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Heparin (Systemic)


VA CLASSIFICATION
Primary: BL110

Commonly used brand name(s): Calcilean; Calciparine; Hepalean; Heparin Leo; Liquaemin.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticoagulant. —

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Note: Some of the indications for heparin therapy are identical to those for thrombolytic (alteplase [tissue-type plasminogen activator, recombinant], anistreplase [anisoylated plasminogen-streptokinase activator complex, APSAC], streptokinase, or urokinase) or coumarin- or indandione-derivative anticoagulant therapy. However, thrombolytic agents are used primarily to lyse obstructive thrombi and restore blood flow in a recently occluded blood vessel, whereas anticoagulants are used primarily to prevent thrombus formation and extension of existing thrombi. {14} For treatment of acute deep venous thrombosis and acute pulmonary embolism, a thrombolytic agent may be the treatment of choice in selected patients. However, the selection of thrombolytic therapy or anticoagulant therapy as opposed to other forms of treatment, including vascular surgery, must be based on determination of the severity of thrombotic disease and assessment of patient condition and history.
Heparin is the anticoagulant of choice when an immediate effect is required. When long-term anticoagulant therapy is required, a coumarin or indandione derivative is usually administered as a follow-up to heparin therapy. However, in some patients (especially pregnant women) long-term anticoagulation with heparin may be desirable.


Accepted

Thrombosis, deep venous (prophylaxis and treatment) and
Thromboembolism, pulmonary (prophylaxis and treatment)—Heparin is indicated using a full-dose regimen in the treatment of patients with recent thrombosis or thrombophlebitis of the deep veins to prevent extension and embolization of the thrombus and to reduce the risk of pulmonary embolism or recurrent thrombus formation. In acute pulmonary embolism, full-dose heparin is indicated to decrease the risk of extension, recurrence, or death.
—Heparin is also indicated using a low-dose regimen to prevent the development of venous thrombosis and pulmonary embolism following major abdominal or thoracic surgery in high-risk patients, such as patients with a history of thromboembolism and patients requiring prolonged immobilization following surgery, especially if they are 40 years of age or older. Low-dose heparin may be ineffective for this purpose in some patients, especially following hip surgery. Many clinicians question the validity of data showing the efficacy and safety of low-dose heparin prophylaxis.
—[Low-dose heparin prophylaxis is also used to prevent thrombus formation in selected immobilized medical patients who are not at risk of hemorrhage.]
—Heparin is also administered using an adjusted-dose regimen for prophylaxis against thromboembolic complications when low-dose heparin may not be effective, e.g., for general abdominal or thoracic surgery in very high-risk patients, high-risk orthopedic procedures such as elective hip surgery or knee reconstruction, and [the second half of the third trimester in pregnant women with a history of venous thrombosis or pulmonary embolism]1 {01} {02} {03} {04}.
—Adjusted-dose subcutaneous heparin is also recommended when long-term anticoagulation is required and use of a coumarin- or indandione-derivative anticoagulant is contraindicated or inadvisable (e.g., during pregnancy) {01} {02} {03} {04}. In addition, after the dosage of heparin has been stabilized (i.e., the desired level of anticoagulation has been achieved and maintained for a 2-week period without additional dosage adjustment) {06}, further anticoagulant monitoring and dosage adjustment are not needed (except during pregnancy, when heparin requirements increase with the patient's blood volume as pregnancy progresses) {05} {06}. Therefore, this regimen can be utilized for the long-term treatment of nonpregnant patients when anticoagulant therapy cannot be monitored on a regular basis {01} {02} {03} {04}.

Thromboembolism (prophylaxis)—Heparin is indicated prior to and during attempted cardioversion or surgery to prevent systemic thromboembolism that may occur in patients with chronic atrial fibrillation, especially those with rheumatic mitral stenosis, congestive heart failure, left atrial enlargement, or cardiomyopathy.
—Heparin is indicated as adjunctive therapy in acute myocardial infarction to reduce the risk of thromboembolic complications, especially in high-risk patients such as those with shock, congestive heart failure, prolonged arrhythmias (especially atrial fibrillation), previous myocardial infarction, or history of venous thrombosis or pulmonary embolism. Also, heparin may be administered to help prevent reocclusion following thrombolytic therapy in patients with acute myocardial infarction. {15}
—[Heparin is also used to prevent catheter-induced thromboembolism during coronary angiography and percutaneous transluminal angioplasty.]1

Blood clotting (prophylaxis)—Heparin is indicated to prevent blood clotting during extracorporeal circulation in cardiac surgery and dialysis procedures.
—Heparin is indicated to prevent blood clotting during and following arterial surgery. It is administered systemically or by local intra-arterial injection.
—Heparin is indicated to prevent blood clotting during blood transfusions and in blood sampling for laboratory purposes. However, heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests, or for platelet counts. In addition, leukocyte counts should be performed within 2 hours after heparin is added to the blood sample.
—Heparin is also available as a lock flush solution, which is not intended for anticoagulant therapy. This solution is used to maintain the patency of an indwelling intravascular device.

Coagulation, disseminated intravascular (treatment)—Although heparin is indicated as a temporary measure in the treatment of disseminated intravascular coagulation, especially if there is clinical evidence of intravascular thrombosis, its use in this condition is controversial. The underlying cause of the condition must be determined and treated.

Thromboembolism, arterial (treatment)—Heparin is indicated as adjunctive therapy for peripheral arterial embolism. It may prevent further thrombus formation when surgery must be delayed.

Thrombosis, cerebral (prophylaxis)—Heparin is indicated to decrease the risk of cerebral thrombosis and death in patients with progressive stroke (stroke-in-evolution).

[Thromboembolism, cerebral, recurrence (prophylaxis)]1—Heparin is also used in the treatment of patients with recent cerebral embolism to decrease the risk of recurrence and death; however, this use is controversial. Although administration of an anticoagulant too soon after a cerebral embolism may increase the risk of cerebral hemorrhage, recent studies have indicated that the risk of early recurrence may be greater than the risk of anticoagulant therapy. It is recommended that heparin therapy be initiated only if the patient is not hypertensive and a computerized tomographic (CT) scan performed 24 hours or longer following the onset of the stroke shows no evidence of hemorrhagic transformation. If severe hypertension is present, or the embolic stroke is large, there is a risk of late hemorrhagic transformation and anticoagulant therapy should be delayed for several days. If hemorrhagic transformation is documented, anticoagulant therapy should be postponed for at least 8 to 10 days. Long-term anticoagulation is recommended. {01} {02}

Unaccepted
Prophylactic use of heparin (low-dose or full-dose) is not recommended for patients with bleeding disorders; patients having neurosurgery, ophthalmic surgery, or spinal anesthesia; or patients who are receiving a coumarin- or indandione-derivative anticoagulant or a platelet active agent.

