Warfarin

General characteristics. Structure:

Active ingredient: 1 mg, 2,5 mg or 5 mg of warfarin of sodium salt.

Excipients: lactose anhydrous, prezhelatinizirovanny corn starch, magnesium the stearate (Е 572) painting a pigment - D&C Red #6, quinolinic yellow (Е 104), indigo carmine (Е 132), aluminum the oxide hydrated.

Pharmacological properties:

Pharmacodynamics. Warfarin (4 hydroxycoumarin) - anticoagulant of indirect action which prevents vitamin K-dependent synthesis of blood-coagulation factors of II, VII, IX and X, proteins of C and S at the expense of dozozavisimy inhibition of C1 subunit vitamin K - epoksidreduktaza therefore products K1 epoxide vitamin decrease. The period of semi-life of blood-coagulation factors makes: a factor of II - 60 hours; factor of VII 4-6 hours, factor of IX 24 hour, and X 48-72 hour. The period of semi-life of proteins C and S makes about 8 hours and 30 hours, respectively. Therefore in vivo occurs consecutive oppression of activity of factors of VII, IX, X and Item.

Vitamin K is a necessary cofactor for postribosomalny synthesis vitamin K of dependent blood-coagulation factors. Vitamin promotes synthesis of the remains gamma карбоксиглютаминовой acids in proteins which are necessary for biological activity. Warfarin influences synthesis of blood-coagulation factors by K1 vitamin epoxide regeneration braking. Degree of a depression depends on the applied dosage.

Therapeutic doses of warfarin reduce the total amount of an active form of each factor of coagulant system of blood of the vitamin K created by a liver approximately from 30% to 50%. The anticoagulating effect occurs in 24 hours after administration of drug. However, the maximum anti-coagulative effect occurs in 72-96 hours. Duration of action of a single dose of ratsematny mix of warfarin of 2-5 days. The effect of warfarin amplifies at daily reception. Anticoagulants have no direct effect on the created blood clot and do not recover the fabrics struck from ischemia. If blood clot was formed, the purpose of anticoagulating therapy is prevention of increase in blood clot and tromboembolic episodes which can lead to serious and perhaps fatal effects.

Pharmacokinetics. Warfarin is the mix R-and S-of enantiomer. At the person of S-enantiomer has by 2-5 times bigger anticoagulating activity, than R-enantiomer, however Т½ is longer than the last.

Absorption. At oral administration warfarin is almost completely soaked up from a GIT, the maximum concentration in an organism is reached within the first 4 hours.

Distribution in an organism. Obvious distinctions in volume of distribution of drug as a result of intravenous administration or oral administration of one dose are not observed. Warfarin is distributed in rather small volume of distribution - about 0,14 l/kg. The phase of distribution lasts 6-12 hours, distinguishable after bystry in/in introductions or dissolution after oral administration. Warfarin gets through a placenta and reaches the concentration close to concentration at mother, however in breast milk is not found. About 99% of drug contact proteins of plasma.

Metabolism. Warfarin is removed from an organism in the form of inactive metabolites. Drug is stereoselektivno metabolized by microsomal enzymes of a liver (R-450 cytochrome) to inactive hydroxylated metabolites (the prevailing way) and reductases (thus warfarin alcohols are formed). Alcohols of warfarin have insignificant anticoagulating activity. Metabolites of warfarin are removed, mainly, by kidneys and, to a lesser extent, with bile. The identified warfarin metabolites: дегидроварфарин, two diastereoisomers of alcohol, 4, 6-,7-, 8-and 10 - hydroxywarfarin. In the course of metabolism uchuvstvut such isoenzymes as 2S9, 2S19, 2S8, 2S18, 1A2 and ZA4. The isoenzyme 2C9 is probably the leading form of R-450 cytochrome in a liver of the person which is responsible for anticoagulating activity of in vivo warfarin.

Removal. The terminal elimination half-life of warfarin after the single accepted dose makes about one week; at the same time, the real elimination half-life varies from 20 to 60 hours (on average 40 hours). The clearance of R-warfarin is twice less, than S-warfarin, however as volumes of distribution are similar, the elimination half-life of R-enantiomera is longer, than S-enantiomera. Т½ for R-enantiomera - 37-89 h, for S-enantiomera - 21-43 h. Researches with the help it is radioactive marked warfarin showed that more than 92% of orally accepted drug are found in urine. Only a little warfarin is removed with urine in an invariable look, the main part is excreted in the form of metabolites.

