The composition and form of issue:
Tablets. 1 tablet contains:
warfarin sodium 2.5 mg
excipients: lactose corn starch calcium hydrogen phosphate dihydrate Indigo Carmine povidone 30 magnesium stearate
in plastic bottles of 50 or 100 pieces.
Description pharmaceutical form:
Round, biconvex shaped tablets, with a cruciform mark, a light blue color.
Rapidly absorbed from the gastrointestinal tract almost completely. The plasma protein binding is 97 to 99%. Metabolized in the liver.
Warfarin is a racemic mixture and R – and S-isomers are metabolized in the liver in different ways. Each of the isomers is converted to 2 main metabolites.
The main catalyst for metabolism for the S-enantiomer of warfarin is the enzyme CYP2C9 and the R-enantiomer of warfarin CYP1A2 and CYP3A4. Levo isomer of warfarin (S-warfarin) has 2-5 times more anticoagulant activity than the dextrorotatory isomer (R-enantiomer), however, T1/2 latest more. Patients with a polymorphism of the enzyme CYP2C9, including CYP2C9 alleles*2 and CYP2C9*3, can have increased sensitivity to warfarin and the increased risk of bleeding.
Warfarin is excreted in bile as inactive metabolites which are reabsorbed in the gastrointestinal tract and excreted in the urine. T1/2 is 20 to 60 h. For the R-enantiomer T1/2 ranges from 37 to 89 h and S-enantiomer from 21 to 43 h
Description pharmacological action:
Blocks liver synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X), reduces their concentration in plasma and slows down the process of blood clotting.
The beginning of the anticoagulant action observed after 36 to 72 h from start of treatment with the development of the maximum effect at 5-7-th day from the start of the application. After discontinuation of the drug the restoration of the activity of vitamin K-dependent coagulation factors occurs within 4-5 days.
Treatment and prevention of thromboses and embolism of the blood vessels:
Application of pregnancy and breast-feeding:
Warfarin is rapidly absorbed through the placenta, has a teratogenic effect on the fetus (nasal hypoplasia and chondrodysplasia, optic nerve atrophy, cataract leading to total or partial blindness, delayed mental and physical development and microcephaly) at 6-12 weeks of pregnancy.
Can cause bleeding in late pregnancy and during childbirth. The drug should not be administered in the first trimester of pregnancy and during the last 4 weeks. The use of warfarin is not recommended in other stages of pregnancy, except in cases of extreme necessity.
Is excreted in breast milk in measurable quantities, and does not affect the coagulation activity of blood fed to the baby. Warfarin can be used during lactation.
Very often (>1/10): bleeding.
Often (>1/100, <1/10): increased sensitivity to warfarin after prolonged use.
Infrequently (>1/1000, <1/100): anaemia, vomiting, abdominal pain, nausea, diarrhea.
Rare (>1/10000, <1/1000): eosinophilia, increased activity of liver enzymes, jaundice, rash, urticaria, pruritus, eczema, skin necrosis, vasculitis, hair loss, nephritis, urolithiasis, tubular necrosis.
From the digestive system: vomiting, nausea, diarrhea.
Bleeding. For the year bleeding occur in about 8% of cases among patients receiving warfarin. Only 1% of them classified as severe (intracranial, retroperitoneal) resulting in hospitalization or blood transfusion, and 0.25% as fatal. The most common risk factor for the occurrence of intracranial hemorrhage — untreated or uncontrolled hypertension.
The chance of bleeding increases if MHO is significantly above the target level. If bleeding is started under MHO within the target level, then there are other associated conditions that need to be investigated.
Necrosis. Coumaric necrosis is a rare complication of treatment with warfarin. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks or (rarely) in other places. Later, lesions become necrotic. In 90% of cases necrosis develops in women. The lesions are observed from 3rd to 10th day of treatment, and etiology involves antitromboticescoe deficiency of protein C or S. Congenital deficiency of these proteins could be the cause of complications, so treatment with warfarin must start with small initial doses and concurrent with the introduction of heparin. If there is a complication, then stop taking warfarin and continue heparin until healing or scarring lesions.
