Warfarin

General characteristics. Structure:

Active agent: sodium warfarin кпатрат (warfarin of sodium and isopropanol a clathrate) in terms of warfarin of sodium of 2,5 mg.

Excipients: lactoses monohydrate (sugar milk) —/5,0 mg, cellulose microcrystallic — 15,27 mg, крословидон — 1,0 mg, povidone (polyvinylpirrolidone) — 3,5 mg, starch prezhelatinizirovanny — 2,0 mg, magnesium stearate — 0,50 mg.

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 K-epoksidreduktazy vitamin therefore products K1 epoxide vitamin decrease. Warfarin S-ieomer approximately by 5 times surpasses R-ieomer in activity. In therapeutic doses warfarin reduces the speed of synthesis of factors of coagulation by 30-50% and reduces their biological activity. The beginning of anticoagulative action is observed in 36-72 h from the beginning of administration of drug with development of the maximum effect for 5-7 day of the beginning of use. After the termination of administration of drug activity recovery vitamin of K-dependent blood-coagulation factors occurs within 4-5 days.

Absorption — bystry. The concomitant use of food slows down absorption, but does not reduce it quantitatively. Bioavailability — more than 90%. Time of achievement of the maximum concentration (Tstakh) is 3-9 h. Communication with proteins of plasma — 97-99%. The volume of distribution is about 0.1 l/kg. Gets through a placenta, but not into breast milk. It Metabolizmrutsya in a liver. Warfarin represents racemic mix, and R-and S-isomers metabolieirutsya in a liver in various ways. Each of isomers will be transformed to 2 main metabolites.
S-enantiomer metabolism rutsya by CYP2C9 isoenzyme, and R-enantiomer — CYP1A2 and CYP3A4 ieo-enzymes. S-enantiomer has by 2-5 times bigger anti-коагупянтной activity, than R-enantiomer, however the elimination half-life (T1/2) of the last is longer. Patients with polymorphism of an isoenzyme of CYP2C9, including alleles of CYP2C9*2 and CYP2C9*3, can have hypersensitivity to warfarin and the increased risk of development of bleedings.
Warfarin is removed from an organism in the form of inactive metabolites with bile which reabsorbirutsya in the digestive tract (DT) and are removed by kidneys. Average T1/2 — 20-60 h, for R-enantiomera — 37-89 h, for S-enantiomera — 21-43 h.

Indications to use:

Treatment and prevention of a deep vein thrombosis and embolism of a pulmonary artery, tranzi-even ischemic attacks and ischemic stroke.
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.

Route of administration and doses:

Warfarin is appointed 1 time a day time is desirable in one and too. Duration of treatment is defined by the doctor according to indications to use. Control during treatment:
Before therapy 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.
Patients who did not accept Warfarin earlier:
The initial dose makes 5 mg/days (2 таб. in days) during the first 4 days. For the 5th day of treatment MHO 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/days (1-3 tablet 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 a nakrusheniya of function of a liver. 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 pediatrician. Doses are selected according to the table given below.

Day 1                                If basic MHO value from 1,0 to 1,3, then
                                       the shock dose makes 0,2 mg/kg of body weight
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. 
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
                                      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 metabopizirut варфа¬рин. At this fuppa of patients careful monitoring of pokazatekly 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 ukazakno below.

To define MHO one week prior to the appointed operation. 
To stop reception of warfarin in 1-5 days prior to operation. In case of high risk of thrombosis to the patient for prevention subcutaneously enter low-molecular Hepacrinum. 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 MHO> 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
enteroalimentation after large operations.

