Heparin Sodium (Page 4 of 5)

8.5 Geriatric Use

There are limited adequate and well-controlled studies in patients 65 years and older, however, a higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Warnings and Precautions (5.2)]. Patients over 60 years of age may require lower doses of heparin. Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Bleeding is the chief sign of heparin overdosage.

Neutralization of Heparin Effect

When clinical circumstances (bleeding) require reversal of the heparin effect, 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. Because fatal reactions often resembling anaphylaxis have been reported with protamine, it 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.

11 DESCRIPTION

Heparin is a heterogeneous 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) β-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.

Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. 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.

Structure of Heparin Sodium (representative subunits):

Structure of Heparin Sodium

Heparin Sodium Injection, USP (porcine), preservative free, is available as follows:

Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 9 mg sodium chloride; Water for Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

Each 0.5 mL of the 5,000 units per 0.5 mL preparation contains: 5,000 USP Heparin units (porcine); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available as follows:

Each mL of the 5,000 units per mL preparation contains: 5,000 USP Heparin units (porcine); 6 mg sodium chloride; 15 mg benzyl alcohol (as a preservative); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

Each mL of the 10,000 units per mL preparation contains: 10,000 USP Heparin units (porcine); 5 mg sodium chloride; 10.42 mg benzyl alcohol (as a preservative); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

Heparin Sodium Injection, USP (porcine), preserved with parabens, is available as follows:

Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 9 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

Each mL of the 5,000 units per mL preparation contains: 5,000 USP Heparin units (porcine); 5 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

Each mL of the 10,000 units per mL preparation contains: 10,000 USP Heparin units (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

Each mL of the 20,000 units per mL preparation contains: 20,000 USP Heparin units (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 to 7.5).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

12.2 Pharmacodynamics

Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, they are not measurably affected by low doses of heparin. The bleeding time is usually unaffected by heparin.

12.3 Pharmacokinetics

Absorption

Heparin is not absorbed through the gastrointestinal tract and therefore administered via parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration.

Distribution

Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg.

Elimination

Metabolism

Heparin does not undergo enzymatic degradation.

Excretion

Heparin is mainly cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero order process due to binding to proteins, endothelial cells and macrophage) and b) slower first order elimination. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h.

Specific Populations

Geriatric patients

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 [see Use in Specific Populations (8.5)].

13 NONCLINICAL TOXICOLOGY

13.1 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Heparin Sodium Injection, USP (porcine), preservative free , is available as follows:

Product Code Unit of Sale Strength Each
27602 NDC 63323-276-02Unit of 25 2,000 USP units per 2 mL(1,000 USP units per mL) NDC 63323-276-012 mL single-dose, flip-top vial
504313 NDC 63323-543-13Unit of 25 5,000 USP units per 0.5 mL NDC 63323-543-030.5 mL fill in a 2 mL single-dose, flip-top vial

Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate.

This container closure is not made with natural rubber latex. Discard unused portion.

Heparin Sodium Injection, USP (porcine) contains benzyl alcohol and is available as follows:

Product Code Unit of Sale Strength Each
4710 NDC 63323-047-10Unit of 25 50,000 USP units per 10 mL(5,000 USP units per mL) NDC 63323-047-0110 mL multiple-dose, flip-top vial
504514 NDC 63323-459-14Unit of 25 40,000 USP units per 4 mL(10,000 USP units per mL) NDC 63323-459-044 mL fill in a 5 mL multiple-dose, flip-top vial

Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. This container closure is not made with natural rubber latex.

Heparin Sodium Injection, USP (porcine) contains parabens and is available as follows:

Product Code Unit of Sale Strength Each
504013 NDC 63323-540-13Unit of 25 1,000 USP units per mL NDC 63323-540-031 mL fill in a 2 mL multiple-dose, flip-top vial
504015 NDC 63323-540-15Unit of 25 10,000 USP units per 10 mL(1,000 USP units per mL) NDC 63323-540-0510 mL multiple-dose, flip-top vial
RF504015 NDC 65219-066-10Unit of 25 10,000 USP units per 10 mL(1,000 USP units per mL) NDC 65219-066-0110 mL multiple-dose, flip-top vial This product contains an RFID
504036 NDC 63323-540-36Unit of 25 30,000 USP units per 30 mL(1,000 USP units per mL) NDC 63323-540-3330 mL multiple-dose, flip-top vial
926206 NDC 63323-262-06Unit of 25 5,000 USP units per mL NDC 63323-262-031 mL fill in a 2 mL multiple-dose, flip-top vial
504213 NDC 63323-542-13Unit of 25 10,000 USP units per mL NDC 63323-542-091 mL fill in a 2 mL multiple-dose, flip-top vial
504214 NDC 63323-542-14Unit of 25 50,000 USP units per 5 mL(10,000 USP units per mL) NDC 63323-542-045 mL fill in a 10 mL multiple-dose, flip-top vial
915513 NDC 63323-915-13Unit of 25 20,000 USP units per mL NDC 63323-915-031 mL fill in a 2 mL multiple-dose, flip-top vial

Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate.

This container closure is not made with natural rubber latex.

STORAGE:

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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