Heparin sodium,. 5000 units/ml 5 ml 5 pcs

Pharmacotherapeutic group

Direct acting anticoagulant

ATCode

B01AB01

Pharmacodynamics:

The mechanism of action of sodium heparin is based primarily on its binding to antithrombin III, which is a natural inhibitor of activated clotting factors-IIa (thrombin) IXa Ha XIa and XIIa. Sodium heparin binds to antithrombin III and causes conformational changes in its molecule. As a result, the binding of antithrombin III with clotting factors IIa (thrombin) IXa Ha XIa and XIIa is accelerated and their enzymatic activity is blocked. The binding of sodium heparin with antithrombin III is electrostatic in nature and depends largely on the length and composition of the molecule (pentasaccharide sequence containing 3-0-sulfated glucosamine is required for heparin binding with antithrombin III).

The ability of sodium heparin in combination with antithrombin III to inhibit clotting factors IIa (thrombin) and Xa is the most important. The ratio of activity of sodium heparin against factor Xa to its activity against factor IIa is 09-11.

Sodium heparin reduces blood viscosity reduces vascular permeability stimulated by bradykinin histamine and other endogenous factors and thus prevents the development of stasis. Sodium heparin is able to sorb on the surface of endothelial membranes and blood cells increasing their negative charge that prevents platelet adhesion and aggregation. Sodium heparin slows smooth muscle hyperplasia and activates lipoprotein lipase and thus has hypolipidemic effect and prevents the development of atherosclerosis.

Sodium heparin binds some components of the complement system reducing its activity prevents the cooperation of lymphocytes and the formation of immunoglobulins binds histamine serotonin (i.e. has anti-allergic effect). Heparin increases renal blood flow increases cerebral vascular resistance reduces cerebral hyaluronidase activity reduces surfactant activity in the lungs suppresses excessive aldosterone synthesis in the adrenal cortex binds adrenaline modulates ovarian response to hormonal stimuli increases parathormone activity. As a result of interaction with enzymes, heparin can increase brain tyrosine hydroxylase activity of pepsinogen DNA polymerase and decrease myosin ATPase activity of pyruvate kinase RNA polymerase of pepsin. The clinical significance of these effects of heparin remains uncertain and poorly understood.

In acute coronary syndrome without persistent ST-segment elevation on the ECG (unstable angina pectoris without ST-segment elevation), sodium heparin in combination with acetylsalicylic acid reduces the risk of myocardial infarction and mortality. In ST-segment elevation myocardial infarction on ECG, sodium heparin is effective during primary percutaneous coronary revascularization in combination with glycoprotein IIb/IIIa receptor inhibitors and during thrombolytic therapy with streptokinase (increased rate of revascularization).

In high doses sodium heparin is effective in pulmonary thromboembolism and venous thrombosis in low doses it is effective for prevention of venous thromboembolism including after surgical operations.

After intravenous administration the drug action comes almost immediately, not later than 10-15 minutes and lasts only 3-6 hours. After subcutaneous injection the drug action starts slowly – after 40-60 minutes but lasts for 8 hours. Deficiency of antithrombin III in blood plasma or in the place of thrombosis may reduce the anticoagulant effect of sodium heparin.

Pharmacokinetics:

The maximum concentration (Cmax) after intravenous administration is reached almost immediately after subcutaneous administration in 2-4 h. Binding with plasma proteins – up to 95% volume of distribution is very small – 006 l/kg (does not leave the vascular bed due to strong binding to plasma proteins). It does not penetrate through the placenta and into the breast milk.

It is intensively taken up by endothelial cells and cells of the mononuclear-macrophage system (cells of the reticulo-endothelial system) and concentrated in the liver and spleen.

