Warfarin Nycomed 2,5mg №100 pills
Anticoagulant agent of indirect action
|warfarin sodium||2.5 mg|
lactose; corn starch; calcium hydrogen phosphate dihydrate; indigo carmine; Povidone 30; magnesium stearate
Description of the dosage formRound, biconvex tablet form, with a cross-shaped risk, light blue color.
pharmachologic effect- anticoagulant.
PharmacodynamicsBlocks the synthesis of vitamin K-dependent coagulation factors in the liver (II, VII, IX, X), reduces their concentration in plasma and slows down the process of blood coagulation.
The onset of the anticoagulant effect is observed 36–72 hours after the start of the administration of the drug with the development of the maximum effect on the 5–7th day after the start of the application. After discontinuation of the drug, the activity of vitamin K-dependent coagulation factors is restored within 4–5 days.
PharmacokineticsQuickly absorbed from the digestive tract almost completely. Plasma protein binding is 97–99%. Metabolized in the liver.
Warfarin is a racemic mixture, with the R and S isomers being metabolized in the liver in various ways. Each of the isomers is converted to 2 major metabolites.
The main metabolic catalyst for warfarin S-enantiomer is CYP2C9, and for warfarin R-enantiomer CYP1A2 and CYP3A4. The levorotatory isomer of warfarin (S-warfarin) possesses 2–5 times more anti-coagulant activity than the degrading isomer (R-enantiomer), however T1/2 last more. Patients with a CYP2C9 enzyme polymorphism, including CYP2C9 * 2 and CYP2C9 * 3 alleles, may have an increased sensitivity to warfarin and an increased risk of bleeding.
Warfarin is excreted in the bile as inactive metabolites, which are reabsorbed in the gastrointestinal tract and excreted in the urine. T1/2 ranges from 20 to 60 hours. For the R-enantiomer T1/2 ranges from 37 to 89 hours, and for the S-enantiomer from 21 to 43 hours
Indications drug Warfarin Nycomed
- 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, damage to the heart valves, or with prosthetic heart valves;
- prevention of postoperative thrombosis.
- established or suspected hypersensitivity to the drug;
- acute bleeding;
- pregnancy (I term and the last 4 weeks of pregnancy);
- severe liver or kidney disease;
- acute DIC;
- deficiency of proteins C and S;
- patients with a high risk of bleeding, including patients with hemorrhagic disorders;
- varicose veins of the esophagus;
- artery aneurysm;
- lumbar puncture;
- peptic ulcer and duodenal ulcer;
- severe wounds (including surgery);
- bacterial endocarditis;
- malignant hypertension;
- hemorrhagic stroke, intracranial hemorrhage.
Use during pregnancy and lactationWarfarin quickly penetrates the placenta, has a teratogenic effect on the fetus (nasal hypoplasia and chondrodysplasia, optic nerve atrophy, cataracts leading to complete or partial blindness, mental and physical retardation and microcephaly) at 6–12 weeks of gestation.
May cause bleeding at the end of pregnancy and during labor. The drug can not be prescribed in the first trimester of pregnancy and in the last 4 weeks. The use of warfarin is not recommended during other periods of pregnancy, except in cases of emergency
It is derived from breast milk in immeasurable quantities and does not affect the clotting activity of the blood of the fed child. Warfarin can be used during lactation.
Side effectsVery often (> 1/10): bleeding.
Often (> 1/100, <1/10): increased sensitivity to warfarin after prolonged use.
Infrequently (> 1/1000, <1/100): anemia, vomiting, abdominal pain, nausea, diarrhea.
Rarely (> 1/10000, <1/1000): eosinophilia, increased activity of liver enzymes, jaundice, rash, urticaria, pruritus, eczema, skin necrosis, vasculitis, hair loss, nephritis, urolithiasis, tubular necrosis.
On the part of the digestive system: vomiting, nausea, diarrhea.
Bleeding.During the year, bleeding occurs in about 8% of cases among patients receiving warfarin. Of these, 1% is classified as severe (intracranial, retroperitoneal), resulting in hospitalization or transfusion, and 0.25% as fatal. The most common risk factor for the occurrence of intracranial hemorrhage is untreated or uncontrolled hypertension.
The probability of bleeding increases if the MHO is significantly higher than the target level. If the bleeding started with an MHO that is within the target level, then there are other associated conditions that must be investigated.
Necrosis. Coumarin necrosis is a rare complication of warfarin treatment. Necrosis usually begins with swelling and darkening of the skin of the lower limbs and buttocks or (less often) in other places. Later lesions become necrotic. In 90% of cases, necrosis develops in women. Lesions are observed from the 3rd to the 10th day of taking the drug, and etiology suggests a deficiency of antithrombotic protein C or S. Congenital insufficiency of these proteins can cause complications, therefore treatment with warfarin should begin with small initial doses and simultaneously with the administration of heparin. If a complication occurs, the use of warfarin is stopped and the administration of heparin continues until healing or scarring of the lesions.
