Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/764
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Heparin Sodium (Injection, Solution)
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Heparin Sodium is not effective by oral administration and
intravenous solutions with heparin sodium should not be given orally. They
should be administered by intravenous infusion. Maintenance of Catheter Patency Although
the rate for infusion of the 2 units/mL formulation is dependent upon the
age, weight, clinical condition of the patient, and the procedure being employed,
an infusion rate of 3 mL/hour has been found to be satisfactory. Parenteral
drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. See PRECAUTIONS.
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Intravenous solutions with heparin sodium (derived from porcine
intestinal mucosa) are sterile, nonpyrogenic fluids for intravenous administration.
Each 100 mL contains heparin sodium 200 USP Heparin Units; sodium chloride,
0.9 g; citric acid, monohydrate, 40 mg and dibasic sodium phosphate, heptahydrate,
434 mg added as buffers. Each liter contains the following electrolytes: Sodium
186.4 mEq; phosphate (as HPO=) 32.4 mEq, citrate 5.7 mEq and chloride
154 mEq. Osmolar concentration, 378 mOsmol/liter (calc.); pH 7.0 (5.0���7.5). 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 biologicalassay 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. Dibasic Sodium Phosphate, USP
(Heptahydrate), is chemically designated (NaHPO���7HO), colorless or white granular salt freely soluble in water. Citric
Acid, USP, hydrous (monohydrate) is chemically designated CHO���HO, colorless, translucent crystals or white crystalline powder
very soluble in water. It has the following structural formula: Water
for Injection, USP is chemically designated HO. The
flexible plastic container is fabricated from a specially formulated polyvinylchloride.
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 (t��= 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 containers providing 500 and 1000 mL fluid volumes (List 7620). 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: June, 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,
antihistamines, or I.V. nitroglycerin 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:: Safety and effectiveness in pediatric patients have not been
established.<br/>Geriatric Use:: A higher incidence of bleeding has been reported in patients
over 60 years of age, especially women (see PRECAUTIONS, General and CLINICAL
PHARMACOLOGY). Do not administer unless the solution
is clear and seal is intact. Discard unused portion.
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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 Injection in 0.9% Sodium Chloride at a concentration
of 2 units/mL is indicated as an anticoagulant to maintain catheter patency.
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Heparin Sodium
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