It is metabolized in the liver with the participation of N-desulfamidase and platelet heparinase, which is included in the metabolism of heparin at a later stage. Participation in the metabolism of platelet factor IV (anti-heparin factor), as well as the binding of heparin to the macrophage system explains the rapid biological inactivation and short duration of action. Desulfated molecules under the influence of renal endoglycosidase are converted into low molecular weight fragments. T1/2- 1-6 h (average – 15 h); increases in obesity hepatic and/or renal failure; decreases in pulmonary thromboembolism infections malignant tumors.

Extracted by the kidneys mainly as inactive metabolites and only when administered in high doses is excretion possible (up to 50%) in unchanged form. It is not excreted by hemodialysis.

Indications

Active ingredient

Composition

1 ml contains:

The active ingredient: heparin sodium 5000 ME.

Auxiliary substance: water for injection up to 1 ml.

How to take, the dosage

Heparin is given as a continuous intravenous infusion or as a subcutaneous or intravenous injection.

The initial dose of heparin administered for therapeutic purposes is 5000 ME and is given intravenously, after which treatment is continued with subcutaneous injections or intravenous nifusions.

The maintenance doses are determined according to the route of administration:

– With continuous intravenous infusion, administer a dose of 1000-2000 IU/h (24000-48000 IU/day) diluted with heparin in 09% sodium chloride solution or 5% or 10% glucose solution or 045% sodium chloride and 25% glucose solution or Ringer’s solution;

In regular intravenous injections administer 5000-10000 ME of heparin every 4-6 hours;

In subcutaneous injections administer 15000-20000 ME every 12 hours or 8000-10000 ME every 8 hours.

Before each dose, clotting time and/or activated partial thromboplastin time (APT) should be tested in order to adjust the subsequent dose. Subcutaneous injections should preferably be performed in the anterior abdominal wall; other injection sites (upper arm and thigh) may also be used as an exception.

The re-injection of heparin sodium at the sites of previous injections is undesirable. Before injection it is necessary to remove drops of the solution from the outer surface of the needle.

Doses of sodium heparin when administered intravenously should be chosen so that the AFTV was 15-25 times higher than the control.

The anticoagulant effect of heparin is considered optimal if the clotting time is 2-3 times as long as the normal value of ACTV and the thrombin time is increased by a factor of 2 (if it is possible to monitor the ACTV continuously).

In preventing thrombosis in the postoperative period, the first injection should be given 1-2 hours before surgery; in the postoperative period, it should be given for 7-10 days and for a longer period, if necessary.

The use of sodium heparin in special clinical situations

Primary percutaneous coronary angioplasty for acute coronary syndrome without ST-segment elevation and for myocardial infarction with ST-segment elevation:

Sodium heparin is administered intravenously bolus at a dose of 70-100 IU/kg (if glycoprotein IIb/IIIa receptor inhibitors are not planned) or at a dose of 50-60 IU/kg (when used in combination with glycoprotein IIb/IIIa receptor inhibitors).

Trombolytic therapy in ST-segment elevation myocardial infarction: sodium heparin is administered intravenously in a bolus dose of 60 U/kg (maximum dose of 4000 U) followed by an intravenous infusion in a dose of 12 U/kg (not more than 1000 U/h) for 24-48 h. The target ACTV level is 50-70 sec or 1.5-2.0 times normal; control ACTV at 3 6 12 and 24 hours after initiation of therapy.

Prevention of thromboembolic complications after surgical interventions using low-dose sodium heparin: subcutaneously deep into the abdominal skin fold. The initial dose is 5000 ME 2 hours before surgery. In postoperative period – 5000 ME every 8-12 hours for 7 days or until complete recovery of patient’s mobility (whichever comes first). When sodium heparin is used in low doses to prevent thromboembolic complications, it is not necessary to monitor the AFP. Administration in cardiovascular surgery during surgeries with the use of extracorporeal circulation system: the initial dose is not less than 150 IU/kg. Then, sodium heparin is administered by continuous intravenous infusion at a rate of 15-25 drops/min at 30000 ME per 1 liter of infusion solution. The total dose is usually 300 IU/kg (if the estimated duration of surgery is less than 60 minutes) or 400 IU/kg (if the estimated duration of surgery is 60 minutes or more).

