Warfarin, tablets 2.5mg 100 pcs

Warfarin (4-hydroxycoumarin) is an indirect acting anticoagulant that prevents vitamin K-dependent synthesis of clotting factors II, VII, IX and X, proteins C and S through dose-dependent inhibition of C1-subunit of vitamin K-epoxidoreductase, resulting in reduced production of vitamin K1-epoxide.
S-isomer of warfarin is about 5 times more active than R-isomer. In therapeutic doses warfarin reduces the rate of synthesis of clotting factors by 30-50% and reduces their biological activity. The beginning of the anticoagulation action is observed 36-72 hours after the beginning of the drug administration with maximal effect on the 5th-7th day after the beginning of the drug administration. After discontinuation of the drug activity of vitamin K-dependent clotting factors is restored within 4-5 days.

Indications

Prevention of thrombosis, myocardial infarction, Prevention of heart attacks and strokes

• Treatment and prevention of thrombosis and embolism of blood vessels:
• acute and recurrent venous thrombosis, pulmonary embolism;
• transient ischemic attacks and strokes;
• secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction;
• prevention of thromboembolic complications in patients with atrial fibrillation, heart valve lesions or with prosthetic heart valves;
• prevention of postoperative thrombosis.

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Active ingredient

Warfarin

Composition

1 tablet contains warfarin sodium 2.5 mg.

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How to take, the dosage

Ingestion, once a day, preferably at the same time. The duration of treatment is determined by the physician.
MHO is determined before starting. Thereafter laboratory control is performed regularly every 4-8 weeks. Treatment duration depends on clinical condition of the patient. The treatment can be stopped immediately.
Adults: patients with normal body weight and initial MHO less than 1.2 – 10.5 mg (4.5 mg in patients with hereditary protein S or C deficiency) during 2 days. The dose is then calculated according to MHO: on day 3 with an MHO less than 2 – 10.5 mg (4.5 mg in patients with hereditary protein S or C protein deficiency), 2-2.4 – 6 mg, 2.5-2.9 – 3 mg, 3-3.4 – 1.5 mg, over 4 – should be skipped; on days 4-6 with MHO less than 1.4 – 10.5 mg, 1.4-1.9 – 7.5 mg, 2-2.4 – 6 mg, 2.5-2.9 – 4.5 mg, 3-3.9 – 3 mg, 4-4.5 – need to skip 1 day, the next day take 1.5 mg, over 4.5 – skip 2 days, then take 1.5 mg; from day 7 at INR 1.1-1.4 – the weekly dose of warfarin is increased by 20%, 1.5-1.9 – the weekly dose is increased by 10%, 2-3 – take the same dose, 3.1-4.5 – the weekly dose is increased by 10%, over 4.5 – the drug should be skipped until the INR is less than 4.In elderly patients, patients with low body weight, with the initial MHO over 1.2 or with concomitant diseases, or those receiving other medicines which influence the efficiency of antiplatelet therapy, the dose should be decreased by 10%. The recommended initial dose of warfarin is 4.5 mg for 2 consecutive days. Then the dose is calculated according to the above scheme.
MHO is measured daily until a stable target value is reached, which is usually set on day 5-6 of treatment. In cases of significant MHO abnormalities or in patients with liver disease or diseases affecting vitamin K absorption, measurement intervals may be less than 4 weeks. Prescription of new drugs or cancellation of previously taken drugs requires additional MHO measurements. In long-term therapy, dose adjustment is performed up to the weekly dose of warfarin according to the above scheme. If the dose requires adjustment, the next MHO measurement should be performed 1 or 2 weeks after the adjustment. Thereafter, measurements continue until 4-week intervals are reached.
Anticoagulant therapy in children is supervised by pediatricians. The usual recommended dose is 0.2 mg/kg, and 0.1 mg/kg if liver function is impaired. On day 1 with INR 1-1.3 – 0.2 mg/kg; on days 2-4 with INR 1-1.3 – repeat the initial dose, 1.4-1.9 – 50% of the initial dose, 2-3.0 – 50% of the initial dose, 3.1-3.5 – 25% of the initial dose, over 3.5 – treatment is stopped until INR less than 3.5, then the treatment is resumed in a dose of 50% of the previous dose; from the 4th day, with an INR (per weekly dose) of 1-1.3 – the dose should be increased by 20%, 1.4-1.9 – the dose is increased by 10%, 2-3 – the dose is left unchanged, 3.1-3.5 – the dose is reduced by 10%, over 3.5 – treatment is stopped until the INR is less than 3.5, then the treatment is resumed in a dose 20% less than the previous one.
Pre-, intra- and postoperative anticoagulant therapy:
MHO is determined a week before the scheduled surgery while taking warfarin; 1-5 days before the surgery, warfarin is stopped (the duration of the break in warfarin intake depends on MHO indicator): 5 days before surgery, if MHO more than 4; 3 days, if MHO 3-4; 2 days before surgery, if MHO from 2-3; if MHO over 1.8 determine MHO the evening before surgery and administer 0.5-1 mg of sodium bisulfite menadione (vitamin K) orally or intravenously. If there is a high risk of thrombosis, low-molecular-weight heparin is given by injection to prevent thrombosis. The need for infusion of unfractionated heparin or prophylactic injection of low-molecular-weight heparin on the day of surgery should be taken into account. Within 5-7 days after surgery, low molecular weight heparin is continued p/c with concomitant restored warfarin administration in the usual maintenance dose on the same day in the evening after minor operations, or when the patient is able to self-administer tablets after extensive surgery.

