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

Composition:In 1 ml of the drug contains:
Active substance:
Sodium Heparin 5000 IU
Auxiliary components:
benzyl alcohol - 9.0 mg, sodium chloride - 3.4 mg, hydrochloric acid - q.s., sodium chloride - q.s., water for injection - up to 1.0 ml

Description:Transparent, from a colorless to pale yellow solution, free from mechanical inclusions.

Pharmacotherapeutic group:anticoagulant

ATX: & nbsp

B.01.A.B.01 Heparin

Pharmacodynamics:Anticoagulant direct action. Refers to the group of medium-molecular heparins, slows the formation of fibrin. Anticoagulant effect is detected in vitro and in vivo, occurs immediately after intravenous administration.
The mechanism of action of heparin is based, first of all, on binding to antithrombin III, which serves as a physiological inhibitor of activated coagulation factors IXa, Xa, XIa, XIIa and thrombin.Particularly important is the ability to inhibit the activated factor X involved in the internal and external coagulation system (this action is manifested against a background of much smaller doses of heparin than is required to suppress thrombin activity promoting the formation of fibrin from fibrinogen, which serves as a rationale for the possibility of subcutaneous administration of small doses of heparin for prevention of venous thrombosis and large doses - for treatment).
Heparin also has the ability to suppress platelet aggregation (prolongs bleeding time). Heparin is not able to dissolve the thrombus (not fibrinolytic), but it can reduce the size of the thrombus, stopping its growth, and in this case part of the thrombus dissolves under the action of natural fibrinolytic enzymes. Oppressing the activity of hyaluronidase, has lipid-lowering effect. Anticoagulant action with a single intravenous administration develops in a few minutes and lasts up to 4-5 hours. When the administration is started, the effect begins 20-30 minutes and lasts 12 hours and more (depending on the dose). For unfractionated standard heparin, the ratio of antiplatelet activity (Xa antifactor)and anticoagulant activity (activated partial thromboplastin time - APTT) is 1: 1.
After intravenous administration, the effect of the drug occurs almost immediately, no later than 10-15 minutes and lasts for a short time - 4-5 hours. After subcutaneous administration, the effect of the drug begins slowly - after 20-60 minutes, but lasts 8-12 hours or more. The therapeutic effect - prevention of thrombosis - lasts much longer.

Pharmacokinetics:Heparin is not absorbed from the gastrointestinal tract, therefore it is used only parenterally. The maximum concentration (Cmax) after intravenous administration is achieved almost immediately, after subcutaneous administration - after 4-5 hours.
The connection with plasma proteins is up to 95%, the volume of distribution is 0.06 l / kg (does not leave the vascular bed due to strong binding to plasma proteins).
It does not penetrate the placental barrier and into breast milk.
Intensively captured by endothelial cells and cells of the mononuclear-macrophage system (cells of the reticuloendothelial 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. The half-life of sodium heparin (T1 / 2) is 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:Treatment and prevention: deep vein thrombosis, pulmonary thromboembolism (including peripheral veins), coronary thrombosis, thrombophlebitis, unstable angina, acute myocardial infarction, atrial fibrillation (including those accompanied by embolization), disseminated intravascular coagulation (DVS-syndrome) -1 phase,microthrombosis and microcirculation disorders, renal vein thrombosis, hemolyticuremic syndrome, mitral heart disease (prevention of thrombosis); glomerulonephritis; lupus nephritis.
Prevention of blood coagulation during operations with extracorporeal circulation techniques, during hemodialysis, hemosorption, peritoneal dialysis, cytapheresis, Forced diuresis by washing venous catheters. Postoperative period in patients with thromboembolism in the anamnesis.

Contraindications:Increased sensitivity to heparin and other ingredients, diseases accompanied by bleeding disorders (hemophilia, thrombocytopenia, vasculitis and others), hemorrhage, brain aneurysm, dissecting aortic aneurysm, hemorrhagic stroke, antiphospholipid syndrome, trauma (especially traumatic brain), uncontrolled arterial hypertension, erosive-ulcerative lesions of the gastrointestinal tract; cirrhosis of the liver, accompanied by varicose veins of the esophagus; menstrual period, threatening miscarriage, childbirth (including recent ones),recent surgical interventions on the brain and spinal column, eyes, prostate gland, liver and biliary tract, condition after spinal cord puncture; children's age to 1 month (due to the presence of benzyl alcohol).

