WARFARIN NIKOMED

Active material: Warfarin
When ATH: B01AA03
CCF: Anticoagulant of indirect actions
ICD-10 codes (testimony): G45, I21, i26, i48, I63, I74, I82
When CSF: 01.12.11.06.02
Manufacturer: NEWCOMED DENMARK APS (Denmark)

Pharmaceutical form, composition and packaging

Pills light blue, round, lenticular, Phillips Valium.

Excipients: lactose, corn starch, calcium hydrogen phosphate dihydrate, indigokarmin, povidone 30, magnesium stearate.

50 PC. – plastic bottles.
100 PC. – plastic bottles.

Pharmacological action

Anticoagulant of indirect actions. Blocks in the liver synthesis of vitamin k-dependent clotting factors, namely – II, VII, IX and x. The concentration of these components in the blood is reduced, blood clotting process slows down.

Start protivosvertyvajushhego action is a 36-72 h from the beginning of the use of the drug with the development of maximum effect on 5-7 the day of the application. After receiving the drug rehabilitation activity of vitamin k-dependent clotting factors occur within 4-5 days.

Pharmacokinetics

Absorption and distribution

The drug is rapidly absorbed from the digestive tract. Binding to plasma proteins is 97-99%.

Metabolism

It is metabolized in the liver. Warfarin is a razemicescuu mixture, with R- and S isomers metabolised in the liver by various means. Each of the isomers are converted into 2 osnovnыh metabolite. A major catalyst for the S-enantiomer of metabolism of warfarin is an enzyme CYP2C9, as for the R-enantiomer of warfarin CYP3A4 and CYP1A2. Levovrashhajushhij isomer of warfarin (S-warfarin) has in 2-5 times greater Anticoagulant activity, than clockwise rotating isomer (R-enantiomer), However, T_1/2 last longer. Patients with enzyme CYP2C9 polymorphism, including alleles CYP2C9 * 2 and CYP2C9 * 3, may have a heightened sensitivity to ensuring and an increased risk of bleeding.

Deduction

Warfarin is excreted from the body in the form of inactive metabolites with jelchew, that reabsorbirujutsja in the stomach and stand out with urine. T_1/2 It is between 20 to 60 no. For the R-enantiomer of T_1/2 It is between 37 to 89 no, as for the S-enantiomer of 21 to 43 no.

Testimony

-treatment and prevention of thrombosis and embolism of blood vessels: acute and recurrent venous thrombosis, pulmonary embolism;

-secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction;

-Prevention of thromboembolic complications in patients with atrial fibrillation, lesions of the heart valves or with and without prosthetic heart valves;

-Prevention and treatment of transient ischemic attack and stroke, Prevention of postoperative thrombosis.

Dosage regimen

Warfarin is assigned 1 times/day in one and the same time. Duration of treatment is determined by the physician in accordance with indications for use.

Before therapy define MPE. Further laboratory control regularly every 4-8 weeks.

Duration of treatment depends on the clinical condition of the patient; treatment can be lifted as soon.

Starting dose for patients, not previously used warfarin, is 5 mg / day (2 tab.) during the first 4 days. The 5-day treatment is determined by the MPE and, According to this indicator, assigned a maintenance dose of the drug. Usually supporting dose 2.5-7.5 mg / day (1-3 tab.).

Patient, previously used warfarin, the recommended starting dose is a double dose of known maintenance dose of the drug and is assigned during the first 2 days. Then treatment continued using known maintenance dose. The 5-day treatment of MPE control and correction doses according to this indicator.

It is recommended that you maintain a rate of MPE 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, Atrial Fibrillation, dilated cardiomyopathy, complicated heart valve diseases, prosthetic heart valves bioprotezami. Higher rates of MPE 2.5 to 3.5 recommended for prosthetic heart valves mechanical prostheses and complicated acute myocardial infarction.

Data on the use of warfarin from children limited. Initial dose is usually 0.2 mg/kg/day in normal liver and 0.1 mg/kg/day in violation of the liver. Supporting dose is chosen in accordance with the indicators of MPE. Recommended levels of MPE are the same, as in adults. The decision on the appointment of warfarin in children should take an experienced specialist. Treatment should be under the supervision of an experienced specialist – pediatrician. Dose selected in accordance with the following table.

There is no special recommendations for receiving warfarin from patients Seniors. However, elderly patients should be under close supervision, because they have a higher risk of side effects.

