Warfarex - instructions for use, dose, side effects, contraindications

Active substanceWarfarinWarfarin

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Dosage form: & nbsppills

Composition:

One tablet contains:

active substance: warfarin sodium clathrate (in terms of warfarin sodium) - 3 mg or 5 mg,

Excipients:

tablets 3 mg:

lactose monohydrate - 107.93 mg, microcrystalline cellulose - 30.5 mg, crospovidone - 6.7 mg, magnesium stearate - 1.2 mg,

tablets 5 mg:

lactose monohydrate 105.75 mg, microcrystalline cellulose 30.5 mg, crospovidone 6.7 mg, magnesium stearate 1.2 mg,

dyes:

tablets Zmg: indigo carmine, E 132 (dye blue) 0.4 mg,

tablets 5 mg: colourant (Ponso 4R), E 124 (dye red) 0.4 mg.

Description:

Tablets 3 mg - round plano-cylindrical shape of the tablet is blue with darker patches, with a facet and a risk on one side.

Tablets 5 mg - round, flat-cylindrical shape of a pink colored tablet with darker patches, with a facet and a risk for four pieces on one side.

Pharmacotherapeutic group:Antithrombotic agents.Antagonists of vitamin K

ATX: & nbsp

B.01.A.A.03 Warfarin

B.01.A.A Antagonists of vitamin K

Pharmacodynamics:Warfarex is an indirect anticoagulant that prevents vitamin K-dependent synthesis of clotting factors (II, VII, IX and X) and proteins C and S in the liver due to dose-dependent inhibition of the C1 subunit vitamin K-epoxy reductase, resulting in decreased production of vitamin K1-epoxide. The S-isomer of warfarin is about 5 times higher in activity than the R-isomer. In therapeutic doses warfarin reduces the rate of synthesis of coagulation factors by 30-50% and reduces their biological activity. The beginning of anticoagulant action is observed: 36-72 hours after the beginning of the drug intake with the development of maximum effect on 5-7 days from the beginning of its use. After discontinuation of the drug, the restoration of vitamin K-dependent coagulation factors occurs within 4-5 days.

Pharmacokinetics:Absorption of the warfarex is fast. Simultaneous food intake slows down absorption, but does not reduce it quantitatively. Bioavailability more than 90%. Time to reach the maximum concentration in the plasma. blood (TSMax) - 3-9 hours.The connection with plasma proteins is 97-99%. The volume of distribution is 0.14 l / kg. Penetrates through the placenta, but not into breast milk.

Metabolised in the liver. Warfarin is a racemic mixture, where the R and S isomers are metabolized in the liver by different routes. Each of the isomers is converted into 2 main metabolites. The S-enantiomer is metabolized by the CYP2C9 isoenzyme, and the R-enantiomer is metabolized by the CYP1A2 and CYP3A4 isoenzymes. The S-enantiomer has a 2-5 fold greater anticoagulant activity than the R-enantiomer, but the half-life (T1 / 2) of the latter is longer. Patients with polymorphism of the CYP2C9 isoenzyme, including the alleles CYP2C9 * 2 and CYP2C9 * 3, may have increased sensitivity to warfarin and an increased risk of bleeding. Warfarin is excreted from the body in the form of inactive metabolites with bile, which are reabsorbed in the gastrointestinal tract and excreted by the kidneys. T1 / 2 on the average 20-60 hours, for the R-enantiomer 37-89 hours, for the S-enantiomer 21-43 hours.

Indications:

Treatment and prevention of deep vein thrombosis and pulmonary embolism, transient ischemic attacks and ischemic stroke.

Secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction.

Prophylaxis of thromboembolic complications in patients with atrial fibrillation, lesions of the heart valves or with prosthetic heart valves.

Contraindications:

Hypersensitivity; tendency to bleeding (von Willebrand's disease, hemophilia, thrombocytopenia, platelet function disorders, hemorrhagic diathesis), acute DIC syndrome, deficiency of proteins C and S; conditions predisposing to bleeding (including gastrointestinal hemorrhages in anamnesis, gastric ulcer and duodenal ulcer in the acute stage, diverticulosis, malignant tumors, varicose veins of the esophagus, arterial aneurysm, lumbar puncture); recently suffered intracranial hemorrhage (including aneurysm of cerebral arteries, hemorrhagic stroke); recently transferred or suspected complicated CNS operations, ophthalmic operations and diagnostic procedures; dementia, psychosis, alcoholism and other conditions in which there is insufficient inability to assess the coagulation condition; blood system using laboratory methods; severe arterial hypertension.