Carefully:Patients with polyvalent allergies (including bronchial asthma), arterial hypertension, dental manipulations, diabetes mellitus, endocarditis, pericarditis, intrauterine contraception (IUD), active tuberculosis, radiation therapy, hepatic insufficiency, chronic renal failure (CRF), old age (over 60 years, especially women).
Given the content of benzyl alcohol in the preparation, caution should be exercised when prescribing to children under 3 years due to the risk of developing anaphylactoid reactions in them.

Pregnancy and lactation:Heparin does not penetrate the placental barrier. To date, there are no data indicating the possibility of fetal malformations due to the use of heparin during pregnancy; There are also no results of experiments on animals that would indicate the embryo or fetotoxic effect of 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 in pregnant women with concomitant diseases, as well as in pregnant women receiving additional treatment.
Daily use of high doses of heparin for more than 3 months may increase the risk of osteoporosis in pregnant women. Therefore, continuous use of high doses of 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 is not excreted in breast milk. Daily use of high doses of heparin for more than 3 months may increase the risk of osteoporosis in lactating women.

Dosing and Administration:Heparin is administered subcutaneously, intravenously, bolus or drip.
Heparin is prescribed in the form of continuous intravenous infusion or in the form of regular intravenous injections, as well as subcutaneously (in the abdomen).
Heparin can not be administered intramuscularly.
The usual place for subcutaneous injection is the antero-lateral abdominal wall (exceptionally introduced into the upper shoulder area or thigh) while using a thin needle to be administered deep, perpendicular, in skin fold held between the thumb and index finger to the end of the introduction solution. Each time, alternate injection sites (to avoid the formation of a hematoma). 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.
The initial dose of heparin sodium introduced for therapeutic purposes, usually 5000 ME and administered intravenously, after which the treatment should be continued using a subcutaneous injection or intravenous infusion.
Supporting doses are determined depending on the method of application:
- with continuous intravenous infusion, appoint 1000-2000 IU / h (24000-48000 IU / day), breeding heparin sodium in a 0.9% solution of sodium chloride;
- with regular intravenous injections appoint 5000-10000 ME of sodium heparin every 4-6 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 the clotting time of blood and / or APTT in order to correct the subsequent dose.
Doses of sodium heparin for intravenous administration are selected so that the APTT is 1.5-2.5 times greater 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).
When subcutaneous administration of small doses (5000 IU 2-3 times a day) for the prevention of thrombosis, regular monitoring of APTTV is not required, as it increases insignificantly.
Continuous intravenous infusion is the most effective way of using sodium heparin, better than regular (periodic) injections, as it provides more stable hypocoagulation and less often causes bleeding.
Adults with thromboses of mild and moderate severity are intravenously administered 40000-50000 IU / day for 3-4 injections; with severe thrombosis or embolism - intravenously 20000 IU 4 times a day at intervals of 6 h.
For vital indications, intravenously administered once 25000 ME, then 20000 IU every 4 hours until a daily dose of 80000-120000 ME is given. At intravenous drip introduction to a daily volume of an infusion solution add not less than 40000 ME.
When performing extracorporeal circulation, Heparin is administered at a dose of 140-400 IU / kg or 1500-2000 IU per 500 ml of preserved blood (whole blood, erythrocyte mass).
Patients on dialysis, dose adjustment is conducted according to the results of the coagulogram.
In hemodialysis, 10,000 IU per 500 ml of blood are initially given intravenously, then in the middle of the procedure another 30,000-50000 ME. For elderly patients, especially women, doses should be reduced.
For children, the drug is administered intravenously drip: at the age of 1-3 months - 800 IU / kg / day, 4-12 months -700 IU / kg / day, over 6 years - 500 IU / kg / day under the control of APTTV.
The duration of therapy with Heparin depends on the indications and the method of administration. With intravenous application, the optimal duration of treatment is 7-10 days, after which the therapy is continued with oral anticoagulants (it is recommended to administer oral anticoagulants starting from the 1st day of treatment with Heparin or from 5 to 7 days, and stopping Heparin on 4-5 days of combined therapy) .With extensive thrombosis of the ileum-femoral veins, it is advisable to conduct longer courses of treatment with Heparin.