Hemodialysis use: initial dose is 25-30 IU/kg (or 10000 IU) intravenous bolus followed by continuous infusion of sodium heparin 20000 IU/100 mg sodium chloride solution at 1500-2000 IU/h (unless otherwise specified in the hemodialysis systems manual). The dose of sodium heparin should be adjusted for clotting parameters (target ACTV of 60-85 sec).

The use of sodium heparin in pediatrics: Adequate controlled studies of sodium heparin use in children have not been conducted. The recommendations presented are based on clinical experience.

The initial dose: 75-100 IU/kg intravenously bolus for 10 minutes. Maintenance dose: children 1-3 months of age 25-30 U/kg/h (800 BD/kg/day) children 4-12 months of age 25-30 U/kg/h (700 BD/kg/day) children over 1 year of age 18-20 U/kg/h (500 BD/kg/day) intravenous drip.

Interaction

Pharmaceutical interaction: Sodium heparin solution is compatible only with 09% sodium chloride solution. Heparin sodium solution is incompatible with the following drug solutions: alteplase amikacin sulfate amiodarone ampicillin sodium benzylpenicillin sodium ciprofloxacin cytarabine dacarbazine danorubicin diazepam dobutamine doxorubicin hydrochloride droperidol erythromycin gentamicin sulfate haloperidol lactate hyaluronidase hydrocortisone sodium succinate dextrose fat emulsions idarubicin kanamycin sulfate methicillin sodium netilmicin sulfate opioids oxytetracycline hydrochloride polymyxin B sulfate promazine hydrochloride promethazine hydrochloride streptomycin sulfate sulfafurazole diethanolamine tetracycline hydrochloride tobramycin sulfate cephalothin sodium cephaloridin vancomycin hydrochloride vinblastine sulfate labetalol hydrochloride nicardipine hydrochloride.

Pharmacokinetic interaction: Sodium heparin displaces phenytoin quinidine propranololol and benzodiazepine derivatives from their binding sites with plasma proteins that may lead to enhancement of pharmacological action of the indicated drugs. Sodium heparin is bound and inactivated by sodium protamine by polypeptides having alkaline reaction and by tricyclic antidepressants.

Pharmacodynamic interaction: anticoagulant effect of sodium heparin increases with simultaneous use with other medicinal agents influencing hemostasis including with antiplatelet agents (acetylsalicylic acid clopidogrel prasugrel ticlopidine dipyridamole) indirect anticoagulants (warfarin phenylline syncoumar) thrombolytic agents (alteplase streptokinase urokinase) non-steroidal anti-inflammatory drugs (incl. phenylbutazone), thrombolytic agents (erythrocytes).including phenylbutazone ibuprofen indomethacin diclofenac) glucocorticosteroids and dextran resulting in an increased risk of bleeding. In addition the anticoagulant effect of heparin sodium may be enhanced when combined with hydroxychloroquine sulfinpyrazone probenecid etacrynic acid cytostatics cefamandol cefotetan valproic acid propylthiouracil.

The anticoagulant effect of sodium heparin is reduced when used concomitantly with ACTH antihistamines ascorbic acid ergot alkaloids nicotine nitroglycerin cardiac glycosides thyroxine tetracycline and quinine.

Sodium heparin may decrease the pharmacological effects of adrenocorticotropic hormone glucocorticosteroids and insulin.

Special Instructions

Treatment with high doses is recommended in a hospital setting. Monitoring of platelet count should be carried out before the start of treatment on the first day of treatment and at short intervals during the whole period of administration of heparin sodium especially between day 6 and 14 after the start of treatment. Treatment should be discontinued immediately if there is a dramatic decrease in the platelet count (see “Side effects”).

