Warfarin - instructions for use, dose, side effects, contraindications

Pharmacodynamics:Anticoagulant of indirect action, a derivative of coumarin. Suppresses the synthesis of vitamin K-dependent clotting factors (II, VII, IX and X) and anticoagulant proteins C and S in the liver. The onset of anticoagulant action is observed 36-72 hours after the start of the drug administration with the development of maximum effect on the 5-7th day from the beginning of application. After discontinuation of the drug, restoration of vitamin K-dependent coagulation factors occurs within 4-5 days.

Pharmacokinetics:

After oral administration warfarin quickly absorbed from the digestive tract. It is also absorbed through the skin.

The binding with plasma proteins is high. Penetrates through the placenta. In small amounts excreted in breast milk.

Active substance warfarin is a racemic mixture of isomers that are metabolized in the liver. The S-isomer is more active and metabolizes faster than the R-isomer. Metabolism occurs with the participation of cytochrome P450 - 2C9, 2C19, 2C8, 2C18, 1A2 and 3A4, 2C9 isoenzymes.

The half-life period is on average 40 hours, in the terminal phase approximately 1 week. The clearance of the R-isomer is usually half the clearance of the S-isomer, for close V_d, half-life R-isomer (37-89 h) is greater than that of S-isomer (21-43 h).

Studies with a radioactive label showed that after a single oral intake of about 92% of warfarin is excreted in the urine in the form of metabolites and only a small amount - in unchanged form.

Indications:

Treatment and prevention of thrombosis and embolism of blood vessels: acute venous thrombosis and pulmonary embolism; postoperative thrombosis; repeated myocardial infarction; as an additional tool for surgical or medicamentous (thrombolytic) treatment of thrombosis, as well as for electrical cardioversion of atrial fibrillation; recurrent venous thrombosis; repeated embolism of the pulmonary artery; Prosthesis of valvular and vascular valves (combination with acetylsalicylic acid is possible); thrombosis of peripheral,coronary and cerebral arteries; secondary prevention of thrombosis and thromboembolism after myocardial infarction and atrial fibrillation.

ICD-10

IX.I26-I28.I26 Pulmonary embolism

IX.I20-I25.I21 Acute myocardial infarction

IX.I60-I69.I63 Cerebral infarction

IX.I80-I89.I82 Embolism and thrombosis of other veins

IX.I70-I79.I74 Embolism and thrombosis of the arteries

Contraindications:

Diseases and conditions with a high risk of bleeding, pathological changes in blood. Recent craniocerebral operations, ophthalmic operations, surgical interventions for trauma with an extensive operating field. The tendency to bleed with ulcerative lesions of the gastrointestinal tract, with diseases of the genitourinary system, respiratory system; cerebrovascular hemorrhages; aneurysms; pericarditis, exudative pericarditis, bacterial endocarditis. Severe liver or kidney disease, severe arterial hypertension, acute DVS-syndrome.

Threatening abortion, pregnancy.

Inadequate laboratory conditions for monitoring the patient, lack of observation of patients of senile age, alcoholism, psychosis, disorganization of the patient.

Spinal puncture and other diagnostic procedures with a potential threat of uncontrolled bleeding. Extensive regional anesthesia, blockade.Malignant arterial hypertension.

Carefully:

In case of violations of the liver function, the effects of warfarin may be potentiated due to a violation of the synthesis of clotting factors and a decrease in the metabolism of warfarin.

Contraindicated in severe kidney disease.

The safety and efficacy of warfarin in children and adolescents under the age of 18 years have not been established.

When using warfarin, special care is required for elderly patients.

Pregnancy and lactation:

Warfarin should not be given to pregnant women due to an identified teratogenic effect, the development of bleeding in the fetus and its death.

The drug is excreted in mother's milk in small amounts and has almost no effect on the blood coagulation in the child, so this medicine can be used during lactation, but it is advisable to refrain from breastfeeding during the first 3 days of therapy with warfarin.

Dosing and Administration:

Inside, 1 time per day, preferably at the same time of day. The dose, mode and duration of application of the drug the doctor determines for each patient individually, guided by the severity of the disease and the results of the control of blood clotting (MNO).Without the permission of a doctor, you can not arbitrarily change the dose or discontinue drug treatment.

The initial dose is 2.5-5 mg per day for the first 2 days, then it is gradually adjusted in accordance with the individual patient's blood coagulation reaction (MNO). After reaching the desired level of MNO (2.0-3.0, and in some cases 3.0-4.5), a maintenance dose is prescribed.

Elderly, impaired, or at-risk patients are assigned lower initial doses and are careful when increasing them. Children usually do not prescribe the drug.

At the beginning of the treatment laboratory monitoring of MNO is carried out every day, for the next 3-4 weeks the control is carried out 1-2 times a week, later - every 1-4 weeks. More frequent additional monitoring is necessary in cases where the patient's health changes, before the planned operation or other procedure, and when any other medication is prescribed or canceled.

Side effects:

The most common side effects observed during the treatment with anticoagulants are bleeding and hemorrhage into various organs and tissues. The possible risk of these side effects can be significantly reduced, strictly following the doctor's recommendations regarding the taking of the drug.

In some cases, treatment with anticoagulants can cause circulatory disorders in the extremities or internal organs. About the violation of blood circulation is most often indicated by pain and dark red color of the skin of the toes. If these symptoms appear, consult a doctor immediately.

Other rare side effects are skin allergic reactions (itching, urticaria, dermatitis), nausea, vomiting, diarrhea, abdominal pain, impaired liver function (elevated liver enzymes in the blood, jaundice), fever, general weakness, changes in blood picture, transient alopecia.

