Warfarin

General characteristics. Structure:

Active ingredient: 2,5 mg of warfarin of sodium (in the form of a clathrate) in 1 tablet.

Excipients: magnesium stearate, lactoses monohydrate, starch corn, hydrophosphate calcium dihydrate, K-30 povidone.

Pharmacological properties:

Pharmacodynamics. Anticoagulant of indirect action. Vitamin of K-dependent blood-coagulation factors suppresses synthesis (II, VII, IX and X) and proteins C and S in a liver. Optimal anticoagulating effect is observed for 3-5 day from the beginning of use and stops in 3-5 days after reception of the last dose.

Pharmacokinetics. Absorption - full. Communication with proteins of plasma - 97-99%. Therapeutic concentration in plasma - 1-5 mkg/ml (0,003-0,015 mmol/l). Is in a type of racemic connection, at the same time in a human body L-isomer has bigger activity, than dextrorotatory.

Gets through a placenta, but does not cosecrete with breast milk.

Drug is metabolized by the fermental CYP2C9 system with formation of inactive and slaboaktivny metabolites which reabsorbirutsya from bile, at the same time L-isomer is metabolized quicker. Patients with polymorphism of CYP2C9 enzyme, including alleles of CYP2C9*2 and CYP2C9*3, can have hypersensitivity to warfarin and the increased risk of development of bleedings. An elimination half-life (T 1/2) of racemic warfarin – 40 h. It is removed by kidneys.

Indications to use:

· Treatment and prevention of thrombosis and thromboembolism of vessels:

· acute venous thrombosis and thromboembolism of a pulmonary artery;

· postoperative thrombosis;

· repeated myocardial infarction;

· as additional HP when performing surgical or thrombolytic treatment of thrombosis, and also at electric cardioversion of a ciliary arrhythmia;

· recurrent venous thrombosis;

· repeated thromboembolism of a pulmonary artery;

· prosthetics of valves of heart and vessels (the combination with acetylsalicylic acid (ASK) is possible;

· thrombosis of peripheral, coronary and brain arteries;

· secondary prevention of thrombosis and thromboembolism after a myocardial infarction and at atrial fibrillation.

Route of administration and doses:

Inside, in one step, at the same time days.

Initial dose – 2,5-5 mg/days. The further mode of dosing is set individually depending on results of definition of a prothrombin time or MNO. The prothrombin time has to be increased by 2-4 times from initial, and MNO has to reach 2,2-4,4 depending on a disease, danger of thrombosis, risk of development of bleedings and specific features of the patient.

When determining MNO it is necessary to consider an index of sensitivity of thromboplastin and to use this indicator as a correction factor (1,22 - when using domestic thromboplastin from a brain of a rabbit of "Neoplast" and 1,2 - when using thromboplastin of Roche Diagnostika). The elderly and weakened patient usually appoint lower doses of drug.

Before the forthcoming surgical intervention (at high risk of tromboembolic episodes) treatment is begun in 2-3 days prior to operation.

In case of acute thrombosis treatment is carried out to combinations with heparin until until the effect of peroral anticoagulating therapy completely is shown (not earlier than for 3-5 days of treatment).

At prosthetics of valves of heart, an acute venous vein thrombosis or a thromboembolism (at the initial stages), fibrinferment of a left ventricle and for prevention of ischemia of a myocardium needs to aim at the effective action which is noted at MHO 2,8-4.

In case of atrial fibrillation and when carrying out a maintenance therapy at a vein thrombosis and a thrombembolia try to obtain moderate anticoagulative effect (MHO 2,8-3).

At combined use of warfarin with acetylsalicylic acid the indicator of MNO has to be in limits 2-2,5.

Children. Data on use of warfarin for children are limited. The initial dose usually makes 0,2 mg/kg a day at normal function of a liver and 0,1 mg/kg a day – at disturbance. The maintenance dose is selected according to MNO indicators. The recommended MNO levels same, as well as at adults. At children the experienced specialist has to make the decision on purpose of a vrfarin. Treatment has to be carried out under observation of the pediatrician.

Duration of treatment depends on a condition of the patient. Treatment can be cancelled at once.

