Warfarin-FS tablets 2.5 mg blister No. 100

Instructions Warfarin-FS tablets 2.5 mg blister No. 100

Composition

active ingredient: warfarin sodium clathrate;

1 tablet contains warfarin sodium clathrate equivalent to 3 mg of warfarin sodium;

excipients: lactose monohydrate, corn starch, gelatin, indigo carmine (E 132), magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: tablets of blue color, with inclusions, round shape, with a flat surface with a one-sided notch in the shape of a cross; with a biconvex surface and a score – 3 mg.

Pharmacotherapeutic group

Antithrombotic agents. Vitamin K antagonists.

ATX code B01A A03.

Pharmacological properties

Pharmacodynamics

Warfarin blocks the synthesis of vicasol-dependent blood clotting factors in the liver, namely: factors II, VII, IX and X. Blood clotting factors are formed as a result of carboxylation of their protein precursors, and in this process vitamin K is oxidized to vitamin K 2,3-epoxide. Oral anticoagulants prevent the conversion of vitamin K 2,3-epoxide to vitamin K, which thus leads to the accumulation of vitamin K 2,3-epoxide. This means that there is less vitamin K available, which causes inhibition of the synthesis of blood clotting factors.

The concentration of these components in the blood decreases and the coagulation process slows down. The onset of anticoagulant action is observed 32-72 hours after the start of taking the drug with the development of the maximum effect on the 5th-7th day from the start of using the drug. After stopping using the drug, the activity of Vikasol-dependent blood coagulation factors is restored within 4-5 days.

The S-enantiomer of warfarin has 2-5 times greater anticoagulant activity than the R-enantiomer of warfarin.

Pharmacokinetics

Absorption. The drug is rapidly absorbed from the digestive tract. Depends on the individual characteristics of the patient.

Distribution: Binding to plasma proteins is 97-99%.

Metabolism. In humans, warfarin is present as a racemic compound, with the levorotatory form being more active than the dextrorotatory form. The R- and S-isomers are metabolized in the liver by different pathways. Each isomer is converted to two major metabolites. The main metabolic catalyst for the S-enantiomer of warfarin is CYP2C9, and for the R-enantiomer of warfarin, CYP1A2 and CYP3A4. The levorotatory isomer of warfarin (S-enantiomer) has 2 to 5 times greater anticoagulant activity than the dextrorotatory isomer (R-enantiomer), but the half-life of the latter is longer. Patients with polymorphisms of the CYP2C9 enzyme, including the CYP2C9*2 and CYP2C9*3 alleles, may have increased sensitivity to warfarin and an increased risk of bleeding.

Elimination: Warfarin metabolites are excreted in the bile, reabsorbed in the gastrointestinal tract, and excreted in the urine. The half-life is 20 to 60 hours. The half-life for the R-enantiomer is 37 to 89 hours, and for the S-enantiomer is 21 to 43 hours.

Indication

Prevention and treatment of deep vein thrombosis and pulmonary embolism. Secondary prevention of myocardial infarction and prevention of thromboembolic complications (stroke or systemic embolism) after myocardial infarction. Prevention of thromboembolic complications in patients with atrial fibrillation, heart valve disease or prosthetic heart valves.

Prevention of transient ischemic attacks and stroke.

Contraindication

Hypersensitivity to warfarin or to any of the components of the drug; clinically established bleeding; bleeding tendency (hemophilia, von Willebrand disease, thrombocytopenia and platelet dysfunction); to avoid the risk of severe bleeding within 72 hours after major surgical interventions, within 48 hours in the postpartum period; severe renal and hepatic insufficiency and cirrhosis of the liver; untreated or uncontrolled arterial hypertension; recent hemorrhagic stroke; medical conditions predisposing to intracranial hemorrhage, such as cerebral aneurysm, aortic aneurysm; tendency to fall; lumbar puncture; central nervous system or eye surgery; gastrointestinal or renal bleeding and their complications; diverticulosis; malignant tumors; esophageal varices; endocarditis or pericarditis (including exudative).

