Heparin-indar

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEPARIN-INDAR (HEPARIN-INDAR)

Composition:

Active substance: sodium heparin;

1 ml of injectable solution contains 5000 IU of sodium heparin;

Excipients: benzyl alcohol, sodium chloride, water for injections.

Pharmaceutical form. Injectable solution.

Main physicochemical properties: clear, colorless or light yellow liquid.

Pharmacotherapeutic group.

Antithrombotic agents. Heparin group. ATC code B01AB01.

Pharmacological Properties.

Pharmacodynamics.

Heparin is a glycosaminoglycan (mucopolysaccharide) composed of sulfated residues of D-glucosamine and D-glucuronic acid.

Heparin is a direct-acting anticoagulant. In solution, heparin carries a negative charge, which promotes its interaction with proteins involved in the blood coagulation process. Heparin binds to antithrombin III (heparin cofactor) and inhibits blood coagulation by inactivating factors V, VII, IX, and X. This results in neutralization of factors that activate blood coagulation (kallikrein, IXa, Xa, XIa, XIIa) and disruption of the conversion of prothrombin to thrombin. When thrombus formation has already begun, high doses of heparin can inhibit further coagulation by inactivating thrombin and suppressing the transformation of fibrinogen into fibrin. Heparin also prevents the formation of stable fibrin clots by inhibiting the activation of fibrin-stabilizing factor. After parenteral administration, heparin delays blood coagulation, enhances fibrinolysis, suppresses the activity of certain enzymes (hyaluronidase, phosphatase, trypsin), and slows down the effect of prostacyclin on platelet aggregation induced by adenosine diphosphate.

Pharmacokinetics.

After intravenous infusion, maximum plasma levels are achieved within a few minutes; after slow intravenous infusion – no later than 2–3 minutes; after subcutaneous injection – within 40–60 minutes. The volume of distribution of heparin corresponds to plasma volume and increases significantly with higher doses of the drug. Plasma proteins bind up to 95 % of heparin at concentrations of 2 IU/mL of blood, and less at higher concentrations. Heparin is partially metabolized in the liver. Approximately 20 % is excreted in urine in unchanged form and as uroheparin (which has 50 % of the activity of the active substance). The biological half-life is 1.32–1.72 hours. The plasma elimination half-life is 30–60 minutes. Heparin accumulates in hepatic insufficiency. Heparin does not penetrate into breast milk and poorly crosses the placenta.

Clinical Characteristics.

Indications.

• Prevention and treatment of thromboembolic diseases and their complications (acute coronary syndrome, thrombosis and embolism of major veins and arteries, cerebral and ocular vessels, phase I of disseminated intravascular coagulation syndrome, permanent atrial fibrillation with embolization);
• prevention of postoperative venous thrombosis and pulmonary artery embolism (in low-dose regimen) in patients undergoing surgical procedures or those at risk of thromboembolic disease for any other reasons;
• prevention of blood coagulation during laboratory tests, dialysis, extracorporeal circulation, cardiac and vascular surgery, direct blood transfusion.

Contraindications.

Hypersensitivity to heparin and/or benzyl alcohol, hemophilia, hemorrhagic diatheses, suspected heparin-induced immune thrombocytopenia, peptic ulcer of the stomach and duodenum, severe arterial hypertension, liver cirrhosis associated with esophageal varices, severe renal and hepatic insufficiency, bacterial endocarditis, menstruation, recent surgical interventions, especially neurosurgical and ophthalmological procedures, ulcerative colitis, malignant tumors, hemorrhagic stroke (first 2–3 days), cranio-cerebral trauma, retinopathy, intraocular hemorrhage, destructive pulmonary tuberculosis; encephalomalacia; hemorrhagic pancreonecrosis; bleeding of any localization (open gastric ulcer, intracranial hemorrhage), except hemorrhage occurring on the background of embolic pulmonary infarction (hemoptysis) or kidneys (hematuria); recurrent bleeding in history regardless of localization; increased vascular permeability (e.g., in Werlhof’s disease); shock state; threatened abortion.

