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

Heparin is a sulfated mucopolysaccharide consisting of glucosamine-N-sulfuric acid residues and sulfated glucuronic acid residues linked together by a glycosidic linkage. Due to the fact that the heparin molecule has a pronounced negative charge, it forms complexes with certain proteins, changing their biological activity.In particular, by the formation of a complex with heparin, the activity of antithrombin III (AT III) increases approximately 700-fold.

Activated antithrombin inhibits various proteases acting on serine, including clotting factors XIIa XIa, Xa, VIIa and IIa. Factor VIIa, has a moderate sensitivity, and factor IIa (thrombin), on the contrary, is characterized by high sensitivity to the action of the complex of AT III-heparin. Even low doses of heparin accelerate the inactivation of factors IIa (thrombin) and Ha. This explains the effectiveness of low doses of heparin in the prevention of thrombosis. The anticoagulant effect of heparin depends on the concentration of antithrombin and fibrinogen. Heparin in high doses inactivates formed in excess thrombin and, thus, prevents the formation of fibrin from fibrinogen. Heparin also affects the function of platelets.

Some substances contained in platelets (eg, platelet factor 4) neutralize heparin.

Pharmacokinetics:

Suction

Heparin can be administered by subcutaneous injection and by intravenous injection and infusion. When administered by injection or infusion, its bioavailability is 100%.

Due to the high relative molecular weight and the negative charge of the molecule, heparin is not absorbed in the intestine, despite the possible absorption of heparin by inhalation.

With intravenous administration, the action of heparin occurs immediately after administration. After subcutaneous administration, the action of heparin occurs in 20 to 30 minutes. The half-life of heparin is 90-120 minutes and depends on the dose administered, the function of the liver and kidneys, and on the concomitant diseases.

Distribution

Heparin binds to a high degree with plasma proteins (low density lipoproteins, globulins, in particular antithrombin, and fibrinogen). The volume of heparin distribution in adults is about 0.07 l / kg.

Metabolism and excretion

After parenteral administration, heparin is excreted from the blood by capture by the cells of the mononuclear-macrophage system, cleavage in the liver by heparinases, and excretion in the urine mainly in the form of depolymerized inactivated heparin. The excretion of heparin is carried out through glomerular filtration and tubular secretion.

The pharmacokinetics of heparin in children and adults does not differ.

Indications:

- Prevention of thrombosis and thromboembolism;

- Treatment of acute venous and arterial thrombosis and thromboembolism as an anticoagulant (including, early treatment of myocardial infarction and unstable angina);

- Prevention of blood coagulation in the process of extracorporeal circulation (using the device of artificial circulation and hemodialysis).

Contraindications:

Heparin-sodium Brown should not be used in the following cases:

- Hypersensitivity to heparin or other components of the drug.

- Heparin-induced thrombocytopenia of type II, as known from an anamnesis, of the patient, and presumed based on clinical observations such as episodes of thrombocytopenia or manifestations of arterial and / or venous thromboembolic complications with heparin.

- Disorders associated with hemorrhagic diathesis, such as:

- coagulopathy;

- thrombocytopenia;

- severe diseases of the liver, kidneys and pancreas.

- Diseases in which vascular damage is possible, for example:

- ulcers of the gastrointestinal tract;

- arterial hypertension with diastolic arterial pressure more than 105 mm Hg;

- intracranial bleeding;

- CNS damage or neurosurgical interventions;

- intracranial arterial aneurysm;

- retinopathy, bleeding into the vitreous;

ophthalmic surgical interventions;

infectious endocarditis.

- Threatening abortion.

- Spinal or epidural anesthesia, lumbar puncture.

- Disorders of organs associated with hemorrhagic diathesis.

Since Heparin-sodium Brown contains benzyl alcohol, its use is contraindicated in newborns, especially preterm infants.

Carefully:

The appointment of the drug Heparin-sodium Brown is possible only if the expected benefit from treatment with the drug exceeds the possible risk of complications in the following cases:

- Suspicion of a malignant tumor with a risk of bleeding;

- Presence of stones in the kidneys or in the ureters;

- Chronic alcoholism.