Palmar and plantar syndrome. A very rare complication of warfarin therapy, its development is typical for men with atherosclerotic diseases. Warfarin is believed to cause hemorrhages in the area of atheromatous plaques, leading to microemboli. There are symmetrical purple lesions of the skin of the fingers and soles of the feet, accompanied by burning pains. After discontinuation of warfarin, these symptoms gradually disappear.
Other: hypersensitivity reactions, manifested as a skin rash and characterized by reversible increases in liver enzyme levels, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and tracheal calcification.
Independent risk factors for the development of serious bleeding when treating with warfarin are: advanced age, high intensity of concomitant anticoagulant and antiplatelet therapy, history of stroke and gastrointestinal bleeding.
The risk of bleeding is increased in patients with CYP2C9 gene polymorphism.
InteractionIt is not recommended to start or stop taking the drug, as well as to change the dose of drugs taken without consulting with your doctor.
With simultaneous appointment, it is also necessary to take into account the effects of the termination of induction and / or inhibition of the effect of warfarin by other drugs.
The risk of severe bleeding increases with simultaneous use of warfarin with drugs that affect platelet levels and primary hemostasis: acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most NSAIDs (with the exception of COX-2 inhibitors), penicillin antibiotics in large doses.
You should also avoid the combined use of warfarin with drugs that have a pronounced inhibitory effect on the cytochrome P450 system, such as cimetidine and chloramphenicol, which, if taken, increases the risk of bleeding for several days. In such cases, cimetidine can be replaced, for example, ranitidine or famotidine.
warfarin effect may be increased by simultaneous administration with the following drugs: acetylsalicylic acid, allopurinol, amiodarone, azapropazone, azithromycin is, alpha- and beta-interferon, amitriptyline, bezafibrate, vitamin A, vitamin E, glibenclamide, glucagon, gemfibrozil, heparin, grepafloksatsin, danazol, dextropropoxifen, diazoxide, digoxin, disopyramide, disulfiram, zafirlukast, indomethacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, levamisole, lovastatin, metolazone, methotrexrexrex. azole, miconazole (including oral gel), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyfenbutazone, paracetamol (especially after 1–2 weeks of continuous use), paroxetine, piroxicam, proguanil, propafenone, propranolol, influenza vaccine, roxithromycin, sertraline, simvastatin, sulfafurazol, sulfamethizole, sulfamethoxazole-trimethoprim, sulfaphenazole, sulfinpyrazone, sulindac, steroids (anabolic and / or androgenic), tamoxifen, tegafur, testosterone, tetracycline, thienyl acid, tolmetin, trastnuyu cyclophosphamide, erythromycin, etoposide, ethanol.
Preparations of some medicinal plants (official or unofficial) can also enhance the effect of warfarin: for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), medicinal dagger (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza); so and reduce: for example ginseng (Panax ginseng), St. John's wort (Hypericum perforatum).
It is impossible to take warfarin and any preparations of Hypericum at the same time, it should be borne in mind that the effect of inducing the action of warfarin may persist for another 2 weeks after discontinuation of the preparations of Hypericum. In the event that the patient is taking Hypericum, should be measured MHO and stop taking. Monitoring the MHO must be thorough, because its level may increase with the abolition of hypericum. After that, you can assign warfarin.
The effect of warfarin can also be enhanced by quinine contained in tonic drinks.
Warfarin may enhance the action of oral hypoglycemic agents of sulfonylurea derivatives.
The effect of warfare on the other hand is that with the aid of , primidone, retinoids, ritonavir, rifampicin, rofecoksibom, spironolactone, sucralfate, trazodone, phenazone, chlordiazepoxide, chlorthalidone, cyclospor otherwise. Reception of diuretics in the case of a pronounced hypovolemic action can lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants. In the case of combined use of warfarin with other drugs listed in the above list, it is necessary to monitor the MHO at the beginning and at the end of treatment, and, if possible, 2-3 weeks from the start of therapy.
Foods rich in vitamin K weaken the effects of warfarin; a decrease in vitamin K absorption caused by diarrhea or the intake of laxatives potentiates the effects of warfarin. Most of the vitamin K is found in green vegetables, so the following products should be used with caution when treating warfarin: amaranth greens, avocados, broccoli, Brussels sprouts, cabbage, canola oil, shayo leaf, onion, coriander (cilantro), cucumber peel, chicory, kiwi fruit, lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red seaweed, spinach greens, spring onions, soybeans, tea leaves (but not tea, drink), turnip greens , watercress.