Heparin must not be used: in patients who have consumed high doses of alcohol; by intramuscular injection; in acute and chronic leukemias; aplastic and hypoplastic anemias; acute cardiac and aortic aneurysm; during surgery on the brain or spinal cord, eyeball, ears; after surgical procedures in areas where bleeding may be life-threatening; in diabetes mellitus, during epidural anesthesia in childbirth. Conducting anesthesia is contraindicated in patients receiving therapeutic doses of heparin undergoing planned surgical operations, since heparin use in rare cases may cause epidural or spinal hematomas, leading to prolonged or irreversible paralysis.

Interaction with other medicinal products and other types of interactions.

Oral anticoagulants (dicoumarol) and antiplatelet agents (acetylsalicylic acid, dipyridamole) should be discontinued at least 5 days before any surgical intervention, as they may enhance the risk of bleeding during or after surgery.

Direct and indirect-acting anticoagulants potentiate the effect of heparin. Concurrent use of ascorbic acid, antihistamine agents, digitalis preparations, tetracyclines, nicotine, nitroglycerin, corticotropin, thyroxine may suppress the anticoagulant effect of the drug. Agents that reduce platelet aggregation (acetylsalicylic acid, dextrin, phenylbutazone, ibuprofen, metindol, dipyridamole, hydroxychloroquine, fibrinolytics, ascorbic acid, ergot alkaloids, indomethacin, sulfinpyrazone, probenecid, cephalosporins, ketorolac, epoprostenol, clopidogrel, ticlopidine, streptokinase, intravenous penicillins, ethacrynic acid, cytostatics) may cause hemorrhage when used concomitantly with heparin and therefore must be used with extreme caution. The risk of hemorrhage is also increased when heparin is combined with ulcerogenic, immunosuppressive, and thrombolytic agents.

Heparin may displace phenytoin, quinidine, propranolol, benzodiazepines, and bilirubin from plasma protein binding sites. Concurrent use of alkaline medicinal products, enalapril, tricyclic antidepressants may bind to heparin, resulting in mutual reduction of efficacy.

ACE inhibitors, angiotensin II antagonists: hyperkalemia may develop.

Alcohol: concurrent consumption of alcoholic beverages may significantly increase the risk of bleeding.

The risk is also increased when Heparin-Indar is used concomitantly with ulcerogenic, immunosuppressive, and thrombolytic medicinal products.

Effect on laboratory test results. False elevation of total thyroxine and triiodothyronine levels. False-positive metabolic acidosis and hypocalcemia (in patients undergoing hemodialysis). Inhibition of chromogenic lysate tests for endotoxin detection. Heparin-Indar may interfere with determination of aminoglycosides by immunoassay.

Special precautions for use.

When prescribing heparin for therapeutic purposes, intramuscular administration of the drug is contraindicated. Biopsies, epidural anesthesia, and diagnostic lumbar punctures should be avoided.

Heparin should be used with caution in patients with a history of hypersensitivity reactions to low-molecular-weight heparins.

Platelet count should be determined before initiation of treatment, on the first day of therapy, and every 3–4 days throughout the entire period of heparin administration. Sudden drop in platelet count requires immediate discontinuation of the drug, as well as further investigation to determine the etiology of thrombocytopenia. If heparin-induced thrombocytopenia type I or II is suspected, heparin therapy should be discontinued.

When switching from heparin therapy to oral anticoagulants, heparin should be discontinued only when the indirect anticoagulants have achieved a therapeutic prolongation of prothrombin time for at least 2 consecutive days.

To prevent significant hypocoagulation, the dose of heparin should be reduced without increasing the intervals between injections.

During heparin administration, hematological parameters should be monitored, and the patient's clinical condition and the development of hemorrhagic complications should be observed.