Elderly people. At elderly people at the age of 60 years is also more senior more the ratio PT/INR (prothrombin time / the international normalized relation) at warfarin reception changes. Cases of increase in sensitivity to warfarin in this age group were not noted. Increase in anticoagulating effect of warfarin can be connected with pharmacokinetic or pharmakodinamichesky factors. The clearance of racemic warfarin can remain invariable or decrease with age. It is supposed that distinction in clearance of S-warfarin at elderly people does not change in comparison with young people with age. At the same time, the clearance of R-warfarin can slightly decrease. Thus, with age it is usually necessary to select a smaller therapeutic dose of warfarin for the patient.

Renal failure. The renal clearance slightly influences anticoagulating activity of warfarin. Correction of a dose of warfarin with a renal failure is not required from patients.

Liver failure. The liver failure can strengthen effect of warfarin through disturbance of synthesis of anti-coagulating factors of coagulation and delay of metabolism of warfarin. At in administration of drug, as well as at oral administration in blood identical concentration, however time of achievement of the maximum concentration are reached at in introduction in plasma it is reached earlier. The full anticoagulating effect of warfarin is reached not earlier than in 71-96 hours after introduction. It testifies, in/in administration of warfarin will not bark advantage before oral administration concerning bigger anticoagulating activity and earlier term of manifestation of therapeutic effect.

Indications to use:

Treatment and prevention of thromboses and embolism of blood vessels: acute and recurrent venous thrombosis, embolism of a pulmonary artery. Secondary prevention of a myocardial infarction and prevention of tromboembolic episodes after a myocardial infarction. Prevention of tromboembolic episodes at patients with fibrillation of auricles, damages of heart valves or with the fitted a prosthesis heart valves. Treatment and prevention of the passing ischemic attacks and strokes, prevention of postoperative thromboses.

Route of administration and doses:

Inside, 1 time a day it is desirable at the same time. Duration of treatment is defined by the doctor. Before the beginning define the international normalized relation (MHO). Further laboratory control is carried out regularly by each 4-8 weeks. Duration of treatment depends on a clinical condition of the patient. Treatment can be cancelled at once. The prothrombin time has to be increased by 2-4 times from initial, and MNO has to reach 2,2-2,4 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 thromboplastin from a brain of a rabbit of "Neoplast" and 1,2 when using thromboplastin of production "Roche Diagnostika").

Patients who did not accept Warfarin earlier. The initial dose makes 5 mg/days during the first 4 days. For the 5th day of treatment MNO is defined and, according to this indicator, the maintenance dose of drug is appointed. Usually maintenance dose of drug makes 2,5-7,5 mg/day (1-3 tablets a day).

Patients who accepted Warfarin earlier. The recommended starting dose makes a double dose of the known maintenance dose of drug and is appointed during the first 2 days. Then treatment is continued by means of the known maintenance dose. For the 5th day of treatment carry out control of MHO and dose adjustment according to this indicator. It is recommended to support an indicator of MHO from 2 to 3 in case of prevention and treatment of venous thrombosis, an embolism of a pulmonary artery, fibrillation of auricles, a dilyatatsionny cardiomyopathy, the complicated diseases of valves of heart, prosthetics of valves of heart of bioprostheses. Higher rates of MHO from 2,5 to 3,5 are recommended at prosthetics of valves of heart by mechanical prostheses and the complicated acute myocardial infarction.

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 an abnormal liver function. The maintenance dose is selected according to MHO indicators. The recommended MHO levels same, as well as at adults. At children the experienced specialist has to make the decision on purpose of warfarin. Treatment has to be carried out under observation of the experienced specialist - the pediatrician. Doses are selected according to the table given below:

I. Day 1	If basic MHO value from 1.0 to 1.3, then a shock dose makes 0.2 mg/kg of body weight.
II. Days with 2 on 4, if MHO value:	Actions:
from 1 to 1.3	To repeat a shock dose;
from 1.4 to 1.9	50% of a shock dose;
from 2.0 to 3.0	50% of a shock dose;
from 3.1 to 3.5	25% of a shock dose;
> 3.5	To stop administration of drug before achievement of MHO <3.5, then to resume treatment by the dose making 50% of the previous dose.
III. Maintenance, if MHO value:	Actions (week dose):
from 1 to 1.3	To raise a dose for 20%;
from 1.4 to 1.9	To raise a dose for 10%;
from 2.0 to 3.0	Without changes;
from 3.1 to 3.5	To lower a dose by 10%;
> 3.5	To stop administration of drug before achievement of MHO <3.5, then to resume treatment by a dose for 20% smaller, than previous.

