis and treatment of acute and chronic consumptive coagulopathies (disseminated intravascular 


Prevention of clotting in arterial and cardiac surgery; 

Prophylaxis and treatment of peripheral arterial embolism. 

Heparin may also be employed as an anticoagulant in blood transfusions, extracorporeal circulation, 

and dialysis procedures and in blood samples for laboratory purposes. 



Heparin sodium should NOT be used in patients with the following conditions: 

Severe thrombocytopenia; 

When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, 

etc., 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). 

An uncontrolled active bleeding state (see WARNINGS), except when this is due to disseminated 

intravascular coagulation. 


Heparin is not intended for intramuscular use. 


Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-

threatening situations. (See ADVERSE REACTIONSHypersensitivity.) 

NDA 17-037/S-158 

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Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in 

hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious 

consideration of a hemorrhagic event. 

Heparin sodium should be used with extreme caution in disease states in which there is increased 

danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: 



Subacute bacterial endocarditis, severe hypertension. 



During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially 

involving the brain, spinal cord, or eye. 



Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and 

some vascular purpuras. 



Ulcerative lesions and continuous tube drainage of the stomach or small intestine. 



Menstruation, liver disease with impaired hemostasis. 

Coagulation Testing 

When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by 

frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, 

heparin sodium should be promptly discontinued. (See OVERDOSAGE.) 


Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence 

of 0 to 30% up to 30%.  Platelet counts should be obtained at baseline and periodically during heparin 



Mild thrombocytopenia (count greater than 100,000/mm


) may remain stable or 

reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored 

closely.  If the count falls below 100,000/mm


 or if recurrent thrombosis develops (see Heparin-

induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis),


the heparin 

product should be discontinued

and, if necessary, an alternative anticoagulant administered.  



Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia 

Thrombosis (HITT) 

Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from 

irreversible aggregation of platelets.  HIT may progress to the development of venous and arterial 

thromboses, a condition referred to 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 thrombosis, renal arterial thrombosis, skin necrosis, gangrene 

of the extremities that may lead to amputation, and possibly death.  Thrombocytopenia of any degree 

should be monitored closely. If the platelet count falls below 100,000/mm

or if recurrent thrombosis 

develops, the heparin product should be promptly discontinued and alternative anticoagulants 

considered, if patients require continued anticoagulation.    

NDA 17-037/S-158 

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Delayed Onset of HIT and HITT 

Heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and 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 and 



Use in Neonates  

This product contains the preservative benzyl alcohol and is not recommended for use in neonates. 

There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) 

following the administration of intravenous solutions containing the preservative benzyl alcohol. 

Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and 

cardiovascular collapse. 





Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced 

Thrombocytopenia and Thrombosis (HITT):   



Heparin Resistance 

Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, 

infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. 

Increased Risk to Older Patients, Especially Women 

A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. 

Laboratory Tests 

Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the 

entire course of heparin therapy, regardless of the route of administration. (See DOSAGE AND 


Drug Interactions 

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. 

Platelet 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. 

Other Interactions 

Digitalis, tetracyclines, nicotine or antihistamines 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 

NDA 17-037/S-158 

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nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are 

recommended during coadministration of heparin and intravenous nitroglycerin. 

Drug/Laboratory Tests Interactions 


Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) 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, increases that might be caused by drugs (like heparin) should be 

interpreted with caution. 

Carcinogenesis, Mutagenesis, Impairment of Fertility 

No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. 

Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment 

of fertility. 


Teratogenic Effects—Pregnancy Category C 

Animal reproduction studies have not been conducted with heparin sodium. It is also not known 

whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect 

reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed.


Nonteratogenic Effects 

Heparin does not cross the placental barrier. 

Nursing Mothers 

Heparin is not excreted in human milk. 

Pediatric Use 


Geriatric Use 

A higher incidence of bleeding has been reported in patients over 60 years of age, especially women 

(see PRECAUTIONSGeneral). Clinical studies indicate that lower doses of heparin may be 

indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND 




Hemorrhage is the chief complication that may result from heparin therapy. (See WARNINGS.) An 

overly prolonged clotting time or minor bleeding during therapy can usually be controlled by 

withdrawing the drug. (See OVERDOSAGE.) It should be appreciated that 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. 

NDA 17-037/S-158 

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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 


c. Retroperitoneal 


Thrombocytopenia, Heparin-induced thrombocytopenia (HIT) and Heparin-induced 

Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT:   



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. 


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 side of the feet, may occur. 

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence 

of 0 to 30%. While often mild and of no obvious clinical significance, such thrombocytopenia can be 

accompanied by severe thromboembolic complications such as skin necrosis, gangrene of the 

extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and 

possibly death. (See WARNINGS and PRECAUTIONS.) 

Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic 

vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated 

complications remains to be determined. 


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. 

Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred 

in a high percentage of patients (and healthy subjects) who have received heparin. 



Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be 

noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. 


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 1/2 hour after intravenous injection. 

NDA 17-037/S-158 

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Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. 

Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given 

only when resuscitation techniques and treatment of anaphylactoid shock are readily available. 

For additional information consult the labeling of Protamine Sulfate Injection, USP products. 


Parenteral drug products should be inspected visually for particulate matter and discoloration 

prior to administration, whenever solution and container permit. Slight discoloration does not 

alter potency. 

When heparin is added to an infusion solution for continuous intravenous administration, the container 

should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in 

the solution. 

Heparin sodium is not effective by oral administration and should be given by intermittent intravenous 

injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal 

fat layer) injection. The intramuscular route of administration should be avoided because of the 

frequent occurrence of hematoma at the injection site. 

The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results. 

When heparin is given by continuous intravenous infusion, the coagulation time should be determined 

approximately every 4 hours in the early stages of treatment. When the drug is administered 

intermittently by intravenous injection, coagulation tests should be performed 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 normal or when the 

whole blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep 

subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 

to 6 hours after the injection. 

Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the 

entire course of heparin therapy, regardless of the route of administration. 

Converting to Oral Anticoagulant 

When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving 

heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time 

when heparin activity is too low to affect the prothrombin time. This is about 5 hours after the last 

intravenous bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is 

used, prothrombin time can usually be measured at any time. 

In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the 

usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To 

ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after 

the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued 

without tapering. 


NDA 17-037/S-158 

Page 10 


Therapeutic Anticoagulant Effect With Full-Dose Heparin 

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: 





[based on 150 lb (68 kg) patient] 

Deep Subcutaneous  

(Intrafat) Injection 

Initial dose 

5000 units by IV injection, followed 

by 10,000 to 20,000 units of a 

concentrated solution, subcutaneously 


A different site should be used for 

each injection to prevent the 

development of massive 



Every 8 hours 




8000 to 10,000 units of a 

concentrated solution 


Every 12 hours 

15,000 to 20,000 units of a 

concentrated solution 

Intermittent Intravenous Injection 

Initial dose 

10,000 units, either undiluted or in 50 

to 100 mL of 0.9

% Sodium Chloride 

Injection, USP 



Every 4 to 6 hours 

5000 to 10,000 units, either undiluted 

or in 50 to 100 mL of 0.9

% Sodium 

Chloride Injection, USP 

Intravenous Infusion 

Initial dose 

5000 units by IV injection 




20,000 to 40,000 units/24 hours in 

1000 mL of 0.9

% Sodium Chloride 

Injection, USP (or in any compatible 

solution) for infusion 

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