[Heparin has also been used to reduce the risk of thrombosis and/or occlusion of the aortocoronary bypass following coronary bypass surgery; however, its efficacy has not been established and this use is controversial. Also, platelet aggregation inhibitors, especially aspirin, are more commonly used for this indication.]

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Mechanism of action/Effect:

Heparin acts indirectly at multiple sites in both the intrinsic and extrinsic blood clotting systems to potentiate the inhibitory action of antithrombin III (heparin cofactor) on several activated coagulation factors, including thrombin (factor IIa) and factors IXa, Xa, XIa, and XIIa, by forming a complex with and inducing a conformational change in the antithrombin III molecule. Inhibition of activated factor Xa interferes with thrombin generation and thereby inhibits the various actions of thrombin in coagulation. Heparin also accelerates the formation of an antithrombin III–thrombin complex, thereby inactivating thrombin and preventing the conversion of fibrinogen to fibrin; these actions prevent extension of existing thrombi. Larger doses of heparin are required to inactivate thrombin than are required to inhibit thrombin formation. Heparin also prevents formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor by thrombin. Heparin has no fibrinolytic activity.

Full-dose heparin prolongs partial thromboplastin time, thrombin time, whole blood clotting time, and activated clotting time (ACT).


Other actions/effects:

Heparin reduces the concentration of triglycerides in plasma by releasing the enzyme lipoprotein lipase from tissues and stabilizing the enzyme. The resultant hydrolysis of triglycerides leads to increased blood concentrations of free fatty acids.

Protein binding:

Very high; primarily to low-density lipoproteins; also bound to globulins and to fibrinogen.

Biotransformation:

Hepatic; however, the primary route of removal from the circulation is uptake by the reticuloendothelial system.

Half-life:

1 to 6 hours (average 1.5 hours); dose and route dependent and subject to inter- and intrapatient variation. May be increased above the average in patients with renal failure, hepatic function impairment, or obesity. May be decreased in patients with pulmonary embolism, infections, or malignancy.

Onset of action:

Direct intravenous injection—Immediate.

Intravenous infusion—Immediate when infusion is preceded by the recommended intravenous loading dose. If no loading dose is given, the onset of action may depend upon the rate of infusion.

Subcutaneous—Generally within 20 to 60 minutes but subject to interpatient variability.

Elimination:
    Renal, usually as metabolites. However, after intravenous administration of high doses, up to 50% of a dose may be excreted unchanged.
    In dialysis—Not removed via hemodialysis.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients with a history of allergies, especially those who are allergic to swine, beef, or other animal proteins, may be allergic to this medication also (depending on heparin source).

Pregnancy/Reproduction

Pregnancy—
Heparin does not cross the placenta and is the anticoagulant of choice for use during pregnancy because it does not affect blood clotting mechanisms in the fetus. Although heparin has not been reported to cause birth defects, use during pregnancy has been reported to increase the risk of stillbirth or prematurity. However, the underlying condition, rather than heparin itself, may have been responsible. Also, the reported incidence (13 to 22%) of these complications is lower than that reported with coumarin-derivative anticoagulants (31%). In addition, caution is recommended when heparin is used during the last trimester of pregnancy or during the postpartum period because of the increased risk of maternal bleeding.

Especially careful monitoring of the patient and attention to dosage are recommended during pregnancy. Heparin requirements increase, because of expansion of the patient's blood volume, as pregnancy progresses {05} {06} {07}. Readjustment of heparin dosage may be needed following delivery {07}.

FDA Pregnancy Category C.

Breast-feeding

Heparin is not distributed into breast milk. However, administration to lactating women has rarely been reported to cause rapid (within 2 to 4 weeks) development of severe osteoporosis and vertebral collapse.

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of heparin in children. However, heparin injections that contain benzyl alcohol should not be administered to premature neonates because the preservative has been associated with a fatal “gasping syndrome” in these patients.


Geriatrics


Patients 60 years of age or older, especially females, may be more susceptible to hemorrhaging during heparin therapy. Also, elderly patients are more likely to have age-related renal function impairment, which may increase the risk of bleeding in patients receiving anticoagulants.


Dental

Bleeding from gingival tissue may be a symptom of heparin overdose.

Heparin therapy increases the risk of localized hemorrhage during and following oral surgical procedures. Consultation with the prescribing physician may be advisable prior to oral surgery, to determine whether a temporary dosage reduction or withdrawal of heparin therapy is feasible. Also, local measures to minimize bleeding should be used at the time of surgery.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Interactions listed below may not apply to short-term use of heparin followed by protamine reversal, as in cardiovascular surgery.
In addition to the documented interactions listed below, the possibility should be considered that multiple effects leading to further impairment of blood clotting and/or increased risk of bleeding may occur if heparin is administered to a patient receiving any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.

Acid citrate dextrose (ACD)–converted blood—blood collected in heparin and later converted to ACD blood    (heparin anticoagulant activity lasts for up to 22 days after conversion to ACD blood when refrigerated; use of ACD blood in heparin-treated patients may increase the risk of hemorrhage)


Adrenocorticoids, glucocorticoid or
Corticotropin, especially chronic therapeutic use or
Ethacrynic acid or
Salicylates, nonacetylated    (the potential occurrence of gastrointestinal ulceration or hemorrhage during therapy with these medications may cause increased risk of bleeding in patients receiving anticoagulant therapy)

    (large [antirheumatic] doses of salicylates may cause hypoprothrombinemia, which may increase the risk of bleeding in patients receiving anticoagulant therapy)


Anticoagulants, coumarin- or indandione-derivative    (although these medications are commonly used concurrently with heparin, the fact that concurrent use may lead to a severe deficiency of vitamin K–dependent procoagulant factors, leading to increased risk of bleeding, must be considered)

    (heparin may prolong the prothrombin time used for dosage adjustments of these agents)


Antihistamines or
Digitalis glycosides or
Nicotine or
Tetracyclines    (these medications may partially counteract the anticoagulant effect of heparin; heparin dosage adjustment may be required during and following concurrent use)


Anti-inflammatory drugs, nonsteroidal (NSAIDs) or
» Platelet aggregation inhibitors, other, (See Appendix II ) especially:
» Aspirin
» Sulfinpyrazone    (inhibition of platelet function by these agents may lead to hemorrhage because it impairs a hemostatic mechanism on which heparin-treated patients depend to prevent bleeding)

    (hypoprothrombinemia induced by large [antirheumatic] doses of aspirin, and the potential occurrence of gastrointestinal ulceration or hemorrhage during therapy with NSAIDs, aspirin, or sulfinpyrazone, may also cause increased risk of bleeding in patients receiving heparin therapy)


» Cefamandole or
» Cefoperazone or
» Cefotetan or
» Plicamycin or
» Valproic acid    (these medications may cause hypoprothrombinemia; in addition, plicamycin or valproic acid may inhibit platelet aggregation; concurrent use with heparin may increase the risk of hemorrhage and is not recommended)


