Heparin sodium - instructions for use, dose, side effects, contraindications

The mechanism of action of heparin sodium is based, first of all, on its binding to antithrombin III, which is a natural inhibitor of activated blood coagulation factors - IIa (thrombin), IXa, Xa, XIa and XIIa. Sodium Heparin is bound by antithrombin III and causes conformational changes in its molecule. As a result, the binding of antithrombin III to blood coagulation factors IIa (thrombin), IXa, Xa, XIa and XIIa is accelerated, and their enzymatic activity is blocked.The binding of sodium heparin to antithrombin III is of an electrostatic nature and depends to a large extent on the length and composition of the molecule (for the binding of heparin to antithrombin III, a pentasaccharide sequence containing 3-0-sulphated glucosamine).

The greatest value is the ability of heparin sodium in combination with antithrombin III to inhibit coagulation factors IIa (thrombin) and Ha. The ratio of heparin sodium activity with respect to factor Xa to its activity with respect to factor IIa is 0.9-1.1.

Heparin sodium reduces blood viscosity, reduces vascular permeability, stimulated bradykinin, histamine and other endogenous factors, and thus prevents the development of stasis. Sodium Heparin can sorb on the surface of membranes of the endothelium and blood cells, increasing their negative charge, which prevents adhesion and aggregation of platelets. Sodium Heparin slows hyperplasia of smooth muscles, activates lipoprotein lipase and, thus, has a hypolipidemic effect and prevents the development of atherosclerosis.

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

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

In high doses heparin sodium effective in pulmonary embolism and venous thrombosis, in small - effective for the prevention of venous thromboembolism, incl. after surgical operations.

After intravenous administration of drug action occurs almost immediately, no later than 10-15 minutes and lasts long -. 6.3 hours after subcutaneous administration of drug action begins slowly - over 40-60 min, but lasts 8 hours antithrombin III deficiency in the blood or plasma. at the site of thrombosis can reduce the anticoagulant effect of heparin sodium.

Pharmacokinetics:

The maximum concentration (C_max) after intravenous administration is achieved almost immediately, after subcutaneous injection after 2-4 hours. The connection with plasma proteins is up to 95%, the volume of distribution is very small - 0.06 l / kg (does not leave the vascular bed due to strong binding to plasma proteins ).It does not penetrate the placenta and into breast milk.

Intensively captured by endothelial cells and cells of the mononuclear-macrophage system (cells of the reticulo-endothelial system), it is 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 later stages. 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-term action. Desulfated molecules under the influence of kidney endoglycosidase are converted into low-molecular fragments. T_1/2- 1-6 hours (on average - 1.5 hours); increases with obesity, hepatic and / or renal insufficiency; decreases with thromboembolism of the pulmonary artery, infections, malignant tumors.

It is excreted by the kidneys, mainly in the form of inactive metabolites, and only with the introduction of high doses is it possible to excrete (up to 50%) unchanged. It is not excreted by hemodialysis.

Indications:

- Prevention and treatment of venous thrombosis (including thrombosis of superficial and deep veins of the lower extremities, thrombosis of the renal veins) and pulmonary embolism.

- Prevention and treatment of thromboembolic complications associated with atrial fibrillation.

- Prevention and treatment of peripheral arterial embolism (including associated with mitral heart defects).

- Treatment of acute and chronic coagulopathy of consumption (including the first stage of DIC syndrome).

- Acute coronary syndrome without stable rise of the ST segment on the ECG (unstable angina, myocardial infarction without ST segment elevation on the ECG).

- Myocardial infarction with ST segment elevation: with thrombolytic therapy, with primary percutaneous coronary revascularization (balloon angioplasty with or without stenting) and with a high risk of arterial or venous thrombosis and thromboembolism.

- Prevention and treatment of microthrombogenesis and microcirculatory disorders, incl. with hemolytic-uremic syndrome; glomerulonephritis (including lupus nephritis) and with forced diuresis.

- Prevention of blood coagulation during blood transfusion, extracorporeal circulation systems (extracorporeal circulation in heart surgery, hemosorption, cytarapheresis) and hemodialysis.

- Treatment of peripheral venous catheters.

Contraindications:

- Hypersensitivity to other components of the drug.

- Heparin-induced thrombocytopenia (with or without thrombosis) in the anamnesis or at the present time.

- Bleeding (except when the benefits of sodium heparin outweigh the potential risk).

- Sodium Heparin Therapeutic dose should not be administered if there is no way to provide regular laboratory monitoring of blood coagulability.

- Pregnancy and the period of breastfeeding.

Carefully:

Patients with a polyvalent allergy (including bronchial asthma).

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

- Diseases of the cardiovascular system: acute and subacute infective endocarditis, severe uncontrolled arterial hypertension, exfoliation of the aorta, aneurysm of cerebral vessels.