Pronounced renal and / or hepatic insufficiency, severe liver or kidney disease, mechanical jaundice; infectious endocarditis or exudative pericarditis; diabetes; propensity to fall; pregnancy; deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Carefully:Advanced age, fever, hyper- or hypothyroidism, decompensated heart failure, with concomitant alcoholism liver disease, chronic renal failure, mild to moderate severity, nephrotic syndrome, mild hepatic impairment.

Pregnancy and lactation:Warfarex can not be used during pregnancy. Therefore, against the background of the use of warfarex, it is necessary to use effective methods of preventing pregnancy. Although the drug penetrates into the mother's milk only in a small amount, warfarax should be taken during breastfeeding, observing caution and strictly taking into account all the doctor's recommendations.

Dosing and Administration:

Inside at one time, preferably in one and the same time of day. Duration treatment is determined by the doctor in according to the indications for application.

Control during treatment

Prior to treatment, an international normalized ratio (MHO). Further 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.

Adults

Patients with normal body weight and baseline MHO less than 1.2 prescribe 10.5 mg of warfarin for a sin consecutive days. The dose is then calculated according to the following table, based on the measurement MHO on the fourth day of therapy.

In outpatient settings and in patients with thrombophilia (hereditary deficiency of protein C or S) the recommended initial dose of warfarin is 4.5 mg during the sin of consecutive days. The dose is then calculated according to the following table, based on the measurement MHO on the fourth day of therapy.

For elderly patients, patients with a small body weight with MHO more than 1,2, or having concomitant diseases, or receiving any medications that affect the effectiveness of anticoagulant therapy, the recommended initial dose of warfarin is 4.5 mg within twoconsecutive days. The dose is then calculated according to the following table, based on the measurement MHO on the third day of therapy.

Day	INR	Dose of warfarin, mg / day
1	-	10,5 (4,5*)
2	-	10,5 (4,5*)
3	<2,0 from 2.0 to 2.4 from 2.5 to 2.9 from 3.0 to 3.4 >4.0	10,5 (4,5*) 6 3 1,5 miss one day
4-6	<1,4 from 1.4 to 1.9 from 2.0 to 2.4 from 2.5 to 2.9 from 3.0 to 3.9 from 4.0 to 4.5 >4,5	10,5 7,5 6 4,5 3 skip one day, then 1.5 skip two days, then 1.5
7-	from 1,1 to 1,4 from 1.5 to 1.9 2.0 to 3.0 from 3,1 to 4,0 >4,5	week dose of warfarin increases by 20% The weekly dose of warfarin is increased by 10% the dose persists decreases by 10% skip for now MHO will not decrease up to <4.5, then continue treatment with a dose reduced by 20%

* Initial doses for patients with hereditary protein deficiency S or with.

The INR is measured daily until a stable target level is reached, which is usually set on the 5th-6th day of treatment. In the case of large deviations in the level of INR or in patients with liver disease or diseases that affect the absorption of vitamin K, the measurement intervals may be less than 4 weeks. The appointment of new or cancellation of previously taken medications requires additional measurements of INR.With prolonged therapy, the adjustment is carried out before the weekly dose of warfarin according to the table above. If the dose requires adjustment, the next INR measurement should be done 1 or 2 weeks after the adjustment. After this, the measurements are continued until 4 week intervals are reached. If there is no possibility of routine monitoring of INR necessary for the use of warfarin, they switch to other oral anticoagulants (dabigatran, apixaban, rivaroxaban). It is important to avoid the simultaneous use of warfarin and another drug in therapeutic doses. You must cancel warfarin, and further monitor the INR daily. When MNO <2.0 (usually within three days after warfarin abolition), apixaban or dabigatran is started; When the INR <3.0 is reached, rivaroxaban is taken.

Patients who had previously taken warfarin

The recommended starting dose is a double dose of a known maintenance dose of warfarin and is administered within the first 2 days. The treatment is then continued with a known maintenance dose. On the 5th day of treatment, MHO and dose adjustment in accordance with this indicator. It is recommended that the indicator MHO from 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve diseases, prosthetic repair of the heart valves with bioprostheses. Higher performance 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 are limited. The initial dose is usually 0.2 mg / kg per day with normal liver function and 0.1 mg / kg per day if liver function is impaired. The maintenance dose is selected in accordance with the indicators MHO. Recommended Levels MHO the same as in adults. The decision to prescribe warfarin in children should be taken by an experienced specialist. Treatment should be conducted under the supervision of an experienced pediatrician. Doses are selected in accordance with the table below.