A condition in which therapy cannot be carried out safely enough (e.g. psychosis, dementia, alcoholism).

The drug is contraindicated for use in women in the first trimester of pregnancy and during the last four weeks of pregnancy (see section "Use during pregnancy or breastfeeding").

Patients receiving warfarin treatment should not use preparations (including herbal preparations) containing hypericum perforatum (St. John's wort), as their concomitant use causes a decrease in warfarin plasma concentrations, which leads to a decrease in the clinical effect (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Warfarin has a narrow therapeutic index, other drugs may affect the action of warfarin. Before starting treatment, when changing the dosage or when ending the course of treatment, it is necessary to consult a doctor. The effect of other drugs is determined by pharmacodynamic and/or pharmacokinetic properties.

It is not recommended to start or stop taking other medications, as well as change the doses of medications used, without consulting a doctor.

This also applies to non-prescription medicines, herbal medicines, food supplements and vitamins used in doses exceeding the recommended ones. The intervals between treatment monitoring can be gradually increased during the course of treatment. However, intensive monitoring is necessary at the beginning and end of taking other medicines.

Pharmacokinetic interactions

Warfarin is metabolized by hepatic enzymes. Other drugs that are metabolized by the above enzymes may inhibit or enhance the action of these enzymes. This may lead to increased or decreased warfarin levels.

Warfarin is highly protein bound. Interactions may occur due to mechanisms of competition for binding.

A significant number of drugs interact with oral anticoagulants.

The most important of them are: broad-spectrum antibiotics, salicylates, nonsteroidal anti-inflammatory drugs, clofibrate, barbiturates, phenytoin, oral antidiabetic drugs.

Warfarin in combination with nonsteroidal anti-inflammatory drugs significantly increases the risk of bleeding. This also applies to other platelet aggregation inhibitors such as dipyridamole and valproic acid. Such combinations should be avoided.

This may also apply to compounds with a pronounced inhibitory effect on the cytochrome P450 system, such as cimetidine and chloramphenicol, the use of which for several days increases the risk of bleeding. In such cases, cimetidine can be replaced by, for example, ranitidine or famotidine. If treatment with chloramphenicol is necessary, anticoagulant therapy should be temporarily suspended. The use of diuretics in case of pronounced hypovolemic effect may lead to an increase in the concentration of coagulation factors, which reduces the effect of anticoagulants.

In case of treatment in combination with other drugs listed below, it is necessary to monitor the treatment International Normalized Ratio (INR) at the beginning and end of treatment, 2-3 weeks after the start of therapy. This applies to drugs that induce liver enzymes (barbiturates, phenytoin, carbamazepine) and thereby reduce the anticoagulant effect of warfarin. In case of prescribing drugs that can increase bleeding either by reducing the normal coagulation process, or by inhibiting clotting factors or by incomplete inhibition of liver enzymes, for example, laxatives, the strategy of anticoagulant therapy will depend on the possibility of laboratory monitoring. If possible, frequent laboratory monitoring of therapy is necessary, which allows at the beginning of additional treatment to adjust the dose of warfarin, for example, by reducing or increasing it by 5-10%. With limited possibilities for laboratory monitoring of therapy, the prescription of these drugs should be avoided. It should be emphasized that the list of drugs below, the interactions with which must be considered, is far from complete.

The effect of warfarin is enhanced when used concomitantly with allopurinol, amiodarone, anabolic steroids (testosterone and other C-17 alkylated steroids), acetylsalicylic acid, paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), heparin, glucagon, danazol, diazoxide, disapyramide, disulfiram, isoniazid, ketoconazole, clofibrate, levamisole, metronidazole, miconazole, nalidixic acid, flutamide, omeprazole, serotonin reuptake inhibitors (fluoxetine, fluvoxamine, paroxetine, sertraline), proguanil, sulfonylureas (glibenclamide), sulfonamide, tamoxifen, thyroxine, quinine, quinidine, antifungals drugs (fluconazole, itraconazole, ketoconazole), fluorouracil, capecitabine, imatinib, ifosfamide, quinols, chloral hydrate, chloramphenicol, cephalosporins, cimetidine, erythromycin, ethacrynic acid, penicillin antibiotics (cloxacillin, amoxicillin), macrolides (clarithromycin, azithromycin), sulfamethoxazole, clopidogrel, eptifibatide, tirofiban, abciximab, lipid-modifying agents (simvastatin, rosuvastatin, fluvastatin, gemfibrozil), propafenone, quinolones (ciprofloxacin, norfloxacin), leflunomide, phenylbutazone, tramadol, antiepileptic drugs (fosphenytoin, phenytoin) and disulfiram. Ethanol may enhance the effect of warfarin.

