Heparin Sodium Vials :: Lilly

WARNING --This is a potent drug, and serious consequences may result if used without constant medical supervision.

DESCRIPTION

Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars in heparin are: (1) (alpha)-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-(alpha)-glucose 6-sulfate, (3) (beta)-D-glucuronic acid, (4) 2-acetamido-2-deoxy-(alpha)-D-glucose, and (5) (alpha)-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions.

Structure of Heparin Sodium (representative subunits):

data/images/14/60031601.jpg

Heparin Sodium Injection, USP, is a sterile solution of heparin sodium derived from porcine intestinal mucosa, which is standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.

Each mL of Vial No. 520 contains 10,000 USP heparin units (derived from porcine intestinal mucosa) and sodium chloride, 0.1%.

During manufacture, 1% benzyl alcohol is added as a preservative to each vial of heparin sodium. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

CLINICAL PHARMACOLOGY

Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor.

Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses.

Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. Log linear plots of heparin plasma concentrations with time for a wide range of dose levels are linear, which suggests the absence of zero order processes. The liver and the reticuloendothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining (alpha) phase (t 1/2 = 10') and, after the age of 40, a slower (beta) phase indicate uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin.

Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

INDICATIONS AND USAGE

Heparin sodium is indicated for:

Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension

Prevention (in a low-dose regimen) of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease ( see Dosage and Administration )

Prophylaxis and treatment of pulmonary embolism

Atrial fibrillation with embolization

Diagnosis and treatment of acute and chronic consumption coagulopathies (eg, disseminated intravascular coagulation)

Prevention of clotting in arterial and heart surgery

Prophylaxis and treatment of peripheral arterial embolism

As an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures and in blood samples for laboratory purposes

CONTRAINDICATIONS

Heparin sodium should not be used in patients with severe thrombocytopenia or patients for whom suitable blood coagulation tests (eg, tests for whole-blood clotting time and partial thromboplastin time) cannot be performed at appropriate intervals. (This restriction refers to full-dose administration of heparin; it is usually unnecessary to monitor coagulation parameters in patients receiving low-dose heparin). In addition, heparin sodium should not be administered to patients in an uncontrollable active bleeding state ( see Warnings ), except when this condition is the result of disseminated intravascular coagulation.

WARNINGS

Heparin is not intended for intramuscular use.

Hypersensitivity  --Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations.

Hemorrhage  --Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, a fall in blood pressure, or any other unexplained symptom warrants 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 this danger exists are as follows:

Cardiovascular  --Subacute bacterial endocarditis. Severe hypertension.

Surgical  --During and immediately following (a) 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 and 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 result is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly ( see Overdosage ).

Thrombocytopenia  --Thrombocytopenia occurs in patients receiving heparin with a reported incidence of 0% to 30%. 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 Precautions , White-Clot Syndrome ), the heparin product should be discontinued. If continued heparin therapy is essential, utilize heparin from a different organ source and reinstitute therapy with caution.

Miscellaneous  --This product contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "gasping syndrome" in premature infants.

PRECAUTIONS

General  -- White-Clot Syndrome  --It has been reported that patients taking heparin may develop new thrombus formation in association with thrombocytopenia. This development is the result of the irreversible aggregation of platelets induced by heparin, ie, the so-called "white-clot syndrome." The process may lead to severe thromboembolic complications such as skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. Therefore, heparin administration should be promptly discontinued if a patient develops new thrombosis in association with thrombocytopenia.

Heparin Resistance  --Increased resistance to heparin is frequently encountered in cases involving fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, and cancer. Increased resistance can also occur in postsurgical patients.

Increased Risk in Older Women  --A higher incidence of bleeding has been reported in women over 60 years of age.

Laboratory Tests  --Periodic platelet counts, hematocrit determinations, and tests for occult blood in the 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, if a valid prothrombin time is to be obtained when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn.

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.

When clinical circumstances require reversal of heparinization, consult the labeling of Protamine Sulfate Injection, USP.

Drug/Laboratory Test Interactions  --Hyperaminotransferasemia. Significant elevations of aminotransferase (SGOT and SGPT) 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 (eg, heparin) should be interpreted with caution.

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

Pregnancy  -- Teratogenic Effects: Pregnancy Category C  --Animal reproduction studies have not been conducted with heparin sodium. It is also not known whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed.

Nonteratogenic Effects:   Heparin does not cross the placental barrier.

Nursing Mothers  --Heparin is not excreted in human milk.

Pediatric Use  -- See Dosage and Administration .

ADVERSE REACTIONS

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 ). 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:

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 be delayed for laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient' death.

Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. If unrecognized, this complication may be fatal.

Retroperitoneal hemorrhage has occurred.

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; therefore, such use is not recommended.

Hypersensitivity  --Generalized hypersensitivity reactions have been reported, with chills, fever, and urticaria as the most common manifestations; asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions (including shock) have occurred more rarely. Itching and burning, especially on the plantar site of the feet, may occur.

The occurrence of thrombocytopenia has been reported in patients receiving heparin, with an incidence of 0% to 30%. Although often mild and of no obvious clinical significance, such thrombocytopenia can be accompanied by severe thromboembolic complications, such as skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death ( see Warnings and Precautions ).

Certain episodes of painful, ischemic, and cyanosed limbs have, in the past, been attributed to allergic vasospastic reactions. Whether these are, in fact, identical to the thrombocytopenia-associated complications remains to be determined.

Miscellaneous  --Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia occurring after discontinuation of heparin sodium have also been reported.

Significant elevations of aminotransferase (SGOT and SGPT) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin.