- Erosive-ulcerative lesions of the digestive tract, varicose veins of the esophagus with cirrhosis of the liver and other diseases, prolonged use of gastric and intestinal drainage, ulcerative colitis, hemorrhoids.

- Diseases of blood and blood lymphatic system: leukemia, hemophilia, thrombocytopenia, hemorrhagic diathesis.

- Diseases of the central nervous system: hemorrhagic stroke, craniocerebral trauma.

- Malignant neoplasms.

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

Other physiological and pathological conditions: the period of menstruation, the threat of miscarriage, the early postpartum period, severe liver disease with impaired protein-synthetic function, chronic renal failure, recent surgery for the eyes, brain or spinal cord, recent spinal (lumbar) puncture or epidural anesthesia, proliferative diabetic retinopathy, vasculitis, advanced age (over 60 years, especially women).

Pregnancy and lactation:

Heparin sodium does not penetrate the placental barrier. To date, there are no data indicating the possibility of malformations of the fetus due to the use of heparin sodium during pregnancy; there are also no results of animal experiments,which would indicate the embryo or fetotoxic effect of sodium heparin. However, there is evidence of an increased risk of preterm labor and spontaneous abortion associated with bleeding. It is necessary to take into account the likelihood of complications when using heparin sodium in pregnant women with concomitant diseases, as well as in pregnant women receiving additional treatment.

Daily use of high doses of heparin sodium for more than 3 months may increase the risk of osteoporosis in pregnant women. Therefore, the continuous use of high doses of sodium heparin should not exceed 3 months. Epidural anesthesia should not be used in pregnant women who undergo anticoagulant therapy. Anticoagulant therapy is contraindicated if there is a threat of bleeding, for example, with a threatening abortion.

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

In case of need of application in the specified periods it is necessary to correlate the benefit / risk.

Dosing and Administration:

Heparin is administered in the form of continuous intravenous infusion or in the form of subcutaneous or intravenous injections.

The initial dose of heparin administered for therapeutic purposes is 5000 IU and is administered intravenously, after which treatment is continued using subcutaneous injections or intravenous nifusias.

Supporting doses are determined depending on the method of application:

- with continuous intravenous infusion, administer 1000-2000 IU / h (24000-48000 IU / day), diluting heparin in a 0.9% solution of sodium chloride, or 5% or 10% glucose solution, or sodium chloride solution 0.45 % and glucose 2.5%, or Ringer's solution;

- with regular intravenous injections, 5000-10000 IU of heparin is administered every 4 to 6 hours;

- when administered subcutaneously, every 12 hours, 15,000 to 20,000 ME or every 8 hours to 8000-10000 ME.

Before the administration of each dose, it is necessary to conduct a study of blood coagulation time and / or activated partial thromboplastin time (APTT) in order to correct the subsequent dose. Subcutaneous injections are preferably performed in the anterior abdominal wall area, other places of administration (shoulder, thigh) can be used as an exception.

It is undesirable to re-administer sodium heparin at the sites of previous injections.Before injection, remove the droplets of solution from the outer surface of the needle.

Doses of heparin sodium with intravenous administration are selected so that the APTT is 1.5-2.5 times higher than the control one.

The anticoagulant effect of heparin is considered optimal if the clotting time is 2-3 times longer than normal, APTTV and thrombin time are increased by a factor of 2 (with the possibility of continuous monitoring of the APTT).

In the prevention of thrombosis in the postoperative period, the first injection should be performed 1-2 hours before the operation; In the postoperative period, administer within 7-10 days, and if necessary - for a longer time.

Use of heparin sodium in special clinical situations

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

heparin sodium is administered intravenously bolus at a dose of 70-100 units / kg (if no glycoprotein IIb / IIIa receptor inhibitors are planned) or at a dose of 50-60 U / kg (when combined with glycoprotein IIb / IIIa receptor inhibitors).

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

Prevention of thromboembolic complications after surgical interventions using low doses of heparin sodium: subcutaneously, deep into the crease of the skin of the abdomen. The initial dose is -5000 IU for 2 hours before the operation. In the postoperative period - 5000 ME every 8-12 hours for 7 days or until the patient's mobility is completely restored (whichever comes first). When sodium heparin is used in low doses for the prevention of thromboembolic complications, it is not necessary to control the APTT. Application in cardiovascular surgery in operations using the extracorporeal circulation system: the initial dose is not less than 150 IU / kg. Further heparin sodium is introduced by continuous intravenous infusion at a rate of 15-25 drops / min at 30,000 IU per 1 liter of the infusion solution.The total dose is usually 300 IU / kg (if the expected duration of the operation is less than 60 minutes) or 400 IU / kg (if the estimated duration of the operation is 60 minutes or more).

