Heparin-novopharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEPARIN-NOVOFARM (HepariN-NOVOFARM)

Composition:

Active substance: sodium heparin;

1 ml of solution contains 5000 IU of sodium heparin;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or pale yellow liquid free from foreign particles.

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 promote 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 activation of the fibrin-stabilizing factor. After parenteral administration, heparin delays blood coagulation, activates the fibrinolysis process, 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, the maximum plasma concentration is achieved within a few minutes; after slow intravenous infusion, not later than 2–3 minutes; after subcutaneous injection, within 40–60 minutes. The volume of distribution of heparin corresponds to the plasma volume and increases significantly with higher doses of the drug. Plasma proteins bind up to 95% of heparin at a concentration of 2 IU/mL of blood; at higher concentrations, binding is lower. Heparin is partially metabolized in the liver. Approximately 20% is excreted in urine as unchanged heparin and uroheparin (which has 50% of the activity of the parent compound). The biological half-life ranges from 1.32 to 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.

• Prophylaxis and treatment of thromboembolic disorders 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 in those who, for any other reasons, are at risk of developing thromboembolic disease;
• prevention of blood coagulation during laboratory tests, dialysis, extracorporeal circulation, cardiovascular and vascular surgery, direct blood transfusion.

Contraindications.

Hypersensitivity to heparin and/or benzyl alcohol; hemophilia; hemorrhagic diathesis; thrombocytopenia; 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 neoplasms; hemorrhagic stroke (first 2–3 days); head injuries; retinopathy; hemorrhage into ocular tissues; 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; threat of abortion.

Heparin must not be used in: patients who have consumed high doses of alcohol; via intramuscular injections; in acute and chronic leukemias; aplastic and hypoplastic anemias; acute aneurysm of the heart and aorta; during surgical procedures on the brain or spinal cord, eyeball, ears; after surgical operations in areas where bleeding may be life-threatening; in diabetes mellitus when epidural anesthesia is used during labor. Conduction anesthesia is contraindicated in patients receiving heparin for therapeutic purposes undergoing elective surgical procedures, 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 forms of interactions.

Oral anticoagulants (dicoumarol) and antiplatelet agents (acetylsalicylic acid, dipyridamole) should be discontinued at least 5 days before any surgical procedure, 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, antihistamines, digitalis preparations, tetracyclines, nicotine, nitroglycerin, corticotropin, and thyroxine may suppress the anticoagulant effect of the drug. Agents that reduce platelet aggregation (acetylsalicylic acid, dextrin, phenylbutazone, ibuprofen, metindole, 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 bleeding is also increased during combined therapy of heparin with ulcerogenic, immunosuppressive, and thrombolytic agents.

Heparin may displace phenytoin, quinidine, propranolol, benzodiazepines, and bilirubin from their plasma protein binding sites. When used concomitantly, alkaline medicinal products, enalaprilat, and tricyclic antidepressants may bind to heparid, resulting in mutual reduction of efficacy.

Angiotensin-converting enzyme inhibitors, angiotensin II antagonists: hyperkalemia may occur.

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

The risk is also increased with concomitant use of heparin and ulcerogenic, immunosuppressive, and thrombolytic medicinal products.

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

Special precautions for use.

When prescribing heparin for therapeutic purposes, intramuscular administration of the medicinal product 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 initiating treatment, on the first day of treatment, and every 3–4 days throughout the entire period of heparin therapy, especially between days 6 and 14 after the start of treatment. Sudden drop in platelet count requires immediate discontinuation of the medicinal product and 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 indirect anticoagulants, heparin should only be discontinued once the indirect anticoagulants have achieved a therapeutic prolongation of prothrombin time for at least 2 consecutive days.

Except for low-dose regimens, coagulation tests should always be performed before initiating therapy.

Heparin should be prescribed with great caution in patients with conditions associated with an increased risk of bleeding (e.g., arterial hypertension).

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

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

The medicinal product contains benzyl alcohol as an excipient; therefore, it should not be administered to premature infants and newborns. Benzyl alcohol may cause toxic and allergic reactions in infants and children under 3 years of age.

Discontinuation of the medicinal product should be gradual.

In patients aged 60 years and older, heparin may cause hemorrhagic events, particularly in women and in patients with impaired renal function.

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

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

Heparin use requires caution during the postoperative and postpartum periods within the first 3–8 days (except for vascular surgeries 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 supplements, serum potassium levels should be frequently monitored during treatment due to increased risk of hyperkalemia.

Use during pregnancy or breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage.

