Heparin (solution for injection 5000 U/mL)

Solutio Heparini pro injectionibus 5000 ED/ml

International Non-proprietary Name

Heparin sodium.

Heparin Sodium.

Pharmacotherapeutic group

Anticoagulants.

Composition

1 mL of the solution for injection contains 5000 U of heparin.

Pharmacological action

Pharmacodynamics

Heparin is an anticoagulant of direct action. Binds with antithrombin III, causes conformational changes in its molecule and accelerates antithrombin III complex forming with serine proteinase of coagulation system; the result of this is a blockade of thrombin, enzymic activity of IX, X, XI, XII factor, plasmin and kallikrein. Heparin does not exhibit thrombolytic action. Injection of small doses of the preparation into blood is accompanied by a slight and temporary increase of blood fibrinolytic activity; as a rule large doses of heparin cause the suppression of fibrinolysis. Heparin decreases blood viscosity, prevents the development of stasis. Heparin can be sorbed on the surface of endothelin membranes and blood corpuscles, increasing their negative charge, which prevents platelet, red blood cells and leucocytes adhesion and aggregation. Heparin molecules having low affinity with antithrombin III cause suppression of hyperplasia of smooth muscles, as well as inhibit activation of lipoprotein lipase, which prevents the development of atherosclerosis. Heparin has an antiallergic effect: it binds certain components of complement system, decreasing its activity, prevents lymphocytes cooperation and immunoglobulin formation, binds histamine, serotonin. Inhibits hyaluronidase activity. Exhibits mild vasodilatory effect.

In patients with coronary heart disease (in combination with acetylsalicylic acid) it decreases the risk of acute coronary arteries thrombosis, myocardial infarction and sudden death. It decreases the frequency of repeated infarctions and  fatality rate in patients after myocardial infarction. In high dosages it is effective during lung vessels embolism and venous thrombosis, in small dosages - for the prophylaxis of venous thromboembolism, including after surgical operations.

The action of heparin is fast, but relatively short-term. Following intravenous injection blood clotting rate decreases almost immediately, following intramuscular – within 15 -30 min, following subcutaneous injection – within 40 - 60 min, after inhalation the maximum effect is seen in one day; the duration of anticoagulation effect is 4-5 h, 6 h, 8 h, 1-2 weeks, , respectively, therapeutic effect (prevention of thrombosis) is retained much longer. Antithrombin III deficiency in plasma or at the site of thrombosis can limit the antithrombotic effect of heparin.

Pharmacokinetics

Following subcutaneous injection bioavailability is low, C_max is reached within 2 - 4 h; Т_1/2 is 1-2 h. In plasma heparin is present mainly in protein blinded state; it is intensively captured by endothelial cells of mononuclear-macrophage system, it is concentrated in liver and spleen; following inhalation it is absorbed by alveolar macrophages, by the endothelium of capillary, large blood and lymphatic vessels. Undergoes desulfation by N-desulphamidase and heparinase of platelets. Desulfated molecules under the influence of renal endoglycosidase   are transformed into fragments of low molecular weight. Excreted by kidneys in the form of metabolites, and only following the injection of large doses it can be excreted in unchanged form. Heparin poorly crosses placenta due to high molecular weight. Not excreted with breast milk.

Indications

Unstable angina, acute myocardial infarction, thromboembolic complications during myocardial infarction, heart and blood vessels surgery, thromboembolism of lung and cranial vessels, thrombophlebitis (prophylaxis and treatment), DIC, prophylaxis of microthrombosis and impaired microcirculation, renal veins thrombosis, hemolytic-uremic syndrome, atrial fibrillation, mitral heart defects (prophylaxis of thrombosis), bacterial endocarditis, glomerulonephritis, lupus nephritis, rheumatic fever, bronchial asthma, extracorporal technique (extracorporal circulation during heart surgery, hemosorption, hemodialysis, peritoneal lavage, cytapheresis), forced diuresis, lavage of venous catheters.

Administration and dosing regimen

Heparin is administered intravenously or intramuscularly (every 4 hours), subcutaneously (every 8—12 hours) and as intraarterial infusion, as well as by electrophoresis. In acute myocardial infarction in Day 1 the first dose (10000—15000 units) is administered intravenously, then - in divided intravenous or intramuscular injections at a dose of 40000 units daily with the aim that estimated coagulation time is 2.5—3-fold higher the normal value. Starting from the Day 2 daily dose is 600 U/kg body weight (30000—60000 units), so that coagulation time is 1.5—2-folds higher than normal values. Heparin therapy in continued for 4—8 days. In 1—2 days before heparin withdrawal the daily dose is gradually decreased (5000—2500 units daily per each injection without the increase of intervals between them) before complete withdrawal of the preparation, after which treatment is continued only with anticoagulants of indirect action (neodicumarin, phenylin and others), which are prescribed from 3—4 day of treatment.

When heparin is used in complex conservative therapy of acute venous or arterial obstruction the treatment is started from continuous intravenous dropwise infusion within 3-5 days. Daily dose of heparin (400—450 units/kg) is diluted in 1200 mL of isotonic solution of sodium chloride or Ringer-Lock solution and infused at a rate of 20 drops per minute. Then heparin is injected in divided doses of 600 units/kg daily (100 units/kg per one injection). In case of impossibility of intravenous injection of heparin, it is administered intramuscularly or subcutaneously at a dose of 600 units /kg daily. Heparin therapy is continued for 14—16 days. In 3—4 days before heparin withdrawal the daily dose is decreased to 2500—1250 units daily per each injection without the increase of intervals between them. After the preparation withdrawal treatment with anticoagulants of indirect action is initiated, which are prescribed one day before the first decrease of heparin dose.

