Warfarin

Monitoring

A prerequisite for therapy with Warfarin is the patient's strict adherence to the recommended dose of the drug.

The target INR value for oral anticoagulant therapy to prevent thromboembolic complications in patients with prosthetic heart valves is 2.5-3.0; for other indications - 2.0-3.0.

Patients suffering from alcoholism or dementia may be unable to adhere to the prescribed regimen of Warfarin.

Factors influencing the effect of warfarin

In conditions such as fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage, the effect of Warfarin may be enhanced. Increased effects of warfarin, requiring dose reduction, may also occur with weight loss, acute comorbidities, and smoking cessation.

The effect of warfarin may be reduced in hypothyroidism. A decrease in the effect of warfarin, requiring an increase in the dose of the drug, is possible with weight gain, as well as with diarrhea and vomiting.

Patients with a mutation of the gene encoding the CYP2C9 isoenzyme

Patients with a mutation in the gene encoding the CYP2C9 isoenzyme have a longer T1/2 of warfarin. These patients require lower doses of Warfarin, since the risk of bleeding increases when using normal therapeutic doses. If it is necessary to achieve a rapid antithrombotic effect, it is recommended to begin therapy with the administration of heparin; then, for 5-7 days, combination therapy with heparin and warfarin should be carried out until the target INR value is maintained for 2 days (see section "Dosage and Administration").

In the case of rare individual resistance to warfarin (extremely rare), 5-20 loading doses of Warfarin are required to achieve a therapeutic effect.

If the use of Warfarin in such patients is ineffective, other possible reasons should be identified, for example, concomitant use of other drugs (see section “Interaction with other drugs”), inadequate diet, laboratory errors.

Calciphylaxis

Calciphylaxis is a rare syndrome characterized by calcification of blood vessels with skin necrosis and is associated with high mortality. This complication is mainly observed in patients with end-stage renal disease on dialysis, or in patients with known risk factors such as protein C or S deficiency, hyperphosphatemia, hypercalcemia, or hypoalbuminemia. Rare cases of calciphylaxis have been described when taking warfarin in patients who do not have kidney disease. If calciphylaxis develops, appropriate treatment should be initiated and discontinuation of warfarin therapy should be considered.

Thrombophilia

Patients with protein C deficiency are at increased risk of developing skin necrosis when starting warfarin. In patients with protein C deficiency, treatment with warfarin should be initiated without a loading dose, even if heparin is used concomitantly. With protein S deficiency there is also a risk of skin necrosis, so it is advisable for such patients to start warfarin therapy with low doses.

Ischemic stroke

Anticoagulant therapy after ischemic stroke increases the risk of secondary hemorrhage in the necrotic area of the brain. In patients with atrial fibrillation, long-term use of warfarin is beneficial. However, the risk of early recurrence of embolism is low, so temporary cessation of therapy after an ischemic stroke is advisable. Warfarin treatment should be restarted 2 to 14 days after an ischemic stroke, depending on the size of the infarction and blood pressure. In patients with major embolic stroke or uncontrolled hypertension, warfarin should be discontinued for 14 days.

Surgical interventions

Surgeries not associated with the risk of severe bleeding can be performed with an INR < 2.5. If there is a risk of serious bleeding, warfarin should be discontinued 3 days before surgery. If it is necessary to continue anticoagulant therapy (for example, with a high risk of life-threatening thromboembolic complications), the INR should be reduced to <2.5 and heparin therapy should be started (see section "Dosage and Administration").

If surgery is necessary and warfarin cannot be stopped 3 days before surgery, the anticoagulant effect of warfarin should be stopped with low-dose vitamin K supplements.

The timing of resumption of warfarin therapy depends on the risk of postoperative bleeding. In most cases, warfarin can be restarted as soon as the patient can take the tablets by mouth.

Dental procedures

You should not stop taking warfarin before routine dental procedures (for example, before a tooth extraction).

Renal dysfunction

In chronic renal failure or nephrotic syndrome, the concentration of the free fraction of warfarin in the blood plasma increases, which, depending on concomitant diseases, can lead to either an increase or decrease in the effect. In cases of moderate renal failure, the effect of warfarin is enhanced. Caution is recommended when using warfarin in patients with impaired renal function. In all of the above conditions, careful monitoring of INR values should be carried out.

Thyroid diseases

The rate of warfarin metabolism depends on the functional state of the thyroid gland. Therefore, patients with hyper- or hypothyroidism require careful monitoring when initiating warfarin therapy.

Elderly patients

Treatment of elderly patients should be carried out with caution, because the synthesis of blood coagulation factors and hepatic metabolism in such patients is reduced, as a result of which the effect of warfarin may be enhanced.

Warfarin Nycomed

Release form, composition and packaging

The tablets are light blue, round, biconvex, with a cross-shaped score. 1 tab. warfarin sodium 2.5 mg Excipients: lactose, corn starch, calcium hydrogen phosphate dihydrate, indigo carmine, povidone 30, magnesium stearate. Clinical and pharmacological group: Anticoagulant of indirect action.

pharmachologic effect

Indirect anticoagulant. It blocks the synthesis of vitamin K-dependent blood clotting factors in the liver, namely II, VII, IX and X. The concentration of these components in the blood decreases, and the blood clotting process slows down. The onset of the anticoagulant effect is observed 36-72 hours after the start of use of the drug with the development of the maximum effect on days 5-7 from the start of use.