Elderly people. There are no special recommendations about reception of warfarin at elderly people. However elderly patients have to is under careful observation since they have higher risk of development of side effects.

Patients with a liver failure. Disturbance of functions of a liver increases sensitivity to warfarin as the liver produces blood-coagulation factors, and also metabolizes warfarin. At this group of patients careful monitoring of indicators of MHO is necessary.

Patients with a renal failure. Patients with a renal failure do not need any special recommendations about selection of a dose of warfarin. The patients who are on peritoneal dialysis do not need additional increase in a dose of warfarin.

Planned (elective) surgical interventions. Pre-, peri-and post-operational anticoagulating therapy is carried out as shown below (if urgent cancellation of peroral anticoagulating effect - see the section "Overdose" is necessary).

Overdose. To define MNO one week prior to the appointed operation. To stop reception of warfarin for 1 - 5 days before operation. In case of high risk of thrombosis to the patient for prevention subcutaneously enter low-molecular heparin.

Pause duration in reception of warfarin depends on MHO. Reception of warfarin is stopped:

- in 5 days prior to operation, if MHO> 4,0

- in 3 days prior to operation, if MHO from 3,0 to 4,0

- in 2 days prior to operation, if MHO from 2,0 to 3,0

To define MHO in the evening before operation and to enter 0,5 - 1,0 mg of K1 vitamin orally or intravenously if MNO> 1,8.

To take into account need of infusion of unfractionated heparin or preventive administration of low-molecular heparin in day of operation.

To continue hypodermic administration of low-molecular heparin within 5-7 days after operation with the accompanying recovered warfarin reception.

To continue reception of warfarin from a usual maintenance dose on the same day in the evening after small operations, and in day when the patient begins to receive an enteroalimentation after large operations.

Features of use:

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.

Precautionary measures. Such states as fever, a hyperthyroidism, dekompensirovanny heart failure, alcoholism with the accompanying damages 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 MHO level has to be carried out.

The patients receiving warfarin as the anesthetizing drugs are recommended to appoint paracetamol, трамадол or opiates.

Patients with a mutation of the gene coding CYP2C9 enzyme have longer period of a poluvshedeniye of warfarin. Lower doses of drug since at reception of usual therapeutic doses the risk of bleedings increases are required for these patients. It is not necessary to accept warfarin to patients with hereditary intolerance of a galactose, deficit of enzyme of lactase, disturbance of absorption of glucose and a galactose. In case of need approaches of bystry antitrombichesky effect, treatment is recommended to begin 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 MHO does not remain within 2 days (see the section Route of administration and doses).

In order to avoid a coumarinic necrosis to patients with hereditary insufficiency of an antitrombichesky 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.

In case of individual resistance to warfarin (meets very 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 as that: a concomitant use of warfarin with other medicines (see appropriate section of this 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.

Features of influence of medicine on ability to manage the vehicle or potentially dangerous mechanisms: there are no data on adverse influence of warfarin on ability to control of vehicles and to service of other mechanisms.

Use during pregnancy and in the period of a lactation. Use of warfarin during pregnancy is contraindicated. Warfarin breaks a placental barrier and can cause bleeding in a fruit. There are messages on congenital anomalies and disturbances of development in children which mothers during pregnancy accepted warfarin. It is necessary to weigh carefully indications to use of warfarin for women of childbearing age, patients it is necessary to warn about need of effective contraception. It is known that warfarin gets into mother's milk only in a minute quantity and usually does not influence a blood coagulation of babies, however, at purpose of warfarin during breastfeeding it is recommended to define MHO at children. If drug has to be used in high doses, feeding by a breast is recommended to be stopped.