Features of use:

Use at pregnancy and during breastfeeding. Warfarin quickly gets through a placenta, has teratogenic effect on a fruit (the nasal hypoplasia and a chondrodysplasia, an atrophy of an optic nerve, a cataract leading to a total or partial blindness, a delay of intellectual and physical development, a nanocephalia). Can cause bleeding at the end of pregnancy and at the time of delivery in this connection pregnant women should not appoint drug. Warfarin to be removed with breast milk in insignificant quantity and does not influence coagulability of blood at the child therefore drug can be used in the period of a lactation. The nursing mother has to be under observation of the doctor, control a prothrombin time, the international normalized relation (INR). Prior to use of warfarin it is necessary to investigate the content of vitamin K at the baby in order to avoid development of bleeding in it. It is desirable to refrain from feeding by a breast in the first three days of therapy by warfarin.

Indispensable condition of therapy by warfarin is strict observance sick reception of the appointed drug dose.

The patients having alcoholism and also patients with dementia, can be incapable to observe the ordered warfarin reception mode. Such states as fever, a hyperthyroidism, dekompensirovanny heart failure, alcoholism with the accompanying damage of a liver, can strengthen effect of warfarin. At a hypothyroidism the effect of warfarin can be reduced. In case of a renal failure or a nephrotic syndrome the level of free fraction of warfarin in a blood plasma which depending on associated diseases can lead both to strengthening, and to decrease in effect increases. In case of a moderate liver failure the effect of warfarin amplifies. In all above-mentioned states careful monitoring of the MNO level has to be carried out.

The patients receiving warfarin as the anesthetizing drugs are recommended to appoint paracetamol, трамадол or opiates. In case of need treatment is recommended to begin approaches of bystry antitrombotichesky effect with administration of heparin; then within 5-7 days it is necessary to carry out a combination therapy by heparin and warfarin until the target objective of MNO does not remain within 2 days. In order to avoid a coumarinic necrosis to patients with hereditary insufficiency of an antitrombotichesky protein of C or S at first heparin has to be entered. The accompanying initial dose of loading should not exceed 5 mg. Administration of heparin has to continue within 5-7 days.

During treatment by warfarin it is necessary to abstain from the ethanol use (risk of development of a prothrombinopenia and bleedings).

In case of individual resistance to warfarin (meets seldom) achievement of therapeutic effect requires from 5 to 20 shock doses of warfarin. If reception of warfarin at such patients is inefficient, it is necessary to establish also other possible reasons among which are possible: a concomitant use of warfarin with other HP (see appropriate section of the instruction), an inadequate diet, laboratory mistakes.

Treatment of patients of advanced age has to be carried out with special precautions since synthesis of factors of coagulation and hepatic metabolism at such patients decreases owing to what the overshot effect from effect of warfarin can occur.

Side effects:

Most often:> 1/10 - bleeding.

Often:> 1/100, <1/10 – increase in sensitivity to warfarin after prolonged use.

Infrequently:> 1/1 000, <1/100 – anemia, vomiting, an abdominal pain, nausea, diarrhea.

Seldom:> 1/10 000, <1/1 000 – an eosinophilia, increase in activity of enzymes of a liver, jaundice, rash, urticaria, an itch, eczema, a skin necrosis, vasculites, a hair loss, nephrite, an urolithiasis, a tubular necrosis.

Bleedings. The most frequent risk factor for emergence of intracraneal hemorrhage. The probability of bleeding increases if MNO is much higher than the target objective. If bleeding began at MNO which is in limits of the target objective means there are other accompanying conditions which have to be investigated.

From the alimentary system. Vomiting, nausea, diarrhea.

Necroses. Coumarinic necrosis. The necrosis develops in 90% of cases at women. Defeats are observed from the 3rd to the 10th day of administration of drug and the etiology assumes insufficiency of an antitrombotichesky protein of C or S.

Palmar and bottom syndrome. Very rare complication at therapy by warfarin, its development is characteristic of men with atherosclerotic diseases.

Others. The hypersensitivity reactions which are shown in the form of skin rash and characterized by reversible increase in concentration of enzymes of a liver, cholestatic hepatitis, a vasculitis, a priapism, a reversible alopecia and calcification of a trachea. Independent risk factors of development of serious bleedings at treatment by warfarin are: advanced age, high intensity of the accompanying anticoagulating and antiagregantny therapy, existence in the anamnesis of strokes and gastrointestinal bleedings. The risk of bleedings is increased at patients with polymorphism of a gene of CYP2C9.

Recommendations about warfarin use.

In case of insignificant bleeding:

- at the MNO level <5,0 - to pass the following dose of warfarin and to continue reception of lower doses at achievement of the MNO therapeutic level;

- at the MHO 5,0-9,0 level - to pass 1-2 doses of warfarin and to continue reception of lower doses at achievement of the MNO therapeutic level. Or to pass 1 dose of warfarin and to appoint vitamin K in doses of 1-2,5 mg orally.
 