After stopping the drug, restoration of the activity of vitamin K-dependent blood coagulation factors occurs within 4-5 days.

Pharmacokinetics

Absorption and distribution The drug is quickly absorbed from the gastrointestinal tract. Plasma protein binding is 97-99%.

Metabolism

Metabolized in the liver. Warfarin is a racemic mixture, with the R and S isomers being metabolized in the liver by different pathways. Each isomer is converted into 2 main metabolites. The main catalyst for metabolism 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 greater anticoagulant activity than the dextrorotatory isomer (R-enantiomer), but the T1/2 of the latter is greater. Patients with polymorphisms of the CYP2C9 enzyme, including the CYP2C92 and CYP2C93 alleles, may have increased sensitivity to warfarin and an increased risk of bleeding.

Removal

Warfarin is excreted from the body in the form of inactive metabolites in bile, which are reabsorbed in the gastrointestinal tract and excreted in the urine. T1/2 ranges from 20 to 60 hours. For the R-enantiomer, T1/2 ranges 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;
secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction;
prevention of thromboembolic complications in patients with atrial fibrillation, lesions of the heart valves or with prosthetic heart valves;
treatment and prevention of transient ischemic attacks and strokes, prevention of postoperative thrombosis.

Dosage regimen

Warfarin is prescribed 1 time/day at the same time. The duration of treatment is determined by the doctor in accordance with the indications for use.

Before starting therapy, determine

International Normalized Ratio (MHO). Subsequently, laboratory monitoring 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. The initial dose for patients who have not previously used Warfarin is 5 mg/day (2 tablets) 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. Typically, the maintenance dose of the drug is 2.5-7.5 mg/day (1-3 tablets). For patients who have previously used warfarin, the recommended starting dose is double the known maintenance dose of the drug and is prescribed for 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 in accordance with this indicator. It is recommended to maintain an MHO value of 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve diseases, and bioprosthetic heart valve replacement. Higher MHO values from 2.5 to 3.5 are recommended for mechanical heart valve replacement and complicated acute myocardial infarction.

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 MHO levels. Recommended MHO levels are the same as for adults. The decision to prescribe warfarin in children should be made by an experienced specialist.

Treatment should be carried out under the supervision of an experienced specialist - a pediatrician. There are no specific recommendations for the use of warfarin in elderly patients. However, elderly patients should be closely monitored as they are at higher risk of developing side effects. Impaired liver function increases sensitivity to warfarin because the liver produces clotting factors and also metabolizes warfarin.

In this group of patients, careful monitoring of MHO levels is necessary. Patients with renal failure do not require any special recommendations regarding the selection of the dose of warfarin.

Patients on peritoneal dialysis do not need to further increase the dose of warfarin. Pre-, peri- and postoperative anticoagulant therapy is carried out as indicated below. Determine MHO one week before the scheduled surgery. Stop taking warfarin 1-5 days before surgery.

In case of a high risk of thrombosis, low molecular weight heparin is administered subcutaneously to the patient for prophylaxis. The duration of the pause in taking warfarin depends on the MHO. Warfarin is stopped: - 5 days before surgery if MHO > 4.0; — 3 days before surgery with MHO from 3.0 to 4.0; - 2 days before surgery with MHO from 2.0 to 3.0. The INR should be determined the evening before surgery and 0.5-1.0 mg of vitamin K1 administered orally or IV if the INR is > 1.8.

Consider the need for unfractionated heparin infusion or prophylactic low molecular weight heparin on the day of surgery. Subcutaneous administration of low molecular weight heparin should be continued for 5-7 days after surgery, with concomitant warfarin reinstated. Continue warfarin at the usual maintenance dose on the same day in the evening after minor surgery and on the day the patient begins receiving enteral nutrition after major surgery.

Side effect

Very often (>1/10) - bleeding. Often (>1/100, <1/10) - increased sensitivity to warfarin after long-term use.

Uncommon (>1/1000, <1/100) - anemia, vomiting, abdominal pain, nausea, diarrhea. Rarely (>1/10,000, <1/1000) - eosinophilia, increased activity of liver enzymes, jaundice, rash, urticaria, itching, eczema, skin necrosis, vasculitis, hair loss, nephritis, urolithiasis, tubular necrosis. Over the course of a year, bleeding occurs in approximately 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 MHO is significantly higher than the target level. If bleeding begins with MHO within the target level, there are other underlying conditions that should be investigated.

Independent risk factors for the development of serious bleeding during treatment with warfarin are: older 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 polymorphism of the CYP2C9 gene. From the digestive system: vomiting, nausea, diarrhea.

Dermatological reactions: 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 the 10th day of use of the drug and the etiology suggests a deficiency of antithrombotic protein C or S. Congenital deficiency of these proteins can cause complications, so warfarin should be started simultaneously with the introduction of heparin and small initial doses of the drug.