Overdose:

Symptoms of chronic intoxication: bleeding from the gums, epistaxis, excessive menstrual bleeding, severe or prolonged bleeding with minor superficial injuries, bleeding in the skin, the presence of blood in the urine and feces, and others.

Treatment: with minor bleeding it is necessary to reduce the dose of the drug or stop treatment for a short time. In case of development of severe bleeding, transfusion of the concentrates of factors of the prothrombin complex, or fresh frozen plasma, or whole blood.

Interaction:

With simultaneous use with anticoagulants and drugs with antiaggregant activity increases the risk of bleeding.

With simultaneous use with anticholinergic drugs, memory and attention disorders in elderly patients are possible.

With simultaneous use with inhibitors of microsomal liver enzymes, the anticoagulant effect of warfarin increases and the risk of bleeding increases.

When used simultaneously with hypoglycemic agents - derivatives of sulfonylureas - it is possible to increase their hypoglycemic effect.

With simultaneous application of anticoagulant effects of warfarin reduce: inducers of microsomal enzymes of the liver (including barbiturates, phenytoin, carbamazepine), glutetimide, griseofulvin, dicloxacillin, coenzyme Q10, mianserin, paracetamol, retinoids, rifampicin, sucralfate, phenazone, colestramine, glutetimide, vitamin K, acitretin, diuretics (spironolactone and chlorthalidone), aminoglutethimide, mercaptopurine, mitotane, cisapride, preparations of ginseng, glucagon.

It is possible to increase the anticoagulant effect of warfarin and increase the risk of bleeding when used simultaneously with heparin,non-steroidal anti-inflammatory drugs (including acetylsalicylic acid), pyrazolone derivatives (including phenylbutazone, sulfinpyrazone), tramadol, dextropropoxyphene, combination of paracetamol and codeine, antiarrhythmics (including amiodarone, quinidine, propafenone, moracizine), antimicrobial and antifungal agents (including chloramphenicol, metronidazole, cefamandol, cefmetazole, cefoperazonom, cefazolin, erythromycin, azithromycin, rooxithromycin, and clarith rimycin, co-trimoxazole, miconazole, ketoconazole, itraconazole, fluconazole, nalidixic acid, ciprofloxacin, norfloxacin, ofloxacin, aminosalicylic acid, benzylpenicillin, doxycycline, isoniazid, neomycin, tetracyclines, aztreonam), glibenclamide, valproic acid, quinine, proguanil, cyclophosphamide, methotrexate, fluorouracil, with combinations of etoposide and vindesine or carboplatin, ifosfamide with mesenchyme, tamoxifen, flutamide, interferon alpha (for chronic hepatitis C), interferon he beta, saquinavir, clofibrate, ciprofibrate,fenofibrate, gemfibrozil, cimetidine, lovastatin, fluvastatin, simvastatin, piracetam, danazol, tramadol.

With simultaneous use with tricyclic antidepressants, disopyramide, felbamate, terbinafine, allopurinol, dipyridamole, chloral hydrate, ranitidine, ascorbic acid, tocopherol, the data on drug interaction are ambiguous.

In patients with chronic alcoholism, taking disulfiram increased effects of warfarin.

With simultaneous application with colestyramin, absorption and bioavailability of warfarin decreases.

With simultaneous use with ticlopidine, cases of liver damage are described. The anticoagulant effect of warfarin does not change.

With simultaneous application with phenazone, the concentration of warfarin in the blood plasma decreases.

With simultaneous application with phenytoin, an initial increase in anticoagulant activity is reported, followed by a decrease.

When used simultaneously with fluoxetine, trazodone, vitamin E, there are reports of increased effects of warfarin.

With simultaneous application with cyclosporine, there is a mutual decrease in effects.

When used concomitantly with enoxacin, the clearance of the R isomer is reduced, but not of the S-isomer, but the prothrombin time is not increased.

With simultaneous use with ethacrynic acid, the diuretic effect may increase, hypokalemia, because as a result of competition for binding to plasma proteins, the concentration of free (active) ethacrynic acid rises.

With regular use of alcohol, it is possible to reduce the effects of warfarin, apparently due to the induction of liver enzymes. However, if the liver is damaged, the effects of warfarin may worsen.

If you accidentally take a large amount of alcohol may increase the effect of warfarin.

Special instructions:

The risk of bleeding increases with intensive and prolonged anticoagulant therapy.

During the treatment period, doses should be monitored and prothrombin time or other coagulation parameters should be determined periodically.

When using warfarin simultaneously with other drugs, the high probability of drug interaction should be taken into account.

Anticoagulant therapy with warfarin may increase the risk of embolism with particles of atherosclerotic plaques.

With special care and after careful analysis of the relationship between risk and benefit, warfarin in the following cases: infectious diseases (including sprue) or dysbacteriosis (due to antibiotic therapy); with trauma that can cause internal bleeding; surgical intervention or trauma with an extensive bleeding surface; permanent catheters; severe and moderate arterial hypertension; known or expected deficiency of protein C; true polycythemia, vasculitis, severe diabetes; moderate and severe allergic reactions, anaphylactic reactions.

Patients with congestive heart failure require more frequent laboratory monitoring and correction of warfarin doses.

It is not recommended simultaneous use of warfarin with urokinase and streptokinase.

When using warfarin, special care is required for elderly patients, people with intellectual disabilities.

It is believed that renal clearance slightly affects the intensity of warfarin.

In case of violations of the liver function, the effects of warfarin may be potentiated due to a violation of the synthesis of clotting factors and a decrease in the metabolism of warfarin.

The safety and efficacy of warfarin in children and adolescents under the age of 18 years have not been established.

Instructions

Warfarin (Warfarinum)