- at the MNO level> 9,0 - drug withdrawal is shown;

- at the MHO 5,0-9,0 level at the planned operation - to stop reception of warfarin and to appoint vitamin K in doses of 2,0-4,0 mg orally (in 24 hours prior to the planned operation);

- at the MNO level> 20,0 or at severe bleeding - to appoint vitamin K in doses of 10 mg by slow intravenous infusion. Transfusion of concentrates of factors of a prothrombin complex or freshly frozen plasma or whole blood. If necessary repeated administration of vitamin K each 12 hours.

Interaction with other medicines:

Non-steroidal anti-inflammatory drugs (NPVP), Dipiridamolum, valproic acid, P450 cytochrome inhibitors (Cimetidinum, chloramphenicol) increase risk of development of bleedings. It is necessary to avoid the combined use of these medicines (M) and warfarin (Cimetidinum can be replaced with ranitidine or famotidine). In need of treatment by chloramphenicol anticoagulating therapy should be stopped temporarily.

Diuretics can reduce effect of anticoagulants (in case of the expressed hypovolemic action which can lead to increase in concentration of blood-coagulation factors).

Weaken effect of warfarin: barbiturates, vitamin K, глутетимид, griseofulvin, диклоксациллин, carbamazepine, миансерин, paracetamol, retinoids, rifampicin, сукральфат, phenazone, Colestyraminum.

Strengthen effect of warfarin: Allopyrinolum, Amiodaronum, anabolic steroids (alkylated in situation C17), ASK, etc. NPVP, heparin, glibenclamide, a glucagon, даназол, diazoxide, Disopyramidum, Disulfiramum, an isoniazid, кетоконазол, кларитромицин, Clofibratum, levamisole, metronidazole, Miconazolum, Acidum nalidixicum, нилутамид, омепразол, пароксетин, proguanil, peroral hypoglycemic HP - derivatives of streptocides, симвастатин, streptocides, Tamoxifenum, thyroxine, quinine, quinidine, флувоксамин, флуконазол, ftoruratsit, hinolona, Chlorali hydras, chloramphenicol, cephalosporins, Cimetidinum, erythromycin, Acidum etacrynicum, ethanol. In case of the combined use of warfarin with above-mentioned drugs it is necessary to carry out control of MNO at the beginning and at the end of treatment and whenever possible in 2-3 weeks from the beginning of therapy.

When using HP (for example, laxatives) which can increase risk of development of bleedings because of decrease in normal coagulation (inhibition of blood-coagulation factors or enzymes of a liver), the strategy of anticoagulating therapy has to be defined by a possibility of carrying out laboratory control. If frequent laboratory control is possible, then in need of therapy in similar HP the dose of warfarin can be reduced by 5-10%. If carrying out laboratory control is complicated, then in case of need purposes of the specified HP warfarin should be cancelled.

Contraindications:

Hypersensitivity, acute bleeding, serious illness of a liver or kidneys, heavy arterial hypertension, acute IDCS, deficit of proteins C and S, hemorrhagic diathesis, thrombocytopenia, peptic ulcer of a stomach and 12-perstny gut in aggravation stages, hemorrhage in a brain, alcoholism, a renal failure, pregnancy, a hereditary lactose intolerance, deficit of lactase, glyukozo-galaktozny malabsorption.

Overdose:

The indicator of efficiency of treatment to be on border of development of bleedings therefore the patient can have insignificant bleedings, for example, a microhematuria, bleeding of gums, etc. In mild cases it is enough to lower a dose of drug or to stop treatment for short term. At insignificant bleedings it is enough to stop administration of drug before achievement of MNO of the target objective. In case of development of heavy bleeding – administration of vitamin K (intravenously) and absorbent carbon, a concentrate of factors of coagulation or freshly frozen plasma. If peroral anticoagulants are shown to appointment further, it is necessary to avoid high doses of vitamin K since resistance to warfarin develops within 2 weeks.

After performing treatment long observation of the patient is necessary, considering that the elimination half-life of warfarin makes 20-60 hours.

Storage conditions:

In the dry place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 2,5 mg. On 5, 10, 14, 20 or 25 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 2, 3, 4, 5 either 10 blister strip packagings or to bank with the application instruction in a pack from a cardboard. On 50, 100 or 250 tablets in a polymeric or glass jar with a cover.