A particularly careful observation is necessary:

- during pregnancy, especially in the case of prolonged use of heparin;

- in elderly patients, especially women;

- in the course of treatment with fibrinolytics, oral anticoagulants, platelet aggregation inhibiting agents, such as acetylsalicylic acid, tylopidine, clopidogrel, blockers of glycoprotein Ilb / IIIa receptor platelets;

- patients receiving drugs that raise the level of potassium in the blood serum, as well as in patients at risk of developing hyperkalemia (for example, diabetes mellitus, renal dysfunction). In this case, the potassium level in serum should be monitored.

With caution should be applied Heparin-sodium Brown in infants and children up to -3 years, since the benzyl alcohol included in its composition can cause toxic and anaphylactoid reactions.

Pregnancy and lactation:

Pregnancy

Heparin does not penetrate the placental barrier. To date, there are no data indicating the possibility of malformations of the fetus due to the appointment 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 spontaneous abortions and stillbirths.

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 administration of high doses of heparin for more than 3 months may increase the risk of osteoporosis in pregnant women. Therefore, the continuous administration 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.

Breast-feeding

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

Reproductive function

Data on the effect of heparin on reproductive function are absent.

Dosing and Administration:

Subcutaneous or intravenous administration.

The dose of heparin is determined individually for each patient and depends on the actual values of the parameters of the blood coagulation system, the nature and course of the disease, the response to the therapy, the nature and severity of adverse reactions, and the age and body weight of the patient.It is necessary to take into account the individual sensitivity to heparin, as well as the change in tolerance to heparin treatment.

Recommended doses

1) Prevention of thromboembolism

To prevent thromboembolism, a subcutaneous route of administration of the drug is recommended. The general recommendations for dose selection are as follows:

Preventive maintenance of a thromboembolism before and after operation

Before the surgery: 5,000 - 7500 IU of heparin are injected subcutaneously 2 hours prior to the commencement of the operation.

After the operation: Depending on the risk of thrombosis, 5000 IU of heparin is injected subcutaneously every 8-12 hours or 7500 IU of heparin every 12 hours until the patient regains self-activity or until the vitamin K antagonists are effective enough. To adjust the dose, it may be necessary to determine the values of the indicators of the blood coagulation system.

Preventing thromboembolism with non-surgical treatment

Patients who require bed rest for a long period, patients with a high risk of thrombosis or diseases associated with an increased risk of thrombosis:

Depending on the risk of thrombosis, 5000 IU of heparin is injected subcutaneously every 8 to 12 hours or 7500 IU of heparin every 12 hours.

The dose should be adjusted in accordance with the indicators of coagulation status of the patient, the activity of the blood coagulation system and the individual risk of thrombosis.

2) Treatment of acute venous or arterial thromboembolism

In the presence of thrombi in the blood vessels, continuous intravenous administration is recommended.

Adults:

Initially, 5000 IU of heparin is administered as an intravenous bolus injection followed by a continuous intravenous infusion of 1000 IU of heparin per hour using an infusion pump.

Children:

Initially, 50 IU of heparin per kg of body weight is administered, followed by 20 IU of heparin per kg of body weight per hour.

If it is not possible to conduct continuous intravenous infusion, heparin can be administered subcutaneously, and the daily dose is divided into 2 to 3 subcutaneous injections (eg 10,000 IU-12500 IU of heparin every 12 hours) with careful monitoring of the therapeutic effect.

As a rule, therapy control and dose adjustment are performed in accordance with the values of activated partial thromboplastin time (APTT), which should be 1.5-2.5 times higher than normal. During continuous infusion it is recommended to determine APTT in 1-2 hours, 6 hours, 12 hours and 24 hours after the start of treatment.With subcutaneous administration, the determination of the indices should be performed 6 hours after the second dose is given.

When choosing a dose, the following recommendations should be considered:

Treatment of venous thromboembolism:

Initially, intravenously, as a bolus injection, administered heparin 5000 ME, followed by a continuous infusion at a rate of 1000 ME heparin per hour using an infusion pump.

The dose should be corrected according to the APTT value, which should be 1.5 to 2.5 times the control value. Such a value of APTT should be achieved within the first 24 hours of therapy.

