Warfarin, pills 2.5mg 50pcs

Composition

1 tablet contains:

Active ingredient:

warfarin sodium 2.5 mg

Pharmacological action

Pharmacodynamics

Warfarin blocks the synthesis of vitamin K-dependent blood clotting factors (II, VII, IX, X) in the liver, reduces their concentration in plasma and slows down the blood clotting process.

The onset of anticoagulant action is observed in 36-72 hours from the start of taking the drug, with the development of the maximum effect on the 5th-7th day from the start of use. After discontinuation of the drug, the activity of vitamin K-dependent blood clotting factors is restored within 4-5 days.

Pharmacokinetics

It is rapidly absorbed from the gastrointestinal tract almost completely. Binding to plasma proteins is 97-99%. It is metabolized in the liver.

Warfarin is a racemic mixture, and the R – and S-isomers are metabolized in the liver in various ways. Each of the isomers is converted to 2 major metabolites.

The main metabolic catalyst for the S-enantiomer of warfarin is the enzyme CYP2C9, 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 right-handed isomer (R-enantiomer), but T1 / 2 of the latter is greater. Patients with a CYP2C9 polymorphism, including the CYP2C9*2 and CYP2C9*3 alleles, may have an increased sensitivity to warfarin and an increased risk of bleeding.

Warfarin is eliminated from the body with bile in the form of inactive metabolites, which are reabsorbed in the gastrointestinal tract and excreted in the urine. T1 / 2 is between 20 and 60 hours. For the R-enantiomer, T1 / 2 is from 37 to 89 hours, and for the S-enantiomer, from 21 to 43 hours.

Indications

Treatment and prevention of thrombosis and embolism of blood vessels:

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

Use during pregnancy and lactation

Warfarin quickly penetrates the placenta, has a teratogenic effect on the fetus (nasal hypoplasia and chondrodysplasia, optic nerve atrophy, cataracts leading to complete or partial blindness, delayed mental and physical development and microcephaly) at 6-12 weeks of pregnancy.

May cause bleeding at the end of pregnancy and during childbirth. The drug should not be prescribed in the first trimester of pregnancy and during the last 4 weeks. The use of warfarin is not recommended in other periods of pregnancy, except in cases of extreme necessity.

It is excreted in breast milk in immeasurable amounts and does not affect the clotting activity of the blood of the fed child. Warfarin can be used during lactation.

Contraindications

• mounted or suspected hypersensitivity to the drug Warfarin;
• severe bleeding;
• pregnancy (I trimester and the last 4 weeks of pregnancy);
• severe liver disease or kidney disease;
• acute DIC;
• deficiency of proteins C and S;
• thrombocytopenia;
• patients with high risk of bleeding, including patients with hemorrhagic disorders;
• varicose veins of the esophagus;
• aneurysm of the arteries;
• lumbar puncture;
• ulcer disease of stomach and duodenal ulcers;
• wounds (including operating);
• bacterial endocarditis;
• malignant hypertension;
• hemorrhagic stroke, intracranial hemorrhage.

Side effects

Very common (>1/10): bleeding.

Often (>1/100, >

Infrequently (>1/1000, >

Rare (>1/10000, >

From the digestive system: vomiting, nausea, diarrhea.

Bleeding. Over a year, bleeding occurs in approximately 8% of patients receiving warfarin. Of these,1% are classified as severe (intracranial, retroperitoneal), leading to 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 MHO is significantly higher than the target level. If the bleeding started with an MHO that is within the target level, then there are other concomitant conditions that need to be investigated.

Necrosis. Coumarin necrosis is a rare complication of warfarin therapy. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks or (less often) in other places. Later, the lesions become necrotic. In 90% of cases, necrosis develops in women. Lesions are observed from the 3rd to the 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, so treatment with warfarin should begin with small initial doses and simultaneously with the introduction of heparin. If a complication occurs, then warfarin is discontinued and heparin use is continued until the lesions heal or scar.