Increased INR has been reported in patients taking glucosamine and an oral vitamin K antagonist. Therefore, patients receiving an oral vitamin K antagonist should be closely monitored when initiating or discontinuing glucosamine therapy.

Preparations of some medicinal plants can also both enhance the effect of warfarin, for example, ginkgo biloba, garlic, angelica, papaya, sage, and reduce it, for example, ginseng, St. John's wort.

Quinine, which is present in tonic drinks, can also enhance the effect of warfarin.

Concomitant use with cranberry juice and other products containing cranberries should be avoided, as they significantly enhance the effect of warfarin.

Foods that contain large amounts of vitamin K (such as green vegetables) weaken the effect of warfarin.

When warfarin is used concomitantly with acetylsalicylic acid preparations, the INR should be within 2.0-2.5.

When used together with antithrombotic or hemostatic agents, the pharmacological effects of warfarin may be enhanced, increasing the risk of bleeding. Streptokinase and alteplase are contraindicated in patients taking warfarin. When using warfarin, thrombin inhibitors, unfractionated heparins and their derivatives, low molecular weight heparins, fondaparinux, rivaroxaban, glycoprotein IIIb/IIIa receptor antagonists, prostacyclin, serotonin reuptake inhibitors, erlotinib, methylphenidate, oral contraceptives should be avoided. If this is not possible, these drugs should be prescribed with caution under increased clinical and laboratory monitoring. Acute alcohol consumption in large quantities can slow down the metabolism of warfarin and increase the INR.

Chronic alcohol use can accelerate the metabolism of warfarin.

Lactulose may potentiate the effect of warfarin with long-term use.

If temporary pain relief is needed, it is recommended that patients receiving warfarin be prescribed paracetamol or opiates.

Application features

Calciphylaxis is a rare syndrome of vascular calcification with skin necrosis associated with a high fatality rate. This condition occurs predominantly in patients with end-stage renal disease on dialysis or in patients with risk factors such as protein C and S deficiency, hyperphosphatemia, hypercalcemia, or hypoalbuminemia. Rare cases of calciphylaxis have also been reported in patients taking warfarin without renal impairment. If calciphylaxis is diagnosed, appropriate treatment should be initiated and warfarin discontinuation should be considered.

A prerequisite for Warfarin-FS therapy is strict adherence to the prescribed dose of the drug. Patients suffering from alcoholism, as well as patients with dementia, may be unable to adhere to the required warfarin regimen.

At the beginning of warfarin treatment, after the end of treatment, or when changing the course of treatment with other medications, it is necessary to conduct intensive monitoring of the patient's condition, since other medications may change the effect of warfarin.

Various factors can affect the anticoagulant properties of warfarin. These include acute illness, hyper-/hypothyroidism, vomiting, diarrhea, heart failure, alcoholism with concomitant liver damage, concomitant use of other drugs. Significant changes in diet (e.g., switching to a vegetarian diet) can affect the absorption of vitamin K and, therefore, the effect of warfarin on the body. With such changes, the patient should be monitored more closely.

Special caution and careful monitoring of INR levels are necessary when prescribing to patients at risk of serious bleeding. The most likely risk factors for bleeding are high levels of anticoagulation (INR > 4.0); age 65 years and older; unstable INR; recent gastrointestinal bleeding, ischemic stroke, bacterial endocarditis; peptic ulcer; cerebrovascular disease; serious heart disease; anemia; trauma; renal failure; concomitant use of other drugs (e.g. NSAIDs). All patients taking warfarin should have their INR measured regularly, which is extremely important. Patients at increased risk of bleeding require more frequent INR measurements, more careful dose titration to achieve the desired INR, and a shorter duration of therapy. If the INR is high, the dose of warfarin should be reduced or warfarin therapy discontinued. Sometimes, reversal therapy with anticoagulants is necessary. The INR should be measured within 2-3 days to ensure that it has decreased. Other antiplatelet drugs should be used with extreme caution due to the increased risk of bleeding.

Anticoagulant therapy after a recent ischemic stroke increases the risk of secondary cerebral hemorrhage. A break in treatment after ischemic stroke and in patients on long-term warfarin therapy with atrial fibrillation is justified, given the low risk of early recurrent embolism. Warfarin treatment should be restarted 2-14 days after ischemic stroke, depending on the size of the infarct and blood pressure. In patients with embolic strokes, warfarin treatment should be stopped for 14 days.

Mandatory consultation with a doctor and observation are necessary when planning surgical interventions. Surgical operations are possible in cases with an INR < 2.5, if there is no risk of serious bleeding. Before surgical operations, if there is a risk of serious bleeding, warfarin should be stopped 3 days before surgery. If it is necessary to continue anticoagulant therapy, for example, in case of life-threatening thromboembolism, the INR should be reduced to < 2.5 and heparin therapy should be started. If surgery is necessary and warfarin cannot be stopped 3 days before surgery, anticoagulant therapy should be discontinued using low doses of vitamin K.

Resuming warfarin therapy depends on the risk of postoperative bleeding. Warfarin should not be stopped before routine dental procedures, such as tooth extraction.

Patients with hereditary antithrombotic protein C deficiency are at risk of developing skin necrosis at the beginning of warfarin therapy.
In such patients, therapy should be initiated without a loading dose of warfarin, even if the patient is receiving heparin. Patients with hereditary antithrombotic protein S deficiency are also advised to initiate warfarin therapy slowly.

During treatment, it is necessary to refrain from consuming ethanol (risk of hypoprothrombinemia and bleeding).

Elderly patients should be treated with special caution due to reduced hepatic metabolism and reduced synthesis of blood clotting factors. As a result, excessive warfarin effects may easily occur.

It is also necessary to ensure the patient's ability to adhere to strict rules when taking the drug.

Hyperthyroidism, fever and decompensated heart failure may enhance the effect of warfarin. In hypothyroidism, the effect of warfarin may be reduced. In patients with moderate hepatic insufficiency, the effect of warfarin is enhanced. In the case of renal insufficiency or nephrotic syndrome, the level of the free fraction of warfarin in the blood plasma increases, which, depending on concomitant diseases, may lead to an increase or decrease in the effect of warfarin. In all these cases, the patient's clinical condition and the level of INR should be monitored.

Patients with a mutation in the gene encoding the CYP2C9 enzyme have a longer half-life of warfarin. Such patients require lower doses of the drug, as the risk of bleeding is increased when taking conventional therapeutic doses.

Factors such as weight loss, acute illness, and smoking cessation may increase the effect of warfarin and require a reduction in the dose of warfarin. Weight gain, diarrhea, and vomiting may decrease the effect of warfarin and require a dose increase.

The drug contains lactose, therefore, the use of Warfarin-FS is contraindicated in patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug does not affect the ability to drive or operate machinery.

Use during pregnancy or breastfeeding

Warfarin crosses the placenta. Warfarin therapy in pregnant women can cause warfarin embryopathy (nasal hypoplasia and chondrodysplasia) if warfarin is taken during the period of organogenesis (from 6 to 12 weeks), and even after that it can cause disorders in the development of the central nervous system. These disorders are characterized by striation of cartilage on X-rays (especially in the spine and long tubular bones), small fingers and hands, optic nerve atrophy, microcephaly, oligophrenia and growth retardation, cataracts, which can lead to complete or partial blindness. Fetal death can also occur.

Warfarin can cause fetal hemorrhage, especially in late pregnancy and during labor.

Warfarin embryopathy has been reported to occur in 4-6% of cases when warfarin is used during pregnancy, and the risk increases with daily doses exceeding 5 mg. Therefore, warfarin is contraindicated in the first trimester and during the last four weeks of pregnancy (see Contraindications). The risk of warfarin to the fetus should be carefully weighed against the risk to the mother of not using warfarin.

Antithrombotic therapy during pregnancy should be administered individually under the close supervision of appropriate specialists.

Breastfeeding. Warfarin can be used during breastfeeding. Warfarin is excreted in breast milk, but if the drug is taken in therapeutic doses, no adverse reactions in the newborn are expected.

Method of administration and doses

The optimal dose of the drug is set individually for each patient, taking into account the state of the blood coagulation system. To standardize the results of prothrombin time determination, it is recommended to use MNI, which takes into account the effect of the thromboplastin used on the value of prothrombin time.

Target INR level for oral anticoagulant therapy.

Prevention of thromboembolic complications in patients with prosthetic heart valves: INR 2.5-3.5.

Other indications: INR 2.0-3.0.

Adults: For patients of normal weight with a spontaneous INR below 1.2, administer 10 mg of warfarin for the next three days. Then calculate the dose according to the table below according to the INR measurements on the fourth day.

In patients with hereditary protein C or S deficiency, the recommended initial dose is 5 mg of warfarin for the next three days. The dose should then be calculated according to the table below according to the INR measurements on the fourth day.

Patients with hereditary antithrombotic protein C deficiency are at risk of developing skin necrosis when warfarin therapy is initiated. In such patients, warfarin should be initiated without a loading dose, even if the patient is receiving heparin.

In case of skin necrosis, warfarin should be discontinued.

For elderly patients, patients with low body weight, with a spontaneous INR above 1.2, or those with concomitant diseases or receiving any medications that affect the effectiveness of anticoagulant therapy, the recommended initial dose is 5 mg of warfarin for the next two days. The dose is then calculated according to the table below according to the INR measurements on the third day.

Table 1

Children: Anticoagulant therapy in children should be carried out under the supervision of a pediatrician. Doses should be selected according to Table 2 below.

Table 2

Elective surgeries: Pre-, intra-, and postoperative anticoagulant therapy should be administered as indicated below.

Determine the MNI one week before the scheduled surgery.

Stop warfarin 1-5 days before surgery. In case of high risk of thrombosis, the patient should be given low molecular weight heparin subcutaneously for prophylaxis. The duration of the warfarin break depends on the INR. Stop warfarin:

5 days before surgery if INI > 4.0; 3 days before surgery if INI from 3.0 to 4.0; 2 days before surgery if INI from 2.0 to 3.0.

Determine the INR the evening before surgery and administer 0.5-1.0 mg of vitamin K orally or intravenously if the INR is > 1.8.

Consider the need for infusion of unfractionated heparin or prophylactic administration of low molecular weight heparin on the day of surgery.

Continue subcutaneous administration of low molecular weight heparin for 5-7 days after surgery with concomitant resumption of warfarin.

Continue warfarin at the usual maintenance dose on the same day in the evening after minor surgery and in the afternoon when the patient begins receiving enteral nutrition after major surgery.

Children

The decision to prescribe the drug to children is made by a pediatrician, under whose supervision the treatment is carried out.

Overdose

An elevated INR is an indicator of warfarin overdose, which increases the risk of bleeding. A halving of coagulation factor IV indicates an elevated INR. An elevated INR occurs within 24 hours and reaches a maximum value within 36-72 hours after taking the drug.

Clinical manifestations begin to appear several days or weeks after taking the drug and are characterized by nosebleeds, bleeding gums, pallor, hematomas around the joints and buttocks, blood in the urine and feces. Other symptoms may include back pain, bleeding lips, bleeding mucous membranes, abdominal pain, vomiting and petechiae.

Later, central paralysis due to bleeding, profuse bleeding, and death may occur.

Treatment. Symptomatic and supportive therapy in case of overdose. In cases of gradual overdose with minor bleeding, it is necessary to reduce the dose of the drug or stop treatment for a short time until the target INR level is reached. In case of acute overdose, gastric emptying is not recommended due to the risk of bleeding; to prevent absorption, it is advisable to prescribe activated charcoal.

In case of severe bleeding, prescribe vitamin K (intravenously at a dose of 5-10 mg), transfusion of coagulation factor concentrate, fresh frozen plasma or blood.

In life-threatening bleeding, transfusion of prothrombin complex factor concentrate, or fresh frozen plasma, or whole blood is indicated. Since the half-life of warfarin is 20-60 hours, the patient must be monitored for a long time.

In the treatment of overdose, take the following measures:

Adverse reactions

The most common adverse reactions of warfarin are hemorrhages and bleeding, including: nosebleeds, hemoptysis, hematuria, bleeding gums, bruising, vaginal bleeding, conjunctival hemorrhage, gastrointestinal bleeding, prolonged and profuse bleeding after surgery and after trauma. Bleeding can be serious and lead to death, hospitalization, and blood transfusion in patients who have been on long-term anticoagulant treatment.

The risk of bleeding during warfarin treatment is influenced by the following factors: advanced age, high intensity of concomitant anticoagulant therapy, history of stroke and gastrointestinal bleeding, comorbid disorders, atrial fibrillation, and patients with a polymorphism of the CYP2C9 gene.

Hemoglobin and INR levels should be carefully monitored.

Other adverse reactions that may occur during warfarin treatment.

Adverse effects are classified by frequency of occurrence into the following categories: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/1000 and <1/1000), very rare (<1/10000), frequency unknown.

From the blood and lymphatic system: very often - bleeding; often - hypersensitivity to warfarin after prolonged treatment; infrequently - anemia; rarely - eosinophilia.

On the part of the digestive tract: infrequently - vomiting, abdominal pain, nausea, diarrhea; very rarely - melena.

On the part of the hepatobiliary system: rarely - increased levels of liver enzymes, jaundice.

Skin and subcutaneous tissue disorders: rarely - eczema, vasculitis, skin necrosis, alopecia, rash, urticaria, itching; frequency unknown - calciphylaxis.

From the genitourinary system: rarely - nephritis, urolithiasis, tubular necrosis.

From the cardiovascular system: rarely - purple finger syndrome; very rarely - cholesterol embolism.

On the part of the immune system: often - hypersensitivity reactions.

The following adverse reactions are known to have occurred in the post-marketing period with warfarin: decreased hematocrit; fever; tracheal calcification; cholestatic hepatitis, pancreatitis; priapism; allergic reactions; purpura. Intracranial hemorrhage, subdural hematoma; hemothorax, rectal bleeding, hematemesis, melena. The most common risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension. The likelihood of bleeding increases if the INR is significantly higher than the target level. If bleeding begins with an INR within the target level, this indicates the presence of other concomitant conditions that should be investigated. Even in the case of minor bleeding, the doctor should be informed about this.

Erythematous edema of the skin, leading to ecchymosis, infarction, and skin necrosis.

Coumarin necrosis. Necrosis usually begins with swelling of the skin of the lower extremities or buttocks, which darkens, but can also appear in other places. Later, such lesions become necrotic. 90% of such patients are women.

Lesions are observed from the 3rd to the 10th day of administration, the etiology suggests a deficiency of antithrombotic protein C or S. Congenital deficiency of these proteins can cause complications. For this reason, warfarin should be started simultaneously with the administration of heparin in small initial doses. If complications occur, warfarin should be discontinued and heparin should be continued until the lesions heal or scar.

Purple finger syndrome is a rare complication of warfarin.

This is typical for male patients with atherosclerotic disease. It is suggested that warfarin causes hemorrhages of atheromatous plaques, which lead to microembolism.

Symmetrical purpuric skin lesions on the fingers and soles of the feet may also occur, and these lesions are accompanied by burning pain. Warfarin should be discontinued; the skin lesions usually resolve gradually.

Expiration date

3 years.

Storage conditions

Store out of the reach of children, in the original packaging at a temperature not exceeding 25 °C.