Chloroquine or
Hydroxychloroquine    (these agents may cause thrombocytopenia, which may increase the risk of hemorrhage because heparin-treated patients depend on platelet aggregation to prevent bleeding)


» Methimazole or
» Propylthiouracil    (these medications may cause hypoprothrombinemia, which may enhance the anticoagulant effect of heparin and increase the risk of bleeding)


Nitroglycerin, intravenous    (the anticoagulant effect of heparin may be decreased in patients receiving nitroglycerin via intravenous infusion; adjustment of heparin dosage may be required to maintain the desired degree of anticoagulation during and following administration of a nitroglycerin infusion {08} {09})


» Probenecid    (probenecid may increase and prolong the anticoagulant effect of heparin)


» Thrombolytic agents, such as:
» Alteplase (tissue-type plasminogen activator, recombinant)
» Anistreplase (anisoylated plasminogen-streptokinase activator complex; APSAC)
» Streptokinase
» Urokinase    (concurrent or sequential use with heparin increases the risk of bleeding complications; although heparin is sometimes given before, and is usually given to decrease the risk of reocclusion following, thrombolytic therapy, caution and especially careful monitoring of the patient are recommended {10})


Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Blood pool imaging studies    (heparin may impair blood pool images by decreasing the radiolabeling of red blood cells with sodium pertechnetate Tc 99m {12})


125I-fibrinogen uptake test    (some reports have indicated that heparin may cause false-negative test results in patients with actively forming or established venous thrombosis)


Platelet scintigraphy using indium In 111 oxyquinoline    (although studies of the effect of heparin on In 111–labeled platelet accumulation on venous thrombi have yielded contradictory results, the possibility should be considered that false negative test results may occur in heparin-treated patients {17})


Prothrombin-time test, one-stage    (may be prolonged; single intravenous injections or subcutaneous injection of full therapeutic doses of heparin may prolong the prothrombin time considerably because of the high concentrations of heparin in the blood, whereas usual prophylactic [low] doses of heparin given subcutaneously or full therapeutic doses given by continuous intravenous infusion usually do not increase the prothrombin time by more than a few seconds; to minimize problems, draw blood for the prothrombin time test just prior to, or at least 5 hours after, a single intravenous dose or 12 to 24 hours following subcutaneous injection of a full therapeutic dose)


Radionuclide imaging using technetium Tc 99m sulfur colloid    (heparin may reduce the quantity of technetium Tc 99m sulfur colloid reaching the site being studied by causing the radiotracer to accumulate in the lung, probably by increasing the number of free intravascular macrophages, which may migrate to, and phagocytize colloidal particles in, the pulmonary capillary bed {13})


Skeletal imaging, radionuclide    (subcutaneously administered heparin calcium may cause extraosseus accumulation of technetium Tc 99m medronate, technetium Tc 99m oxidronate, or technetium Tc 99m pyrophosphate, thereby interfering with the bone scan, if injected near the site to be studied; the interference involves precipitation of calcium, which may occur if the tissue concentration of calcium exceeds its solubility limits, and therefore does not occur with subcutaneously administered heparin sodium {16})


Thyroid function tests    (increases in serum thyroxine concentrations may occur, depending on the test method used; also, resin T 3 uptake may be increased)

With physiology/laboratory test values
Plasma free fatty acid concentration    (may be increased)


Plasma triglyceride concentration    (may be decreased)


Serum alanine aminotransferase (ALT [SGPT]) activity and
Serum aspartate aminotransferase (AST [SGOT]) activity    (may be increased during, and for a time following, heparin therapy; the usefulness of determinations of these enzymes in the differential diagnosis of myocardial infarction, pulmonary embolism, or liver disease may therefore be decreased)


Serum cholesterol concentration    (may be decreased with doses of 15,000 to 20,000 USP Units of heparin)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Abortion, threatened or
» Aneurysm, cerebral or dissecting aorta, except in conjunction with corrective surgery or
» Cerebrovascular hemorrhage, confirmed or suspected    (increased risk of uncontrollable hemorrhage)


» Hemorrhage, active uncontrollable, except in disseminated intravascular coagulation
» Hypertension, severe uncontrolled    (increased risk of cerebral hemorrhage)


» Thrombocytopenia, severe, heparin-induced, within past several months    (risk of recurrence, which may cause resistance to heparin and new thromboembolic complications)


Risk-benefit should be considered when the following medical problems exist
Allergic reaction to heparin, history of
Allergy or asthma, history of    (increased risk of allergic reactions because heparin is derived from animal tissue)


Any medical or dental procedure or condition in which the risk of bleeding or hemorrhage is present, such as:
» Anesthesia, regional or lumbar block
» Blood dyscrasias, hemorrhagic, especially thrombocytopenia or hemophilia; or other hemorrhagic tendency
» Childbirth, recent
Diabetes, severe
» Endocarditis, subacute bacterial
Gastrointestinal ulceration, history of
Intrauterine contraceptive device, use of
» Neurosurgery, recent or contemplated
» Ophthalmic surgery, recent or contemplated
» Pericarditis or pericardial effusion
Radiation therapy, recent
Renal function impairment, mild to moderate
» Renal function impairment, severe
» Spinal puncture, recent
» Surgery, major, or wounds resulting in large open surfaces
» Trauma, severe, especially to the central nervous system (CNS)
Tuberculosis, active
» Ulceration or other lesions of the gastrointestinal, respiratory, or urinary tract, active
» Vasculitis, severe
Hepatic function impairment, mild to moderate
» Hepatic function impairment, severe
Hypertension, mild to moderate    (increased risk of cerebral hemorrhage)


» Caution in use is also recommended for lactating women, who may develop severe osteoporosis after only 2 to 4 weeks of heparin therapy, and geriatric patients, who may be at increased risk of heparin-induced hemorrhage.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood coagulation tests    (except in rare acute or emergency situations, should be performed prior to full-dose therapy to establish a baseline or control value; also, recommended prior to initiation of low-dose prophylaxis to identify pre-existing coagulation defects and aid in determining whether the patient is a suitable candidate for such treatment)


» Blood coagulation tests, heparin-specific, such as:
Activated clotting time (ACT) test or
Partial thromboplastin time (PTT) tests    (must be performed at periodic intervals during full-dose therapy as a guide to dosage, efficacy, and safety)

    (PTT tests are used to establish dosage requirements during the initial phase of adjusted-dose therapy; they are also required at periodic intervals throughout adjusted-dose therapy, as a guide to dosage and efficacy, if the patient is pregnant)


Hematocrit determinations and
Stool tests for occult blood loss    (should be performed at regular intervals during full-dose therapy)


» Platelet counts    (recommended prior to initiation of therapy and at intervals of every 2 to 3 days during full-dose, adjusted-dose, or low-dose therapy to detect thrombocytopenia)