Hand-foot syndrome. A very rare complication of treatment with warfarin, its development is typical for men with atherosclerotic diseases. As expected, warfarin causes hemorrhage in the region of atheromatous plaques, leading to microembolism. Meet purple symmetrical skin lesions of the fingers and soles of the feet, accompanied by burning pain. After discontinuation of warfarin these symptoms gradually disappear.
Other: hypersensitivity reactions manifesting as skin rash and is characterized by a reversible increase in the levels of liver enzymes, cholestatic hepatitis, vasculitis, glomerulonephritis, reversible alopecia and calcification of the trachea.
Independent risk factors for major bleeding in the treatment of warfarin are: older age, high intensity of concomitant anticoagulant and antiplatelet therapy, a history of stroke and gastrointestinal bleeding.
The risk of bleeding is increased in patients with polymorphism of CYP2C9 gene.
Do not start or stop taking a drug or change dose of medication without consulting your doctor.
While the appointment should also take into account the effects of the termination of the inducing and/or inhibiting the action of warfarin other drugs.
The risk of heavy bleeding increased with concomitant use of warfarin with drugs that affect the platelets and primary hemostasis: acetylsalicylic acid, clopidogrel, tiklopidin, dipyridamole, most NSAIDs (except COX-2 inhibitors), antibiotics penicillin in large doses.
You should also avoid combined use of warfarin with drugs, has a pronounced inhibitory effect on the cytochrome P450, such as cimetidine and chloramphenicol, which upon receipt within a few days increases the risk of bleeding. In such cases, cimetidine can be replaced, e.g. ranitidine, or famotidine.
The effect of warfarin may increase when administered simultaneously with the following drugs: acetylsalicylic acid, allopurinol, amiodarone, azapropazone, azithromycin, alpha – and beta-interferon, amitriptyline, bezafibrat, vitamin a, vitamin E, glibenclamide, glucagon, gemfibrozil, heparin, grepafloxacin, danazol, dextropropoxyphene, diazoxide, digoxin, disopyramide, disulfiram, zafirlukast, and indomethacin, ifosfamide, Itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, levamisole, lovastatin, metolazone, methotrexate, metronidazole, miconazole (incl. in the form of a gel for the mouth), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol (especially after 1-2 weeks of admission), paroxetine, piroxicam, proguanil, propafenone, propranolol, influenza vaccine, roxithromycin, sertraline, simvastatin, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfafurazole, sulfinpirazon, sulindac, steroid hormones (anabolic and/or androgenic), tamoxifen, tegafur, testosterone, tetracycline, tienilova acid, tolmetin, trastuzumab, troglitazone, phenytoin, phenylbutazone, fenofibrate, feprazone, fluconazole, fluoxetine, fluorouracil, fluvastatin, fluvoxamine, flutamid, quinine, quinidine, chloral hydrate, chloramphenicol, celecoxib, cefamandole, cephalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, cimetidine, ciprofloxacin, cyclophosphamide, erythromycin, etoposide, ethanol.
Preparations of certain medicinal plants (official or unofficial) may also how to increase the effect of warfarin: for example, Ginkgo (Ginkgo biloba), garlic (Allium sativum), Dong Quai (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza) and to reduce: for example, ginseng (Panax ginseng), St. John’s wort (Hypericum perforatum).
Do not take warfarin and any drugs St. John’s wort, you should take into account that the effect of inducing the action of warfarin may persist for 2 weeks after discontinuation of St. John’s wort preparations. In that case, if a patient takes St. John’s wort preparations should be measured MHO and stop taking. Monitoring MHO should be careful, because it can be increased with the abolition of St. John’s wort. You can then assign warfarin.
Also increase the effects of warfarin can quinine contained in tonic drinks.
Warfarin may potentiate the effects of oral gipoglikemicakih funds derived sulfonylureas.
The effect of warfarin may be weakened while taking the following drugs: azathioprine, aminoglutetimid barbiturates, valproic acid, vitamin C, vitamin K, glutetimid, griseofulvin, dicloxacillin, dizopiramidom, carbamazepine, kolestiraminom, CoQ10, mercaptopurine, mesalazine, mianserina, mitotane, nafcillin, primidon, retinoids, ritonavir, rifampicin, rofecoxib, spironolactone, sucralfate, trazodone, phenazone, chlordiazepoxide, chlorthalidone, cyclosporine. Diuretics in the case of hypovolemic Express actions may lead to increased concentration of clotting factors, which reduces the effects of anticoagulants. In the case of combined use of warfarin with other drugs that are listed in the list above, it is necessary to control MHO at the beginning and at the end of treatment, and, if possible, 2-3 weeks from start of therapy.
