HEPARIN SOD
DESCRIPTION:
Heparin Sodium Injection, USP, is a sterile solution. Each mL contains
1,000, 2,500, 5,000, 7,500, 10,000, 25,000 USP units heparin sodium,
derived from porcine intestinal mucosa (standardized for use as an
anticoagulant), in water for injection, and not more than 10 mg benzyl alcohol
as a preservative.
The potency is determined by biological assay, using a USP reference standard
based upon units of heparin activity per milligram. The pH range is 5.0 to 7.5.
Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides,
called glycosaminoglycans, having anticoagulant properties. Although others may
be present, the main sugars occurring in heparin are: (1) alpha- L-iduronic acid
2-sulfate, (2) 2-deoxy- 2-sulfamino-alpha-D-glucose 6-sulfate, (3) beta- D-
glucuronic acid, (4) 2-acetamido-2-deoxy-alpha- D-glucose, and (5) alpha-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.
ACTIONS/CLINICAL PHARMACOLOGY:
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.
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 reticulo-endothelial system are the sites of biotransformation. The biphasic
elimination curve, a rapidly declining alpha phase (t1/2 = 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; in low-dose regimen for
prevention of postoperative deep venous thrombosis and pulmonary embolism in
patients undergoing major abdominothoracic surgery who are at risk of developing
thromboembolic disease (see "Dosage and Administration"); for prophylaxis and
treatment of pulmonary embolism; in atrial fibrillation with embolization; for
diagnosis and treatment of acute and chronic consumptive coagulopathies
(disseminated intravascular coagulation); for prevention of clotting in arterial
and cardiac surgery; and for prophylaxis and treatment of peripheral arterial
embolism.
Heparin may also be employed as an anticoagulant in blood transfusions,
extracorporeal circulation, dialysis procedures, and in blood samples for
laboratory purposes.
CONTRAINDICATIONS:
Heparin sodium should not be used in patients:
with severe thrombocytopenia;
in whom 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);
with an uncontrollable active bleeding state (see "Warnings"), except when this
is due to disseminated intravascular coagulation.
WARNINGS:
Heparin is not intended for intramuscular use.
HYPERSENSITIVITY
Patients with documented hypersensitivity to heparin should be given the drug
only in clearly life-threatening situations.
HEMORRHAGE
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:
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.
Gastrointestinal--Ulcerative lesions and continuous tube drainage of the stomach
or small intestine.
Other--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 discontinued
promptly (see "Overdosage").
THROMBOCYTOPENIA
Thrombocytopenia has been reported to occur in patients receiving heparin with a
reported incidence of 0 to 30%. Mild thrombocytopenia (count greater than
100,000/mm(cubed)) 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(cubed) or if recurrent thrombosis develops (see
PRECAUTIONS, General, White-clot Syndrome), the heparin product should be
discontinued. If continued heparin therapy is essential, administration of
heparin from a different organ source can be reinstituted with caution.
MISCELLANEOUS
This product contains benzyl alcohol as preservative. Benzyl alcohol has been
reported to be associated with a fatal "Gasping Syndrome" in premature neonates.
PRECAUTIONS:
GENERAL
White-Clot Syndrome
It has been reported that patients on heparin may develop new thrombus formation
in association with thrombocytopenia, resulting from irreversible aggregation of
platelets induced by heparin, the so-called "white-clot syndrome." The process
may lead to severe thromboembolic complications like skin necrosis, gangrene of
the extremities that may lead to amputation, myocardial infarction, pulmonary
embolism, stroke, and possibly death. Therefore, heparin administration should
be promptly discontinued if a patient develops new thrombosis in association
with thrombocytopenia.
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 In Older Women
A higher incidence of bleeding has been reported in 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 Administration").
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.
DRUG/LABORATORY TEST INTERACTIONS
Hyperaminotransferasemia
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.
PREGNANCY
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
See "Dosage and Administration."
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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
HEMORRHAGE
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.
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 fatal.
c. Retroperitoneal hemorrhage.
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.
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 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," "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.
MISCELLANEOUS
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.
OVERDOSAGE:
SYMPTOMS
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.
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 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 alter potency.