Side/Adverse Effects

Note: The occurrence of hemorrhage (especially in the gastrointestinal tract) during heparin therapy, especially if blood coagulation tests are within the therapeutic range, may indicate the presence of an underlying occult lesion such as a tumor or ulcer.
Two forms of reversible thrombocytopenia related to heparin therapy have been identified, either of which may occur in up to 30% of patients receiving the medication. A mild form may occur on the second to fourth day of heparin therapy and may improve despite continuing heparin usage. This condition is characterized by a moderate decrease in platelet count and by the absence of thrombotic or hemorrhagic complications; it may occur more frequently with bovine lung heparin than with porcine mucosal heparin. A severe form of thrombocytopenia, associated with the development of heparin-dependent antiplatelet antibodies resulting in greatly increased platelet aggregation, has also been reported. This condition usually occurs after the eighth day of therapy, although it has occurred within as little as 2 days in some patients, and is characterized by reduction of platelet count to as low as 5000 per cu. mm. and by increased resistance to heparin therapy. Continued use of heparin may lead to the “white clot syndrome”, i.e., the formation of new thrombi composed primarily of fibrin platelet aggregates, which may cause thrombotic complications including organ infarction, skin necrosis, gangrene of the extremities, pulmonary embolism, and stroke. Rarely, hemorrhage may occur. This severe form of thrombocytopenia is independent of the source of heparin, dosage, or route of administration; however, patients who have recently received a prior course of heparin therapy may be at greater risk of developing this complication. Heparin should be discontinued immediately if severe thrombocytopenia occurs or is suspected. Severe thrombocytopenia may recur if heparin is administered to the patient within several months following the development of this complication.
Adrenal hemorrhage resulting in acute adrenal insufficiency has been reported to occur rarely during anticoagulant therapy. Diagnosis may be difficult because the initial symptoms (abdominal pain, apprehension, diarrhea, dizziness or fainting, headache, loss of appetite, nausea or vomiting, and weakness) are nonspecific and variable. If acute adrenal insufficiency is suspected, anticoagulant therapy must be discontinued and high-dose adrenocorticoid therapy (preferably with hydrocortisone, since other glucocorticoids do not provide sufficient sodium retention) instituted immediately. Delay of treatment while laboratory confirmation of the diagnosis is awaited may prove fatal to the patient. It has been proposed that abdominal computerized axial tomographic (CAT) scanning may be of use in diagnosing this condition more rapidly.
Heparin may suppress aldosterone synthesis. Rarely, with prolonged use, inhibition of renal function, hyperkalemia, and metabolic acidosis may result.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Allergic reaction (fever with or without chills; runny nose; headache; nausea with or without vomiting; shortness of breath, troubled breathing, wheezing, or tightness in chest; skin rash, itching, or hives; tearing of eyes)
    
anaphylactoid reaction, possibly including anaphylactic shock (changes in facial skin color; skin rash, hives, and/or itching; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; sudden, severe decrease in blood pressure and collapse)
    
chest pain
    
frequent or persistent erection
    
itching and burning feeling, especially on the plantar site of the feet
    
pain, coldness, and blue color of skin of arms or legs
    
peripheral neuropathy (numbness or tingling in hands or feet)

Note: Signs and symptoms suggestive of ischemia may occur in one or more limbs approximately 6 to 10 days following initiation of therapy. If heparin therapy is continued, progression of the reaction may lead to cyanosis, tachypnea, and headache. Protamine sulfate will not reverse these effects, which in the past have been attributed to an allergic vasospastic reaction. Whether these effects are actually identical to complications associated with heparin-induced thrombocytopenia has not been determined.




Signs and symptoms of hemorrhage indicating need for medical attention
Early signs of hemorrhage
    
Bleeding from gums when brushing teeth
    
heavy bleeding or oozing from cuts or wounds
    
unexplained bruising or purplish areas on skin
    
unexplained nosebleeds
    
unusually heavy or unexpected menstrual bleeding

Note: Unexplained bleeding or bruising may also indicate thrombocytopenia.


Signs and symptoms of internal bleeding
—incidence 5 to 15%    
Abdominal pain or swelling
    
back pain or backaches
    
blood in urine
    
bloody or black, tarry stools
    
constipation caused by hemorrhage-induced paralytic ileus or intestinal obstruction
    
coughing up blood
    
dizziness
    
headaches, severe or continuing
    
joint pain, stiffness, or swelling
    
vomiting of blood or material that looks like coffee grounds



Those occurring during long-term (6 months or longer) therapy and indicating need for medical attention
    
Osteoporosis (back or rib pain; decrease in height)
    
unusual hair loss


Those occurring at site of administration and indicating need for medical attention
Incidence less frequent or rare with deep subcutaneous injections
    
Hematoma (collection of blood under skin [blood blister])
    
histamine-like reaction
    
hives, localized
    
irritation, pain, redness, or ulceration
    
necrosis, cutaneous (peeling or sloughing of skin)—several cases of tissue necrosis, possibly associated with cutaneous hemorrhage, have also been reported following intravenous administration





Overdose
For specific information on the agents used in the management of heparin overdose, see the Protamine (Systemic) monograph.

For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Early signs of excessive anticoagulation
    
Bleeding from gums when brushing teeth
    
heavy bleeding or oozing from cuts or wounds
    
unexplained bruising or purplish areas on skin
    
unexplained nosebleeds
    
unusually heavy or unexpected menstrual bleeding

Note: Unexplained bleeding or bruising may also indicate thrombocytopenia.


Signs and symptoms of internal bleeding
    
Abdominal pain or swelling
    
back pain or backaches
    
blood in urine
    
bloody or black, tarry stools
    
constipation caused by hemorrhage-induced paralytic ileus or intestinal obstruction
    
coughing up blood
    
dizziness
    
headaches, severe or continuing
    
joint pain, stiffness, or swelling
    
vomiting of blood or material that looks like coffee grounds



Treatment of overdose
For mild effects of heparin overdose, withdrawal of heparin therapy may be sufficient.


Specific treatment:
For more severe overdose, administration of the heparin antagonist protamine is required. One milligram of protamine sulfate will neutralize approximately 100 USP Units of heparin. However, heparin blood concentrations decrease rapidly following intravenous administration; 30 minutes after intravenous administration of heparin, half as much protamine sulfate may be sufficient to neutralize the remaining heparin. In most cases, it is recommended that protamine sulfate be administered intravenously, slowly (over a one- to three-minute period), and in doses not exceeding 50 mg in any ten-minute period. It is strongly recommended that blood coagulation tests be used to determine optimum protamine dosage, especially when neutralizing large doses of heparin given during cardiac or arterial surgery.

Because absorption of heparin may be prolonged following subcutaneous administration, it has been recommended that protamine (when used to neutralize heparin administered via that route) be administered as an initial loading dose of 25 to 50 mg that is followed by continuous intravenous infusion (over a period of 8 to 16 hours) of the remainder of the calculated dose. It is recommended that blood coagulation tests and/or direct titration of a sample of the patient's blood with protamine be used as a guide to protamine dosage.