Food rich in vitamin K reduces the effect of warfarin decrease the absorption of vitamin K caused by diarrhoea or taking laxatives, potentiates the action of warfarin. Most vitamin K is found in green vegetables, therefore, when treatment with warfarin should exercise caution when eating the following foods: green amaranth, avocado, broccoli, Brussels sprouts, headed cabbage, canola oil, leaf Chaillot, onion, coriander (cilantro), cucumber peel, chicory, kiwifruit, lettuce, mint, mustard greens, olive oil, parsley, peas, pistachios, red algae, green spinach, spring onions, soya beans, tea leaves (not tea-drink) turnip greens, watercress.
Method of application and dose:
Inside, 1 times per day, preferably at the same time.
The duration of treatment is determined by a physician in accordance with the indications for use.
Control during treatment. Before therapy define MHO. Further laboratory testing is carried out regularly every 4-8 weeks.
The duration of treatment depends on the clinical condition of the patient. The treatment can be cancelled immediately.
Patients who had not previously taken warfarin: initial dose of 5 mg/day (2 table. per day) during the first 4 days. On the 5th day of treatment is determined by the MHO and, in accordance with this indicator, the assigned maintenance dose. Usually supporting dose is 2.5–7.5 mg/day (see table 1-3. a day).
Patients who had previously taken warfarin: the recommended starting dose is a double dose is known to a maintenance dose of the drug and is assigned for the first 2 days. Then treatment is continued using known maintenance dose. On the 5th day of treatment control MHO and dose adjustment in accordance with this indicator. It is recommended to maintain the MHO increased from 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated by disease of the heart valves, heart valve replacement with bioprostheses. Higher rates of MHO from 2.5 to 3.5 are recommended for the replacement of heart valves with mechanical prostheses and complicated acute myocardial infarction.
Children: data on the use of warfarin in children is limited. Starting dose is usually 0.2 mg/kg/day with normal liver and 0.1 mg/kg/day in the liver. The maintenance dose is selected in accordance with the indicators of MHO. Recommended levels MHO are the same as in adults. The decision on the appointment of warfarin and monitoring of treatment in children is conducted by experienced specialist pediatrician. The doses were chosen in accordance with the table below (table. 1).
Selection of the maintenance dose of warfarin in accordance with the performance of MHO
Day 1If the base value MHO from 1 to 1.3, the loading dose of 0.2 mg/kg of body weight
Days from the 2nd to 4th if the value is MHO:
Steps:from 1 to 1.3Repeat loading dosefrom 1,4 to 1,950% of loading dosefrom 2 to 350% of loading dosefrom 3,1 to 3,525% of loading dose>3,5To stop the introduction of the drug to achieve MHO <a 3.5, then resume treatment dose, component 50% from the previous
Maintaining, if the value is MHO:
Actions (weekly dose):from 1 to 1,3Increase the dose by 20%from 1,4 to 1,9Increase the dose by 10%from 2 to 3No changefrom 3,1 to 3,5To reduce the dose by 10%>3,5To stop the introduction of the drug to achieve MHO <a 3.5, then resume treatment with a dose 20% lower than the previous
Elderly: no specific recommendations for use of warfarin in the elderly. However, elderly patients should be closely monitored, because they have a higher risk of side effects.
Patients with hepatic impairment: impaired liver function increases sensitivity to warfarin, because the liver produces clotting factors and warfarin metaboliziruet. In this group of patients need careful monitoring of indicators of MHO.
Patients with renal insufficiency: patients with renal failure do not need any special recommendations on the selection of warfarin. Patients undergoing peritoneal dialysis, which require no additional increase in the dose of warfarin.
Planned (elective) surgical intervention: pre-, peri – and postoperative anticoagulant therapy is conducted, as indicated below (if necessary urgent cancellation of oral anticoagulant treatment, see “Overdose”).