I. Day 1

If the base value MHO from 1.0 to 1.3, the shock dose is 0.2 mg / kg body weight.

II.Days 2 to 4, if the value MHO:

from 1 to 1.3

from 1.4 to 1.9

2.0 to 3.0

from 3.1 to 3.5

>3,5

Actions:

Repeat the shock dose;

50% of the impact dose;

25% of the impact dose;

Stop the introduction preparation before MHO <3.5, then resume treatment with a dose of 50% of the previous dose.

III.Maintain if the value MHO:

from 1 to 1.3

from 1.4 to 1.9

2.0 to 3.0

from 3.1 to 3.5

>3,5

Actions (weekly dose):

Increase the dose by 20%;

Increase the dose by 10%;

Without changes;

Reduce the dose by 10%;

Stop the introduction of warfarin before reaching MHO <3.5, then resume treatment with a dose that is 20% less than the previous one.

Patients with hepatic insufficiency

Violation of the functions of the liver increases the sensitivity to warfarin, as the liver produces clotting factors, and also metabolizes warfarin. This group of patients requires careful monitoring of indicators MHO.

Patients with renal insufficiency

In patients with impaired renal function, a dose of warfarin should be reduced and careful monitoring should be carried out.

Scheduled (elective) surgical interventions

Pre-, peri- and post-operative anticoagulant therapy is performed as indicated below (if urgent cancellation of the oral anticoagulant effect is necessary - see the section "Overdose").

Identify MHO a week before the scheduled operation.

Stop taking warfarin 1-5 days before surgery. In the case of a high risk of thrombosis, low molecular weight heparin is administered subcutaneously to the patient for prophylaxis.

The duration of the pause in taking warfarin depends on the INR.

Acceptance of warfarin is discontinued:

- 5 days before surgery, if INR> 4.0

- 3 days before surgery, if the INR is between 3.0 and 4.0

- 2 days before surgery, if the INR is 2.0 to 3.0

Determine the INR in the evening before the operation and enter 0.5-1, 0 mg of vitamin K1 orally or intravenously if INR> 1.8.

Consider the need for infusion of unfractionated heparin or preventive administration of low-molecular-weight heparin on the day of surgery.

Continue subcutaneous administration of low molecular weight heparin for 5-7 days after surgery with concomitant reconstituted warfarin.

Continue taking warfarin with a normal maintenance dose on the same day in the evening after small surgeries, and the day the patient begins to receive enteral feeding after major surgery.

If you missed taking another dose of warfarin and noticed it within 12 hours, as soon as possible, take the missed dose.Take the next dose as usual. If more than 12 hours have passed after the missed dose, do not take it. Take the next dose as usual. If more than one dose is missed, seek medical advice. Do not take a double dose to replace the missed dose. It is recommended to keep a record of taking doses of warfarin.

Side effects:

Frequency: very often more than 1/10, often more than 1/100 and less than 1/10, infrequently more than 1/1 000 and less than 1/100, rarely more than 1/10 000 and less than 1/1 000. Very often: increased bleeding.

Often: hypersensitivity to warfarin after prolonged use. Infrequent: anemia, vomiting, abdominal pain, nausea, diarrhea.

Rarely: eosinophilia, increased activity of "liver" enzymes, jaundice, rash, hives, itching, eczema, skin necrosis, vasculitis, hair loss, nephritis, urolithiasis, tubular necrosis, palmar-plantar syndrome.

Overdose:

Symptoms: bleeding.

Treatment: depending on the INR indicator. For INRs of less than 5, the next dose should be skipped and lower doses should be continued until the therapeutic value of INR is reached. With INR 5-9, you should skip 1-2 doses and continuereception of lower doses until the therapeutic value of INR is reached or 1 dose of warfarin is passed and 1-2.5 mg of menadione sodium bisulphite (vitamin K) is ingested. With INR more than 9 should stop taking warfarin, take in 3-5 mg of menadione sodium bisulfite. With INR 5-9 24 hours prior to surgery, stop taking warfarin and take 2-4 mg of menadione sodium bisulfite; with INR more than 20 or severe bleeding warfarin 10 mg of menadione sodium bisulphite should be withdrawn and injected intravenously, the concentrate of clotting factors, freshly frozen plasma or whole blood should be poured. If necessary, repeat the introduction of menadione sodium bisulfite every 12 hours.