The medicinal product should be administered as intravenous or subcutaneous bolus or intermittent injections. Prior to administration of the drug, blood coagulation time, thrombin time, and activated partial thromboplastin time (aPTT), as well as platelet count, should be determined. For heparin dilution, use only 0.9% sodium chloride solution.

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

For prophylaxis of acute thrombosis, administer heparin subcutaneously at a dose of 5,000 IU every 6–8 hours. In the first phase of disseminated intravascular coagulation (DIC) in adults, administer heparin subcutaneously for a prolonged period at a daily dose of 2,500–5,000 IU under control of thrombin time. Reduce the daily dose gradually 1–2 days before discontinuation of heparin.

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

For prophylactic purposes, administer heparin 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, administration of 5,000 IU three times daily or 10,000–12,500 IU twice daily may be indicated in patients at increased risk of thrombolytic complications, such as:

• in recurrent myocardial infarction;
• in permanent atrial fibrillation with embolization.

In acute coronary syndrome (unstable angina or myocardial infarction), initially administer 5,000 IU of heparin as an intravenous bolus, followed by continuous intravenous infusion of the drug 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 above the normal value during the first 2–3 days.

In children, administer heparin according to the following regimen: 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 neonates, administer 2–10 IU/kg/hour intravenously (continuously or intermittently). For subcutaneous administration in neonates, the daily dose is 200–300 IU/kg, divided into 4–6 injections.

In all cases, during heparin therapy, initiate indirect anticoagulants 1–3 days before discontinuation of heparin.

Children. The medicinal product should be used in children according to their body weight. Do not use in premature infants or newborns. The medicinal product contains benzyl alcohol, which may cause allergic reactions, including toxic ones, in children under 3 years of age.

Overdose.

Severe hemorrhagic complications, bleeding. Depending on the severity of hemorrhagic complications, either reduce the dose of heparin or discontinue it. If bleeding persists after discontinuation of heparin, administer intravenously the heparin antagonist – protamine sulfate (or chloride) (1 mL of protamine sulfate neutralizes 100 IU of heparin). Within 90 minutes after intravenous administration of heparin, administer 50% of the calculated dose of protamine sulfate, and the remaining 50% over the next 3 hours.

In case of individual intolerance or development of allergic reactions, discontinue heparin immediately and administer desensitizing agents. If continuation of anticoagulant therapy is necessary, use indirect-acting anticoagulants.

Adverse Reactions

The most commonly reported 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 disorders: Thrombocytopenia type I; type II; epidural and spinal hematomas, hemorrhages, hematuria, gingival bleeding, epistaxis, renal hemorrhages, hemorrhages in adrenal glands, hemoptysis.

Psychiatric disorders: Depression.

Nervous system disorders: Headache, dizziness.

Gastrointestinal disorders: Nausea, vomiting, diarrhea.

Hepatobiliary disorders: Increased levels of liver transaminases – alanine aminotransferase (ALT) and aspartate aminotransferase (AST), lactate dehydrogenase, gamma-glutamyl transferase, and hyperlipidemia (these abnormalities are reversible and resolve upon discontinuation of the drug).

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

Musculoskeletal and connective tissue disorders: Osteoporosis, bone demineralization.

Reproductive system disorders: Priapism.

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

Endocrine and metabolic disorders: Hypoaldosteronism, metabolic acidosis, hyperkalemia, increased thyroxine levels, decreased cholesterol levels, elevated blood glucose levels.

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

Injection site reactions: At the injection site, especially with improper injection technique, minor hemorrhages (subcutaneous and mucosal, internal), irritation, ulcers, pain, hemorrhages, hematomas, and atrophy at injection sites may occur.

Other: Rhinitis, fever, malaise.

Thrombocytopenia as a complication of heparin therapy occurs in 6% of patients. It may arise either as a direct consequence of platelet aggregation induced by heparin or due to an immune reaction where 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 develop, accompanied by recurrent venous thromboembolism, gangrene, myocardial infarction, and stroke. Heparin therapy must be discontinued if severe thrombocytopenia occurs (a decrease in platelet count by half from baseline levels).

Elevated transaminase activity (ALT and AST), increased levels of free fatty acids and thyroxine, and reversible potassium retention may also be observed.

Shelf life. 2 years.

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

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

Dobutamine hydrochloride and heparin must not be mixed or administered intravenously together, as chelate complexes are formed.

Packaging. 2 mL, 4 mL, or 5 mL in a vial; 5 vials in a blister pack; 1 blister pack per cardboard box.

Prescription status. Prescription only.

Manufacturer. Limited liability company "Novofarm-Biosyntez".

Manufacturer's address and location of business activity.
Ukraine, 11700, Zhytomyr Oblast, Zvyagel Raion, city of Zvyagel, Zhytomyrska Street, 38.