Dosage and administrationInside
Once a day, preferably at the same time of day.
The duration of treatment is determined by the doctor in accordance with the indications for use.
Control during treatment. Before starting therapy, determine the MHO. In the future, laboratory monitoring is carried out regularly every 4–8 weeks.
The duration of treatment depends on the clinical condition of the patient. Treatment can be canceled immediately.
Patients who have not previously taken warfarin: the initial dose is 5 mg / day (2 pills per day) for the first 4 days. On the 5th day of treatment, the MHO is determined and, in accordance with this indicator, a maintenance dose of the drug is prescribed. Usually, the maintenance dose of the drug is 2.5–7.5 mg / day (1-3 pills per day).
Patients who have previously taken warfarin: The recommended starting dose is a double dose of the known maintenance dose of the drug and is prescribed for the first 2 days. Treatment is then continued using a known maintenance dose. On the 5th day of treatment, MHO is monitored and the dose is adjusted in accordance with this indicator. It is recommended to maintain the MHO from 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated valvular heart disease, prosthetic heart valves with bioprostheses. Higher rates of MHO from 2.5 to 3.5 are recommended for prosthetic heart valves with mechanical prostheses and complicated acute myocardial infarction.
Children: data on the use of warfarin in children is limited. The initial dose is usually 0.2 mg / kg / day for normal liver function and 0.1 mg / kg / day for abnormal liver function. Maintenance dose is selected in accordance with the indicators of MHO. Recommended levels of MHO are the same as in adults. The decision on the appointment of warfarin and monitoring the treatment of children should be carried out by an experienced specialist - pediatrician. Doses are selected in accordance with the table below (Table 1).
Table 1Selection of the maintenance dose of warfarin in accordance with the indicators of MHO
If the base value of MHO is from 1 to 1.3,|
then the loading dose - 0.2 mg / kg body weight
|Days 2 through 4, if the value of MHO:||Actions:|
|from 1 to 1.3||Repeat dose dose|
|from 1.4 to 1.9||50% of the loading dose|
|from 2 to 3||50% of the loading dose|
|from 3.1 to 3.5||25% of the loading dose|
Discontinue the drug before reaching|
MHO <3.5, then resume treatment dose,
component of 50% of the previous
|Maintain, if the value of MHO:||Actions (weekly dose):|
|from 1 to 1.3||Increase the dose by 20%|
|from 1.4 to 1.9||Increase the dose by 10%|
|from 2 to 3||Without changes|
|from 3.1 to 3.5||Reduce the dose by 10%|
Discontinue the drug before reaching|
MHO <3.5, then resume treatment dose
20% less than the previous one
Elderly people:There are no special recommendations for taking warfarin in the elderly. However, elderly patients should be carefully monitored, as they have a higher risk of side effects.
Patients with liver failure:an abnormal liver function increases sensitivity to warfarin, since the liver produces blood clotting factors and also metabolizes warfarin. In this group of patients, careful monitoring of MHO indicators is necessary.
Patients with renal failure:patients with renal failure do not need any special recommendations on the selection of the dose of warfarin. Patients on peritoneal dialysis do not need an additional increase in the dose of warfarin.
Planned (elective) surgical interventions:Pre-, peri- and postoperative anticoagulant therapy is carried out as indicated below (if urgent cancellation of oral anticoagulant treatment is necessary - see “Overdose”).
1. Determine the MHO a week before the scheduled operation.
2. Stop taking warfarin 1–5 days before surgery. In the case of a high risk of thrombosis, low-molecular-weight heparin is administered to the patient for prophylaxis of s / c. The duration of the pause in the reception of warfarin depends on the MHO. Reception of warfarin is stopped:
- 5 days before the operation, if MHO> 4;
- 3 days before the operation, if the MHO is from 3 to 4;
- 2 days before the operation, if the MHO is from 2 to 3.
3. Determine MPE in the evening before the operation and inject 0.5–1 mg of vitamin K1 orally or in / in, if the INR> 1.8.
4. Take into account the need for infusion of unfractionated heparin or prophylactic administration of low molecular weight heparin on the day of surgery.
5. Continue s / c the introduction of low molecular weight heparin for 5-7 days after surgery with concomitant restored reception of warfarin.
6. Continue taking warfarin with a regular maintenance dose on the same day in the evening after small surgeries and on the day when the patient begins to receive enteral nutrition after major surgeries.
OverdoseThe cure rate is on the borderline of bleeding, so the patient may develop minor bleeding (for example, microhematuria, gingival bleeding, etc.).
Treatment: in mild cases, reducing the dose of the drug or stopping treatment for a short period; with minor bleeding - discontinuation of the drug to achieve the MHO target level. In the case of severe bleeding - in / in the introduction of vitamin K, the appointment of activated carbon, coagulation factor concentrate or fresh frozen plasma.
