Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/64
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Heparin Sodium (Injection, Solution)
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Heparin sodium is not effective by oral administration and
these premixed formulations should be given by intermittent intravenous injection
or intravenous infusion. 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 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, 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. If continuous I.V. 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: *Based on 150 lb. (68 kg) patient. Pediatric Use: Follow recommendations of
appropriate pediatric reference texts. In general, the following dosage schedule
may be used as a guideline: Geriatric Use: Patients
over 60 years of age may require lower doses of heparin. 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 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. Extracorporeal
Dialysis: Follow equipment manufacturer's operating directions
carefully. 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. See PRECAUTIONS. Do not administer unless the
solution is clear and seal is intact. Discard unused portion.
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Intravenous solutions with heparin sodium (derived from porcine
intestinal mucosa) are sterile, nonpyrogenic fluids for intravenous administration.
They contain no bacteriostat or antimicrobial agent or added buffer. Edetate
disodium, anhydrous is added as a stabilizer. The solution may contain sodium
hydroxide and/or hydrochloric acid for pH adjustment. See Table for summary
of contents and characteristics of these solutions. Heparin
Sodium, USP 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)��- L-iduronic
acid 2-sulfate, (2) 2-deoxy-2-sulfamino-��-D-glucose 6-sulfate, (3)��-D-glucuronic
acid, (4) 2-acetamido-2-deoxy-��-D-glucose, and (5)��-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.
The potency is determined by a biological assay using a USP reference standard
based on units of heparin activity per milligram. Structure
of Heparin Sodium (representative subunits): Sodium
Chloride, USP is chemically designated NaCl, a white crystalline compound
freely soluble in water. Water for Injection, USP is
chemically designated HO. The flexible plastic
container is fabricated from a specially formulated polyvinyl chloride. Water
can permeate from inside the container into the overwrap but not in amounts
sufficient to affect the solution significantly. Solutions inside the plastic
container also can leach out certain of its chemical components in very small
amounts before the expiration period is attained. However, the safety of the
plastic has been confirmed by tests in animals according to USP biological
standards for plastic containers.
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Heparin inhibits reactions that lead to the clotting of blood
and the formation of fibrin clots both invitro 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 in 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 site of biotransformation. The
biphasic elimination curve, a rapidly declining alpha phase (��= 10') 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. Hypotonic concentrations of sodium chloride are
suited for parenteral maintenance of water requirements when only small quantities
of salt are desired. Sodium chloride in water dissociates
to provide sodium (Na) and chloride (Cl��) ions. Sodium (Na)
is the principal cation of the extracellular fluid and plays a large part
in the therapy of fluid and electrolyte disturbances. Chloride (Cl��)
has an integral role in buffering action when oxygen and carbon dioxide exchange
occurs in the red blood cells. The distribution and excretion of sodium (Na)
are largely under the control of the kidney which maintains a balance between
intake and output. Water is an essential constituent
of all body tissues and accounts for approximately 70% of total body weight. Average
normal adult daily requirements range from two to three liters (1.0 to 1.5
liters each for insensible water loss by perspiration and urine production). Water
balance is maintained by various regulatory mechanisms. Water distribution
depends primarily on the concentration of electrolytes in the body compartments
and sodium (Na) plays a major role in maintaining physiologic
equilibrium.
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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.
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Intravenous solutions with heparin sodium are supplied in
single-dose flexible plastic containers in varied sizes and concentrations
as shown in the accompanying Table. Exposure of pharmaceutical products to heat should be minimized.
Avoid excessive heat. Protect from freezing. It is recommended that the product
be stored at room temperature (25��C); however, brief exposure up to
40��C does not adversely affect the product. Rev:
October, 2004 HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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General:: a. 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. b.
Heparin Resistance: Increased resistance to
heparin is frequently encountered in fever, thrombosis, thrombophlebitis,
infections with thrombosing tendencies, myocardial infarction, cancer and
in postsurgical patients. c.
Increased Risk to Older Patients, Especially Women: A higher incidence of bleeding has been reported in patients, particularly
women, over 60 years of age.<br/>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).<br/>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 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.<br/>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, rises that might be caused by drugs (like heparin) should be interpreted
with caution.<br/>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.<br/>Pregnancy:: Teratogenic Effects:Pregnancy Category C. Animal reproduction studies
have not been conducted with heparin sodium or sodium chloride. It is also
not known whether heparin sodium or sodium chloride can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Heparin
sodium or sodium chloride should be given to a pregnant woman only if clearly
needed. Nonteratogenic Effects: Heparin does not cross the placental barrier.<br/>Nursing Mothers:: Heparin is not excreted in human milk.<br/>Pediatric Use:: See DOSAGE AND ADMINISTRATION.<br/>Geriatric 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 ADMINISTRATION).
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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,
the labeling of Protamine Sulfate Injection, USP products should be consulted. In
the event of overhydration or solute overload, re-evaluate the patient and
institute appropriate corrective measures. See WARNINGS and PRECAUTIONS.
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Heparin Sodium
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Heparin Sodium (Injection, Solution)
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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 site 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. 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. Reactions
which may occur because of the solution or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis
or phlebitis extending from the site of injection, extravasation and hypervolemia. If
an adverse reaction does occur, discontinue the infusion, evaluate the patient,
institute appropriate therapeutic countermeasures and save the remainder of
the fluid for examination if deemed necessary.
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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)
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/mmor
if recurrent thrombosis develops (see White Clot Syndrome, PRECAUTIONS), 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. Solutions containing sodium ions should
be used with great care, if at all, in patients with congestive heart failure,
severe renal insufficiency and in clinical states in which there exists edema
with sodium retention. The intravenous administration
of these solutions can cause fluid and/or solute overloading resulting in
dilution of serum electrolyte concentrations, overhydration, congested states
or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of administered parenteral
solutions. The risk of solute overload causing congested states with peripheral
and pulmonary edema is directly proportional to the electrolyte concentrations
of such solutions. In patients with diminished renal
function, administration of solutions containing sodium ions may result in
sodium retention. Excessive administration of potassium-free
solutions may result in significant hypokalemia. As
the dosage of solutions of heparin sodium must be titrated to individual patient
response, additive medications should not be delivered via this solution.
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Heparin sodium is indicated for: Atrial
fibrillation with embolization; Diagnosis and treatment
of acute and chronic consumption coagulopathies (disseminated intravascular
coagulation); Prevention of clotting in arterial and
heart surgery; Prophylaxis and treatment of peripheral
arterial embolism; As an anticoagulant in extracorporeal
circulation, and dialysis procedures
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Heparin Sodium
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