Warfarin Nikomed

General characteristics. Structure:

Active component: Warfarin of sodium of 2,5 mg
Auxiliary components: lactose, starch corn, hydrophosphate calcium dihydrate, indigo carmine, povidone 30, magnesium stearate.

Description
Round tablets of a biconvex form with crosswise risky, light blue color.

Pharmacological properties:

Warfarin blocks in a liver synthesis vitamin K of dependent blood-coagulation factors, namely, a factor of II, VII, IX and X. Concentration of these components in blood decreases, process of coagulability is slowed down. The beginning of anticoagulative action is observed in 36-72 hours 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.

Pharmacokinetics. Drug is quickly soaked up from digestive tract. Linkng with proteins of a blood plasma makes 97-99%. It is metabolized in a liver. Warfarin represents racemic mix, and R-and S-isomers are metabolized in a liver in various ways. Each of isomers will be transformed to 2 main metabolites. The main catalyst of metabolism for S-enantiomer of warfarin is CYP2C9 enzyme, and for R-enantiomer of CYP1A2 and CYP3A4 warfarin. Left-handed isomer of warfarin (S - warfarin) has by 2-5 times bigger anticoagulating activity, than dextrorotatory isomer (R-enantiomer), however the elimination half-life of the last is more. 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. Warfarin is removed from an organism in the form of inactive metabolites with bile which reabsorbirutsya in a GIT and are allocated with urine. The elimination half-life makes from 20 to 60 hours. For R-enantiomera the elimination half-life makes from 37 to 89 hours, and for S-enantiomera from 21 to 43 hours.

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:

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 day) 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/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: 

> 3,5                                    to Repeat a shock dose; 

from 1 to 1,3                          50% of a shock dose; 

from 1,4 to 1,9                       50% of a shock dose; 

from 2,0 to 3,0                       25% of a shock dose; 

from 3,1 to 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): 
> 3,5                                     to Raise a dose for 20%;
от 1 до 1,3                           To raise a dose for 10%; 
от 1,4 до 1,9                        Without changes; 
от 2,0 до 3,0                        To lower a dose by 10%;
от 3,1 до 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).
To define MHO 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.
Such states as fever, 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 as 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 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.
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.

Side effects:

Very often:> 1/10 - bleeding.
Often:> 1/100, <1/10 - increase in sensitivity to warfarin after prolonged use.
Infrequently:> 1/1 Ltd companies, <1/100 - 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 stop 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 sole 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, клопидогрель, 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, троглитазон, Phenytoinum, phenylbutazone, фенофибрат, фепразон, флуконазол, fluoxetine, ftoruratsit, флувастатин, флувоксамин, флутамид, quinine, quinidine, Chlorali hydras, chloramphenicol, целекоксиб, цефамандол, cefalexin, tsefmenoksy, цефметазол, цефоперазон, tsefuroksy, Cimetidinum, ciprofloxacin, cyclophosphamide, erythromycin, этопозид, ethanol.
Drugs of some medicinal plants (official or informal) 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: 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.

Pregnancy and lactation. 
Warfarin quickly gets through a placenta, has teratogenic effect on a fruit (a 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 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 not 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 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.

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 more
                                   low 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
                                    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
           Recommendation MHO level
5,0 - 9,0 -
it is planned
                     the operation Stop Reception of Warfarin and Appoint Vitamin K in doses of 2 - 4 mg
                                     orally (in 24 hours prior to the planned operation) 
> 20,0 or strong
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:

Period of validity of 5 years. Not to use after a period of validity. At a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets on 2,5 mg; on 50 or 100 tablets in the plastic bottle corked by the screw-on cover under which the laying with a ring for a separation providing control of the first opening is built in. A part of the label is attached to a bottle by a special adhesive tape which allows to raise the label. The application instruction is made in the form of the developing leaf placed under a mobile part of the label, the edge of the instruction is fixed to a bottle.