Discontinuation of the drug should be gradual.

In patients over 60 years of age, heparin may cause hemorrhages, especially in women and in patients with impaired renal function.

Patients sensitive to animal proteins may also be sensitive to heparin.

If a hypersensitivity reaction is suspected, a diluted test dose of 1000 IU should be administered slowly intravenously several minutes before the full dose.

The use of Heparin-Indar requires caution during the postoperative and postpartum periods within the first 3–8 days (except for vascular surgery and cases where heparinization is indicated for life-threatening conditions).

Particular caution is required within 36 hours after delivery.

In patients with arterial hypertension, blood pressure should be monitored.

In patients with diabetes mellitus, renal insufficiency, metabolic acidosis, elevated blood potassium levels, or those receiving potassium-containing medications, frequent monitoring of serum potassium levels is recommended due to increased risk of hyperkalemia.

Use during pregnancy or breastfeeding.

Heparin is not contraindicated during pregnancy. The drug does not cross the placenta. Although heparin does not pass into breast milk, its use in breastfeeding women has in individual cases been associated with rapid (within 2–4 weeks) development of osteoporosis and spinal damage. The decision to use the drug should be made individually, weighing the benefit to the mother against the potential risk to the fetus.

Ability to influence reaction rate while driving or operating machinery.

There are no data regarding the effect of heparin on the ability to drive or operate machinery.

Method of Administration and Dosage

Heparin-Indar should be administered as intravenous bolus or intermittent injections or by subcutaneous injection. Prior to administration, determine blood clotting time, thrombin time, activated partial thromboplastin time (aPTT), and platelet count. For dilution of heparin, use only 0.9% sodium chloride solution.

Adults
For acute thrombosis, initiate treatment with intravenous administration of 10,000–15,000 IU of Heparin-Indar under monitoring of venous blood clotting time, thrombin time, and activated partial thromboplastin time. Subsequently, administer 5,000–10,000 IU of Heparin-Indar intravenously every 4–6 hours. The adequate dose is considered to be one that prolongs blood clotting time by 2.5–3 times and activated partial thromboplastin time by 1.5–2 times.

For prophylaxis of acute thrombosis, administer Heparin-Indar subcutaneously at 5,000 IU every 6–8 hours. In the first phase of disseminated intravascular coagulation (DIC) in adults, administer heparin subcutaneously over a prolonged period at a daily dose of 2,500–5,000 IU under control of thrombin time. One to two days before discontinuation of Heparin-Indar, gradually reduce the daily dose.

During open-heart surgery with extracorporeal circulation, administer Heparin-Indar at an initial dose of at least 150 IU per kg of body weight. If the procedure lasts less than 60 minutes, administer a dose of 300 IU/kg; if longer than 60 minutes, administer 400 IU/kg.

For prophylactic purposes, administer Heparin-Indar subcutaneously at a dose of 5,000 IU 2 hours before surgery, followed by 5,000 IU every 6–8 hours for 7 days.

As an adjunct to streptokinase, Heparin-Indar at 5,000 IU three times daily or 10,000–12,500 IU twice daily may be indicated in patients at increased risk of thromboembolic complications, such as:

• recurrent myocardial infarction;
• persistent atrial fibrillation with embolization.

In acute coronary syndrome (unstable angina or myocardial infarction), initially administer 5,000 IU of Heparin-Indar as an intravenous bolus, followed by continuous intravenous infusion at a rate of 1,000 IU/hour. The infusion rate should be adjusted to maintain activated partial thromboplastin time at 1.5–2 times the normal value during the first 2–3 days.

Children
Administer Heparin-Indar according to body weight: initial dose is 50 IU/kg (intravenous injection/infusion), maintenance dose is 100 IU/kg every 4 hours. The average daily dose in children is 300 IU/kg.

In infants, administer 2–10 IU/kg/hour intravenously (continuously or intermittently). For subcutaneous administration in infants, the daily dose is 200–300 IU/kg, divided into 4–6 injections.