Interaction:

Do not start or stop taking other drugs, or change their doses without consulting your doctor.

- With the simultaneous use of warfarin and drugs that affect blood clotting (acetylsalicylic acid (ASA), clopidogrel, ticlopidine, dipyridamole, most NSAIDs (with the exception of low doses of COX-2 inhibitors)), penicillins at high doses increase the risk of bleeding.

- Because of the increased risk of bleeding, combined use of warfarin with inhibitors of microsomal liver enzymescimetidine, chloramphenicol). In such cases cimetidine can be replaced with ranitidine or famotidine.

- The anticoagulant effect of warfarin is enhanced: ASA, allopurinol, amiodarone, azapresene, azitromycin, interferon alfa, interferon beta, amitriptyline, bezafibrate, a vaccine for the prevention of influenza, vitamin E, glibenclamide, glucagon, gemfibrozil, heparin, grapafloxacin, danazol, dextropropoxyphene, diazoxide,

. digoxin, disopyramide, disulfiram, zafirlukast, indomethacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, co-trimoxazole, levamisole, lovastatin, metolazone, methotrexate, metronidazole, miconazole, male sex hormones (testosterone), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol, paroxetine, piroxicam, proguanil, propafenone, propranolol, retinol, roxithromycin, sertraline, simvastatin, sulfafurazole, sulfamethisole, sulfafenazole, sulfinpyrazone, sulindac, tamoxifen, tegafur, tetracyclines, thienyl acid, tolmetine, trastuzumab, troglitazone, phenytoin, phenylbutazone, fenofibrate, feprazone, fluconazole, fluoxetine, fluorouracil, fluvastatin, fluvoxamine, flutamide, quinine, quinidine, chloral hydrate, chloramphenicol, celecoxib, cefamandol, cephalexin, cefmenoxime, cefmethazole, cefoperazone, cefuroxime, cimetidine, ciprofloxacin, cyclophosphamide, erythromycin, etoposide, ethanol.

- Some medicinal plants can also:

- intensify the effect of warfarin, for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica officinalis (Angelica sinensis), papayaCarica papaya), sage (Salvia miltiorrhiza),

- reduce the effect of warfarin, for example, ginseng (Panax ginseng), St. John's wort (Hypericum perforatum).

Do not take warfarin and preparations of St. John's wort perfumed, since the effect of the inducing action of warfarin on cytochrome P450 can persist for another 2 weeks after stopping the intake of St. John's wort preparations. In the event that the patient takes St John's wort preparations, it is necessary to determine MHO and stop receiving. Control MHO must be careful, because its value may increase with the withdrawal of preparations of St. John's wort perfumed.After that, you can assign warfarin.

- The effect of warfarin can enhance quinine, contained in tonic beverages.

- Warfarin may enhance the hypoglycemic effect of oral hypoglycemic agents - sulfonylurea derivatives.

The effect of warfarin may be weakened when taken simultaneously with azathioprine, aminoglutethimide, ascorbic acid, barbiturates, valproic acid, menadione sodium bisulfite, glutheiramide, griseofulvin, dicloxacillin, disopyramide, carbamazepine, colestyramine, mercaptopurine, mesalazine, mianserin, mitotane, nafcillin, prymidone, retinoids, ritonavir, rifampicin, rofecoxib, spironolactone, sucralfate, trazodone, ubidekarenonom, phenazone, chlordiazepoxide, chlorthalidone, cyclosporine.

- Diuretics when expressed hypovolemic action may result in an increased concentration of blood clotting factors, thereby reducing the effects of anticoagulants. In the case of combined use of warfarin with other drugs is necessary to monitor the INR in the beginning and end of the treatment and, if possible, after 2-3 weeks of therapy.

Food rich in vitamin K weakens the effect of warfarin; a decrease in the absorption of vitamin K, caused by diarrhea or the use of laxatives, increases the effect of warfarin. Most of the vitamin K is found in green vegetables, so when treating with warfarin, you should use the following foods with caution: amaranth greens, avocado, broccoli, Brussels sprouts, cabbage, canola oil, leaf shayo, onion, coriander, cucumber, chicory , kiwi fruits, lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red seaweed, spinach greens, spring onions, soybeans, tea leaves, turnip greens, watercress.