If a complication occurs, warfarin is discontinued and heparin is continued until the lesions heal or scar. Hand-foot syndrome is a very rare complication of warfarin therapy; its development is typical among men with atherosclerotic diseases. Presumably, warfarin causes hemorrhages of atheromatous plaques, leading to microembolism. There are symmetrical purple lesions on the skin of the fingers and soles of the feet, accompanied by burning pain. After stopping warfarin, these symptoms gradually disappear.

Other: hypersensitivity reactions manifested as skin rash and characterized by a reversible increase in the concentration of liver enzymes, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and tracheal calcification.

Contraindications

acute bleeding;
severe liver disease;
severe kidney disease;
acute DIC syndrome;
deficiency of proteins C and S;
thrombocytopenia;
patients at high risk of bleeding, including patients with hemorrhagic disorders, esophageal varices, arterial aneurysm, lumbar puncture, gastric and duodenal ulcers, severe wounds (including operating rooms), bacterial endocarditis, malignant arterial hypertension, hemorrhagic stroke, intracranial hemorrhage ;
pregnancy (first trimester and last 4 weeks);
established or suspected hypersensitivity to the components of the drug.

Pregnancy and lactation

The use of the drug is contraindicated in the first trimester of pregnancy (the use of warfarin is not recommended during the remaining stages of pregnancy, except in cases of emergency) and during the last 4 weeks. Warfarin quickly penetrates the placental barrier and has a teratogenic effect on the fetus (nasal hypoplasia and chondrodysplasia, optic nerve atrophy, cataracts leading to complete blindness, delayed mental and physical development, microcephaly) at 6-12 weeks of pregnancy.

Warfarin Nycomed tab 2.5 mg N50 (Nizhpharm)

It is not recommended to start or stop taking drugs, as well as change the doses of drugs taken without consulting your doctor. When prescribing simultaneously, 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 severe bleeding increases when taking warfarin simultaneously with drugs affecting platelet levels and primary hemostasis: acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most NSAIDs (except for COX-2 inhibitors), antibiotics of the penicillin group in large doses. The combined use of warfarin with drugs that have a pronounced inhibitory effect on cytochrome P450 system, such as cimetidine and chloramphenicol, which when taken for several days increases the risk of bleeding. In such cases, cimetidine can be replaced, for example, with ranitidine or famotidine. The effect of warfarin may be enhanced when taken simultaneously with the following drugs: acetylsalicylic acid, allopurinol, amiodarone, azapropazone, azithromycin, alpha and beta interferon, amitriptyline, bezafibrate, vitamin A, vitamin E, glibenclamide, glucagon, gemfibrozil, heparin, grepafloxacin, danazol, dextropropoxyphene, diazoxide, digoxin, disopyramide, disulfiram, zafirlukast, indomethacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, levamisole, lovastatin, metolazone, methotrexate, metronidazole, miconazole (including in the form of an oral gel), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol (especially after 1–2 weeks of continuous use), paroxetine, piroxicam, proguanil, propafenone, propranolol, influenza vaccine , roxithromycin, sertraline, simvastatin, sulfafurazole, sulfamethizole, 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, cefamandole, cephalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, cimetidine, qi profloxacin, cyclophosphamide, erythromycin, etoposide, ethanol. Preparations of some medicinal plants (official or informal) can also enhance the effect of warfarin: for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza); and reduce: for example, ginseng (Panax ginseng), St. John's wort (Hypericum perforatum). Warfarin and any St. John's wort preparations should not be taken at the same time, but it should be borne in mind that the inducing effect of warfarin may persist for another 2 weeks after stopping the use of St. John's wort preparations. If the patient is taking St. John's wort preparations, MHO should be measured and discontinuation. MHO monitoring must be careful because... its level may increase when St. John's wort is discontinued. After this, warfarin can be prescribed. Quinine contained in tonic drinks can also enhance the effect of warfarin. Warfarin can enhance the effect of oral hypoglycemic drugs sulfonylurea derivatives. The effect of warfarin can be weakened when taken simultaneously with the following drugs: azathioprine, aminoglutethimide barbiturates, valproic acid, vitamin C , vitamin K, glutethimide, griseofulvin, dicloxacillin, disopyramide, carbamazepine, cholestyramine, coenzyme Q10, mercaptopurine, mesalazine, mianserin, mitotane, nafcillin, primidone, retinoids, ritonavir, rifampicin, rofecoxib, spironolactone, sucra phate, trazodone, phenazone, chlordiazepoxide, chlorthalidone , 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 combined 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, after 2-3 weeks from the start of therapy. Food rich in vitamin K weakens the effect of warfarin; Decreased absorption of vitamin K caused by diarrhea or laxatives potentiates the effect of warfarin. The most vitamin K is found in green vegetables, so when treating with warfarin you should eat the following foods with caution: amaranth greens, avocados, broccoli, Brussels sprouts, cabbage, canola oil, chayo leaf, onions, coriander (cilantro), cucumber peel, chicory, kiwi fruit, lettuce, mint, mustard greens, olive oil, parsley, peas, pistachios, red seaweed, spinach greens, spring onions, soybeans, tea leaves (but not tea-beverage), turnip greens , watercress.