In all cases, during Heparin-Indar therapy, indirect anticoagulants should be initiated 1–3 days before discontinuation of the drug.

Children

The drug should be used in children according to body weight. Do not use in premature infants or newborns. Allergic reactions, including toxic ones, may occur in children under 3 years of age.

Overdose

Overdose may lead to hemorrhage. In cases of minor bleeding, reducing the dose or temporarily discontinuing administration may be sufficient. In cases of severe bleeding, immediately discontinue heparin and administer the antidote – 1% protamine sulfate solution (administered slowly intravenously), with 1 mg of protamine sulfate neutralizing 85 IU of heparin.

Adverse Reactions

The most common adverse reactions include hemorrhages, elevated liver enzymes, reversible thrombocytopenia, and various dermatological disorders. Isolated cases of generalized allergic reactions, skin necrosis, and priapism have also been reported.

Blood system:
Type I thrombocytopenia; Type II thrombocytopenia; epidural and spinal hematomas.

Psychiatric disorders:
Depression.

Nervous system:
Headache.

Gastrointestinal tract:
Nausea, vomiting, diarrhea.

Hepatobiliary system:
Elevated levels of liver transaminases (ALT and AST), lactate dehydrogenase, glutamyl transferase, and hyperlipidemia (these disorders are reversible and resolve upon discontinuation of the drug).

Skin and subcutaneous tissue:
Rash (erythematous, maculopapular), urticaria, pruritus, itching and burning of the skin of the feet, skin necrosis, erythema multiforme, alopecia.

Musculoskeletal system:
Osteoporosis, bone demineralization.

Reproductive system:
Priapism.

Immune system:
Skin rashes, conjunctivitis, lacrimation, rhinorrhea, bronchospasm, asthma, tachypnea, cyanosis, urticaria, allergic vasospasm in limbs, anaphylactoid reactions, anaphylactic shock.

Endocrine system and metabolism:
Hypoaldosteronism, hyperkalemia, increased thyroxine levels, decreased cholesterol levels, elevated blood glucose.

Cardiovascular system:
Hemorrhages and hematomas in any organ or organ system (subcutaneous, intramuscular, retroperitoneal, nasal, gastrointestinal, gastric, uterine).

Injection site reactions:
Irritation, ulcers, pain, hemorrhages, hematomas, and atrophy at injection sites.

Other:
Rhinitis, fever.

Thrombocytopenia as a complication of heparin therapy occurs in 6% of patients. It may arise either as a direct consequence of heparin-induced platelet aggregation or due to an immune response in which antibodies target platelets and endothelium. First-type reactions are usually mild and resolve after discontinuation of therapy, whereas second-type reactions are severe. As a result of thrombocytopenia, skin necrosis and arterial thrombosis ("white clot") may occur, accompanied by recurrent venous thromboembolism, gangrene, myocardial infarction, and stroke. Heparin therapy must be discontinued upon development of severe thrombocytopenia (a reduction in platelet count by half from baseline values).

Increased transaminase activity (ALT and AST), elevated levels of free fatty acids and thyroxine, and reversible potassium retention may also occur.

Shelf life.
3 years.

Storage conditions.
Store in original packaging protected from light at a temperature not exceeding 25°C.
Keep out of reach of children.

Incompatibility.
Heparin-Indar should not be mixed with other medicinal products in the same infusion container or syringe due to possible precipitation.

Dobutamine hydrochloride and heparin should not be mixed or administered intravenously together, as chelate complexes may form.

Packaging.
Injection solution, 5000 IU/mL, 5 mL (25,000 IU) in vials of №1, №5, №100.

Prescription status.
Prescription only.

Manufacturer.
JSC "Insulin Production Plant "INDAR".

Manufacturer's address and location of business activity.
5 Zroshuvalna St., Kyiv, 02099, Ukraine.