Violation of the liver increases sensitivity to ensuring, because the liver produces coagulation factors, and also metabolizes warfarin. This group of patients requires careful monitoring of indicators for MHO.

Patients with renal failure don't need any special recommendations on selection of warfarin. Patients, are on peritoneal dialysis, do not require further increasing doses of warfarin.

Pres-, peri- and postoperative anticoagulant therapy is performed as specified below. Define MHO a week before the scheduled operation. Stop taking warfarin for 1-5 days before the operation. In the case of a high risk of thrombosis patient to prevent p/to introduce low-molecular heparin. The duration of a pause in the admission of warfarin depends on MPE. Receiving warfarin cease:

— for 5 days before the operation at MPE > 4.0;

— for 3 days before surgery in MHO from 3.0 to 4.0;

— for 2 days before surgery in MHO from 2.0 to 3.0.

You must define the MPE on the evening before the operation and enter 0.5-1.0 mg of vitamin k₁ oral or/, When ITO> 1.8.

Take into account the need for an infusion of unfractionated heparin or prophylactic low molecular weight heparin on the day of surgery. Should continue to the p/to the introduction of low molecular weight heparin for 5-7 days after surgery with concomitant restored taking warfarin.

To continue receiving warfarin with the usual maintenance dose on the same day in the evening after a small operations, and on the day, When the patient starts to receive enteral feeding after major operations.

Side effect

Often (>1/10) – angiostaxis.

Often (>1/100, <1/10) – increased sensitivity to ensuring after prolonged use.

Infrequently (>1/1000, <1/100) – anemia, vomiting, abdominal pain, nausea, diarrhea.

Rarely (>1/10 000, <1/1000) – eozinofilija, increase in liver enzymes, jaundice, rash, hives, itch, eczema, skin necrosis, vasculitis, hair loss, jade, urolithiasis, tubular necrosis.

During the year, the bleeding is observed in approximately 8% cases among patients receiving warfarin. From them 1.0% classified as a heavy (Intracranial, retroperitonialnye), resulting in hospitalization or blood transfusion, and 0.25% How fatal. The most frequent risk factor for the occurrence of intracranial hemorrhage – nelechennaja or uncontrolled hypertension. The likelihood of bleeding increases, If MPE is significantly above target level. If the bleeding started at MPE, within the target level of, that means there are other related conditions, that should be investigated.

Independent risk factors for severe bleeding during treatment with warfarin are: advanced age, high intensity related anticoagulant and antiplatelet therapy, history of strokes and gastrointestinal bleeding. The risk of bleeding is increased in patients with the gene CYP2C9 polymorphism.

From the digestive system: vomiting, nausea, diarrhea.

Dermatological reactions: kumarinovy necrosis – a rare complication of treatment with warfarin. Necrosis typically begins with swelling and darkening of skin of lower limbs and buttocks, or (less often) in other places. Later lesions become necrotic. IN 90% cases of necrosis develops in women. The lesions are observed from 3rd to 10th day of the drug and etiology implies failure antitrombicheskogo protein c or S. Congenital deficiency of these proteins may be causing complications, Therefore, receiving warfarin should start simultaneously with the introduction of heparin and low initial doses of the drug. If there is a complication, the receiving warfarin stop and continue the introduction of heparin to healing or scarring lesions.

Hand-foot syndrome – a very rare complication of therapy with warfarin, its development is typical among men with Atherosclerotic diseases. Suspected warfarin causes hemorrhage of atheromatous plaques, leading to mikrojembolijam. Meet symmetric purple skin of the fingers and the soles of feet, accompanied by acute pain.

After you stop taking warfarin the symptoms gradually fade.

Other: hypersensitivity reactions, manifested in the form of skin rashes, and characterized by reversible increases in liver enzymes, holetsaticakim hepatitis, vasculitis, first, reversible alopecia and tracheal kalcifikaciej.

Contraindications

- Severe bleeding;

- Severe liver disease;

- Severe kidney disease;

-acute disseminated intravascular coagulation syndrome;

— proteins c and S;

- Thrombocytopenia;

-patients with a high risk of bleeding, including patients with haemorrhagic disorders, esophageal varices, artery aneurysm, lumbar puncture biopsy, gastric ulcer and duodenal ulcer, with heavy wounds (including operating), Bacterial Endocarditis, malignant arterial hypertension, haemorrhagic stroke, intracranial hemorrhage;

- Pregnancy (The first trimester and the last 4 of the week);

is installed or suspected hypersensitivity to the preparation components.