When protamine is used to neutralize large doses of heparin, such as those used during cardiopulmonary bypass surgery, a rebound of heparin activity resulting in hemorrhage may occur despite initial complete neutralization of heparin. Prolonged monitoring of the patient is necessary; additional protamine should be administered as determined by coagulation test results. Also, it is recommended that no more than 100 mg of protamine sulfate be administered over a short period of time (2 hours) unless accurate titrations or other tests indicate that larger doses are required.

For severe hemorrhaging, transfusion of whole blood or plasma may also be required. This may dilute, but will not neutralize the effects of, heparin.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Heparin (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergies, especially to heparin or to swine, beef, or other animal proteins

Pregnancy—Although heparin does not cross the placenta and is not likely to adversely affect the fetus or neonate, there is a risk of maternal bleeding





Breast-feeding—Although heparin is not distributed into breast milk and poses no danger to the infant, severe osteoporosis and vertebral collapse may develop rapidly in lactating women





Use in the elderly—Increased risk of hemorrhage, especially in elderly females
Other medications, especially platelet aggregation inhibitors, hypoprothrombinemia-inducing medications, and probenecid
Other medical problems, especially hypertension; hemorrhagic blood dyscrasias; recent childbirth, spinal puncture, surgery, or other trauma; endocarditis; hepatic function impairment; renal function impairment; ulcers or other lesions of the gastrointestinal, respiratory, or urinary tract; and history of heparin-induced thrombocytopenia

Proper use of this medication
» Proper administration of injections at home (if applicable)

» Importance of strict compliance with dosage measurement and dosage schedule to achieve maximum effectiveness and to lessen chance of bleeding

» Regular visits to physician and regular blood coagulation tests to check progress during therapy

» Proper dosing
Missed dose: Using as soon as possible; not using if almost time for next dose; not doubling doses; keeping record of doses taken to avoid mistakes; keeping record of missed doses to give physician

» Proper storage—if dispensed to patient

Precautions while using this medication
» Not taking aspirin while using this medication; checking all medications for aspirin content; not taking ibuprofen or other platelet-active medications (unless prescribed by physician) while using heparin

» Need to inform all physicians and dentists that this medication is being used

Need to carry identification stating that medication is being used

Avoiding activities that may lead to injuries

Using care in brushing teeth and shaving


Side/adverse effects
Signs of potential side effects, especially allergic reactions, including anaphylaxis and anaphylactic shock; bleeding, including internal bleeding; chest pain; pain, coldness, or blue color of skin of arms or legs; peripheral neuropathy; skin necrosis; and local reactions at the injection site

Notifying physician immediately if signs and symptoms of bleeding are evident


General Dosing Information
Full-dose heparin is administered by deep subcutaneous (intrafat) injection, direct intravenous injection, or intravenous infusion. Heparin should not be administered by intramuscular injection because of the increased incidence of hematomas, irritation, and pain at the injection site. Low-dose heparin is generally administered by deep subcutaneous injection.

The deep subcutaneous (intrafat) injections should be made deep into fatty tissue such as above the iliac crest or into the abdominal fat layer, and the sites should be rotated to prevent formation of hematomas. Aspiration of blood should not be attempted, and the needle should not be moved while the solution is being injected. Other measures recommended to reduce the risk of tissue trauma during subcutaneous injections include use of a small needle, use of a concentrated heparin solution to minimize the injection volume, and injection of the solution into a 2 to 2.5 cm (l to 2 inch) area of fat which is grasped and held away from deeper tissues. The injection sites should not be massaged before or after the injections; however, application of pressure over the injection sites for up to two minutes following each injection has been recommended.

For intravenous administration, many clinicians prefer continuous intravenous infusion because several studies have indicated that a more constant degree of anticoagulation may be achieved with lower total daily dosages and that the incidence of bleeding complications may be decreased. However, other clinicians prefer intermittent intravenous administration. Use of an indwelling, rubber-capped needle (heparin-lock) has been recommended for intermittent intravenous therapy. Use of a constant infusion pump or mechanical syringe pump has been recommended for administration of the continuous intravenous infusion, to control the flow rate and infusion volume. It is recommended that other medications not be added to infusion solutions containing heparin, even if compatibility has been established, because changes in the infusion rate that may be needed to adjust heparin dosage will also affect the delivery rate of other medications present in the solution.

When heparin is administered using a full-dose regimen, the dosage must be individualized and adjusted according to the results of periodic coagulation tests. Full-dose heparin therapy is contraindicated whenever suitable blood coagulation tests cannot be performed at the required intervals. However, the effect of low-dose heparin usually does not require monitoring if the patient has normal pretreatment coagulation parameters. During the first day of treatment, a coagulation test is usually performed prior to each injection (if given via an intermittent dosage schedule). When the medication is given by continuous intravenous infusion, the test is usually performed 11/2 to 2 hours after the infusion is started, then every 4 hours during the early stages of treatment. However, the frequency of testing must be adjusted to the needs of the individual patient. Coagulation tests should be performed at least once daily for the duration of therapy; however, increased monitoring may be necessary in patients who may be more sensitive to the effects of heparin, such as elderly patients or those with hypertension, renal function impairment, or hepatic function impairment.

When heparin is administered using an adjusted-dose regimen, dosage must be established according to the results of daily coagulation tests. When no dosage adjustments have been needed for two weeks, further monitoring at regular frequent intervals may be unnecessary for most patients. However, pregnant women should be monitored throughout therapy because their dosage requirements increase as pregnancy progresses.

The standard tests used for measuring heparin's general effect on clotting include the Lee-White whole blood clotting time, the whole blood activated partial thromboplastin time (WBAPTT), the activated partial thromboplastin time (APTT), and the activated clotting time (ACT). Other tests may be used in some cases. The Lee-White whole blood clotting time has been reported to be less reproducible than other tests and has largely been replaced by partial thromboplastin time tests. If the Lee-White whole blood clotting time is used to monitor therapy, the clotting time should be elevated to 21/2 to 3 times the control value in minutes. The generally accepted value for the APTT is 11/2 to 21/2 times the control value in seconds. However, the specific reagent used must be considered when evaluating APTT test results because the various reagents used in the APTT test vary widely in their sensitivity to heparin. The generally accepted value for the ACT test is 2 to 3 times the control value in seconds. The ACT has been recommended as being particularly useful during extracorporeal circulation because it can be performed at the bedside; however, one study has indicated that the ACT may be ineffective for monitoring heparin dosage and protamine neutralization during cardiopulmonary bypass procedures in which hypothermia has been induced. Hypothermia may also interfere with the results of other coagulation tests. It is recommended that a single laboratory be employed for each patient, and that the laboratory understand the test will be used to monitor heparin therapy.