Treatment should be continued for at least 4 days, or until sufficient effect of anticoagulants administered orally.

Application in the treatment of unstable angina or O-non-recurrent myocardial infarction:

As a rule, first intravenously, as a bolus injection, administered heparin ME 5000 followed by a continuous infusion of heparin 1000 ME per hour.

The dose is corrected in accordance with the APTT value, which should be 1.5 to 2.5 times the control value. Heparin should be administered for at least 48 h.

Auxiliary therapy duringthrombolysis with fibrin-specific thrombolytic drugs (eg, recombinant tissue plasminogen activators) in the treatment of acute myocardial infarction

Initially, intravenously, as a bolus injection, 5000 IU of heparin was injected followed by a continuous infusion of 1000 IU of heparin per hour.

The dose is corrected according to the values of APTT, which should be 1.5 to 2.5 times the control value. Heparin should be administered for at least 48 h.

Auxiliary therapy for thrombolysis with fibrin-nonspecific thrombolytic drugs (eg, streptokinase)

In the appointment of fibrin-nonspecific thrombolytic drugs, 12500 IU of heparin can be administered subcutaneously every 12 hours, with the first dose being administered 4 hours after the onset of thrombolysis.

The exact dose of heparin depends on the thrombolytic agent used; it is necessary to act in accordance with the instructions for the medical use of the thrombolytic drug.

3) Application in the process of extracorporeal circulation Hemodialysis:

The dose should be determined individually, depending on the state of the blood coagulation system and the type of apparatus used.

The device of artificial circulation:

The dose should be determined individually, depending on the type of device of the artificial circulation and the duration of the operation.

Method of administration

Heparin is administered by subcutaneous or intravenous injection or by intravenous infusion after dilution in a compatible carrier solution.

Subcutaneous injection

After disinfecting the skin, the dose of heparin is injected strictly subcutaneously into the loosely seized, folded skin on the abdomen or extensor of the thigh, vertically to the longitudinal axis of the body, using a thin needle. Before the injection, it is necessary to remove the droplets of solution from the outer part of the needle, since heparin introduced into the puncture can cause superficial hematoma or, in rare cases, a local allergic reaction.

To avoid disturbance of lymph drainage in patients who underwent resection of lymph nodes in the abdominal or urogenital area, subcutaneous injection of heparin should be performed in the upper part of the shoulder.

Intravenous infusion

For intravenous infusion, Heparin-sodium Brown can be diluted in the following solutions for infusion:

- a solution of sodium chloride 0.9%;

- glucose solution 5%, 10%;

- a solution of sodium chloride 0.45% and glucose 2.5%;

Ringer's solution.

Side effects:

The following classification of adverse reactions by frequency of development is used:

Very frequent (≥1 / 10)

Frequent (≥1 / 100, <1/10)

Not frequent (≥1/1000, <1/100)

Rare (≥1 / 10000, <1/1000)

Very rare (≤1 / 10000)

Are common

The most often adverse adverse reactions appear in the form of local reactions at the site of injection, but most often they are not serious.

Despite this, there may be complications in the form of bleeding.

Heparin-induced type II thrombocytopenia, due to the fact that heparin induces the production of specific antibodies to platelets, appears rarely (<1/1000), but can be pronounced.

Other adverse adverse reactions may include local or systemic allergic reactions.

Violations of the blood and lymphatic system

Very Frequent:

Dose-dependent effect of increasing the degree of bleeding from skin, mucous membranes, wounds, gastrointestinal tract, genitourinary tract, as well as bleeding in the brain and lungs.

Frequent:

At the beginning of treatment with heparin, undeveloped thrombocytopenia may develop with a platelet count from 1000x10⁹/ l up to 150x10⁹/ l, not associated with the production of antibodies and not accompanied by thromboses.

Immune system disorders

Not frequent:

Systemic allergic reactions, manifested as nausea, headache, fever, pain in the extremities, hives, vomiting, pruritus, shortness of breath, bronchoconstriction, reduce blood pressure, local and general hypersensitivity reactions, including allergic angioneurotic edema.

Rare:

- toxic or anaphylactoid reactions to benzyl alcohol;

- severe heparin-induced immune thrombocytopenia of type II.