1. To determine MHO a week before the scheduled surgery.
2. To stop taking warfarin for 1 to 5 days before surgery. In the case of high risk of thrombosis the patient to prevent s/to give low molecular weight heparin. The duration of the pause in the use of warfarin depends on MHO. Treatment with warfarin is stopped:
3. To determine MHO in the evening before the operation and enter 0.5–1 mg vitamin K1 orally or/in, if INR >1.8 times.
4. To take into account the need of the infusion of unfractionated heparin or prophylactic administration of low molecular weight heparin on the day of surgery.
5. To continue the p/to the introduction of low molecular weight heparin for 5-7 days after surgery restored with concomitant use of warfarin.
6. To continue takin warfarin with the usual maintenance dose on the same day in the evening after small operations and in the day when the patient begins to receive enteral feeding after major operations.
The cure rate is on the border of development of hemorrhage, so patients may develop minor bleeding (for example, microscopic hematuria, bleeding gums, etc.).
Treatment: in mild cases a reduction in dose or discontinuation of treatment in the short term for minor bleeding — stopping of the drug to achieve the MHO target level. In case of severe bleeding, in/in the introduction of vitamin K, the appointment of activated carbon, the concentrate of coagulation factors or fresh frozen plasma.
If oral anticoagulants are shown to the destination in the future, you should avoid large doses of vitamin K because warfarin resistance develops within 2 weeks.
The scheme of treatment in overdoseLevel MHORecommendationsIn the case of minor bleeding<5Skip the next dose of warfarin and continue receiving lower doses in the therapeutic level MHO5–9Skip 1-2 doses of warfarin and continue receiving lower doses in the therapeutic level MHO or omit 1 dose of warfarin and prescribe vitamin K in doses of 1-2. 5 mg orally>9To stop taking warfarin, prescribe vitamin K in doses of 3-5 mg orallyShows removal of the drug5-9 (planned operation)Stop taking warfarin and prescribe vitamin K in doses of 2-4 mg orally (within 24 hours before the planned operation)>20 or severe bleedingVitamin K in doses of 10 mg by slow in/in infusion, transfusion of factor concentrates prothrombin complex or fresh frozen plasma, or whole blood. If necessary, repeated administration of vitamin K every 12 hours
The treatment needs long-term observation of the patient, given that T1/2 of warfarin is 20-60 h
Obligatory condition of treatment with warfarin is strict adherence for patients taking the prescribed doses of the drug.
Patients suffering from alcoholism, and patients with dementia may be unable to comply with the prescribed regimen of warfarin.
Conditions such as fever, hyperthyroidism, decompensated cardiac insufficiency, alcoholism with associated liver damage can potentiate the effects of warfarin. In hypothyroidism effect of warfarin may be reduced. In the case of kidney failure or nephrotic syndrome increased levels of free fraction of warfarin in plasma, which, depending on comorbidities can lead to increased, and to decrease the effect. In the case of moderate hepatic insufficiency the effect of warfarin is enhanced.
In all of these States should be a thorough monitoring of the level of MHO.
Patients receiving warfarin, as pain medication is recommended to prescribe paracetamol, tramadol or opiates.
Patients with a mutation of the gene encoding the CYP2C9 enzyme, have longer T1/2 of warfarin. These patients require lower doses of the drug because when taking a normal therapeutic doses increases the risk of bleeding.
You should not take warfarin to patients with hereditary galactose intolerance, deficiency of the enzyme lactase, malabsorption of glucose and galactose. If necessary, the rapid onset of antithrombotic effect, it is recommended to begin treatment with heparin and then for 5-7 days should be combined therapy with heparin and warfarin as long as the target level MHO will not be retained for 2 days (see “Method of application and dosage”).
Avoid coumaric necrosis in patients with hereditary deficiency antitromboticescoe protein C or S must first be put on heparin. And related initial load dose should not exceed 5 mg. heparin should be continued for 5-7 days.
In the case of individual resistance to warfarin (occurs very rarely) to achieve therapeutic effect requires from 5 to 20 shock doses of warfarin. If the use of warfarin in these patients is ineffective, you must set the other possible causes — concomitant use of warfarin with other drugs (see “Interactions”), inadequate diet, laboratory errors.
Treatment of elderly patients should be undertaken with particular caution, because the synthesis of coagulation factors and hepatic metabolism in these patients is reduced, so that there may occur excessive effect of warfarin.
|The purpose of the medication||Anti-coagulants|