Because heparin is derived from animal tissue, it is recommended that patients with a history of allergies or asthma be given a test dose of 1000 USP Units before therapy is initiated.

Postsurgical patients and those with active thromboembolic disease (especially pulmonary embolism or myocardial infarction), infections with thrombosing tendency, malignancy, or a fever may be resistant to the effects of heparin and may require larger doses than other patients. Resistance to the effects of heparin also occurs in patients with familial antithrombin III deficiency. However, this type of resistance cannot always be overcome by increasing the dosage of heparin; a coumarin- or indandione-derivative anticoagulant is indicated for such patients. Also, local antithrombin III depletion resulting in loss of heparin effect may occur when heparin is administered intraperitoneally during peritoneal dialysis procedures.

If clinical evidence of thromboembolism occurs in a patient receiving low-dose heparin prophylaxis, full therapeutic doses of an anticoagulant should be administered. However, before full therapeutic doses of heparin are given, the possibility that the thrombosis may be due to the severe form of heparin-induced thrombocytopenia must be ruled out.

Heparin may be administered prior to or following thrombolytic therapy with alteplase (tissue-type plasminogen activator, recombinant), streptokinase, or urokinase. However, heparin should be discontinued and the patient's TT or APTT should be less than twice the control value prior to initiation of intravenous thrombolytic therapy. Also, following thrombolytic therapy, the patient's TT or APTT should return to less than twice the control value prior to administration of heparin.

When anticoagulant therapy is initiated with heparin and continued with a coumarin or indandione derivative, it is recommended that both agents be given concurrently until prothrombin time determinations indicate an adequate response to the coumarin or indandione derivative. The fact that early changes in prothrombin time may reflect initial depletion of factor VII rather than peak antithrombogenic activity must be kept in mind. Some clinicians recommend continuation of heparin therapy for several days after prothrombin time determinations have shown a reduction of activity to ensure that peak antithrombogenic activity has been reached.

Intramuscular injection of other medications is not recommended in patients receiving heparin because hematomas and bleeding into adjacent areas may occur.

A concentration of 400 to 600 USP Units of heparin per 100 mL of whole blood is usually used to prevent clotting during blood transfusion; a concentration of 70 to 150 USP Units of heparin per 10 to 20 mL of whole blood is usually used to prevent clotting in blood used for laboratory sampling. Consult manufacturers' prescribing information for specific directions. For use of heparin lock-flush solution in maintaining the patency of an indwelling venipuncture device, consult manufacturers' prescribing information. For use of heparin to prevent clotting during extracorporeal dialysis procedures, consult the equipment manufacturers' operating directions.


Parenteral Dosage Forms

Note: The following doses are given in USP Heparin Units. The strengths of heparin preparations available in the U.S. are labeled in USP Heparin Units per mL. The strengths of heparin preparations available in Canada may be labeled in USP Units or in International Units (IU) per mL. The strengths of heparin preparations available in many other countries, including the U.K., are labeled only in IU per mL. USP Heparin Units are not identical to IU. The relative potency between USP Units and IU may vary, depending upon the test method and specific reagents used to measure heparin activity. Also, a new International Standard for Heparin (used to calibrate potency in IU) was adopted in 1983. Therefore, equivalence in USP Units of dosages in clinical studies using heparin preparations labeled in IU may be difficult to determine.


Consult current labeling for specific dosage recommendations for heparin preparations labeled in IU.


At one time, 1 mg of heparin sodium was equivalent to 100 USP Units. However, this is no longer the case because of increased purification.


HEPARIN CALCIUM INJECTION USP

Usual adult dose
Full-dose (therapeutic) regimen
Subcutaneous, deep (intrafat), 10,000 to 20,000 USP Units initially, then 8000 to 10,000 USP Units every eight hours or 15,000 to 20,000 USP Units every twelve hours, or as determined by coagulation test results. This dosage schedule is usually preceded by a loading dose of 5000 USP Units administered by intravenous injection.

Intravenous, 10,000 USP Units initially, then 5000 to 10,000 USP Units every four to six hours or 100 USP Units per kg of body weight every four hours, or as determined by coagulation test results. The dose may be administered undiluted or diluted with 50 to 100 mL of 0.9% sodium chloride injection.

Intravenous infusion, 20,000 to 40,000 USP Units in 1000 mL of 0.9% sodium chloride injection, administered over a twenty-four-hour period. This dosage schedule is usually preceded by a loading dose of 35 to 70 USP Units per kg of body weight or 5000 USP Units, administered by intravenous injection. The infusion is often administered at a rate of l000 USP Units per hour; however, dosage must be adjusted as determined by coagulation test results.


Note: Recommendations for specific indications include:
Heart and blood vessel surgery—Intravenous, initially not less than l50 USP Units per kg of body weight. Doses of 300 USP Units per kg of body weight are often used for procedures expected to last less than 60 minutes and doses of 400 USP units per kg of body weight are often used for procedures expected to last longer than 60 minutes. It is recommended that subsequent doses be based on coagulation test results.
Disseminated intravascular coagulation—Intravenous, 50 to 100 USP Units per kg of body weight every four hours, administered by continuous infusion or as a single injection. The medication should be discontinued if no improvement occurs within 4 to 8 hours.

Adjusted-dose regimen
Subcutaneous, deep (intrafat), an established dose to be injected every twelve hours. The required dose is determined by adjusting heparin dosage until the midinterval (six hours after an injection) activated partial thromboplastin time (APTT) is maintained at one and one-half times the control value.

Low-dose (prophylactic) regimen
Subcutaneous, deep (intrafat), 5000 USP Units two hours before surgery and every eight to twelve hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer.


Usual pediatric dose
Intravenous, 50 USP Units per kg of body weight initially, then 50 to 100 USP Units per kg of body weight every four hours, or as determined by coagulation test results.

Intravenous infusion, 50 USP Units per kg of body weight as a loading dose initially, then 100 USP Units per kg of body weight added and absorbed every four hours or 20,000 USP Units per square meter of body surface every twenty-four hours, or as determined by coagulation test results.

Note: Recommendations for specific indications include:
Disseminated intravascular coagulation—Intravenous, 25 to 50 USP Units per kg of body weight every four hours, administered by continuous infusion or as a single injection. The medication should be discontinued if no improvement occurs within 4 to 8 hours.
Heart and blood vessel surgery—Intravenous, initially not less than l50 USP Units per kg of body weight. Doses of 300 USP Units per kg of body weight are often used for procedures expected to last less than 60 minutes. It is recommended that subsequent doses be based on coagulation test results.


