Heparin Sodium In Sodium Chloride Injection, Solution
FDA Label NDC 0338-0433

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

Structure of Heparin Sodium (representative subunits):

Heparin Sodium Structural Formula (Image 01)

Heparin Sodium and 0.9% Sodium Chloride Injection is a buffered, sterile, nonpyrogenic solution of Heparin Sodium, USP derived from porcine intestinal mucosa, standardized for anticoagulant activity supplied in single dose containers for vascular administration. It contains no antimicrobial agents. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Composition, osmolarity, pH and ionic concentration are shown in Table 1.

This VIAFLEX PLUS plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). VIAFLEX PLUS on the container indicates the presence of a drug additive in a drug vehicle. The VIAFLEX PLUS plastic container system utilizes the same container as the VIAFLEX plastic container system. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

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 of heparin.

Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age.

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

Heparin Sodium and 0.9% Sodium Chloride Injection at a concentration of 2 units/mL is indicated as an aid in the maintenance of catheter patency.

Heparin sodium should not be used in patients:

With severe thrombocytopenia;

In whom suitable blood coagulation tests - e.g., the whole-blood clotting time, partial thromboplastin time, etc. - cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin);

With an uncontrollable active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation.

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

General 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, 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.

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 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.

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 hemorrhage 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 depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient’s death.

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.

Retroperitoneal hemorrhage.

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

See WARNINGS.

When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly (see OVERDOSAGE).

Thrombocytopenia 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/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 (see Heparin-induced Thrombocytopenia (HIT) With or Without Thrombosis), the heparin product should be discontinued and, if necessary, an alternative anticoagulant administered.

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, 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.

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 sodium should be evaluated for HIT (with or without thrombosis).

Solutions containing sodium ion should be used with great care in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention.

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

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

In patients with diminished renal function, administration may result in sodium retention.

Baxter Healthcare Corporation
Deerfield, IL 60015 USA

Printed in USA

Baxter, Viaflex and Viaflex Plus are trademarks of Baxter International Inc.

07-19-00-0140

Rev. April 2018

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

See WARNINGS.

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

A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age.

These solutions should be used with caution in patients receiving corticosteroids or corticotropin.

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).

Oral anticoagulants: Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose 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.

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

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.

Animal reproduction studies have not been conducted with heparin sodium. It is 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.

Heparin is not excreted in human milk.

Safety and effectiveness in pediatric patients have not been established.

See DOSAGE AND ADMINISTRATION.

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 PRECAUTIONS, General and CLINICAL PHARMACOLOGY).

Do not administer unless solution is clear and seal is intact.

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.

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.

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.

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.

Heparin sodium is not effective by oral administration and Heparin Sodium and 0.9% Sodium Chloride Injection should not be given orally.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible.

Although the rate for infusion of the 2 units/mL formulation is dependent upon age, weight, clinical condition of the patient and the procedure being employed, an infusion rate of 3 mL/hour has been found to be satisfactory.

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.

All injections in VIAFLEX PLUS plastic containers are intended for administration using sterile equipment.

Because dosages of this drug are titrated to response, no additives should be made to Heparin Sodium and 0.9% Sodium Chloride Injection.

Heparin Sodium and 0.9% Sodium Chloride Injection in VIAFLEX PLUS plastic container is supplied as follows:

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product.

Warning: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

Tear overwrap down side at slit and remove solution container. Visually inspect the container.  If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found discard solution as sterility may be impaired. Do not add supplementary medication.

• 1.Suspend container from eyelet support.
• 2.Remove plastic protector from outlet port at bottom of container.
• 3.Attach administration set. Refer to complete directions accompanying set.

Heparin Sodium Container Label Ndc 0338-0431-03 (Image 02)

Container Label

LOT EXP

NDC 0338-0431-03

Heparin
Heparin Sodium and 0.9% Sodium Chloride
Injection

1,000 units per 500 mL

(2 units/mL)

500 mL STERILE SINGLE DOSE CONTAINER EACH
mL CONTAINS 2 USP HEPARIN UNITS HEPARIN SODIUM
(PORCINE INTESTINAL MUCOSA) USP 9 mg SODIUM
CHLORIDE USP 4.34 mg DIBASIC SODIUM PHOSPHATE
HEPTAHYDRATE USP 400 mcg CITRIC ACID USP
pH 7.0 (6.0 TO 8.0) SODIUM 186 mEq/L
CHLORIDE 154 mEq/L PHOSPHATE (AS HPO4=) 32 mEq/L
CITRATE 6 mEq/L OSMOLARITY 322 mOsmol/L
(ACTUAL) USUAL DOSAGE SEE INSERT DO NOT ADD
SUPPLEMENTARY MEDICATION STORE IN MOISTURE
BARRIER OVERWRAP AT ROOM TEMPERATURE (77°F OR
25°C) UNTIL READY TO USE RX ONLY

Baxter Logo

USA 2B0953

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Heparin Sodium Representative Carton Label 0338-0431-03 (Image 03)

Carton Label

Lot: T123456
QTY: 18-500mL

Exp: JAN 9999
Code: 2B0953

NDC: 0338-0431-03

HEPARIN SODIUM AND 0.9% SODIUM
CHLORIDE INJECTION
1000 UNITS per 500 mL

Bar Code
(01)50303380431033(17)990100(21)000000000024(10)T123456

Bar Code
(01)50303380431033
(17)990100
(21)000000000024
(10)T123456

Representative Container Label Ndc 0338-0433-04 (Image 04)

Container Label

LOT EXP

NDC 0338-0433-04

Heparin
Heparin Sodium and 0.9% Sodium
Chloride Injection

2,000 units per 1,000 mL

1,000 mL STERILE SINGLE DOSE CONTAINER
EACH mL CONTAINS 2 USP HEPARIN UNITS HEPARIN
SODIUM (PORCINE INTESTINAL MUCOSA) USP 9 mg SODIUM
CHLORIDE USP 4.34 mg DIBASIC SODIUM PHOSPHATE
HEPTAHYDRATE USP 400 mcg CITRIC ACID USP
pH 7.0 (6.0 TO 8.0) SODIUM 186 mEq/L CHLORIDE
154 mEq/L PHOSPHATE (AS HPO₄=) 32 mEq/L CITRATE
6 mEq/L OSMOLARITY 322 mOsmol/L (ACTUAL) USUAL
DOSAGE SEE INSERT DO NOT ADD SUPPLEMENTARY
MEDICATION STORE IN MOISTURE BARRIER OVERWRAP AT
ROOM TEMPERATURE (77°F OR 25°C) UNTIL READY TO USE
RX ONLY

Baxter Logo
USA 2B0944

07-25-58-614

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3

4

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Heparin Sodium Representative Carton Label 0338-0433-04 (Image 05)

Carton Label

Lot: T123456
QTY: 12-1000mL

Exp: JAN 9999
Code: 2B0944

NDC: 0338-0433-04

HEPARIN SODIUM AND 0.9% SODIUM
CHLORIDE INJECTION
2000 UNITS per 1000 mL

Bar Code
(01)50303380433044(17)990100(21)000000000001(10)T123456

Bar Code
(01)50303380433044
(17)990100
(21)000000000001
(10)T123456