Special instructions:

A prerequisite for the therapy with warfarex is strict adherence to the recommended dose of the drug.

The target value of INR 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 and dementia may not be able to follow the prescribed mode of taking warfarin.

With fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage, the effect of warfarin may worsen. With hypothyroidism, the effect of warfarin can be reduced. In chronic renal failure (CRF) or nephrotic syndrome, the concentration of the free fraction of warfarin in the plasma increases, which, depending on the concomitant diseases, can lead to both an increase and a decrease in the effect. With moderate CRF, the effect of warfarin is enhanced. In all these states, the INR should be closely monitored.

Patients receiving warfarin, as analgesic drugs are recommended paracetamol, tramadol or narcotic analgesics. In 1 year of treatment bleeding is observed in about 8% of cases. Of these, 1% is classified as severe (intracranial, retroperitoneal), leading to hospitalization or blood transfusion; 0,25% - as fatal. The most frequent risk factor for intracranial hemorrhage is uncontrolled arterial hypertension. The probability of bleeding rises if the INR is significantly higher than the target value.If bleeding started with an INR that is within the target value, then there are other risk factors that need to be investigated.

Coumarin necrosis is a rare complication in the treatment with warfarin. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks, less often in other places. Later, the lesions become necrotic. In 90% of cases, necrosis develops in women; lesions are observed from the 3rd to the 10th day of the drug and the etiology assumes a deficiency of protein C or S. Congenital insufficiency of these proteins can be the cause of complications, therefore, taking warfarin should begin: concomitantly with the administration of heparin and small initial doses of the drug. If a complication occurs, then warfarin is discontinued and heparin is continued until the lesions are healed or scarring.

Palmar-plantar syndrome is a rare complication in the therapy with warfarin, its development is typical for men with atherosclerosis. Warfarin causes hemorrhages 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.When you stop taking warfarin, these symptoms gradually disappear. When using warfarin, hypersensitivity reactions can occur that are manifested to skin rashes and are characterized by a reverse increase in the activity of "liver" enzymes, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and trachea cadification.

Risk factors for severe bleeding are elderly, high intensity of concomitant anticoagulant and antiplatelet therapy, strokes and gastrointestinal hemorrhages in the anamnesis, polymorphism of the isoenzyme gene CYP2C9.

Patients with a mutation of the CYP2C9 isoenzyme gene have a longer T1 / 2 warfarin, so they need lower doses of warfarin. If it is necessary to achieve a rapid antithrombotic effect, treatment should begin with the administration of heparin; then within 5-7 days should be combined therapy with heparin and warfarin until the target value of INR is maintained for two days.

To avoid coumarin necrosis, patients with hereditary deficiency of protein C and S should first enter heparin.

The initial loading dose should not exceed 5 mg.The administration of heparin should continue for 5-7 days.

In the case of a rare individual resistance to warfarin, to achieve a therapeutic effect, 5-20 loading doses of warfarin are necessary. If the reception of warfarin in such patients is ineffective, other possible causes should be identified, for example, simultaneous intake of other drugs, inadequate diet, laboratory errors.

Treatment of the elderly should be done with caution, because the synthesis of blood coagulation factors and hepatic metabolism in such patients is reduced, so that the effect of warfarin can be enhanced.

Effect on the ability to drive transp. cf. and fur:Does not affect the ability to drive vehicles, mechanisms.

Form release / dosage:

Tablets 3 mg or 5 mg.

Packaging:

For 30 or 100 tablets in tightly ukuporennye plastic bottles with lids with control of the first autopsy.

One bottle together with the instruction for use is placed in a pack of cardboard.

Storage conditions:Store in a dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

5 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N 015623/01

Date of registration:17.03.2009 / 11.09.2012

Expiration Date:Unlimited

The owner of the registration certificate:GRINDEX, JSC GRINDEX, JSC Latvia

Manufacturer: & nbsp

GRINDEX, AO Latvia

Representation: & nbspGrindeks Rus, Open CompanyGrindeks Rus, Open CompanyRussia

Information update date: & nbsp23.01.2017

Illustrated instructions

Instructions

Warfarex® (Warfarex®)