During surgical treatment of the mentioned conditions at the time of operation immediately before thrombectomy from main veins or immediately after the emboli thrombectomy from arteries, heparin is injected intravenously or intraarterial at a dose of 100 units/kg. Then during the first 3—5 days of post-operative period heparin is administered intravenously dropwise at a rate of 20 drops per minute regionally into the vein from which the thrombus was removed at a dose of 200—250 units/kg daily intravenously into general circulation at a dose of 300—400 units/kg daily. Starting from day 4—6 after the operation heparin therapy is similar to conservative treatment. After surgery due to acute arterial obstruction, heparin treatment is continued for 10—12 days, heparin dose reduction is initiated starting from days 6—7 of the treatment.

In ophthalmology heparin is used for the treatment of all types of eye retina vascular occlusion, as well as for all the types of angiosclerotic and dystrophic processes of vascular tract and eye retina. In acute obstruction of retina vessels the first heparin dose (5000—10000 units) is administered intravenously. After that heparin is used in divided intramuscular injections of  20000—40000 units daily. Treatment is conducted in accordance with clinical picture of the disease within 2—7 days. On day 2 or 3 heparin can be administered in combination with anticoagulant agents of indirect action.

During direct blood transfusion heparin is administered to a donor at a dose of 7500—10000 units intravenously.

Special indications

Heparin therapy should be performed under thorough control of clotting. Coagulation tests are conducted according to the following scheme: during the first 7 days of treatment — not less than once per 2 days, then once per 3 days; on the first of post-operative period not less than twice per day, on days 2 and 3 - not less than once per day. When heparin is administered in divided doses blood samples are drawn immediately before the injection of the preparation.

Abrupt withdrawal of heparin therapy can lead to violent activation of thrombotic process, therefore the dose of heparin should be decreased gradually with simultaneous initiation of the treatment with anticoagulants of indirect action. Exceptions are the cases of the appearance of severe hemorrhagic complications and individual heparin intolerance.

Side effects

The following effects can be observed during heparin therapy: dizziness, headaches, nausea, anorexia, vomiting, alopecia, early (2—4 day of treatment) and delayed (autoimmune) thrombocytopenia, hemorrhagic complications — gastro-intestinal or urinary tract hemorrhage, retroperitoneal bleeding into ovaries, suprarenal glands (°accompanied by the development of acute paranephric insufficiency), osteoporosis, soft tissues calcification, inhibition of aldosterone synthesis, increase of blood transaminase levels, allergic reactions (pyrexia, rash, bronchial asthma, anaphylactoid reaction), local irritation, hematoma, painfulness during the injection).

In case of individual intolerance and the appearance of allergic complications heparin should be withdrawn immediately and desensitizing agents should be applied. In case of the necessity to continue anticoagulant therapy anticoagulants of indirect action should be applied.

Depending on the severity of hemorrhagic complications heparin dose should be decreased or withdrawn. If after the heparin withdrawal hemorrhage persists heparin antagonist — protamine sulfate (5 mL 1% solution) should be administered intravenously. Protamine sulfate dose can be repeated if necessary.

Contraindications

Heparin use is contraindicated in patients with individual intolerance and the following conditions: hemorrhage of any localization, with the exception of hemorrhage, due to embolic lung infarction (hemoptysis) or renal infarction (hematuria); hemorrhagic diathesis and other diseases, accompanied by the decrease of blood coagulation; increased vessels permeability, e.g., in Werlhof's disease; history of repeated hemorrhage regardless of its localization; subacute bacterial endocarditis; severe impairment of hepatic and renal functions; acute and chronic leukosis, aplastic and hypoplastic anemia; acute heart aneurysm; venous gangrene.

The preparation should be used with caution in the following conditions: in ulcerative and neoplastic GI lesions, cachexia regardless of its etiology, high blood pressure (more than 180/90 mm Hg), within 3-8 days following surgery and postpartum period (with the exception of surgery on blood vessels and in cases when heparin therapy is life saving).

The risk of adverse consequences for pregnant women exposed to heparin varies from 10.4 % to 21 %. In normal course of pregnancy it is 3.6 %. When exposed to heparin the risk of death and premature delivery is 2.5 % and 6.8 % and similar to the risk in natural population. Consequences of heparin exposure during pregnancy can include: hemorrhage, thrombocytopenia, osteoporosis. The risk of the thromboembolic complication during pregnancy removed by the administration of heparin is more life threatening, because of this heparin administration during pregnancy is possible, but only on strict indications, under close medical monitoring. Heparin does not cross placenta and adverse effects on foetus are unlikely. Can be used during lactation (breast feeding) according to the indications.

Precautions

Hemorrhagic complications can occur in any condition, including blood hypercoagulation. Measures to prevent hemorrhagic complication include: application of heparin only in inpatient surroundings; limiting the quantity of injections (subcutaneous & intramuscular), with the exception of heparin itself; thorough monitoring of blood coagulation; in case of severe athrombia — immediate decrease of heparin doses without the increase of the interval between administrations. In order to avoid hematoma at the site of the injection  it is preferable to use intravenous injection of heparin.

Drug interactions

Heparin effects are potentiated by acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, warfarin, dicoumarin(the risk of hemorrhage increases), suppressed by cardiac glycosides, tetracyclines, antihistamines, nicotinic acid, ethacrynic acid.

Presentation

Solution for injection (5000 units in 1 mL). 5  ml  in bottles or 5 ml in ampoules. 1 or 5 bottles in a carton. 5 ampoules in a carton or blister. 1 or 2 blisters in a carton.