Application for hemodialysis: initial dose - 25-30 IU / kg (or 10,000 IU) i.v. bolus, followed by continuous infusion of sodium heparin 20000 IU / 100 mg sodium chloride solution at a rate of 1500-2000 IU / h (unless otherwise specified in the manual for the application systems for hemodialysis ). The dose of heparin sodium should be selected taking into account the parameters of blood coagulation (the target level of APTT is 60-85 sec).

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

Initial dose: 75-100 units / kg intravenously bolus for 10 minutes. Maintenance dose: children aged 1-3 months - 25-30 U / kg / h (800 DB / kg / day), children aged 4-12 months - 25-30 U / kg / h (700 U / kg / day), children older than 1 year - 18-20 units / kg / h (500 units / kg / day) intravenously drip.

Side effects:

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

At the beginning of treatment with heparin, transient thrombocytopenia can sometimes occur with a platelet count in the range of 80x10⁹/ l up to 150 x 10⁹/ l. Usually this situation does not lead to the development of complications and the treatment with heparin can be continued. In rare cases, severe thrombocytopenia (white clot syndrome) can occur, sometimes fatal. This complication should be assumed in case of a decrease in the number of platelets below 80x10⁹/ l or more than 50% of the baseline, the administration of heparin in such cases is urgently discontinued. Patients with severe thrombocytopenia may develop coagulopathy of consumption (depletion of fibrinogen stores).

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

With prolonged use: osteoporosis, spontaneous bone fractures, calcification of soft tissues, hypoaldosteronism, transient alopecia, priapism.

On the background of heparin therapy, changes in biochemical parameters of blood can be observed (an increase in the activity of "hepatic" transaminases, free fatty acids and thyroxine in the blood plasma, hyperkalemia, recurrent hyperlipidemia with a reversal of heparin sodium, a false increase in blood glucose level and an error in the results of bromsulphal and th test).

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

Bleeding: typical - from the gastrointestinal tract and urinary tract, at the site of injection, in areas undergoing pressure, from operating wounds; hemorrhages in various organs (including adrenal glands, yellow body, retroperitoneal space).

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

Symptoms: signs of bleeding.

Treatment: with small bleeding caused by an overdose of heparin, it is enough to stop using it. With extensive bleeding, excess heparin is neutralized with protamine sulfate (1 mg protamine sulphate per 100 IU of heparin).1% protamine sulphate solution is administered intravenously very slowly. Every 10 minutes, you can not administer more than 50 mg (5 ml) of protamine sulfate. Given the rapid metabolism of heparin sodium, the required dose of protamine sulfate decreases with time. To calculate the required dose of protamine sulfate, it can be considered that T1 / 2 of sodium heparin is 30 minutes. When protamine was used, severe anaphylactic reactions with a lethal outcome were noted, and therefore, the drug should be administered only under conditions of separation, equipped to provide emergency medical care for anaphylactic shock. Hemodialysis is ineffective.

Interaction:

Pharmaceutical interaction: solution of sodium heparin is compatible only with 0.9% sodium chloride solution. A solution of sodium heparin 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, sodium methicillin, netilmicin sulfate, opioids, oxytetracycline hydrochloride, polymyxin B sulfate, promazine hydrochloride, promethazine hydrochloride, streptomycin sulfate, sulfafurazola diethanolamine, tetracycline hydrochloride, tobramycin sulfate, sodium cephalothin, cephaloridine, vancomycin hydrochloride, vinblastine sulfate, labetalol hydrochloride , nicardipine hydrochloride.

Pharmacokinetic interaction: heparin sodium expels phenytoin, quinidine, propranolol and benzodiazepine derivatives from the sites of their binding to plasma proteins, which may lead to an increase in the pharmacological effect of these drugs. Sodium Heparin is bound and inactivated by sodium protamine, polypeptides having an alkaline reaction, and tricyclic antidepressants.

Pharmacodynamic interaction: anticoagulant effect of sodium heparin is enhanced with simultaneous use with other drugs that affect hemostasis, including. with antiplatelet agents (acetylsalicylic acid, clopidogrel, prasugrel, ticlopidine, dipyridamole), anticoagulants of indirect action (warfarin, phenylin, syncumar), thrombolytic drugs (alteplase, streptokinase, urokinase), non-steroidal anti-inflammatory drugs (incl. phenylbutazone, ibuprofen, indomethacin, diclofenac), glucocorticosteroids and dextran, which increases the risk of bleeding. In addition, the anticoagulant effect of sodium heparin can be enhanced when combined with hydroxychloroquine, sulfinpyrazone, probenecid, ethacrynic acid, cytostatics, cefamandole, cefotetan, valproic acid, propylthiouracil.

The anticoagulant effect of sodium heparin decreases with simultaneous use with ACTH, antihistamine drugs, ascorbic acid, ergot alkaloids, nicotine, nitroglycerin, cardiac glycosides, thyroxine, tetracycline and quinine.