Palmar-plantar syndrome. A very rare complication in warfarin therapy, its development is typical for men with atherosclerotic diseases. Warfarin is suspected to cause hemorrhages in the area of atheromatous plaques, leading to microembolism. There are symmetrical purple lesions of the skin of the fingers and soles of the feet, accompanied by burning pains. After discontinuation of warfarin, these symptoms gradually disappear.

Other: hypersensitivity reactions that manifest as a skin rash and are characterized by a reversible increase in liver enzyme levels, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and tracheal calcification.

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

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

Interaction

It is not recommended to start or stop taking drugs, as well as to change the dose of medications taken without consulting your doctor.

The risk of severe bleeding increases when warfarin is co-administered with drugs that affect platelet levels and primary hemostasis: acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most NSAIDs (with the exception of COX-2 inhibitors), high-dose penicillin antibiotics.

You should also avoid concomitant use of warfarin with drugs that have a pronounced inhibitory effect on the cytochrome p450 system, such as cimetidine and chloramphenicol, which increase the risk of bleeding for several days. In such cases, cimetidine can be substituted, for example, with ranitidine or famotidine.

The effect of warfarin may be enhanced when taken concomitantly with the following medications: acetylsalicylic acid, allopurinol, amiodarone, azapropazone, azithromycin, alpha – and beta-interferon, amitriptyline, bezafibrate, vitamin A, vitamin E, glibenclamide, glucagon, gemfibrozil, heparin, grepafloxacin, danazol, dextropropoxifene, diazoxide, digoxin, disopyramide, disulfiram, zafirlukast, Indometacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, levamizole, lovastatin, metolazone, methotrexate, metronidazole, miconazole (including in the form of oral gel), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxifenbutazone, paracetamol (especially after 1-2 weeks of continuous use), paroxetine, piroxicam, proguanil, propafenone, propranolol, influenza vaccine, roxithromycin, sertraline, simvastatin, sulfafurazole, sulfamethisole, sulfamethoxazole-trimethoprim, sulfafenazole, sulfinpyrazone, sulindac, steroid hormones (anabolic and/or androgenic), tamoxifen, tegafur, testosterone, tetracyclines, thienylic acid, tolmetin, trastuzumab, troglitazone, phenytoin, phenylbutazone, fenofibrate, feprazone, fluconazole, fluoxetine, fluorouracil, fluvastatin, fluvoxamine, flutamide, quinine, quinidine, chloral hydrate, chloramphenicol, celecoxib, cefamandol, cephalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, cimetidine, ciprofloxacin, cyclophosphamide, erythromycin, etoposide, ethanol.

Preparations of certain medicinal plants (official or unofficial) can also enhance the effect of warfarin: for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica sinensis, papaya (Carica papaya), sage (Salvia miltiorrhiza); and reduce: for example, ginseng (Panax ginseng), St. John’s wort (Hypericum perforatum).

You can not simultaneously take warfarin and any St. John’s wort preparations, but it should be borne in mind that the effect of inducing the action of warfarin may persist for another 2 weeks after stopping taking St. John’s wort preparations. If the patient is taking St. John’s wort medications, the MHO should be measured and stopped. Monitoring of MHO should be careful, as its level may increase when St. John’s wort is discontinued. After that, you can prescribe warfarin.

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

Warfarin may enhance the effect of oral hypoglycemic agents of sulfonylureas.

The effect of warfarin may be weakened when taken concomitantly with the following medications: azathioprine, aminoglutetimide, barbiturates, valproic acid, vitamin C, vitamin K, glutetimide, griseofulvin, dicloxacillin, disopyramide, carbamazepine, colestyramine, coenzyme Q10, mercaptopurine, mesalazine, mianserin, mitotan, nafcillin, primidone, retinoids, ritonavir, rifampicin, rofecoxib, spironolactone, sucralfate, trazodone, phenazone, chlordiazepoxide, chlortalidone, cyclosporine. Taking diuretics in the case of a pronounced hypovolemic effect can lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants. In the case of concomitant use of warfarin with other drugs listed in the above list, it is necessary to monitor MHO at the beginning and end of treatment, and, if possible,2-3 weeks after the start of therapy.