Side effects:

Very often - bleeding; often: - increase in sensitivity to warfarin after prolonged use; infrequently - anemia, vomiting, an abdominal pain, nausea, diarrhea; seldom:> 1/10000, <1/1000 - 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. For a year of bleeding are observed approximately in 8% of cases among the patients receiving warfarin. From them 1,0% 0,25% as fatal are classified as heavy (intracranial, retroperitoneal), leading to hospitalization or hemotransfusion, and. The most frequent risk factor for emergence of intracraneal hemorrhage - not treated or uncontrollable hypertensia. The probability of bleeding increases if MHO is much higher than the target objective. If bleeding began at MHO 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. A coumarinic necrosis - a rare complication at treatment by warfarin. The necrosis usually begins with swelling and darkening of skin of the lower extremities and buttocks, or (more rare) in other places. After defeat become necrotic. 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 antitrombichesky protein of C or S. Inborn insufficiency of these proteins can be the cause of complications therefore reception of warfarin has to begin along with administration of heparin and small initial doses of drug. If there is a complication, then reception of warfarin is stopped and continue administration of heparin before healing or scarring of defeats.

Palmar and bottom syndrome. Very rare complication at therapy by warfarin, its development is characteristic among men with ateroskolerotichesky diseases. As assume, warfarin causes the hemorrhages of atheromatous plaques leading to microembolisms. The symmetric purple damages of skin of fingers and a podopsha of feet which are followed by thermalgias meet. After the warfarin reception termination the specified symptoms gradually disappear.

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, vasculitis, priapism, 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.

Interaction with other medicines:

It is not RECOMMENDED to begin or stop reception of other medicines, and also to change doses of the accepted drugs without consultation with the attending physician. At co-administration it is also necessary to consider effects of the termination of induction and/or inhibition of effect of warfarin other medicines.

The risk of development of heavy bleedings increases at a concomitant use of warfarin with the drugs influencing the level of thrombocytes and primary hemostasis: acetylsalicylic acid, klopidogret, тиклопидин, Dipiridamolum, the majority of non-steroidal anti-inflammatory drugs (except for cyclooxygenase-2 inhibitors), antibiotics of group of penicillin in high doses.

Also it is necessary to avoid the combined use of warfarin with the drugs possessing the expressed inhibiting effect on system of P450 cytochrome, for example, Cimetidinum and chloramphenicol at which reception during several days danger of bleeding increases. In similar cases Cimetidinum can be replaced, for example, with ranitidine or famotidine.

The effect of warfarin can amplify at a concomitant use with the following medicines: acetylsalicylic acid, Allopyrinolum, Amiodaronum, азапропазон, azithromycin, alpha and beta interferon, amitriptyline, безафибрат, vitamin A, vitamin E, glibenclamide, a glucagon, gemfibrozit, heparin, грепафлоксацин, даназол, dextropropoxyphene, diazoxide, digoxin, Disopyramidum, Disulfiramum, зафирлукаст, indometacin, ифосфамид, итраконазол, кетоконазол, кларитромицин, Clofibratum, codeine, levamisole, ловастатин, метолазон, a methotrexate, metronidazole, Miconazolum (including in the form of oral cavity gel), Acidum nalidixicum, norfloxacin, ofloxacin, омепразол, оксифенбутазон, paracetamol (especially after 1 - 2 weeks of constant reception), пароксетин, piroxicam, proguanil, пропафенон, propranolol, an anti-influenza vaccine, рокситромицин, sertraline, симвастатин, сульфафуразол, сульфаметизол, sulfamethoxazole Trimethoprimum, сульфафеназол, Sulfinpyrazonum, сулиндак, steroid hormones (anabolic and/or androgenic), Tamoxifenum, Tegafurum, testosterone, tetracyclines, thiensilt acid, толметин, трастузумаб, гроглитазон, Phenytoinum, phenylbutazone, фенофибрат, фепразон, флуконазол, fluoxetine, ftoruratsit, флувастатин, флувоксамин, флутамид, quinine, quinidine, Chlorali hydras, chloramphenicol, целекоксиб, цефамандол, cefalexin, tsefmenoksy, цефметазол, цефоперазон, tsefuroksy, cytidine, ciprofloxacin, cyclophosphamide, erythromycin, этопозид, ethanol.