Pregnancy and lactation

Do not use this drug in the I trimester of pregnancy (the use of warfarin is not recommended in the remaining stages of pregnancy, except in cases of extreme necessity) and in the past 4 weeks.

Warfarin quickly penetrates through the placental barrier, has a teratogenic effect on the fetus (the nasal hypoplasia and hondrodisplazija, optic atrophy, Cataract, leading to complete blindness, delayed mental and physical development, microcephaly) on 6-12 week of pregnancy. The drug may cause bleeding late in pregnancy and during delivery.

Warfarin is the breast milk in small quantities and has no effect on blood clotting at the baby. Hence, the drug can be used during lactation (breast-feeding).

Cautions

The obligatory condition of therapy with warfarin is strict adherence to the patient receiving the assigned dosage. Patients, suffering from alcoholism, as well as patients with dementia, may be unable to comply with the prescribed regimen of warfarin.

Fever, hyperthyroidism, decompensated heart failure, alcoholism is associated with lesions of the liver, may exacerbate the effects of warfarin.

In gipotireoze effect of warfarin can be reduced.

In the case of renal failure or nephrotic syndrome increases free fraction of warfarin in plasma, that, Depending on Comorbidities, may result as strengthening, and to reduce the effect. In the case of moderate liver failure effect racumin intensifies. In all of these conditions should be careful monitoring of the level of MPE.

Patients, receiving warfarin, as a best practice, assign painkillers paracetamol, tramadol or opiates.

Patients with a mutation of the gene, CYP2C9 enzyme coding, have a longer T_1/2 varfarina. These patients require lower doses of the drug, because when receiving the usual therapeutic doses increases the risk of bleeding.

Should not take warfarin for patients with hereditary intolerance Galactose, a deficiency of the enzyme lactase, violation of intake of glucose and galactose.

In case you need a quick offensive effect antitrombicheskogo, It is recommended to begin treatment with the introduction of heparin; then for 5-7 days should be heparin and warfarin combination therapy until, until the target level of MHO will not persist for 2 days.

Avoid coumarin necrosis in patients with hereditary antitrombicheskogo deficiency of protein c or S must first be introduced heparin. Accompanying loading dose should not exceed 5 mg. Introduction of heparin should continue throughout 5 – 7 days.

In the case of individual resistance to ensuring (rare) to achieve a therapeutic effect must be from 5 to 20 shock doses of warfarin. If the warfarin in these patients is inefficient, other possible causes should be set: simultaneous reception of warfarin with other drugs, inadequate diet, laboratory errors.

Treatment of elderly patients should be performed with special precautions, Since the synthesis of coagulation factors and hepatic metabolism in these patients is reduced, as a result of which there may be an excessive effect of action of warfarin.

Overdose

Symptoms: cure rate is on the border of hemorrhages, Therefore, the patient may be minor bleeding (incl. mikrogematuriâ, krovotochivosty right).

Treatment: in mild cases enough to reduce the dose or stop treatment for short term. Minor bleeding enough to stop taking the drug before reaching the MPE level target. In the case of severe bleeding is recommended in/with the introduction of vitamin k, the concentrate of coagulation factors or fresh frozen plasma, reception activated carbon inside.

If oral anticoagulants are shown to the appointment in the future, You must avoid high doses of vitamin k, since ensuring resistance develops over 2 weeks.

The drug overdose treatment schema

After conducting treatment to long-term monitoring of the patient, taking into account the, that T_1/2 warfarin is 20-60 no.

Drug Interactions

It is not recommended to start or stop taking other medicines, to change doses of drugs taken without consultation with the doctor.

While appointing effects must also be taken into account from the induction and/or inhibiting action of warfarin other drugs.

The risk of heavy bleeding increases while receiving warfarin with drugs, influencing the level of platelets and primary hemostasis: acetylsalicylic acid, Clopidogrel, ticlopidine, dipiridamol, most NSAIDS (with the exception of Cox-2 inhibitors), antibiotics penicillin in large doses.