Foods rich in vitamin K weaken the effects of warfarin; a decrease in vitamin K absorption caused by diarrhea or laxatives potentiates the effects of warfarin. Most vitamin K is found in green vegetables, so when treating with warfarin, you should carefully eat the following foods: amaranth greens, avocado, broccoli, Brussels sprouts, cabbage, canola oil, chaillot leaf, onion, coriander (coriander), cucumber peel, chicory, kiwi fruit, lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red sea peas seaweed, spinach greens, spring onions, soybeans, tea leaves (but not tea-drink), turnip greens, watercress.

How to take, course of use and dosage

Inside. 1 time a day, preferably at the same time of day.

The duration of treatment is determined by the doctor in accordance with the indications for use.

Monitoring during treatment. Before starting therapy, MHO is determined. In the future, laboratory monitoring is carried out regularly every 4-8 weeks.

The duration of treatment depends on the patient’s clinical condition. 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, MHO is determined and, in accordance with this indicator, a maintenance dose of the drug is prescribed. Usually, the 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 administered within the first 2 days. Treatment is then continued with a known maintenance dose. On the 5th day of treatment, MHO is monitored and the dose is adjusted according to this indicator. It is recommended to maintain the MHO index from 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve diseases, prosthetic heart valves with bioprostheses. Higher MHO values from 2.5 to 3.5 are recommended for prosthetic heart valves with mechanical prostheses and complicated acute myocardial infarction.

Children: Data on the use of warfarin in children are limited. The initial dose is usually 0.2 mg / kg / day for normal liver function and 0.1 mg / kg / day for impaired liver function. The maintenance dose is selected in accordance with the MHO indicators. Recommended MHO levels are the same as for adults. The decision to prescribe warfarin and monitor treatment in children should be made by an experienced pediatrician. Doses are selected according to the table below (Table 1).

Table 1

Selection of the maintenance dose of warfarin in accordance with MHO indicators

Day 1 If the base MHO value is from 1 to 1.3, then the shock dose is 0.2 mg/kg of body weight from day 2 to day 4, if the MHO value is:Actions:from 1 to 1.3 Repeat the shock dose from 1.4 to 1.950% of the shock dose from 2 to 350% of the shock dose from 3.1 to 3.525% of the shock dose>3.5 Discontinue use of the drug until multi-maintenance is achieved, if the MHO value:Actions (weekly dose):1 to 1.3 Increase dose by 20% 1.4 to 1.9 Increase dose by 10% 2 to 3 Unchanged 3.1 to 3.5 Reduce dose by 10%>3.5 Discontinue drug use until MHO is reached>

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

Patients with hepatic insufficiency: impaired liver function increases sensitivity to warfarin, as the liver produces clotting factors and also metabolizes warfarin. In this group of patients, careful monitoring of MHO indicators is necessary.

Patients with renal insufficiency: patients with renal insufficiency do not need any special recommendations for the selection of the dose of warfarin. Patients undergoing peritoneal dialysis do not need an additional increase in the dose of warfarin.

Elective surgery: pre -, peri – and post-operative anticoagulant therapy is performed as indicated below (if urgent discontinuation of oral anticoagulant treatment is required — see “Overdose”).

1. Determine the MHO one week before the scheduled operation.

2. Stop taking warfarin 1-5 days before surgery. If there is a high risk of thrombosis, the patient is given subcutaneous injection of low-molecular-weight heparin for prevention. The duration of the warfarin pause depends on the MHO. Stop taking warfarin:

– 5 days before surgery if the MHO is >4;>

– 3 days before surgery if the MHO is from 3 to 4;

– 2 days before surgery if the MHO is from 2 to 3.3

. Determine the MHO in the evening before surgery and administer 0.5-1 mg of vitamin K1 orally or intravenously if the INR is >1.8. >

4. Take into account the need for an infusion of unfractionated heparin or prophylactic use of low-molecular-weight heparin on the day of surgery.