Features of use:

Indispensable condition of therapy by warfarin is strict observance sick reception of the recommended drug dose.
Target MHO value for peroral anticoagulating therapy for a profiklaktika of tromboembolic episodes at patients with the fitted a prosthesis heart valves — 2.5-3; for other indications — 2-3.
Patients with alcoholism or dementia, can be incapable to observe the ordered warfarin reception mode.
At such states as fever, a hyperthyroidism, dekompensirovanny heart failure, alcoholism with the accompanying damages of a liver, effect of warfarin can amplify. At a hypothyroidism the effect of warfarin can be reduced. In case of a chronic renal failure or a nephrotic syndrome concentration of free fraction of warfarin in plasma which depending on associated diseases can lead both to strengthening, and to decrease in effect increases. In case of a moderate chronic renal failure the effect of warfarin amplifies. In all above-mentioned states careful control of MHO has to be carried out.
The patients receiving warfarin as analgeziruyushchy medicines are recommended to appoint paracetamol, трамадол or narcotic analgetics.
For 1 year of treatment of bleeding are observed approximately in 8% of cases. From them 1% is classified as heavy (intracranial, retroperitoneal), leading to hospitalization or hemotransfusion, and 0.25% — as fatal. The most frequent risk factor of intracraneal hemorrhage — uncontrollable arterial hypertension. The probability of bleeding increases if MHO is much higher than target value. If bleeding began at MHO which is in limits of target value, so there are other risk factors which have to be investigated.
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, is 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 deficit of 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. A palmar and bottom syndrome — a rare complication at therapy by warfarin, its development is characteristic of men with ateroskolerozy. Warfarin causes the hemorrhages of atheromatous plaques leading to microembolisms. There are symmetric purple damages of skin of fingers and soles of feet which are followed by thermalgias. After the warfarin reception termination the specified symptoms gradually disappear. At use of warfarin there can be hypersensitivity reactions which are shown in the form of skin rash and characterized by reversible increase in activity of "hepatic" enzymes, cholestatic hepatitis, a vasculitis, a priapism, a reversible alopecia and calcification of a trachea. Risk factors of development of serious bleedings: advanced age, high intensity of the accompanying anticoagulating and antiagregantny therapy, strokes and gastrointestinal bleedings in the anamnesis, polymorphism of a gene of an isoenzyme of CYP2C9.
Patients with CYP2C9 isoenzyme gene mutation, have longer elimination half-life of warfarin. Lower doses of drug since at reception of usual therapeutic doses the risk of bleedings increases are required for these patients. In case of need achievements of bystry antitrombotichesky 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 target MHO value does not remain within 2 days. In order to avoid a coumarinic necrosis patients with hereditary insufficiency of protein of C or S at first should enter heparin.
The initial load dose should not exceed 5 mg. Administration of heparin has to continue within 5-7 days.
In case of rare individual resistance to warfarin achievement of therapeutic effect requires 5-20 load doses of warfarin. If reception of warfarin at such patients is inefficient, it is necessary to establish also other possible reasons, for example, a concomitant use of other medicines, an inadequate food allowance, laboratory mistakes. Treatment of elderly has to be carried out with care since synthesis of blood-coagulation factors and hepatic metabolism at such patients decreases owing to what effect of warfarin can amplify.
Impact on ability to drive the car and to work with the equipment
Does not render impact on ability to drive the car and to work with the equipment.

Side effects:

Frequency: very often — more than 1/10, it is frequent — more than 1/100 and less than 1/10, infrequently — more than 1/1000 and less than 1/100, is rare — more than 1/10000 and less than 1/1000. Very often: the raised bleeding.
Often: increase in sensitivity to warfarin after prolonged use. Infrequently: anemia, vomiting, abdominal pain, nausea, diarrhea.
Seldom: eosinophilia, increase in activity of "hepatic" enzymes, jaundice, rash, urticaria, itch, eczema, skin necrosis, vasculitis, hair loss, nephrite, urolithiasis, tubular necrosis, palmar and bottom syndrome.