Strength(s) usually available
U.S.—



Derived from porcine intestinal mucosa


25,000 USP Units per mL (Rx) [Calciparine (in single unit-dose containers providing 5000 USP Units per 0.2 mL; 12,500 USP Units per 0.5 mL; and 20,000 USP Units per 0.8 mL)]

Canada—



Derived from porcine intestinal mucosa


25,000 International Units (IU) per mL (Rx) [Calcilean (in single unit-dose containers providing 20,000 IU per 0.8 mL)] [Calciparine (in single unit-dose containers providing 5000 IU per 0.2 mL; 12,500 IU per 0.5 mL; and 20,000 IU per 0.8 mL)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Do not use if the solution is discolored or contains a precipitate. Some studies have indicated that loss of heparin activity may occur if heparin is diluted with 5% dextrose injection and the diluted solution is not used within 24 hours, or if diluted solutions of heparin in any diluent are stored in glass containers.

Incompatibilities:
Heparin is strongly acidic and is incompatible with many solutions containing medications, although no loss of activity occurs when the agents are given via separate administration sites. Also, heparin may be incompatible with solutions containing a phosphate buffer, sodium carbonate, or sodium oxalate. It is recommended that heparin not be mixed, or administered through the same intravenous line, with other medications unless compatibility has first been established. In addition, heparin may be inactivated when used in conjunction with an artificial kidney because of an influx of calcium, magnesium, and acetate ions from the dialysate.

Note: When preparing the label, indicate that heparin calcium is of porcine mucosal origin.



HEPARIN SODIUM INJECTION USP

Usual adult dose
Full-dose (therapeutic) regimen
Subcutaneous, deep (intrafat), 10,000 to 20,000 USP Units initially, then 8000 to 10,000 USP Units every eight hours or 15,000 to 20,000 USP Units every twelve hours, or as determined by coagulation test results. This dosage schedule is usually preceded by a loading dose of 5000 USP Units administered by intravenous injection.

Intravenous, 10,000 USP Units initially, then 5000 to 10,000 USP Units every four to six hours or 100 USP Units per kg of body weight every four hours, or as determined by coagulation test results. The dose may be administered undiluted or diluted with 50 to 100 mL of 0.9% sodium chloride injection.

Intravenous infusion, 20,000 to 40,000 USP Units in 1000 mL of 0.9% sodium chloride injection, administered over a twenty-four-hour period. This dosage schedule is usually preceded by a loading dose of 35 to 70 USP Units per kg of body weight or 5000 USP Units, administered by intravenous injection. The infusion is often administered at a rate of l000 USP Units per hour; however, dosage must be adjusted as determined by coagulation test results.


Note: Recommendations for specific indications include:
Heart and blood vessel surgery—Intravenous, initially not less than l50 USP Units per kg of body weight. Doses of 300 USP Units per kg of body weight are often used for procedures expected to last less than 60 minutes and doses of 400 USP units per kg of body weight are often used for procedures expected to last longer than 60 minutes. It is recommended that subsequent doses be based on coagulation test results.
Disseminated intravascular coagulation—Intravenous, 50 to 100 USP Units per kg of body weight every four hours, administered by continuous infusion or as a single injection. The medication should be discontinued if no improvement occurs within 4 to 8 hours.

Adjusted-dose regimen
Subcutaneous, deep (intrafat), an established dose to be injected every twelve hours. The required dose is determined by adjusting heparin dosage until the midinterval (six hours after an injection) activated partial thromboplastin time (APTT) is maintained at one and one-half times the control value.

Low-dose (prophylactic) regimen
Subcutaneous, deep (intrafat), 5000 USP Units two hours before surgery and every eight to twelve hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer.


Usual pediatric dose
Intravenous, 50 USP Units per kg of body weight initially, then 50 to 100 USP Units per kg of body weight every four hours, or as determined by coagulation test results.

Intravenous infusion, 50 USP Units per kg of body weight as a loading dose initially, then 100 USP Units per kg of body weight added and absorbed every four hours or 20,000 USP Units per square meter of body surface every twenty-four hours, or as determined by coagulation test results.

Note: Recommendations for specific indications include:
Disseminated intravascular coagulation—Intravenous, 25 to 50 USP Units per kg of body weight every four hours, administered by continuous infusion or as a single injection. The medication should be discontinued if no improvement occurs within 4 to 8 hours.
Heart and blood vessel surgery—Intravenous, initially not less than l50 USP Units per kg of body weight. Doses of 300 USP Units per kg of body weight are often used for procedures expected to last less than 60 minutes. It is recommended that subsequent doses be based on coagulation test results.


Strength(s) usually available
U.S.—



Derived from beef lung: With preservative


1000 USP Units per mL (Rx)[Generic]


5000 USP Units per mL (Rx)[Generic]


10,000 USP Units per mL (Rx)[Generic]


20,000 USP Units per mL (Rx)[Generic]



Derived from beef lung: Without preservative


1000 USP Units per mL (Rx)[Generic]


5000 USP Units per mL (Rx)[Generic]



Derived from porcine intestinal mucosa: With preservative


1000 USP Units per mL (Rx) [Liquaemin (benzyl alcohol)][Generic]


2500 USP Units per mL (Rx)[Generic]


5000 USP Units per mL (Rx) [Liquaemin (benzyl alcohol)][Generic]


7500 USP Units per mL (Rx)[Generic]


10,000 USP Units per mL (Rx) [Liquaemin (benzyl alcohol)][Generic]


15,000 USP Units per mL (Rx)[Generic]


20,000 USP Units per mL (Rx) [Liquaemin (benzyl alcohol)][Generic]


25,000 USP Units per mL (Rx)[Generic]


40,000 USP Units per mL (Rx) [Liquaemin (benzyl alcohol)][Generic]



Derived from porcine intestinal mucosa: Without preservative


1000 USP Units per mL (Rx) [Liquaemin][Generic]


5000 USP Units per mL (Rx) [Liquaemin][Generic]

Note: Single unit-dose containers may also provide the quantities of heparin sodium listed above in volumes other than 1 mL.


Canada—



Derived from porcine intestinal mucosa: With preservative


1000 International Units (IU) per mL (Rx) [Heparin Leo (chlorobutanol)]


1000 USP Units per mL (Rx) [Hepalean (benzyl alcohol)][Generic]


10,000 IU per mL (Rx) [Heparin Leo (chlorobutanol)]


10,000 USP Units per mL (Rx) [Hepalean (benzyl alcohol)][Generic]


25,000 IU per mL (Rx) [Heparin Leo (in 2-mL containers) (chlorobutanol)]


25,000 USP Units per mL (Rx) [Hepalean (in single-dose containers providing 5000 USP Units in 0.2 mL and in 2-mL containers) (benzyl alcohol)]



Derived from porcine intestinal mucosa: Without preservative


1000 IU per mL (Rx) [Heparin Leo]


1000 USP Units per mL (Rx) [Hepalean]


10,000 IU per mL (Rx) [Heparin Leo]


25,000 IU per mL (Rx) [Heparin Leo (in single-dose containers providing 5000 IU in 0.2 mL)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Do not use if the solution is discolored or contains a precipitate. Some studies have indicated that loss of heparin activity may occur if heparin is diluted with 5% dextrose injection and the diluted solution is not used within 24 hours, or if diluted solutions of heparin in any diluent are stored in glass containers.

