Hypersensitivity

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

Because Heparin Sodium in 5% Dextrose Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy.

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 should be discontinued promptly (See OVERDOSAGE).

Thrombocytopenia

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) 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/mm3 or if recurrent thrombosis develops (SeeHeparin-induced Thrombocytopenia (HIT) With or Without Thrombosis), the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered.

Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis)

HIT is a serious immune-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and fatal outcomes.

Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used.  Future use of heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided.

Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin sodium, or platelet activation induced by heparin sodium. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin sodium in heparin sodium-naïve individuals, and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin sodium initiation), especially in patients with a recent exposure to heparin sodium (i.e. previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT.

Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 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 (With or Without Thrombosis)

Heparin-induced Thrombocytopenia (with or without 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 (with or without thrombosis).

This product contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

The administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentration.

Solutions containing dextrose without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility of agglomeration.

Excessive administration of potassium-free solutions may result in significant hypokalemia.

Because dosages of this drug are titrated to response (See DOSAGE AND ADMINISTRATION), no additives should be made to Heparin Sodium in 5% Dextrose Injection.

General

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

Drug/Laboratory Tests Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals to evaluate the carcinogenic potential, reproduction studies in animals to determine effects on fertility of males and females, and the studies to determine mutagenic potential have not been conducted with Heparin Sodium in 5% Dextrose Injection.

Pregnancy

Nursing Mothers

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. Exercise caution when administering Heparin Sodium to a nursing mother.

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).

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:

1. 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.
    
2. 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.
    
3. Retroperitoneal hemorrhage.

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis)

(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 site of the feet, may occur. (See WARNINGS.)

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 AST (SGOT) and ALT (SGPT) 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.

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.

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 USP units/kg (IV bolus over 10 minutes)

Maintenance Dose      Infants: 25 to 30 USP units/kg/hour; Infants less than 2 months have the highest requirements (average 28 USP units/kg/hour)

                                    Children greater than 1 year of age: 18 to 20 USP 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. (See PRECAUTIONS.)

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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.

Storage in automated dispensing machines: Brief exposure up to 2 weeks to ultraviolet or fluorescent light does not adversely affect the product labeling legibility; prolonged exposure can cause fading of the red label. Rotate stock frequently.

To Open

Tear overwrap down at notch and remove solution container. Check for minute leaks by squeezing solution container firmly. If leaks are found, discard solution as sterility may be impaired.

Preparation for Administration

1. Remove plastic protector from sterile set port at bottom of container.
2. Attach administration set. Refer to complete directions accompanying set.