Interaction

It is not recommended to start or stop taking other drugs.
It is not recommended to start or stop other drugs, as well as to change doses of these drugs without consulting a physician.
Concomitant use of warfarin and other drugs that affect blood clotting (including ASA, clopidogrel, ticlopidine, dipyridamole, most NSAIDs (except low-dose COX-2 inhibitors), penicillins in high doses increases the risk of bleeding.
Combined administration of warfarin with potent inhibitors of microsomal liver enzymes (including cimetidine and chloramphenicol) should be avoided – increased risk of bleeding. In such cases, cimetidine may be replaced by ranitidine or famotidine.
Anticoagulant effect of warfarin increases: ASA, allopurinol, amiodarone, azapropazone, azithromycin, interferon alpha, interferon beta, amitriptyline, bezafibrate, flu vaccine, vitamin E, glibenclamide, glucagon, gemfibrozil, heparin, grepafloxacin, danazol, dextropropoxifen, diazoxide, digoxin, disopyramide, disulfiram, zafirlukast, indomethacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, co-trimoxazole, levamisole, lovastatin, metolazone, metotrexate, metronidazole, miconazole (incl.for topical and external use), male sex hormones (anabolic and/or androgenic, including testosterone), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol (especially after 1-2 weeks of continuous use), paroxetine, piroxicam, proguanil, propafenone, propranolol, retinol, roxithromycin, sertraline, simvastatin, sulfafurazole, sulfamethiazole, sulfinpyrazone, sulindac, tamoxifen, tegafur, tetracyclines, thienilic acid, tolmetine, trastuzumab, troglitazone, phenytoin, phenylbutazone, fenofibrate, feprazone, fluconazole, fluoxetine, fluorouracil, fluvastatin, fluvoxamine, flutamide, quinidine, quinidine chloral hydrate, chloramphenicol, celecoxib, cephamandol, cephalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, cimetidine, ciprofloxacin, cyclophosphamide, erythromycin, etoposide, ethanol.
Some medicinal plants may also increase the effect of warfarin, such as ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica sinensis, papaya (Carica papaya), sage (Salvia miltiorrhiza), or decrease it, such as ginseng (Panax ginseng), St. John’s wort (Hypericum perforatum).
Do not take warfarin and St. John’s wort simultaneously, because the effect of warfarin inducing action on cytochrome P450 may persist for another 2 weeks after stopping the use of St. John’s wort. If the patient takes St. John’s wort preparations, MHO should be determined and administration should be discontinued. MHO should be closely monitored because its value may increase if St. John’s Wort is withdrawn. After that, warfarin can be administered.
The effects of warfarin may be enhanced by quinine contained in tonic beverages.
Warfarin may enhance the hypoglycemic effects of oral hypoglycemic sulfonylurea derivatives.
The effect of warfarin may be impaired when concomitantly administered with the following drugs: azathioprine, aminoglutethimide, ascorbic acid, barbiturates, valproic acid, sodium bisulfite menadione, glutethimide, griseofulvin, dicloxacillin, disopyramide, carbamazepine, colestyramine, mercaptopurine, mesalazine, mianserin, mitotane, nafcillin, primidone, retinoids, ritonavir, rifampicin, rofecoxib, spironolactone, sucralfate, trazodone, ubidekarenone, phenazone, chlordiazepoxide, chlortalidone, cyclosporine.
Administration of diuretics in case of significant hypovolemic action may lead to increased concentration of clotting factors, which reduces the effect of anticoagulants. In case of combined use of warfarin with other drugs it is necessary to conduct control (MHO) at the beginning and at the end of treatment, and, if possible, after 2-3 weeks from the beginning of therapy.
Food rich in vitamin K weakens warfarin action; decrease of vitamin K absorption caused by diarrhea or laxatives intake increases warfarin action. Green vegetables contain the most vitamin K, so the following foods should be eaten with caution when treated with warfarin: Amaranth greens, avocado, broccoli sprouts, Brussels sprouts, white cabbage, canola oil, chayo leaf, onions, coriander (cilantro), cucumber peels, chicory, kiwi fruit, lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red seaweed, spinach greens, spring onions, soybeans, tea leaves (but not drink tea), turnip greens, watercress.