Incompatibilities:
Heparin is strongly acidic and is incompatible with many solutions containing medications, although no loss of activity occurs when the agents are given via separate administration sites. Also, heparin may be incompatible with solutions containing a phosphate buffer, sodium carbonate, or sodium oxalate. It is recommended that heparin not be mixed, or administered through the same intravenous line, with other medications unless compatibility has first been established. In addition, heparin may be inactivated when used in conjunction with an artificial kidney because of an influx of calcium, magnesium, and acetate ions from the dialysate.

Note: When preparing the label, indicate the organ and species from which the heparin is derived.


Additional information:
Heparin sodium injections that contain benzyl alcohol should not be administered to premature neonates because the preservative has been associated with a fatal “gasping syndrome” in these patients.


HEPARIN SODIUM IN DEXTROSE INJECTION

Usual adult dose
Intravenous infusion, 20,000 to 40,000 USP Units, administered over a twenty-four-hour period. This dosage schedule is usually preceded by a loading dose of 35 to 70 USP Units per kg of body weight or 5000 USP Units, administered by intravenous injection. The infusion is often administered at a rate of 1000 USP Units per hour; however, dosage must be adjusted as determined by coagulation test results.

Usual pediatric dose
Intravenous infusion, 50 USP Units per kg of body weight as a loading dose initially, then 100 USP Units per kg of body weight added and absorbed every four hours or 20,000 USP Units per square meter of body surface every twenty-four hours, or as determined by coagulation test results.

Strength(s) usually available
U.S.—



Derived from porcine intestinal mucosa


20 USP Units per mL (10,000 USP Units per 500 mL), with 5% of dextrose (Rx)[Generic]


40 USP Units per mL (20,000 USP Units per 500 mL), with 5% of dextrose (Rx)[Generic]


50 USP Units per mL (12,500 USP Units per 250 mL and 25,000 USP Units per 500 mL), with 5% of dextrose (Rx)[Generic]


100 USP Units per mL (10,000 USP Units per 100 mL and 25,000 USP Units per 250 mL), with 5% of dextrose (Rx)[Generic]

Canada—



Derived from porcine intestinal mucosa


40 USP Units per mL (20,000 USP Units per 500 mL), with 5% of dextrose (Rx)[Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Incompatibilities:
Heparin is strongly acidic and is incompatible with many solutions containing medications, although no loss of activity occurs when the agents are given via separate administration sites. Also, heparin may be incompatible with solutions containing a phosphate buffer, sodium carbonate, or sodium oxalate. It is recommended that heparin not be mixed, or administered through the same intravenous line, with other medications unless compatibility has first been established.


HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION

Usual adult dose
Intravenous infusion, 20,000 to 40,000 USP Units, administered over a twenty-four-hour period. This dosage schedule is usually preceded by a loading dose of 35 to 70 USP Units per kg of body weight or 5000 USP Units, administered by intravenous injection. The infusion is often administered at a rate of l000 USP Units per hour; however, dosage must be adjusted as determined by coagulation test results.

Usual pediatric dose
Intravenous infusion, 50 USP Units per kg of body weight as a loading dose initially, then 100 USP Units per kg of body weight added and absorbed every four hours or 20,000 USP Units per square meter of body surface every twenty-four hours, or as determined by coagulation test results.

Strength(s) usually available
U.S.—



Derived from porcine intestinal mucosa


2 USP Units per mL (1000 USP Units per 500 mL and 2000 USP Units per 1000 mL), with 0.9% of sodium chloride (Rx)[Generic]


50 USP Units per mL (12,500 USP Units per 250 mL and 25,000 USP Units per 500 mL), with 0.45% of sodium chloride (Rx)[Generic]


100 USP Units per mL (25,000 USP Units per 250 mL), with 0.45% of sodium chloride (Rx)[Generic]

Canada—



Derived from porcine intestinal mucosa


2 USP Units per mL (1000 USP Units per 500 mL and 2000 USP Units per 1000 mL), with 0.9% of sodium chloride (Rx)[Generic]


5 USP Units per mL (5000 USP Units per 1000 mL), with 0.9% of sodium chloride (Rx)[Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Incompatibilities:
Heparin is strongly acidic and is incompatible with many solutions containing medications, although no loss of activity occurs when the agents are given via separate administration sites. Also, heparin may be incompatible with solutions containing a phosphate buffer, sodium carbonate, or sodium oxalate. It is recommended that heparin not be mixed, or administered through the same intravenous line, with other medications unless compatibility has first been established.



Revised: 08/23/1994



References
  1. ACCP-NHLBI National Conference on Antithrombotic Therapy. American College of Chest Physicians and the National Heart, Lung and Blood Institute. Chest 1986; 89(2 suppl): 1S-106S.
  1. 2nd ACCP Conference on Antithrombotic Therapy. American College of Chest Physicians. June 21, 1988. Proceedings. Chest 1989; 95(2 suppl): 1S-169S.
  1. Hull RD, Raskob GE, Hirsh J, et al. A cost-effectiveness analysis of alternative approaches for long-term treatment of proximal venous thrombosis. JAMA 1984; 252: 235-9.
  1. Hull RD, Raskob GE, Hirsh J. Prophylaxis of venous thromboembolism. An overview. Chest 1986; 89(5 suppl): 374S-83S.
  1. Panel comment.
  1. Panel comment.
  1. Letsky E, de Swiet M. Annotation. Thromboembolism in pregnancy and its management. Br J Haematol 1984; 57: 543-52.
  1. Heparin sodium product information (Lilly—US), Rev 12/89, Rec 3/90.
  1. Hansten PD, Horn JR. Drug interactions. 6th ed. Philadelphia: Lea & Febiger, 1989: 55.
  1. Anistreplase (Systemic) monograph. USP DI-Volume I, Drug information for the health care professional, 1991.
  1. Not used.
  1. Technetium Tc 99m (Pyro- and Trimeta-) Phosphates (Systemic) monograph. USP DI-Volume I, Drug information for the health care professional, 1990.
  1. Technetium Tc 99m Sulfur Colloid (Systemic) monograph. USP DI-Volume I, Drug information for the health care professional, 1990.
  1. Panel comment.
  1. Thrombolytic Agents (Systemic) monograph. USP DI-Volume I, Drug information for the health care professional, 1990.
  1. Hladik WB, Ponto JA, Lentle BC, et al. Iatrogenic alterations in the biodistribution of radiotracers as a result of drug therapy: reported instances. In: Hladik WB, Saha GB, Study KT, editors. Essentials of nuclear medicine science. Baltimore: Williams and Wilkins, 1987: 195, 201-2.
  1. Panel comment.

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