Very rare:

- anaphylactic shock, especially in sensitized patients who had previously received heparin;

- delayed development of thrombocytopenia type II in a few weeks after the treatment with heparin.

Disorders from the endocrine system:

Rare:

Gipoaldosteronizm resulting in metabolic acidosis and hyperkalaemia, especially in patients with impaired kidney function, and diabetes.

Vascular disorders

Very rare:

Spasm of blood vessels.

Disturbances from the liver and bile ducts

Very Frequent:

Increased serum transaminase concentrations (aspartate aminotransferase (AsAT), alanine aminotransferase (ALT)), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH) and lipase, which is reversible and clinically insignificant.

Disturbances from the skin and subcutaneous tissue

Not frequent:

Transient alopecia, necrosis of the skin.

Disturbances from musculoskeletal and connective tissue

Patients with a predisposition may develop osteoporosis after prolonged use of heparin (for several months), especially in high doses.

Violations of the genitals and mammary gland Very rare:

Priapism.

General disorders and disorders at the site of administration

Frequent:

Local reactions at the injection site, such as compaction, redness, depigmentation and minor hematomas.

Very rare:

Calcium injection site, mainly in patients with severe renal failure.

Information on specific adverse reactions

Heparin-induced thrombocytopenia of type II

Heavy heparin-induced immune thrombocytopenia of type II is characterized by a decrease in the number of platelets below 100 x 10⁹/ l or rapid decrease, the number of platelets is not less than 50 percent of the original quantity and is accompanied by arterial or venous thrombosis or embolism, consumption coagulopathy, necrosis of the skin at the site of injection, spot hemorrhages (petechia) and tarry stool (melena). In this case, anticoagulation effects of heparin can be reduced.

Reducing the number of platelets in patients who were not hypersensitized to heparin, begins between 6 and 14 days from the initiation of heparin therapy. In patients with existing hypersensitivity to heparin, such a decrease in the number of platelets can begin within a few hours after the initiation of heparin therapy.

As soon as signs of type II thrombocytopenia appear, the use of heparin should be discontinued immediately. Emergency treatment depends on the characteristics and severity of the symptoms. The repeated use of heparin in this case is absolutely contraindicated.

Overdose:

Symptoms

Bleeding, most often from skin, mucous membranes, wounds, gastrointestinal tract, urinary tract (for example, epistaxis, haematuria, melena, hematoma, pinpoint hemorrhage).Reducing blood pressure, reducing hematocrit or other symptoms suggestive of latent bleeding.

Treatment

With minor bleeding, it is sufficient to reduce the dose of heparin.

With moderate, non-life-threatening bleeding, the use of heparin should be discontinued.

In the event of a serious, life-threatening patient bleeding, after excluding such causes of bleeding as a deficiency of clotting factors or coagulopathy of consumption, it is necessary to use protamine to neutralize the action of heparin.

Protamine should be used with great caution only with bleeding-threatening bleeding, because complete neutralization of heparin is associated with an increased risk of thrombosis. After applying protamine treatment should continue in the intensive care unit and accompanied by careful monitoring of the patient.

Protamine is a protein with a high content of arginine, which is usually used in the form of chloride or sulfate. As a rule, 1 mg of protamine neutralizes 100 IU of heparin. In this case, it is necessary to take into account the half-life of heparin from serum and the method of its administration.

In this way:

- 90 minutes after intravenous administration of heparin, only half of the calculated dose of protamine should be administered;

- 3 hours after the administration of heparin, only 25% of the calculated dose of protamine. Excessive administration of protamine may lead to activation of fibrinolysis, thus increasing the tendency to bleed. Too rapid intravenous administration of protamine may be the cause of lowering blood pressure, bradycardia, breathing disorders, discomfort. Protamine is removed from the bloodstream much faster than heparin. Neutralization of heparin is assessed by the indices of thrombin time and APTT.

With respect to heparin, hemodialysis is ineffective.