A dramatic decrease in platelet counts requires further investigation for heparin-induced immune thrombocytopenia. If this occurs, the patient should be told that heparin should not be administered in the future (even low molecular weight heparin). If there is a high probability of heparin-induced immune thrombocytopenia, heparin should be withdrawn immediately.

In case of development of heparin-induced thrombocytopenia in patients receiving heparin for thromboembolic disease or in case of development of thromboembolic complications, other antithrombotic agents should be used. Patients with heparin-induced immune thrombocytopenia (white clot syndrome) should not undergo hemodialysis with heparinization. If necessary, they should use alternative therapies for renal failure.

In order to avoid overdose, clinical symptoms indicating possible bleeding (mucosal bleeding hematuria, etc.) should be monitored at all times. In patients who do not respond to heparin or who require high doses of heparin it is necessary to monitor the level of antithrombin III.

Resistance to sodium heparin is often seen in fever thrombosis thrombophlebitis infectious disease myocardial infarction malignancies as well as after surgical interventions and in antithrombin III deficiency. In these situations more careful laboratory monitoring is required (monitoring of the ABTV).

While sodium heparin does not cross the placental barrier and is not detectable in breast milk when administered in therapeutic doses, pregnant women and breastfeeding mothers should be monitored closely.

Particular caution should be exercised for 36 h after delivery.

An appropriate control laboratory study should be performed (blood clotting time activated partial thromboplastin time and thrombin time).

In women over 60 years of age, heparin may increase bleeding, and therefore the dose of sodium heparin should be decreased in this category of patients.

When heparin is used in patients with arterial hypertension, blood pressure should be monitored continuously.

A coagulogram study should always be performed before initiating therapy with sodium heparin except for the use of low doses.

Patients who are transferred to oral anticoagulant therapy should continue sodium heparin until clotting time and ACTV results are in the therapeutic range. Intramuscular injections should be excluded when administering sodium heparin for therapeutic purposes. Puncture biopsies with infiltration and epidural anesthesia and diagnostic lumbar punctures should also be avoided if possible.

If massive bleeding occurs, sodium heparin should be stopped and the coagulogram should be examined. If the test results are within normal limits, the likelihood of developing this bleeding due to the use of sodium heparin is minimal. Changes in the coagulogram tend to normalize after heparin withdrawal.

The physical and chemical stability after heparin dilution in the above solutions for infusion is maintained for 48 h at room temperature (25 ± 2 °C). If the drug is not used immediately it can be used no later than 24 hours after dilution, and it is allowed to store during this period at 2 to 8 ° C only if aseptic conditions for its dilution are observed.

Contraindications

– Hypersensitivity to heparin and other components of the drug.

– Heparin-induced thrombocytopenia (with or without thrombosis) in the history or currently.

– Bleeding (unless the benefit of using heparin sodium outweighs the potential risk).

– Sodium heparin in a therapeutic dose should not be prescribed unless regular laboratory monitoring of blood clotting is possible.

– Pregnancy and breastfeeding.

Patients with polyvalent allergies (including bronchial asthma).

In pathological conditions associated with an increased risk of bleeding such as:

– Cardiovascular disease: acute and subacute infectious endocarditis severe uncontrolled arterial hypertension aortic dissection aneurysm of cerebral vessels.

– Gastrointestinal erosive and ulcerative lesions varicose esophageal veins in cirrhosis and other diseases long-term use of gastric and small intestinal drains ulcerative colitis hemorrhoids.

– Diseases of the hematopoietic organs of the blood and lymphatic system: leukemia hemophilia thrombocytopenia hemorrhagic diathesis.

– Diseases of the central nervous system: hemorrhagic stroke cerebral injury.

– Malignant neoplasms.

– Congenital deficiency of antithrombin III and replacement therapy with antithrombin III drugs (lower doses of heparin should be used to reduce the risk of bleeding).