Interaction with other medicines:

It is not recommended to begin or stop reception of other medicines, and also to change doses of the accepted medicines without consultation with the attending physician.
At the simultaneous use of warfarin and other medicines influencing a blood coagulation (including acetylsalicylic acid, klopidogret, тиклопидин, Dipiridamolum, the majority of non-steroidal anti-inflammatory drugs (except for low doses of TsOG-2 inhibitors)), penicillin in high doses, the risk of development of bleedings increases.
It is necessary to avoid the combined reception of warfarin with powerful inhibitors of microsomal enzymes of a liver (including Cimetidinum and hporamfenikoly) — increase in risk of development of bleeding. In similar cases Cimetidinum can be replaced with ranitidine or famotidine.
The anticoagulating effect of warfarin is strengthened: acetylsalicylic acid, Allopyrinolum, Amiodaronum, азапропазон, azithromycin, interferon an alpha, interferon a beta, amitriptyline, безафибрат, a vaccine for prevention of flu, vitamin E, glibenclamide, a glucagon, gemfibrozit, heparin, грепафлоксацин, даназол, dextropropoxyphene, diazoxide, digoxin, диэопирамид, Disulfiramum, зафирлукаст, indometacin, ифосфамид, итраконазол, кетоконаэол, кпаритромицин, Clofibratum, codeine, co-trimoxazole, певамизол, ловастатин, метолазон, a methotrexate, metronidazole, Miconazolum (including for topical and external use), male sex hormones (anabolic and/or androgenic, including testosterone), Acidum nalidixicum, norfloxacin, ofloxacin, омепразол, оксифенбутазон, paracetamol (especially after 1-2 weeks of constant reception), пароксетин, piroxicam, proguanil, пропафенон, propranolol, Retinolum, рокситромицин, sertraline, симвастатин, sul-fafurazol, сульфаметизол. сульфафеназол, Sulfinpyrazonum, сулиндак, Tamoxifenum, Tegafurum, tetratsikpina, thiensilt acid, толметин, трастузумаб, троглитазон, Phenytoinum, phenylbutazone, фенофибрат, фепразон, флуконазол, fluoxetine, ftoruratsit, флувастатин, фпувоксамин, флутамид, quinine, quinidine, Chlorali hydras, chloramphenicol, целекоксиб, цефамандол, cefalexin, tsefmenoksy, цефметазол, цефоперазон, tsefuroksy, Cimetidinum, ciprofloxacin, цикпофосфамид, erythromycin, этопозид, ethanol.
Some medicinal plants can also how strengthen effect of warfarin, for example, a ginkgo (Ginkgo biloba), garlic (Allium sativum), an angelica medicinal (Angelica sinensis), a papaya (Carica papaya), a sage (Salvia miltionfiiza), and to reduce, for example, a ginseng (Panax ginseng), a St. John's Wort made a hole (Hypericum perforatum).
It is not necessary to accept at the same time warfarin and drugs of the St. John's Wort which is made a hole as the effect of the inducing effect of warfarin on P450 cytochrome can remain within 2 more weeks after the termination of administration of drugs of the St. John's Wort which is made a hole. If the patient accepts drugs of the St. John's Wort which is made a hole it is necessary to define MHO and to stop reception. Control of MHO has to be careful since its value can increase at cancellation of drugs of the St. John's Wort which is made a hole. After that it is possible to appoint warfarin. Effect of warfarin can strengthen the quinine which is contained in tonics. Warfarin can strengthen hypoglycemic 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, ascorbic acid, barbiturates, valproic acid, sodium Menadionum bisulphite, glutetimidy griseofulvin, dikpoksatsilliny, Disopyramidum, carbamazepine, Colestyraminum, Mercaptopurinum, mesalaziny, mianseriny, Mitotanum, naftsilliny, Primidonum, retinoids, ritonaviry, rifampicin, rofekoksiby, Spironolactonum, sukralfaty, Trazodonum, ubidekarenony, phenazone, chlordiazepoxide, Chlortalidonum, cyclosporine. Reception of diuretics in case of the expressed hypovolemic action can lead to increase in concentration of blood-coagulation factors that reduces effect of anticoagulants. In case of the combined use of warfarin with other drugs 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 decrease in absorption of vitamin K caused by diarrhea or reception of purgatives strengthens effect of warfarin. Most of all vitamin K contains in green vegetables therefore when baking by warfarin it is necessary to eat the following products with care: greens of an amaranth, avocado, broccoli cabbage, Brussels sprout, white 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:

Hypersensitivity to drug components, tendency to bleedings (an angiohemophilia, hemophilia, thrombocytopenia, disturbances of functions of thrombocytes, hemorrhagic diathesis), an acute IDCS. deficit of proteins C and S; the conditions contributing to bleedings (including gastrointestinal bleedings in the anamnesis, a peptic ulcer of a stomach and a 12-perstny gut in aggravation stages, a divertuculosis, malignant tumors, a varicosity of a gullet, an aneurysm of arteries, a lumbar puncture); recently postponed intracraneal hemorrhage (including aneurism of cerebral arteries, a hemorrhagic stroke); recently undergone or alleged difficult operations of the central nervous system, ophthalmologic operations and diagnostic procedures; dementia, psychosis, alcoholism and other states at which the insufficient possibility of assessment of a condition of coagulant system of blood by means of laboratory methods is noted; heavy arterial hypertension. The expressed renal and/or liver failure, a serious illness of a liver or kidneys; mechanical jaundice; infectious endocarditis or exudative pericardis; diabetes mellitus; tendency to falling; pregnancy (I and III trimester). Lactose intolerance, deficit of lactase and syndrome of glyukozo-galaktozny malabsorption.

With CARE — advanced age, fever, hyper - and a hypothyroidism, noncompensated heart failure, alcoholism with the accompanying damages of a liver, a chronic renal failure of easy and moderate degree of manifestation, a nephrotic syndrome, a moderate liver failure.

PREGNANCY AND PERIOD OF THE LACTATION
Warfarin quickly gets through a placenta, has teratogenic effect on a fruit (a nasal hypoplasia and Hondas a sort an isplaziya, an atrophy of an optic nerve, the cataract leading to a total or partial blindness, a delay of intellectual and physical development and a nanocephalia) on 6-12 week of pregnancy. Drug can cause bleeding at the end of pregnancy and at the time of delivery. It is impossible to appoint drug in the 1st trimester of pregnancy and within the last 4 weeks. Use of warfarin is not recommended in remaining periods of pregnancy, except emergency cases. Warfarin is removed with breast milk in the neiz-measured quantities and does not influence coagulant activity of the raised child. Warfarin can be used during a lactation.

Overdose:

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. In mild cases it is enough to lower a dose of drug or to stop baking 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.
SCHEMES OF TREATMENT AT OVERDOSE:

 In case of insignificant bleeding
                             Recommendation MHO level
<5,0                                    to Pass the following dose of warfarin and to continue reception bo-
                                            leu of low doses at achievement of the therapeutic MHO level

5,0-9,0                                To pass 1-2 doses of warfarin and to continue reception more
                                           low doses at achievement of the therapeutic MHO level. OR:
                                           To pass 1 dose of warfarin and to appoint vitamin K in doses
                                           1-2,5 mg orally. 

> 9,0                                    to Stop warfarin reception, to appoint vitamin K in doses
                                          3,0-5,0 mg orally. 
Drug withdrawal is shown 
                                   Recommendation MHO level 

5,0-8,0 — plani-               to Stop reception of warfarin and to appoint vitamin K in doses
operation                 of 2-4 mg orally rutsya (in 24 hours prior to the planned operation)

> 20, or strong              to Appoint vitamin K in doses of 10 mg in the way slow vnutriven-
                                        bleeding ache infusions. Transfusion of concentrates of factors protrombi-
                                         new complex or freshly frozen plasma, or integral
                                        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:

To store in the dry, protected from light place at a temperature not above 25 °C. To store in the place protected from children. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets on 2,5 mg.
On 10,50 tablets place in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 10, 20, 30, 40, 50 or 100 tablets place in a container polymeric for medicines. One container or 1,2, 3,4,5 or 10 blister strip packagings together with the application instruction place in a pack from a cardboard.