Heparin sodium can reduce the pharmacological effect of adrenocorticotropic hormone, glucocorticosteroids and insulin.

Special instructions:

Treatment in large doses is recommended in a hospital.The control of the platelet count should be performed before the start of treatment, on the first day of treatment and at short intervals during the entire period of administration of sodium heparin, especially between 6 and 14 days after initiation of treatment. Immediately stop treatment with a sharp decrease in the number of platelets (see "Side effect").

A sharp decrease in the number of platelets requires further investigation for the detection of heparin-induced immune thrombocytopenia. If this is the case, the patient should be informed that he can not prescribe heparin in the future (even low molecular weight heparin). If there is a high probability of heparin-induced immune thrombocytopenia, heparin should be immediately withdrawn.

When developing heparin-induced thrombocytopenia in patients receiving heparin for thromboembolic disease or in the case 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, alternative methods of treating renal failure should be used.

To avoid overdose, it is necessary to constantly monitor clinical symptoms indicating possible bleeding (bleeding of the mucous membranes, hematuria, etc.). In individuals with a lack of response to heparin or requiring the appointment of high doses of heparin, it is necessary to monitor the level of antithrombin III.

Resistance to sodium heparin is often observed with fever, thrombosis, thrombophlebitis, infectious disease, myocardial infarction, malignant neoplasms, and also after surgical interventions and with the deficiency of antithrombin III. In such situations, more thorough laboratory monitoring (APTT monitoring) is required.

Although heparin sodium does not penetrate the placental barrier and is not detected in breast milk, when prescribed in therapeutic doses, should be carefully monitored by pregnant women and breastfeeding mothers.

Special care should be taken within 36 hours after delivery.

It is necessary to conduct appropriate control laboratory tests (clotting time, activated partial thromboplastin time and thrombin time).

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

When using heparin in patients with hypertension should constantly monitor blood pressure.

Before starting therapy with sodium heparin, a coagulogram study should always be performed, with the exception of the use of low doses.

Patients who are transferred to oral anticoagulant therapy, the appointment of heparin sodium should continue until the results of coagulation time and APTT will not be in the therapeutic range. Intramuscular injections should be excluded when prescribing heparin sodium for medicinal purposes. Puncture biopsies, infiltration and epidural anesthesia and diagnostic lumbar punctures should also be avoided whenever possible.

If there is a massive bleeding, you should cancel heparin sodium and to investigate the coagulogram indices. If the results of the analysis are within the limits of the norm, then the probability of development of this bleeding due to the use of sodium heparin is minimal.Changes in the coagulogram tend to normalize after heparin withdrawal.

Physical and chemical stability after dilution of heparin in the above solutions for infusion is maintained for 48 hours 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 it during this period at a temperature of 2 to 8 ° C, only if aseptic conditions are met when it is diluted.

Effect on the ability to drive transp. cf. and fur:Studies to assess the effect of heparin on the ability to drive vehicles and engage in potentially hazardous activities were not conducted.

Form release / dosage:Solution for intravenous and subcutaneous administration, 5000 IU / ml.

Packaging:

In the production of Hebei Changshan Biochemical Pharmaceutical Co., Ltd.:

By 5 ml in ampoules of colorless glass type I according to Heb. F. with a ring of fracture or with a notch and a dot.

5 ml in bottles of colorless glass type I according to Heb. F., ukuporennyh rubber stopper, with a crumbling aluminum cap.

5 ampoules or 5 bottles per plastic tray.On 1 pallet together with the instruction on application place in a pack a cardboard.

When manufactured in LLC "COMPANY" DECO ":

5 ml per ampoule of colorless glass of the 1 st hydrolytic class.

5 ml in bottles of colorless glass of the first hydrolytic class, hermetically sealed with rubber stoppers, crimped with aluminum or combined caps, applied to the surface of the name of the manufacturer or without the name, or in a package (glass bottles complete with stopper and cap).

5 ampoules / vials are placed in a contour mesh package made of a polyvinyl chloride film.

1 circuit cell pack with instructions for use is placed in a pack of cardboard.

When packing the drug in ampoules, a scarifier or an ampoule knife is additionally placed in the pack.

When using ampoules with a kink ring or with a notch and a point, the scarifier or knife is not ampouled.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002456

Date of registration:07.05.2014 / 23.11.2015

Expiration Date:07.05.2019

The owner of the registration certificate:INDUKERN-RUS, OOO INDUKERN-RUS, OOO Russia

Manufacturer: & nbsp

HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL, Co.Ltd China

Company DEKO, LLC Russia

Representation: & nbspINDUKERN-RUS LLCINDUKERN-RUS LLCRussia

Information update date: & nbsp27.03.2017

Illustrated instructions

Instructions

Sodium Heparin (Heparin sodium)