Other physiological and pathological conditions: menstrual period threatened miscarriage early postpartum severe liver disease with impaired protein-synthetic function chronic renal failure recently undergone eye surgery brain or spinal cord recent spinal (lumbar) puncture or epidural anesthesia proliferative diabetic retinopathy vasculitis elderly age (over 60 years especially women).

Side effects

Allergic reactions: skin hyperemia drug fever urticaria rhinitis skin itching and sensation of heat in the soles bronchospasm collapse anaphylactic shock. Other potential side effects include dizziness headache nausea decreased appetite vomiting diarrhea joint pain increased blood pressure and eosinophilia.

Transient thrombocytopenia with platelet counts ranging from 80×109/L to 150 x 109/L may sometimes be noted at the start of heparin treatment. Usually this situation does not lead to the development of complications and treatment with heparin can be continued. In rare cases, severe thrombocytopenia (white clot syndrome) may occur, sometimes with a lethal outcome. This complication should be assumed if the platelet count drops below 80×109/l or more than 50% of the baseline, heparin administration should be stopped immediately in such cases. In patients with severe thrombocytopenia coagulopathy of consumption (depletion of fibrinogen reserves) may develop.

On the background of heparin-induced thrombocytopenia: skin necrosis arterial thrombosis accompanied by the development of gangrene myocardial infarction stroke.

In long-term use: osteoporosis spontaneous bone fractures calcification of soft tissues hypoaldosteronism transient alopecia priapism.

With heparin therapy, changes in biochemical blood parameters may be observed (increased activity of “hepatic” transaminases of free fatty acids and thyroxine in plasma; hyperkalemia; recurrent hyperlipidemia with sodium heparin withdrawal; false increase in blood glucose and error in bromsulphale and nova test results).

Local reactions: irritation pain hyperemia hematoma and ulceration at the injection site bleeding.

Bleeding: typical – from the gastrointestinal and urinary tract at the site of administration in areas under pressure from surgical wounds; bleeding in various organs (including the adrenal gland, yellow body, retroperitoneal space).

If any of the side effects mentioned in the instructions worsen, or if you notice any other side effects not mentioned in the instructions, tell your doctor.

Overdose

Symptoms: signs of bleeding.

Treatment: in small bleeding caused by heparin overdose it is enough to stop its use. In extensive bleeding excess heparin is neutralized with protamine sulfate (1 mg protamine sulfate per 100 ME heparin). 1% protamine sulfate solution is administered intravenously very slowly. Do not administer more than 50 mg (5 ml) of protamine sulfate every 10 minutes. Given the rapid metabolism of sodium heparin, the required dose of protamine sulfate decreases over time. To calculate the required dose of protamine sulfate, we can assume that the T1/2 of sodium heparin is 30 minutes. Severe anaphylactic reactions with lethal outcome have been reported when using protamine, and therefore the drug should be administered only in a ward equipped for emergency medical aid in anaphylactic shock. Hemodialysis is ineffective.

Pregnancy use

Sodium heparin does not penetrate the placental barrier. So far there are no data indicating the possibility of fetal malformations due to the use of sodium heparin during pregnancy; there are also no results of experiments on animals that would indicate embryo- or fetotoxic effects of sodium heparin. However, there is evidence of an increased risk of preterm labor and spontaneous abortions associated with bleeding. It is necessary to consider the possibility of complications when using sodium heparin in pregnant women with comorbidities, as well as in pregnant women receiving additional treatment.

The daily use of high doses of sodium heparin for more than 3 months may increase the risk of osteoporosis in pregnant women. Therefore, continuous use of high-dose sodium heparin should not exceed 3 months. Epidural anesthesia should not be used in pregnant women on anticoagulant therapy. Anticoagulant therapy is contraindicated if bleeding is threatened, e.g., threatened abortion.

Sodium heparin is not excreted with breast milk. Daily use of high doses of sodium heparin for more than 3 months may increase the risk of osteoporosis in breastfeeding women.

If use during these periods is necessary, the benefit/risk should be weighed.

Similarities