Interaction:

Other medications

Enhance the action of heparin

Clinically significant enhancement of the action of heparin and an increase in the tendency to bleed can be caused by:

- inhibitors, platelet aggregation, for example, acetylsalicylic acid, ticlopidine, clopidogrel, dipyridamole in high doses;

- fibrinolytic;

- other anticoagulants (eg, coumarin derivatives);

- non-steroidal anti-inflammatory drugs (eg, phenylbutazone, indomethacin,sulphinpyrazone);

- blockers of glycoprotein Hb / Sha platelet receptors;

penicillin in high doses;

- cytostatic drugs, except doxorubicin;

- dextrans.

The weakening effect of heparin

The effect of heparin may be impaired:

- doxorubicin;

- nitroglycerin with intravenous administration.

After the cessation of nitroglycerin administration, the APTT may suddenly rise. If heparin is prescribed during the infusion of nitroglycerin, careful monitoring of APTT and correction of the dose of heparin are necessary.

Suppressing the action of heparin

The action of heparin can be suppressed:

- ascorbic acid;

- antihistamines;

- cardiac glycosides;

- tetracyclines.

Effect of heparin on the effect of other drugs:

- Medications associated with plasma proteins (for example, propranolol)

Heparin can displace these drugs from the connection with proteins, leading to an increase in their effect.

- Medications that lead to elevated potassium levels in serum

Must be administered simultaneously with heparin only with close monitoring.

- Drugs with an alkaline reaction (for example, tricyclic psychotropic drugs,antihistamines or quinine)

Heparin forms salts with these drugs, which leads to a mutual weakening of their effect.

Other interactions

- Abuse of nicotine:

Possible oppression of heparin.

Special instructions:

Heparin sodium can not be administered intramuscularly, since it is possible to form a hematoma at the injection site.

In the case of thromboembolic complications in the use of heparin, the possibility of developing heparin-induced thrombocytopenia of type II should be assessed and the number of platelets counted.

A thorough monitoring of the blood clotting system for the administration of heparin to children, including infants, patients with hepatic or renal insufficiency, and the use of heparin for the prevention of thromboembolism (low-dose therapy) is mandatory.

It is necessary to exclude the possibility of injuries in patients receiving more than 22500 IU of heparin per day.

The use of heparin may contribute to the onset of hypermenorrhea. In the case of unusually strong or acyclic uterine bleeding, it is necessary to exclude other organic disorders using an additional gynecological examination,requiring special treatment.

Treatment with heparin should always be followed, by controlling the APTT and counting platelets.

Before the appointment of heparin, you need to make sure that the parameters of APTT and thrombin time are within the normal range.

For the early detection of heparin-induced thrombocytopenia type II, platelet counts should be performed:

- before starting treatment with heparin,

- within 1 day of treatment,

- every 3 or 4 days during the first three weeks of therapy,

- at the end of treatment.

Heparin can affect prothrombin time, which must be considered when choosing a dose of coumarin derivatives.

Heparin affects various laboratory tests, such as erythrocyte sedimentation rate, erythrocyte resistance, and complement fixation, which can lead to incorrect results.

On the background of the use of heparin, thyroid function tests can show erroneously high levels of triiodothyronine (T3) and tyrosine (T4).

Use the solution only if it is clear and the bottle is not damaged.

Do not freeze.

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).

In terms of microbiological safety, the diluted drug should be used immediately. 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:There were no studies of the effect on the ability to drive vehicles.

Form release / dosage:A solution for intravenous and subcutaneous administration of 5000 IU / ml.

Packaging:

5 ml in bottles of hydrolytic class 2 glass (European Pharmacopoeia), sealed with rubber stoppers of red color, sealed with sterile foil.

For 10 bottles of 5 ml with instructions for medical use in a cardboard pack.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:П N012984 / 01

Date of registration:28.10.2011 / 21.07.2016

Expiration Date:Unlimited

The owner of the registration certificate:B. Brown Mehlungen AGB. Brown Mehlungen AG Germany

Manufacturer: & nbsp

B. BRAUN MELSUNGEN, AG Germany

Representation: & nbspB. Brown Medikal, Open CompanyB. Brown Medikal, Open Company

Information update date: & nbsp27.03.2017

Illustrated instructions

Instructions

Heparin-sodium Brown (Heparin-sodium Braun)