Also avoid combined use of warfarin with drugs, having pronounced inhibitory effects on the isozyme cytochrome p 450 system (incl. cimetidine, chloramphenicol), When taken within a few days which increases risk of bleeding. In such cases, you can replace the cimetidine, eg, ranitidine or famotidinom.

The effect of warfarin may increase if you are applying to the following drugs: acetylsalicylic acid, allopurinol, Amiodarone, azapropazon, azithromycin, alpha- and Beta-Interferon, Amitriptyline, bezafibrate, Vitamin A, Vitamin E, glibenclamide, glucagon, gemfibrozil, Heparin, grepafloksacin, danazol, dextropropoxyphene, diazoksid, Digoxin, disopyramide, disulьfiram, zafirlukast, Indomethacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, levamisole, lovastatin, metolazon, methotrexate, metronidazol, mikonazol (in t. no. in gel form for oral cavity), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oksifenʙutazon, paracetamol (particularly after 1-2 weeks of admission), paroxetine, piroxicam, proguanil, propafenone, propranolol, influenza vaccine, roksitromitsin, sertraline, simvastatin, sulfafurazol, sulfametizol, sulfamethoxazole-trimethoprim, sulfafenazol, sulfinpirazon, sulindac, steroid hormones (anabolic and/or androgenic), Tamoxifen, tegafurum, Testosterone, tetracikliny, tienilovaja acid, tolmetin, Trastuzumab, troglitazone, phenytoin, phenylbutazone, fenofibrate, feprazon, fluconazole, fluoxetine, ftoruracil, fluvastatin, fluvoxamine, flutamid, quinones, quinidine, khloralgidrat, chloramphenicol, celecoxib, цefamandol, Cephalexin, tsefmenoksym, cefmetazol, cefoperazone, cefuroxime, cimetidine, Ciprofloxacin, cyclophosphamide, Erythromycin, etoposide, ethanol.

Preparations of some medicinal plants (oficinalnyh or neoficinalnyh) also can both enhance the effect of warfarin: eg, Ginkgo (Ginkgo biloba), garlic (Allium sativum), Angelica archangelica (Angelica sinensis), papaya (Upload papaya), Sage (Salvia miltiorrhiza); and reduce: eg, Ginseng (Panax ginseng), tutsan (Hypericum perforatum).

You cannot take warfarin and any preparations of St. John's wort, It should be borne in mind, the effect of inducing action of warfarin may persist for even 2 weeks after you stop taking St. John's wort preparations. In that case, If the patient takes drugs St. John's wort, measure the MPE and stop taking. Monitoring of MHO should be careful, tk. its level can be increased when canceling St. John's wort. You can then assign warfarin.

Also exacerbate the effects of warfarin can quinine, contained in tonic drinks.

Warfarin could exacerbate the effects of oral gipoglikemicakih funds derived sulfonylureas.

Effect of warfarin can be simultaneous application with azatioprinom, aminoglutetimidom barbiturates, valproic acid, vitamin C, Vitamin k, glutetimidom, griseofulvin, dikloksacillinom, dizopiramidom, karʙamazepinom, kolestiraminom, Coenzyme Q₁₀, mercaptopurine, mesalazinom, mianserinom, mitotanom, nafcillinom, primidone, retinoid, ritonavirom, rifampicin, rofekoksiʙom, spironolactone, sukralfatom, trazodonom, fenazonom, hlordiazepoksidom, hlortalidonom, cyclosporine.

Diuretics in the case expressed hypovolemic actions can lead to an increase in the concentration of clotting factors, that reduces the effect of anticoagulants.

In the case of combined use of warfarin with other drugs, specified in the following list, It is necessary to carry out the monitoring of MHO at the beginning and end of treatment, and, possibly, through 2-3 weeks of therapy.

Food, rich in vitamin c, ters of warfarin; decrease the absorption of vitamin k, caused by diarrhoea or taking laxatives, potenziruet the warfarin. Most vitamin c is contained in green vegetables, Therefore, if treatment with warfarin, You should be careful when you eat the following foods: Amaranth Greens, avocado, broccoli, Brussels sprouts, headed cabbages, canola oil, sheet of Chaillot, onion, coriander (cilantro), cucumber Peel, chicory, fruit Kiwi, lettuce, mint, Green mustard, extra virgin olive oil, parsley, peas, pistachios, Red marine algae, Spinach Greens, spring onions, soy beans, tea leaves (but not tea-drink), turnip greens, Cress.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 5 years.