Drugs of some medicinal plants (ofitsinalny or neofitsinalny) also can how to strengthen effect of warfarin: for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica medicinal (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza); and to reduce: for example: ginseng (Panax ginseng), St. John's Wort (Hypericum perforatum).

It is impossible to accept at the same time warfarin and any drugs of a St. John's Wort, at the same time it is necessary to consider that the effect of induction of effect of warfarin can remain within 2 more weeks after the termination of administration of drugs of a St. John's Wort. If the patient accepts St. John's Wort drugs, it is necessary to measure MHO and to stop reception. Monitoring of MHO has to be careful since its level can increase at cancellation of a St. John's Wort. After that it is possible to appoint warfarin.

Also the quinine which is contained in tonics can strengthen effect of warfarin.

Warfarin can strengthen action of peroral hypoglycemic means of derivatives of sulphonylurea.

The effect of warfarin can be weakened at a concomitant use with the following medicines: Azathioprinum, aminoglutetimidy, barbiturates, valproic acid, vitamin C, vitamin K, glutetimidy, griseofulvin, dikloksatsilliny, Disopyramidum, carbamazepine, Colestyraminum, coenzyme Q10, Mercaptopurinum, mesalaziny, mianseriny, Mitotanum, naftsilliny, Primidonum, retinoids, ritonaviry, rifampicin, rofekoksiby, Spironolactonum, sukralfaty, Trazodonum, phenazone, chlordiazepoxide, Chlortalidonum, cyclosporine. Reception of diuretics in case of the expressed hypovolemic action can lead to increase in concentration of factors of coagulability that reduces effect of anticoagulants. In case of the combined use of warfarin with other drugs specified in the list given below it is necessary to carry out control (MHO) at the beginning and at the end of treatment, and, whenever possible, in 2-3 weeks from the beginning of therapy.

The food rich with vitamin K weakens effect of warfarin; the vitamin K absorption reduction caused by diarrhea or reception of purgatives exponentiates effect of warfarin. Most of all vitamin K contains in green vegetables therefore at treatment by warfarin, it is necessary to eat the following products with care: greens of an amaranth, avocado, broccoli cabbage, Brussels sprout, headed cabbage, oil of the channel, leaf шайо, onions, coriander (cilantro), cucumber peel, chicory, kiwi fruits, lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red algas, spinach greens, spring onions, soybeans, tea leaves (but not tea drink), turnip greens, garden cress.

Contraindications:

The established or suspected hypersensitivity to drug components, acute bleeding, pregnancy (the first trimester and the last 4 weeks of pregnancy), a serious illness of a liver or kidneys, an acute IDCS, deficit of proteins C and S, thrombocytopenia, patients with high risk of bleedings, including patients with hemorrhagic frustration, a gullet varicosity, aneurism of arteries, a lumbar puncture, a peptic ulcer of a stomach and a 12-perstny gut, with heavy wounds (including operating rooms), a bacterial endocarditis, malignant hypertensia, a hemorrhagic stroke, intracraneal hemorrhage.

Overdose:

Symptoms: bleeding, bleeding. The indicator of efficiency of treatment is on border of development of bleedings therefore the patient can have insignificant bleedings, for example, a microhematuria, bleeding of gums, etc.

Treatment: 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 MHO 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.

The scheme of treatment at overdose;

MHO level	Recommendations
<5,0	To pass the following dose of warfarin and to continue reception of lower doses at achievement of the therapeutic MHO level
5,0-9,0	To pass 1-2 doses of warfarin and to continue reception of lower doses at achievement of the therapeutic MHO level. OR: To pass 1 dose of warfarin and to appoint vitamin K in doses of 1 - 2,5 mg orally.
> 9,0	To stop warfarin reception, to appoint vitamin K in doses of 3,0-5,0 mg orally.
Drug withdrawal is shown
5,0-9,0-operation is planned	To stop reception of warfarin and to appoint vitamin K in doses of 2 - 4 mg orally (in 24 hours prior to the planned operation)
> 20,0 or 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

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

Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity: 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Dosage of 1 mg: on 50 tablets in banks polymeric or glass. Each can together with the application instruction is placed in a pack from a cardboard.

Dosages of 2.5 mg and 5 mg: on 30 tablets in banks polymeric or glass. Each can together with the application instruction is placed in a pack from a cardboard.