5. Continue subcutaneous use of low-molecular-weight heparin for 5-7 days after surgery with concomitant restored warfarin intake.

6. Continue taking warfarin with the usual maintenance dose on the same day in the evening after minor operations and on the day when the patient begins to receive enteral nutrition after major operations.

Overdose

The indicator of treatment effectiveness is at the border of bleeding development, so the patient may develop minor bleeding (for example, microhematuria, bleeding gums, etc. ).

Treatment: in mild cases, reduce the dose of the drug or stop treatment for a short time; in case of minor bleeding, stop taking the drug until the MHO target level is reached. In case of severe bleeding — intravenous use of vitamin K, the appointment of activated carbon, coagulation factor concentrate or fresh frozen plasma.

If oral anticoagulants are indicated for use in the future, it is necessary to avoid high doses of vitamin K, since warfarin resistance develops within 2 weeks.

Table 2

Overdose treatment regimens

Level of myrecommendationsin case of minor bleeding, skip the next dose of warfarin and continue taking lower doses when the therapeutic level of MHO5 is reached-9 Skip 1-2 doses of warfarin and continue taking lower doses when the therapeutic level of MHO is reached or skip 1 dose of warfarin and prescribe vitamin K in doses of 1-2.5 mg orally>9 Stop taking warfarin, prescribe vitamin K in doses of 3-5 mg orally Drug withdrawal is indicated 5-9 (surgery is planned)Discontinue taking warfarin and administer vitamin K in doses of 2-4 mg orally (24 hours before the planned operation). >20 or severe bleedingvitamin K in doses of 10 mg by slow intravenous infusion, transfusion of concentrates of prothrombin complex factors or fresh frozen plasma, or whole blood. If necessary, repeat the use of vitamin K every 12 hours.

After treatment, long-term monitoring of the patient is necessary, given that the T 1/2 of warfarin is 20-60 hours.

Special instructions

A prerequisite for warfarin therapy is strict compliance with the prescribed dose of the drug.

Patients suffering from alcoholism, as well as patients with dementia, may not be able to follow the prescribed warfarin regimen.

Conditions such as fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage may 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 fraction of warfarin 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 insufficiency, the effect of warfarin is enhanced.

In all of the above conditions, MHO levels should be carefully monitored.

Patients receiving warfarin are advised to take paracetamol, tramadol, or opiates as painkillers.

Patients with a mutation in the gene encoding the CYP2C9 enzyme have a longer T 1/2 of warfarin. These patients require lower doses of the drug, because when taking the usual therapeutic doses, the risk of bleeding increases.

Do not take warfarin in patients with hereditary galactose intolerance, lactase enzyme deficiency, glucose and galactose malabsorption.If a rapid antithrombotic effect is necessary, it is recommended to start treatment with heparin; then, for 5-7 days, a combination therapy with heparin and warfarin should be carried out until the target MHO level is maintained for 2 days.

To avoid coumarin necrosis, patients with hereditary antithrombotic protein C or S deficiency should first be given heparin. The concomitant initial loading dose should not exceed 5 mg. use of heparin should continue for 5-7 days.

In the case of individual warfarin resistance (very rare),5 to 20 shock doses of warfarin are necessary to achieve a therapeutic effect. If taking warfarin in such patients is ineffective, other possible causes should be identified — concomitant use of warfarin with other drugs, inadequate dietary intake, laboratory errors.

Treatment of elderly patients should be carried out with special precautions, since the synthesis of clotting factors and hepatic metabolism in such patients decreases, as a result of which an excessive effect of warfarin may occur.

Form of production

Tablets

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25 °C

Shelf life

2 years

Active ingredient

Warfarin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

Adults as prescribed by a doctor

Indications

Prevention of thrombosis, Prevention of thromboembolism, Prevention of heart attacks and strokes, Prevention of acute myocardial infarction