Heparin,. 5000 me/ml 5 ml 5 pcs.

Pharmacotherapeutic group: anticoagulant of direct action.
ATH code: B01AB01

Pharmacological properties

Pharmacodynamics
Direct acting anticoagulant. It belongs to the group of medium molecular weight heparins. Inhibits the formation of fibrin. Anticoagulant effect is visible in vitro and in vivo, comes immediately after intravenous administration.
Mechanism of action of sodium heparin is based primarily on binding to antithrombin III – inhibitor of activated blood coagulation factors: IIa (thrombin), IXa, Xa, XIa, XIIa (thrombin and activated factor X is especially important). Sodium heparin increases renal blood flow; increases cerebral vascular resistance, reduces cerebral hyaluronidase activity, activates lipoprotein lipase and has hypolipidemic effect. 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, sodium heparin can increase the activity of brain tyrosine hydroxylase, pepsinogen, DNA polymerase and decrease the activity of myosin ATPase, pyruvate kinase, RNA polymerase, pepsin. The clinical significance of these effects of sodium heparin remains poorly understood.
In patients with coronary heart disease (in combination with acetylsalicylic acid) reduces the risk of acute coronary thrombosis, myocardial infarction and sudden death. Reduces the frequency of recurrent heart attacks and mortality of patients who had a myocardial infarction.
In high doses it is effective for treatment of pulmonary thromboembolism and venous thrombosis; in low doses – for prevention of venous thromboembolism, including after surgical operations.
Anticoagulant effect after a single intravenous injection is achieved in several minutes and lasts up to 4-5 hours. When administered subcutaneously the action begins after 20-30 minutes and lasts for 12 hours or more (depending on the dose). For unfractionated standard heparin the ratio of antiaggregant activity (antifactor Xa) to anticoagulant activity (ACTV) is 1:1.
Deficiency of antithrombin III in plasma or in place of thrombosis may reduce antithrombotic effect of heparin sodium.

Pharmacokinetics

Assimilation
After intravenous administration, maximum concentration (Cmax) is reached almost immediately; after subcutaneous administration, 4-5 hours later.

Distribution
Binding to plasma proteins is up to 95 %; volume of distribution is very small – 0.06 l/kg (does not leave vascular channel due to strong binding to plasma proteins). It does not penetrate through the placental barrier and into breast milk. It is intensively taken up by endothelial cells and cells of mononuclear-macrophage system (reticulo-endothelial system cells – RES) and concentrated in liver and spleen.

Metabolism and elimination
Metabolized in the liver involving N-desulfamidase and platelet heparinase, which is included in the metabolism of sodium heparin at later stages. Participation in the metabolism of platelet factor IV (anti-heparin factor), as well as binding of sodium 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.
The half-life of the drug (T½) is 1-6 hours (on average 1.5 hours). Period of semiejection half-life is increased at obesity, renal and hepatic insufficiency, decreased at pulmonary embolism, infectious diseases, malignant tumors.
Excreted by kidneys as inactive metabolites. After administering high doses it can be excreted (up to 50%) unchanged. It is not eliminated by hemodialysis.

Indications

Active ingredient

Composition

How to take, the dosage

For therapeutic purposes the drug Heparin sodium is administered as a continuous intravenous infusion or as regular intravenous injections, as well as subcutaneously (in the anterolateral wall of the abdomen). The drug is not intended for intramuscular administration.

For prophylactic purposes, subcutaneously, at 5000 IU/day, at intervals of 8-12 hours. The usual site for subcutaneous injections is the anterolateral wall of the abdomen (in exceptional cases the upper arm or the front surface of the thigh); a thin needle should be inserted deeply, perpendicular to the skin fold, held between thumb and forefinger until the solution is finished. The injection sites should be alternated each time (to avoid the formation of a hematoma). The first injection should be made 1-2 hours before the operation; in the postoperative period – administered for 7-10 days, and if necessary – for a longer period.

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

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

– for continuous intravenous infusion administered at 1000-2000 IU/hour (24000-48000 IU/day), diluting the drug with 0.9% sodium chloride solution;

– in regular intravenous injections administer 5000-10000 ME of the drug every 4-6 hours;

– when administered subcutaneously, the drug is administered every 12 hours at 15000-20000 ME or every 8 hours at 8000-10000 ME.

Laboratory monitoring of the effectiveness and safety of therapy with the drug Heparin sodium

The dose of the drug Heparin sodium should be adjusted based on the laboratory parameters of blood clotting. When using the drug it is necessary to monitor the activated partial thromboplastin time (APTT) or the blood clotting time (BCT). The administered dose of the drug is considered adequate if the ACTV is 1.5-2.5 times the normal values or if the patient’s VSC is 2.5-3.0 times the control values.