If oral anticoagulants are indicated for further administration, large doses of vitamin K should be avoided, since resistance to warfarin develops within 2 weeks.
Treatment regimens for overdose
|In case of minor bleeding|
Skip the next dose of warfarin and continue taking|
lower doses when reaching the therapeutic level of MHO
Skip 1-2 doses of warfarin and continue|
taking lower doses when reaching therapeutic
MHO level or skip 1 dose of warfarin and prescribe
vitamin K in doses of 1-2 mg orally
Stop taking warfarin, prescribe vitamin|
K in doses of 3-5 mg orally
|Shown drug withdrawal|
|5–9 (planned operation)||
Stop taking warfarin and prescribe|
vitamin K in doses of 2-4 mg orally
(24 hours before the planned operation)
|> 20 or severe bleeding||
Vitamin K in doses of 10 mg by slow|
iv infusion, transfusion of factor concentrates
prothrombin complex or fresh frozen
plasma, or whole blood.
If necessary, re-introduction of vitamin K every 12 hours.
After treatment, long-term observation of the patient is necessary, given that T1/2 Warfarin is 20–60 h.
special instructionsA prerequisite for warfarin therapy is strict patient compliance with the prescribed dose of the drug.
Patients suffering from alcoholism, as well as patients with dementia may be unable to comply with the prescribed regimen of warfarin.
Conditions such as fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage, may enhance the effect of warfarin. In hypothyroidism, the effect of warfarin can be reduced.In the case of renal failure or nephrotic syndrome, the level of the free fraction of warfarin in the blood plasma increases, which, depending on the associated diseases, can lead to both an increase and a decrease in the effect. In the case of moderate liver failure, the effect of warfarin is enhanced.
In all the above states, thorough monitoring of the level of MHO should be carried out.
Patients receiving warfarin are recommended to prescribe paracetamol, tramadol or opiates as painkillers.
Patients with a mutation of the gene encoding the CYP2C9 enzyme have a longer T1/2 warfarin. These patients require lower doses of the drug, because when taking the usual therapeutic dose increases the risk of bleeding.
Do not take warfarin to patients with hereditary intolerance to galactose, a deficiency of the enzyme lactase, impaired absorption of glucose and galactose. If it is necessary to have a fast antithrombotic effect, it is recommended to begin treatment with the administration of heparin; then, within 5–7 days, combination therapy with heparin and warfarin should be carried out until the target level of MHO is maintained for 2 days (see “Dosage and administration”).
In order to avoid coumarin necrosis, patients with hereditary deficiency of antithrombotic protein C or S must first be given heparin. Concomitant initial loading dose should not exceed 5 mg. Heparin administration should be continued for 5–7 days.
In the case of individual resistance to warfarin (it is very rare), from 5 to 20 shock doses of warfarin are necessary to achieve a therapeutic effect. If reception of warfarin in such patients is ineffective, other possible reasons should be established - simultaneous reception of warfarin with other drugs (see. “Interaction”), inadequate diet, laboratory errors.
Treatment of elderly patients should be carried out with special precautions, because the synthesis of coagulation factors and hepatic metabolism in such patients is reduced, as a result of which an excessive effect from the action of warfarin may occur.
Release formpills, 2.5 mg: in plastic bottles, sealed with screw-on caps, under which are mounted gaskets with tear-off rings, providing control of the first opening, 50 or 100 pcs. 1 fl. in a carton box.
Drug storage conditionsWarfarin Nycomed
At temperatures not above 25 ° C.
Keep out of the reach of children.
The shelf life of the drug Warfarin Nycomed
Do not use after the expiration date printed on the package.
It is a drug. Consultation with a doctor is required.
Compositionpills of light blue color, round, biconvex, with cross-shaped drawing.
1 tab. warfarin sodium 2.5 mg
Excipients: lactose - 50 mg, corn starch - 34.6 mg, calcium hydrogen phosphate dihydrate - 32.2 mg, indigo carmine - 6.4 µg, povidone 30 - 1.0 mg, magnesium stearate - 600 µg.
Mode of applicationInside, at the same time, at the same time of day. Initial dose (1-2 days) 10 mg, supporting - 5-7.5 mg, depending on the nature of the disease and blood clotting parameters - international normalized ratio (INR): for mechanical prosthetic heart valves, acute venous thrombosis and thromboembolism, thrombosis of the left ventricle and for the prevention of a heart attack before reaching an INR (international normalized ratio) 2.8-4.4; in the case of maintenance therapy for thrombosis and thromboembolism, the INR is maintained in the range of 2.8-3.0, against the background of acetylsalicylic acid - no more than 2.0-2.5.
Store at a temperature not higher than 25g. C.