When heparin is added to an infusion solution for continuous intravenous
administration, the container should be inverted at least six times to insure
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 HEPARIN BLUNT POINTE(TM) Sterile Cartridge Unit is suitable for substances
to be administered intravenously only. It is intended for use with injection
sets specifically manufactured as "needle-less" injection systems. As of the
date of this circulation, the HEPARIN BLUNT POINTE(TM) is compatible with
LifeShield(R) Prepierced Reseal injection site, InterLink(R) Injection Site,
SafeLine(R) Injection Site, User- Gard(R) Intermittent Injection Cap, and
SafSite(R) Reflux Valve. Consult manufacturer's recommendations regarding
"Directions for Use" of the "needle-less" system. It is also intended for
admixture with, and convenient administration of, various medicaments when using
Drug Vial Adapters for "needle-less" injection systems.
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 injections.
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 IV
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.
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:
Method of Frequency Recommended Dose (based on 150 lb
Administration (68 kg) patient)
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Deep, Subcutaneous Initial Dose 5,000 units by IV injection followed
(Intrafat) Injection by 10,000-20,000 units of a
concentrated solution, subcutaneously
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A different site Every 8 hours 8,000-10,000 units of a concentrated
should be used solution
for each injection ---------------------------------------------------------------------------------------------------------------------------------
to prevent the (or)
development of massive Every 12 hours 15,000-20,000 units of a concentrated
hematoma. solution
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Intermittent, Initial Dose 10,000 units, either undiluted or in
Intravenous 50-100 mL isotonic sodium chloride
Injection injection
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Every 4 to 6 5,000-10,000 units, either undiluted
hours or in 50-100 mL isotonic sodium
chloride injection
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Intravenous Infusion Initial Dose 5,000 units by IV injection
--------------------------------------------------------------------------------------------------------------------------------------------------------------------
Continuous 20,000-40,000 units in 1,000 mL of
isotonic sodium chloride solution
for infusion/day
PEDIATRIC USE
Follow recommendations of appropriate pediatric reference texts. In general, the
following dosage schedule may be used as a guideline.
Initial Dose: 50 units/kg (IV, drip).
Maintenance Dose: 100 units/kg (IV, drip) every four hours, or 20,000
units/M(square)/24 hours continuously.
SURGERY OF THE HEART AND BLOOD VESSELS
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 of heparin sodium per kilogram of
body weight 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.
LOW-DOSE PROPHYLAXIS OF POSTOPERATIVE THROMBOEMBOLISM
A number of well-controlled clinical trials have demonstrated that low-dose
heparin prophylaxis, given just prior to and after surgery, will reduce the
incidence of postoperative deep-vein thrombosis in the legs, as measured by the
l-125 fibrinogen technique and venography, and of clinical pulmonary embolism.
The most widely used dosage has been 5,000 units 2 hours before surgery and
5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is
fully ambulatory, whichever is longer. The heparin is given by deep,
subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge)
to minimize tissue trauma. A concentrated solution of heparin sodium is
recommended. Such prophylaxis should be reserved for patients over 40 undergoing
major surgery. Patients with bleeding disorders, those having neurosurgery,
spinal anesthesia, eye surgery, or potentially sanguineous operations should be
excluded, as well as patients receiving oral anticoagulants or platelet-active
drugs (see "Warnings"). The value of such prophylaxis in hip surgery has not
been established. The possibility of increased bleeding during surgery or
postoperatively should be borne in mind. If such bleeding occurs, discontinuance
of heparin and neutralization with protamine sulfate is advisable. If clinical
evidence of thromboembolism develops despite low-dose prophylaxis, full
therapeutic doses of anticoagulants should be given unless contraindicated. All
patients should be screened prior to heparinization to rule out bleeding
disorders, and monitoring should be performed with appropriate coagulation tests
just prior to surgery. Coagulation-test values should be normal or only slightly
elevated. There is usually no need for daily monitoring of the effect of low-
dose heparin in patients with normal coagulation parameters.
EXTRACORPOREAL DIALYSIS USE
Follow equipment manufacturer's operating directions carefully.
BLOOD TRANSFUSION
Addition of 400 to 600 USP units per 100 mL of whole blood. Usually, 7,500 USP
units of heparin sodium are added to 100 mL of Sterile Sodium Chloride Injection
(or 75,000 USP units per 1,000mL of Sterile Sodium Chloride Injection) and
mixed, and from this sterile solution, 6 to 8 mL is added per 100 mL of whole
blood.
LABORATORY SAMPLES
Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole
blood is usually employed to prevent coagulation of the sample. Leukocyte counts
should be performed on heparinized blood within two hours after addition of the
heparin. Heparinized blood should not be used for isoagglutinin, complement,
erythrocyte fragility tests, or platelet counts.
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