In continuous intravenous infusion of the drug, it is recommended to determine the initial AHRTB, then determine the AHRTB every 4 hours with subsequent increase or decrease of the infusion rate until the target AHRTB level is reached (1.5-2.5 times the normal value), subsequently determining the AHRTB every 6 hours.

In case of bolus intravenous administration of sodium heparin, it is recommended to determine the baseline AHR, then determine the AHR before each bolus infusion with subsequent increase or decrease of the administered dose of the drug.

When heparin sodium is administered subcutaneously, it is recommended to monitor the AHRTB 4-6 hours after injection with subsequent increase or decrease of the administered dose of the drug.

When using Sodium Heparin at low doses to prevent thromboembolic complications, it is not necessary to monitor the AFTB. If monitoring is still necessary, anti-Xa activity should be tested, since the chTB is not significantly prolonged.

Continuous intravenous infusion is the most effective way of using sodium heparin, better than regular (periodic) injections, because it provides more stable hypocoagulation and is less likely to cause bleeding.

Application of Sodium Heparin in Special Clinical Situations

Heparin SodiumPrimary percutaneous coronary angioplasty for acute coronary syndrome without ST-segment elevation and for myocardial infarction with ST-segment elevation: Heparin sodium 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 for ST-segment elevation myocardial infarction:The drug Heparin sodium is administered intravenously in a bolus dose of 60 IU/kg (maximum dose 4000 ME), followed by an intravenous infusion of 12 IU/kg (maximum 1000 ME/h) for 24-48 hours. Targeted HFV of 50-70 seconds or 1.5-2.0 times normal; control HFV at 3, 6, 12, and 24 hours after initiation of therapy.

Prevention of thromboembolic complications after surgical interventions with low-dose heparin sodium: Subcutaneously, deep into the abdominal skin fold. Initial dose 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 using the drug in low doses to prevent thromboembolic complications, it is not necessary to monitor the AFP.

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

Application in cardiovascular surgery during surgeries using extracorporeal circulation systems:The initial dose of the drug Heparin sodium is at least 150 IU/kg of body weight. The drug is then 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 of the drug is usually 300 IU/kg body weight (if the estimated duration of surgery is less than 60 minutes) or 400 IU/kg body weight (if the estimated duration of surgery is 60 minutes or more).

Application in hemodialysis: Initial dose of sodium heparin: 25-30 IU/kg (or 10000 ME) intravenous bolus, followed by continuous infusion of sodium heparin at a rate of 1500-2000 IU/hr (unless otherwise specified in the hemodialysis systems manual).

Preparation of vascular catheters: To obtain heparinized solution it is necessary to add 0.01 ml of sodium heparin to 1 ml of physiological solution (0.9% sodium chloride solution), i.e. to obtain a solution with a concentration of 50 IU/1 ml. Heparinized solution is injected in the volume equal to the internal volume of the catheter lumen. In pediatrics, the calculation of the dose of the heparinized solution is individual.

Pediatric use:Inadequate controlled studies of heparin sodium in children have not been performed. The recommendations presented are based on clinical experience.

The initial dose: 75-100 IU/kg intravenously bolus for 10 minutes.

The maintenance dose: children 1-3 months of age 25-30 IU/kg/hr (up to 800 IU/kg/day), children 4-12 months of age 25-30 IU/kg/hr (up to 700 IU/kg/day), children over 1 year 18-20 IU/kg/hr (up to 500 IU/kg/day) intravenous drip.

The dose of sodium heparin should be chosen taking into account the blood clotting parameters (target ACTV of 60-85 seconds).

Transition to warfarin therapy:To ensure sustained anticoagulant effect, therapy with Sodium Heparin should be continued in full dose until a stable target INR is achieved. After that, sodium heparin should be discontinued.

Transition to dabigatran therapy:Continuous intravenous heparin sodium should be stopped immediately after the first dose of dabigatran. For fractional intravenous infusions, the patient should take the first dose of dabigatran 1-2 hours before the scheduled administration of the next dose of Heparin Sodium.

Interaction

Pharmaceutical interactions

Sodium heparin solution is diluted only with physiological solution (0.9% sodium chloride solution). Sodium heparin solution is incompatible with the following substances: alteplase, amikacin sulfate, amiodarone, sodium ampicillin, sodium benzylpenicillin, ciprofloxacin, cytarabine, dacarbazine, danorubicin, diazepam, dobutamine, doxorubicin hydrochloride, droperidol, erythromycin, gentamicin sulfate, haloperidol lactate, hyaluronidase, hydrocortisone sodium succinate, dextrose (glucose), 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, cephalothine sodium, cephaloridine, vancomycin hydrochloride, vinblastine sulfate, labetalol hydrochloride, nicardipine hydrochloride.

