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-
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
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:
Sodium Chloride Benzyl
1000 USP units
10,000 USP units
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
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.
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.
INDICATIONS AND USAGE
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
developing thromboembolic disease (see DOSAGE AND ADMINISTRATION);
Prophylaxis and treatment of pulmonary embolism;
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:
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
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 REACTIONS, Hypersensitivity.)
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.
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-
and, if necessary, an alternative anticoagulant administered.
Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia
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
considered, if patients require continued anticoagulation.
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
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.
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
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 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.
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
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
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.
Heparin does not cross the placental barrier.
Heparin is not excreted in human milk.
See DOSAGE AND ADMINISTRATION–Pediatric Use.
A higher incidence of bleeding has been reported in patients over 60 years of age, especially women
(see PRECAUTIONS, General). 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
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
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.
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.
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
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.
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.
DOSAGE AND ADMINISTRATION
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Slight discoloration does not
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
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.
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
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]
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
development of massive
Every 8 hours
8000 to 10,000 units of a
Every 12 hours
Intermittent Intravenous Injection
10,000 units, either undiluted or in 50
to 100 mL of 0.9
% Sodium Chloride
Every 4 to 6 hours
or in 50 to 100 mL of 0.9
Chloride Injection, USP
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