Special Instructions

The target MHO value for oral anticoagulant therapy for the prevention of thromboembolic complications in patients with prosthetic heart valves is 2.5-3; for other indications – 2-3.
Patients with alcoholism or dementia, may be unable to comply with the prescribed regimen of warfarin.
In conditions such as fever, hyperthyroidism, decompensated CH, alcoholism with associated liver damage, warfarin effect may increase. In hypothyroidism, the effect of warfarin may be reduced. In case of CPN or nephrotic syndrome, plasma concentration of free fraction of warfarin increases, which, depending on concomitant diseases, may lead to both enhancement and reduction of the effect. In the case of moderate CPN, the effect of warfarin is enhanced. In all of the above conditions, careful monitoring of MHO should be performed.
Patients receiving warfarin as analgesic drugs are recommended to prescribe paracetamol, tramadol or narcotic analgesics.
In 1 year of treatment, bleeding occurs in about 8% of cases. Of these, 1% are classified as severe (intracranial, retroperitoneal), leading to hospitalization or blood transfusion, and 0.25% are fatal. The most common risk factor for intracranial hemorrhage is uncontrolled arterial hypertension. The likelihood of hemorrhage is increased if MHO is significantly higher than the target value. If bleeding has started at MHOs within the target value, then there are other risk factors that should be investigated.
Coumarin necrosis is a rare complication of warfarin treatment. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks, rarely elsewhere. Later, the lesions become necrotic. In 90% of cases, necrosis develops in women. The lesions occur from day 3 to day 10 of the drug and the etiology suggests a protein C or S deficiency. Congenital deficiency of these proteins may be the cause of complications, so warfarin administration should be started simultaneously with heparin administration and low initial doses of the drug. If a complication occurs, warfarin administration is discontinued and heparin administration is continued until the lesions heal or scar.
Palmarine syndrome is a rare complication of warfarin therapy and its development is common in men with atherosclerosis. Warfarin causes hemorrhages of atheromatous plaques, leading to microemboli. Symmetrical purpuric lesions of the skin of the fingers and soles of the feet appear, accompanied by burning pain. After discontinuation of warfarin, the above symptoms gradually disappear.
When using warfarin, hypersensitivity reactions may occur, manifested in the form of skin rash and characterized by reversible increase in the activity of “hepatic” enzymes, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and calcification of the trachea.
Risk factors for serious bleeding: elderly age, high intensity of concomitant anticoagulant and antiaggregant therapy, history of strokes and gastrointestinal bleeding, CYP2C9 isoenzyme gene polymorphism.
Patients with CYP2C9 isoenzyme gene mutation, have a longer T1/2 of warfarin. These patients require lower doses of the drug, as the risk of bleeding increases with conventional therapeutic doses.

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Contraindications

• established or suspected hypersensitivity to the drug components;
• acute bleeding;
• pregnancy (first trimester and last 4 weeks of pregnancy;
• serious liver or kidney disease;

acute DICpregnancy (first trimester and last 4 weeks of pregnancy);

• severe hepatic or renal disease;
• acute DIC syndrome;
• protein C and S deficiency;
• thrombocytopenia;
• patients at high risk of bleeding, including patients with hemorrhagic disorders;
• varice vein dilation of the esophagus;
• lumbar puncture;
• gastric and duodenal ulcer;
• severe wounds (including operative ones)

Side effects

Frequency: very often more than 1/10, often more than 1/100 and less than 1/10, infrequently more than 1/1000 and less than 1/100, rarely more than 1/10000 and less than 1/1000.
Very often: increased bleeding.
Frequently: increased sensitivity to warfarin after long-term use.
Infrequent: anemia, vomiting, abdominal pain, nausea, diarrhea.
Rare: eosinophilia, increased activity of “liver” enzymes, jaundice, rash, urticaria, pruritus, eczema, skin necrosis, vasculitis, hair loss, nephritis, urolithiasis, tubular necrosis, palmar-sandibular syndrome.

Overdose

Symptoms: bleeding.
Treatment: depending on the INR value. For INR less than 5, skip the next dose and continue lower doses until the therapeutic MHO value is achieved. For INR 5-9 it is necessary to skip 1-2 doses and continue taking lower doses until the therapeutic MHO value is reached, or skip 1 dose of warfarin and take 1-2.5 mg of sodium bisulfite menadione (vitamin K) orally. In INR over 9, stop warfarin, take 3-5 mg of sodium bisulfite menadione orally. In INR 5-9 against the background of a planned surgery 24 hours before it, stop taking warfarin and take 2-4 mg of sodium bisulfite menadione orally. For INR over 20 or severe bleeding, warfarin should be stopped and 10 mg of sodium bisulfite menadione should be slowly administered by IV and blood clotting factor concentrate, fresh frozen plasma or whole blood should be transferred. If necessary, repeat administration of sodium bisulfite menadione every 12 hours.

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