Fatal Medication Errors

Do not use Heparin Sodium Injection as a “catheter lock flush” product.  Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL.  Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials.  Carefully examine all Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of the drug.

Benzyl Alcohol Toxicity

Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants.  The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients.  The minimum amount of benzyl alcohol at which toxicity may occur is not known.  Premature and low-birth weight infants may be more likely to develop toxicity (see PRECAUTIONS, Pediatric Use).

Hypersensitivity

Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations (see ADVERSE REACTIONS, Hypersensitivity).

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 promptly discontinued (see OVERDOSAGE).

Thrombocytopenia

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%.  Platelet counts should be obtained at baseline and periodically during heparin administration.  Mild thrombocytopenia (count greater than 100,000/mm 3) may remain stable or reverse even if heparin is continued.  However, thrombocytopenia of any degree should be monitored closely.  If the count falls below 100,000/mm 3 or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered.

Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT)

Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets.  HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT).  Thrombotic events may also be the initial presentation for HITT.  These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death.  Thrombocytopenia of any degree should be monitored closely.  If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered, if patients require continued anticoagulation.

Delayed Onset of HIT and HITT

Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis can occur up to several weeks after the discontinuation of heparin therapy.  Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

General

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT)

See WARNINGS.

Heparin Resistance—Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients.

Increased Risk to Older Patients, Especially Women—A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age.

Laboratory Tests

Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Oral Anticoagulants—Heparin sodium may prolong the one-stage prothrombin time.  Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least five hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained.

Platelet Inhibitors—Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet- aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium.

Other Interactions—Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium.  Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin.  Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin.

Drug/Laboratory Tests Interactions

Hyperaminotransferasemia—Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin.  Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases that might be caused by drugs (like heparin) should be interpreted with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin.  Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies on heparin use in pregnant women.  In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans.  Heparin sodium does not cross the placenta, based on human and animal studies.  Administration of heparin to pregnant animals at doses higher than the maximum human daily dose based on body weight resulted in increased resorptions.  Use heparin sodium during pregnancy only if the potential benefit justifies the potential risk to the fetus.

If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy.  There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants (see PRECAUTIONS, Pediatric Use).

In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 units/kg/day, approximately 10 times the maximum human daily dose based on body weight.  The number of early resorptions increased in both species.  There was no evidence of teratogenic effects.

Nursing Mothers

If available, preservative-free HEPARIN SODIUM INJECTION is recommended when heparin therapy is needed during lactation.  Due to its large molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk would not be orally absorbed by a nursing infant.  Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant.  Exercise caution when administering HEPARIN SODIUM INJECTION to a nursing mother (see PRECAUTIONS, Pediatric Use).

Pediatric Use

There are no adequate and well-controlled studies on heparin use in pediatric patients.  Pediatric dosing recommendations are based on clinical experience (see DOSAGE AND ADMINISTRATION, Pediatric Use).

Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug.  Pediatric patients, including neonates, have died as a result of medication errors in which HEPARIN SODIUM INJECTION vials have been confused with “catheter lock flush” vials (see WARNINGS, Fatal Medication Errors).

Benzyl Alcohol Toxicity

Use preservative-free Heparin Sodium Injection in neonates and infants.  The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients.  The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants.  Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known.  Premature and low-birth weight infants may be more likely to develop toxicity.  Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

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).

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.

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT

See WARNINGS.

Local Irritation

Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium.  These complications are much more common after intramuscular use, and such use is not recommended.

Hypersensitivity

Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely.  Itching and burning, especially on the plantar side of the feet, may occur (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.

Symptoms

Bleeding is the chief sign of heparin overdosage.  Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding.  Easy bruising or petechial formations may precede frank bleeding.

Treatment

Neutralization of Heparin Effect—When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium.  No more than 50 mg should be administered, very slowly, in any 10 minute period.  Each mg of protamine sulfate neutralizes approximately 100 USP heparin units.  The amount of protamine required decreases over time as heparin is metabolized.  Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection.

Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions.  Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

For additional information consult the labeling of Protamine Sulfate Injection, USP products.

Converting to Oral Anticoagulant

When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time.  This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose.  If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time.

In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals.  To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range.  Heparin therapy may then be discontinued without tapering.

Therapeutic Anticoagulant Effect with Full-Dose Heparin

Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:

Pediatric Use

Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants (see WARNINGS, Benzyl Alcohol Toxicity  and PRECAUTIONS, Pediatric Use).

There are no adequate and well-controlled studies on heparin use in pediatric patients.  Pediatric dosing recommendations are based on clinical experience.  In general, the following dosage schedule may be used as a guideline in pediatric patients:

            Initial Dose               75 to 100 units/kg (IV bolus over 10 minutes)

            Maintenance Dose    Infants: 25 to 30 units/kg/hour;

                                              Infants < 2 months have the highest requirements

                                             (average 28 units/kg/hour)

                                              Children > 1 year of age: 18 to 20 units/kg/hour;

                                              Older children may require less heparin, similar to weight-adjusted

                                              adult dosage

            Monitoring               Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this

                                             reflects an anti-Factor Xa level of 0.35 to 0.70.

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 of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

Low-Dose Prophylaxis of Postoperative Thromboembolism

A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism.  The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer.  The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma.  A concentrated solution of heparin sodium is recommended.  Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery.  Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS).  The value of such prophylaxis in hip surgery has not been established.  The possibility of increased bleeding during surgery or postoperatively should be borne in mind.  If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable.  If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated.  All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery.  Coagulation test values should be normal or only slightly elevated.  There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters.

Extracorporeal Dialysis

Follow equipment manufacturers’ operating directions carefully.

Blood Transfusion

Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation.  Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

Laboratory Samples

Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample.  Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin.  Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts.