Warfarin - OBL tablets 2,5mg, No. 100

Treatment and prevention of thrombosis and embolism of blood vessels: acute and recurrent venous thrombosis, pulmonary embolism; secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction; prevention of thromboembolic complications in patients with atrial fibrillation, heart valve lesions or prosthetic heart valves; treatment and prevention of transient ischemic attacks and strokes, prevention of postoperative thrombosis.

Warfarin is prescribed once a day, preferably at the same time. The duration of treatment is determined by the doctor in accordance with the indications for use.

Monitoring during treatment:
Before starting therapy, determine the International Normalized Ratio (INR). In the future, laboratory control is carried out regularly every 4-8 weeks. The duration of treatment depends on the clinical condition of the patient. Treatment can be canceled immediately.

Patients who have not previously taken Warfarin: The
initial dose is 5 mg / day (2 tablets per day) for the first 4 days. On the 5th day of treatment, the INR is determined and, in accordance with this indicator, a maintenance dose of the drug is prescribed. The usual maintenance dose of the drug is 2.5-7.5 mg / day (1-3 tablets per day).

Patients who have previously taken warfarin: The
recommended starting dose is twice the known maintenance dose of the drug and is given within the first 2 days. The treatment is then continued with a known maintenance dose. On the 5th day of treatment, the INR is monitored and the dose is adjusted in accordance with this indicator. It is recommended to maintain the INR value from 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve diseases, heart valve replacement with bioprostheses. Higher INR values ??from 2.5 to 3.5 are recommended for prosthetic heart valves with mechanical prostheses and complicated acute myocardial infarction.

Children: There are
limited data on the use of warfarin in children. The initial dose is usually 0.2 mg / kg per day for normal liver function and 0.1 mg / kg per day for liver dysfunction. The maintenance dose is selected in accordance with the INR indicators. The recommended INR levels are the same as for adults. The decision to prescribe warfarin in children should be made by an experienced specialist. Treatment should be supervised by an experienced pediatrician.

Elderly:
There are no specific guidelines for taking warfarin in the elderly. However, elderly patients should be closely monitored because they have a higher risk of side effects.

Patients with hepatic impairment:
Liver dysfunction increases sensitivity to warfarin because the liver produces clotting factors and also metabolizes warfarin. This group of patients requires careful monitoring of INR values.

Patients with renal impairment:
In patients with impaired renal function, it is necessary to reduce the dose of warfarin and conduct careful monitoring (see section 'Special instructions').

Planned (elective) surgical interventions:
Pre-, peri- and post-operative anticoagulant therapy is carried out as described below (if urgent cancellation of the oral anticoagulant effect is required - see the Overdose section).

Active ingredient: Warfarin sodium 2.5 mg
Auxiliary components: Lactose - 50.0 mg, corn starch 34.6 mg, calcium hydrogen phosphate dihydrate - 32.2 mg, indigo carmine - 6.4 ?g, povidone 30 - 1.0 mg, magnesium stearate - 600 mcg.

Established or suspected hypersensitivity to drug components, acute bleeding, pregnancy (first trimester and last 4 weeks of pregnancy), severe liver or kidney disease, acute disseminated intravascular coagulation (DIC), protein C and S deficiency, thrombocytopenia, patients at high risk of bleeding, including patients with hemorrhagic disorders, esophageal varicose veins, arterial aneurysms, lumbar puncture, gastric ulcer and duodenal ulcer, with severe wounds (including operating ones), bacterial endocarditis, malignant hypertension, hemorrhagic stroke, intracranial hemorrhage.

Trade name of the drug:

Warfarin

International non-proprietary name:

Warfarin

Dosage form

Pills

Composition

Active ingredient: Warfarin sodium 2.5 mg
Auxiliary components: Lactose - 50.0 mg, corn starch 34.6 mg, calcium hydrogen phosphate dihydrate - 32.2 mg, indigo carmine - 6.4 ?g, povidone 30 - 1.0 mg, magnesium stearate - 600 mcg.

Description

Round biconvex tablets with a cross-shaped line, light blue.

Pharmacotherapeutic group

Indirect anticoagulant.

ATX code:

B01AA03

Pharmacological properties

Warfarin blocks in the liver the synthesis of vitamin K dependent factors of blood coagulation, namely, factor II, VII, IX and X. The concentration of these components in the blood decreases, the coagulation process slows down. The onset of the anticoagulant effect is observed after 36-72 hours from the start of taking the drug, with the development of the maximum effect on the 5-7 day from the start of use. After discontinuation of the drug, the restoration of the activity of vitamin K-dependent blood coagulation factors occurs within 4-5 days.

Pharmacokinetics
The drug is rapidly absorbed from the gastrointestinal tract. Plasma protein binding is 97-99%. It is metabolized in the liver. Warfarin is a racemic mixture, with the R and S isomers metabolized in the liver in different ways. Each of the isomers is converted to 2 main metabolites. The main metabolic catalyst for the S-enantiomer of warfarin is the CYP2C9 enzyme, and for the R-enantiomer of warfarin CYP1A2 and CYP3A4. The levorotatory isomer of warfarin (S-warfarin) has 2-5 times more anticoagulant activity than the dextrorotatory isomer (R-enantiomer), but the half-life of the latter is longer. Patients with CYP2C9 enzyme polymorphism, including CYP2C9 2 and CYP2C9 alleles3, may have an increased sensitivity to warfarin and an increased risk of bleeding.

Warfarin is excreted from the body in the form of inactive metabolites in the bile, which are reabsorbed in the gastrointestinal tract and excreted in the urine. The half-life is 20 to 60 hours. For the R-enantiomer, the half-life is from 37 to 89 hours, and for the S-enantiomer from 21 to 43 hours.

Indications for use

Treatment and prevention of thrombosis and embolism of blood vessels: acute and recurrent venous thrombosis, pulmonary embolism; secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction; prevention of thromboembolic complications in patients with atrial fibrillation, heart valve lesions or prosthetic heart valves; treatment and prevention of transient ischemic attacks and strokes, prevention of postoperative thrombosis.

Contraindications

Established or suspected hypersensitivity to drug components, acute bleeding, pregnancy (first trimester and last 4 weeks of pregnancy), severe liver or kidney disease, acute disseminated intravascular coagulation (DIC), protein C and S deficiency, thrombocytopenia, patients at high risk of bleeding, including patients with hemorrhagic disorders, esophageal varicose veins, arterial aneurysms, lumbar puncture, gastric ulcer and duodenal ulcer, with severe wounds (including operating ones), bacterial endocarditis, malignant hypertension, hemorrhagic stroke, intracranial hemorrhage.

Application during pregnancy and breastfeeding

Warfarin quickly crosses the placenta, has a teratogenic effect on the fetus, leading to the development of warfarin syndrome in the fetus at 6-12 weeks of gestation. Manifestations of this syndrome: nasal hypoplasia (saddle deformity of the nose and other cartilaginous changes) and point chondrodysplasia on X-ray examination (especially in the spine and long bones), short hands and fingers, optic nerve atrophy, cataract leading to complete or partial blindness, retardation of mental and physical development and microcephaly. The drug can cause bleeding at the end of pregnancy and during childbirth. Taking the drug during pregnancy can cause congenital malformations and lead to fetal death. The drug should not be prescribed in the 1st trimester of pregnancy and during the last 4 weeks.The use of warfarin is not recommended during the remainder of pregnancy unless absolutely necessary. Women of reproductive age should use effective contraception while using warfarin.

Warfarin is excreted in breast milk, but with therapeutic doses of warfarin it is not expected to affect the nursing infant. Warfarin can be used while breastfeeding.

There are no data on the effect of warfarin on fertility.

Method of administration and dosage

Warfarin is prescribed once a day, preferably at the same time. The duration of treatment is determined by the doctor in accordance with the indications for use.

Monitoring during treatment:
Before starting therapy, determine the International Normalized Ratio (INR). In the future, laboratory control is carried out regularly every 4-8 weeks. The duration of treatment depends on the clinical condition of the patient. Treatment can be canceled immediately.

Patients who have not previously taken Warfarin: The
initial dose is 5 mg / day (2 tablets per day) for the first 4 days. On the 5th day of treatment, the INR is determined and, in accordance with this indicator, a maintenance dose of the drug is prescribed. The usual maintenance dose of the drug is 2.5-7.5 mg / day (1-3 tablets per day).

Patients who have previously taken warfarin: The
recommended starting dose is twice the known maintenance dose of the drug and is given within the first 2 days. The treatment is then continued with a known maintenance dose. On the 5th day of treatment, the INR is monitored and the dose is adjusted in accordance with this indicator. It is recommended to maintain the INR value from 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve diseases, heart valve replacement with bioprostheses. Higher INR values ??from 2.5 to 3.5 are recommended for prosthetic heart valves with mechanical prostheses and complicated acute myocardial infarction.

Children: There are
limited data on the use of warfarin in children. The initial dose is usually 0.2 mg / kg per day for normal liver function and 0.1 mg / kg per day for liver dysfunction. The maintenance dose is selected in accordance with the INR indicators. The recommended INR levels are the same as for adults. The decision to prescribe warfarin in children should be made by an experienced specialist. Treatment should be supervised by an experienced pediatrician.

Elderly:
There are no specific guidelines for taking warfarin in the elderly. However, elderly patients should be closely monitored because they have a higher risk of side effects.

Patients with hepatic impairment:
Liver dysfunction increases sensitivity to warfarin because the liver produces clotting factors and also metabolizes warfarin. This group of patients requires careful monitoring of INR values.

Patients with renal impairment:
In patients with impaired renal function, it is necessary to reduce the dose of warfarin and conduct careful monitoring (see section 'Special instructions').

Planned (elective) surgical interventions:
Pre-, peri- and post-operative anticoagulant therapy is carried out as described below (if urgent cancellation of the oral anticoagulant effect is required - see the Overdose section).

Side effect

Bleeding. During the year, bleeding occurs in about 8% of cases among patients receiving warfarin. Of these, 1.0% are classified as severe (intracranial, retroperitoneal), resulting in hospitalization or blood transfusion, and 0.25% as fatal. 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 when the INR is within the target level, then there are other associated conditions that need to be investigated.

Examples of such complications are epistaxis, hemoptysis, hematuria, bleeding from the gums, bruising on the skin, vaginal bleeding, subconjunctival bleeding, bleeding from the rectum and other parts of the gastrointestinal tract, intracerebral bleeding, prolonged or heavy bleeding after injury or surgery. You can expect the development of bleeding, including severe, in any organ. In patients receiving long-term anticoagulant treatment, bleeding has been reported, leading to death, hospitalization, or the need for blood transfusion. Independent risk factors for significant bleeding during warfarin use include: advanced age, high levels of anticoagulation, history of stroke, history of gastrointestinal bleeding, concomitant diseases, and atrial fibrillation.Patients with CYP2C9 polymorphism (see Pharmacokinetics section) may have an increased risk of over-anticoagulant effects and bleeding episodes. In such patients, hemoglobin and INR levels should be closely monitored.

From the digestive system: vomiting, nausea, diarrhea.

Necrosis. Coumarin necrosis is a rare complication of warfarin treatment. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks, or (less commonly) elsewhere. Later, the lesions become necrotic. In 90% of cases, necrosis develops in women. Lesions are observed from the 3rd to 10th day of taking the drug and the etiology suggests a lack of antithrombotic protein C or S. Congenital insufficiency of these proteins can cause complications, therefore, warfarin should be started simultaneously with the introduction of heparin and small initial doses of the drug. If a complication occurs, the warfarin is stopped and heparin is continued until the lesions heal or scar.

Palmar-plantar syndrome. A very rare complication of warfarin therapy, its development is typical among men with atherosclerotic diseases. Warfarin is thought to cause hemorrhages in atheromatous plaques, leading to microembolism. Symmetrical purple lesions of the skin of the fingers and soles of the feet, accompanied by burning pains, occur. After you stop taking warfarin, these symptoms gradually disappear.

Others. Hypersensitivity reactions, manifested in the form of a skin rash, and characterized by a reversible increase in the concentration of liver enzymes; cholestatic hepatitis, vasculitis, priapism, reversible alopecia and tracheal calcification.

Independent risk factors for the development of serious bleeding during treatment with warfarin are: advanced age, high intensity of concomitant anticoagulant and antiplatelet therapy, a history of strokes and gastrointestinal bleeding.

The risk of bleeding is increased in patients with CYP2C9 gene polymorphism.

Overdose

The indicator of the effectiveness of treatment is at the border of the development of bleeding, therefore the patient may have minor bleeding, for example, microhematuria, bleeding gums, etc. In mild cases, it is enough to reduce the dose of the drug or stop treatment for a short time. In case of minor bleeding, it is enough to stop taking the drug until the INR is reached. In case of severe bleeding, the administration of vitamin K (intravenously) and activated carbon, concentrate of coagulation factors or fresh frozen plasma.

If oral anticoagulants are indicated for future prescription, large doses of vitamin K should be avoided because resistance to warfarin develops within 2 weeks.

Interaction with other medicinal substances

It is NOT RECOMMENDED to start or stop taking other medicines, or change the doses of medicines taken without consulting your doctor.

With simultaneous administration, it is also necessary to take into account the effects of stopping the induction and / or inhibition of the action of warfarin by other drugs.

The risk of developing severe bleeding increases with the simultaneous administration of warfarin with drugs that affect the level of platelets and primary hemostasis: acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most non-steroidal anti-inflammatory drugs (with the exception of cyclooxygenase-2 inhibitors), antibiotics in the high-dose penach group.

You should also avoid the combined use of warfarin with drugs that have a pronounced inhibitory effect on the cytochrome P450 system, for example, cimetidine and chloramphenicol, when taken for several days, the risk of bleeding increases. In such cases, cimetidine can be substituted for, for example, ranitidine or famotidine.

special instructions

A prerequisite for warfarin therapy is the patient's strict adherence to the prescribed dose of the drug.

Patients with alcoholism as well as patients with dementia may not be able to adhere to the prescribed warfarin regimen.

Conditions such as fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage can increase the effect of warfarin. In hypothyroidism, the effect of warfarin may be reduced. In the case of renal failure or nephrotic syndrome, the level of the free warfarin fraction in the blood plasma increases, which, depending on concomitant diseases, can lead to both an increase and a decrease in the effect. In the case of moderate hepatic impairment, the effect of warfarin is enhanced.

In all of the above conditions, careful monitoring of the INR level should be carried out.

For patients receiving warfarin, paracetamol, tramadol, or opiates are recommended as pain relievers.

Patients with a mutation in the gene encoding the CYP2C9 enzyme have a longer half-life of warfarin. These patients require lower doses of the drug because the risk of bleeding increases with the usual therapeutic doses. Warfarin should not be taken in patients with rare hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome due to the presence of lactose in the preparation (as an excipient).

If a rapid antithrombotic effect is required, it is recommended to start treatment with the introduction of heparin; then, for 5-7 days, a combination therapy with heparin and warfarin should be carried out until the target INR level is maintained for 2 days (see section 'Dosage and Administration').

In patients with protein C deficiency, there is a risk of skin necrosis at the beginning of warfarin therapy. Such therapy should be started without a loading dose of warfarin, even with heparin. Patients with protein S deficiency may also be at this risk, and a slower initiation of warfarin therapy is recommended in these circumstances.

In the case of individual resistance to warfarin (very rare), 5 to 20 loading doses of warfarin are needed to achieve a therapeutic effect. If taking warfarin in such patients is ineffective, other possible reasons should be established, such as: simultaneous administration of warfarin with other drugs (see the section 'Interaction with other medicinal substances'), inadequate diet, laboratory errors.

Treatment of elderly patients should be carried out with special precautions, because the synthesis of coagulation factors and hepatic metabolism in such patients is reduced, as a result of which an excessive effect from the action of warfarin may occur.

It is recommended to exercise caution in patients with impaired renal function, as a result of which the INR level should be monitored more often in patients at risk of hypercoagulability, for example, with severe arterial hypertension or kidney disease (see section 'Dosage and Administration').

Release form

50 or 100 tablets in a plastic bottle, sealed with a screw cap, under which a gasket with a tear-off ring is mounted, providing control of the first opening. 1 bottle together with instructions for use is placed in a cardboard box.
OR
50 or 100 tablets in a plastic bottle, sealed with a screw cap, under which a gasket with a tear-off ring is mounted, which provides control of the first opening. Part of the label is attached to the bottle with a special adhesive tape that allows the label to be lifted. The instructions for use are made in the form of a folding sheet placed under the movable part of the label, the edge of the instructions is fixed to the bottle.

Shelf life

5 years.
Do not use after the expiration date.

Storage conditions

At a temperature not higher than 25 ? C.
Keep out of the reach of children.

Conditions of dispensing from pharmacies

On prescription.