Side effects:Allergic reactions: hyperemia of the skin, drug fever, hives, rhinitis, pruritus and sensation of heat in the soles, bronchospasm, collapse, anaphylactic shock. Given the content of benzyl alcohol in the preparation, caution should be exercised when prescribing to children under 3 years due to the risk of developing anaphylactoid reactions in them. Other potential side effects include dizziness, headache, nausea, vomiting, decreased appetite, diarrhea, joint pain, increased blood pressure, and eosinophilia.
At the beginning of treatment with heparin, transient thrombocytopenia (6% of patients) can sometimes be noted with a platelet count ranging from 80x10⁹/ l up to 150x10⁹/ 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 platelets below 80x10⁹/ l or more than 50% of the baseline, the introduction 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 fractures of bones, calcification of soft tissues, hypoaldosteronism, transient alopecia.
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, reversible potassium retention in the body, a false decrease in cholesterol concentration, a false increase in blood glucose concentration and a false positive result of bromsulfalein test).
Local reactions: 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 subject to pressure,from operating wounds; hemorrhages in various organs (including adrenal glands, yellow body, retroperitoneal space).

Overdose:Symptoms: signs of bleeding.
Treatment: with small bleeding caused by an overdose of heparin sodium, it is enough to stop using it. With extensive bleeding, excess sodium heparin is neutralized with protamine sulfate (1 mg protamine sulphate per 100 IU sodium heparin). It must be borne in mind that heparin sodium It is quickly displayed and if Protamine sulfate appointed 30 minutes after the previous dose of heparin sodium, you only need to enter half the required dose; The maximum dose of protamine sulfate is 50 mg.
Hemodialysis is ineffective.

Interaction:Before any surgical procedures using heparin sodium, oral indirect anticoagulants (for example, coumarin derivatives) and antiplatelet agents (for example, acetylsalicylic acid, dipyridamole), since they can increase bleeding during surgical interventions or in the postoperative period.
The simultaneous use of ascorbic acid, antihistamines, cardiac glycosides or tetracyclines, ergot alkaloids, nicotine, nitroglycerin (intravenous administration), thyroxine, adrenocorticotropic hormone (ACTH), alkaline amino acids and polypeptides, protamine may reduce the effect of heparin sodium.
Dextran, phenylbutazone, indomethacin, sulfinpyrazone, intravenous administration of ethacrynic acid, penicillins and cytostatics can potentiate the action of sodium heparin.
Sodium Heparin replaces phenytoin, quinidine, propranolol, benzodiazepines and bilirubin in the places of their binding with proteins. Mutual reduction in efficacy occurs with the simultaneous use of tricyclic antidepressants, since they can bind to sodium heparin.
Due to the potentially possible precipitation of the active ingredients heparin sodium should not be mixed with other medicinal products.

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 sodium heparin use, especially between 6 and 14 days after initiation of treatment.Immediately stop treatment with a sharp decrease in the number of platelets (see section "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 advised that he can not use heparin drugs in the future (even low-molecular-weight heparin). If there is a high likelihood of heparin-induced immune thrombocytopenia, the drug should be immediately withdrawn. When developing heparin-induced immune thrombocytopenia in patients receiving heparin for thromboembolic disease or in the case of thromboembolic complications, other anticoagulant 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 patients with a lack of response to heparin or requiring the appointment of high doses of heparin should be monitored antithrombin III.
In women over 60 years of age, heparin can increase bleeding.
When using the drug in patients with hypertension should regularly 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 administration of heparin sodium should be continued until the results of coagulation time and APTT are in the therapeutic range.
Intramuscular injections are contraindicated. It should also be avoided as much as possible puncture biopsies, infiltration and epidural anesthesia and diagnostic lumbar punctures on the background of the use of heparin.
If there is a massive bleeding, you should cancel the drug and examine 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. Protamine sulfate is a specific antidote for heparin sodium. One ml of protamine sulfate neutralizes 1000 IU of heparin. Doses of protamine sulfate should be corrected depending on the results of the coagulogram, since an excessive amount of this drug in itself can provoke bleeding.
A solution of sodium heparin can acquire a yellow tint, which does not change its activity or tolerability.
To dilute sodium heparin, only 0.9% sodium chloride solution is used!

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

Packaging:By 5.0 ml of the drug in a vial of clear glass, sealed with a stopper of chlorobutyl rubber, coated with an aluminum ring; 5 bottles per plastic pallet, 1 pallet together with instructions for use in a cardboard box.

Storage conditions:In a dry, protected from light place at a temperature of no higher than 25 ° C. Do not freeze. Keep out of the reach of children!

Shelf life:3 years. Do not use after the expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002030

Date of registration:21.03.2013

The owner of the registration certificate:ELFA NPC, CJSC ELFA NPC, CJSC Russia

Manufacturer: & nbsp

ELFA LABORATORIES India

Representation: & nbspZAO NPC ELFA ZAO NPC ELFA Russia

Information update date: & nbsp2016-01-09

Illustrated instructions

Instructions

Heparin (Heparin)