Pharmacokinetic interaction

Sodium heparin displaces phenytoin, quinidine, propranololol and benzodiazepine derivatives from their binding sites to plasma proteins, which may lead to increased pharmacological effects of the mentioned drugs. Sodium heparin is bound and inactivated by protamine sulfate, polypeptides that have an alkaline reaction, and tricyclic antidepressants.

Pharmacodynamic interaction

The anticoagulant effect of heparin sodium is enhanced when used simultaneously with other drugs affecting hemostasis, including antiplatelet agents (acetylsalicylic acid, clopidogrel, prasugrel, ticlopidine, dipyridamole, epoprostenol/prostaglandins), indirect anticoagulants (warfarin, phenyndione, acenocoumarol), thrombolytics (alteplase, streptokinase, urokinase), nonsteroidal anti-inflammatory drugs (phenylbutazone, ibuprofen, indomethacin, diclofenac, etc.), glucocorticosteroids and other drugs.), glucocorticoids and dextran, resulting in an increased risk of bleeding. In addition, the anticoagulant effect of heparin sodium may increase when combined with hydroxychloroquine, sulfinpyrazone, probenecid, etacrynic acid, cytostatics, cefamandole, cefotetan, valproic acid, propylthiouracil. Anticoagulant effect of heparin sodium is reduced when concomitant use with adrenocorticotropic hormone (ACTH), antihistamines, ascorbic acid, ergot alkaloids, nicotine, nitroglycerin, cardiac glycosides, thyroxine, tetracycline and quinine.

Sodium heparin may decrease the pharmacological effects of ACTH, glucocorticoids and insulin.

Pefore any surgical interventions with sodium heparin, oral anticoagulants and antiaggregants should be discontinued at least 5 days in advance because they may increase bleeding during surgery or in the postoperative period.

Special Instructions

Contraindications

Side effects

WHO classification of adverse reactions by frequency of development

1 per 1,000 appointments

≥ 0.1%, but < 1%

Rarely

1 per 10,000 appointments

≥ 0.01%, but < 0.1%

Very rarely

less than 1 per 10,000 appointments

< 0.01%

Frequency unknown

cannot be estimated from available data

Organ system class

(MedDRA)

Frequency of occurrence

Adverse reactions

Blood and lymphatic system disorders

Very often

Bleeding1

Often

Trombocytopenia2

Immune system disorders

Infrequent

Allergic reactions: Skin hyperemia, urticaria, conjunctivitis, rhinitis, asthma, cyanosis, tachypnea, feeling of tightness, fever, chills, angioedema, skin itching and feeling of heat in the soles, bronchospasm

/p>

Very rare

Severe allergic reactions: anaphylactic shock

Endocrine system disorders

/p>

Infrequent

Hypoaldosteronism3

Frequency unknown

Nausea, vomiting, decreased appetite, diarrhea

Liver and biliary tract disorders

Infrequent

Elevated liver transaminase activity (ALT, AST)3

Skin and subcutaneous tissue disorders

Often

Erythematous nodules, infiltrated, sometimes eczema-like plaques at the site of subcutaneous injections

sup>4

Infrequent

Alopecia3, skin itching, skin rash (including erythematous and maculopapular)

/p>

Rarely

Local irritation

sup>3, skin necrosis3

Musculoskeletal and connective tissue disorders

Infrequent

Osteoporosis3, spontaneous bone fractures3, joint pain3, soft tissue calcification3

Genital and breast disorders

Infrequent

/p>

Priapism3

General disorders and disorders at the site of administration

Very often

Lack of efficacy (based on the ACTV determination)5

Often

Hematoma, irritation, pain, hyperemia, ulceration at the insertion site

/p>

Infrequent

Hyperkalemia, increased concentration of free fatty acids, increased activity of liver transaminases (ALT, AST), increased concentration of thyroxine, false increased concentration of glucose, errors in the bromsulfalein test results, eosinophilia, increased arterial blood pressure

(

frequently/p>

Notes:

In the development of severe thrombocytopenia (reduction of platelet count to half of the original number or below 100 × 109 /l) heparin should be discontinued.

Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) may occur for several weeks after discontinuation of heparin treatment. If a patient presents with thrombocytopenia or thrombosis after heparin withdrawal, the possibility of HIT or HITT should be evaluated.

Overdose

Pregnancy use

Similarities