OVERDOSAGE

Signs and Symptoms  --Overdose of heparin may follow parenteral administration, but oral heparin has little systemic effect. Bleeding is the chief sign of heparin overdosage. Excessive heparin effect also increases whole-blood clotting time and activated partial thromboplastin time (APTT). The half-life of heparin ranges from 0.5 to 2.5 hours and may vary widely in cases involving an overdose.

The intravenous median lethal dose in mice is 1,500 mg/kg.

Treatment  --To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Minor bleeding occurring during therapy with heparin can often be treated by reducing the dose or increasing the dosing interval.

For major bleeding episodes, heparin may be neutralized by protamine; 1 mg of protamine will neutralize approximately 115 units of heparin of porcine intestinal mucosal origin. Protamine dosage may be guided by determining the amount of time by which clotting is shortened in vitro or by the results of other hematologic tests. Note that protamine may cause anaphylactoid reactions that may be life threatening. (See the protamine label for additional information.) The administration of whole blood or fresh frozen plasma should be considered for patients with significant blood losses. Vitamin K will not reverse the activity of heparin.

DOSAGE AND ADMINISTRATION

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration if solution and container permit. Slight discoloration does not alter potency.

When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least 6 times to ensure adequate mixing and prevent pooling of the heparin in the solution.

Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, ie, above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site.

The dosage of heparin sodium should be adjusted according to the patient' coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the APTT is 1.5 to 2 times normal or when the whole-blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injections.

Periodic platelet counts, hematocrit determinations, and tests for occult blood in the stool are recommended during the entire course of heparin therapy, regardless of the route of administration.

Converting to Oral Anticoagulant  --When an oral anticoagulant of the coumarin (or similar) type is to be administered in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at times during which heparin activity is too low to affect the prothrombin time. Such a time usually occurs about 5 hours after the last IV bolus and 24 hours after the last subcutaneous dose. If heparin is continuously infused by IV, prothrombin time can usually be measured at any time.

In converting from heparin to an oral anticoagulant, the oral anticoagulant should be given in the usual initial amount; 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 limit of 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 appropriate laboratory tests, the following dosage schedule may be used as a guideline:

Method of Administration
Frequency Recommended Dose *
Deep Subcutaneous (Intrafat) Injection (A different site should be used for each injection to prevent the development of massive hematoma)
Initial dose
  
Every 8 hours
or
Every 12 hours
5,000 units by IV injection, followed by 10,000-20,000 units of a concentrated solution, subcutaneously
8,000-10,000 units of a concentrated solution   

15,000-20,000 units of a concentrated solution
Initial dose
  
Every 4 to 6
hours
10,000 units, either undiluted or in 50-100 mL of
0.9% Sodium Chloride Injection, USP
5,000-10,000 units, either undiluted or in 50-100 mL
of 0.9% Sodium Chloride Injection, USP
Continuous Intravenous Infusion
Initial dose
Continuous
Infusion
5,000 units by IV injection
20,000-40,000 units/24 hours in 1,000 mL of 0.9%
Sodium-Chloride Injection, USP
(or in any compatible solution) for infusion
* Based on 150-lb (68-kg) patient.

Pediatric Use  --Follow recommendations of appropriate pediatric reference texts. In general, the following dosage schedule may be used as a guideline:

Initial Dose:
50 units/kg (IV, drip)
100 units/kg (IV, drip) every 4 hours, or 20,000 units/m 2 /24 hours, infused continuously

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 kg of body weight. Frequently, a dose of 300 units/ kg is used for procedures estimated to last less than 60 minutes; a dose of 400 units/kg is often used for those procedures likely 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 prior to and after surgery, will reduce the incidences 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 is 5,000 units given 2 hours before surgery and 5,000 units given every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous (intrafat, ie, above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25- to 26-gauge) needle 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 brain or spinal-cord surgery, spinal anesthesia, eye surgery, or potentially sanguineous operations should be excluded from this treatment, as should 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. Prior to initiating heparinization, the physician should rule out the probability of bleeding disorders by taking a thorough history and performing the appropriate laboratory tests. Appropriate coagulation tests should be repeated just prior to surgery. Coagulation test values should be normal or only slightly elevated at these times.

Extracorporeal Dialysis  --Follow equipment manufacturers' operating directions carefully.

Blood Transfusion  --The addition of 400 to 600 USP units to each 100 mL of whole blood for transfusion is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin sodium are mixed with 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP); 6 to 8 mL of this sterile solution is then added to each 100 mL of whole blood used.

Laboratory Samples  --70 to 150 units of heparin sodium are usually added per 10- to 20-mL sample of whole blood to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within 2 hours after the addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or for taking platelet counts.

Clearing Intermittent Infusion (Heparin Lock) Sets  --To prevent clot formation in a heparin lock set following its proper insertion, dilute heparin solution ( see USP monograph for Heparin Lock Flush Solution, USP) should be injected via the injection hub in a quantity sufficient to fill the entire set to the needle tip. This solution should be replaced each time the heparin lock is used. Aspirate before administering any solution via the lock in order to confirm the patency and location of the needle or catheter tip. If the drug to be administered is incompatible with heparin, the entire heparin lock set should be flushed with sterile water or normal saline before and after the medication is administered; following the second cleansing flush, the dilute heparin solution may be reinstilled in the set. The set manufacturer's instructions should be consulted for specifics concerning the heparin lock set being used at a given time.

NOTE: Since repeated injections of small doses of heparin can alter tests for activated partial thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of a heparin lock set.

HOW SUPPLIED

Multiple-Dose Vials:

10,000 USP heparin units/mL, 5 mL (No. 520)--(1s) NDC 0002-7217-01

Protect from light. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [see USP Controlled Room Temperature].

Literature revised December 10, 1998

PA 0711 AMP                                       [121098]



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