Мареван - instructions for use, doses, side effects, contraindications

Description:Tablets of light-blue color (with possible heterogeneity of coloring), flat, with bevelled edge, with dividing risk and code "ORN 17" on one side.

Pharmacotherapeutic group:Anticoagulant of indirect action

ATX: & nbsp

B.01.A.A.03 Warfarin

B.01.A.A Antagonists of vitamin K

Pharmacodynamics:Warfarin (or 4-hydroxycoumarin) is an anticoagulant that prevents the vitamin-K-dependent synthesis of clotting factors. Of the existing isomers, the S-isomer of warfarin is about 5 times stronger than the R-isomer of warfarin. The pharmacological effect is based on the ability of warfarin to prevent the action of vitamin K on the synthesis of clotting factors II, VII, IX and X.In therapeutic doses warfarin reduces the rate of synthesis of coagulation factors by 30-50% and reduces their biological activity. The full effect occurs on the 2nd-7th day (during this time, already circulating blood clotting factors are excreted from the body).

Pharmacokinetics:After oral administration, the bioavailability of warfarin is> 90%, the maximum plasma concentration is achieved within 3-9 hours. Simultaneous food intake slows down absorption, but does not reduce absorption quantitatively. There is some enterohepatic recycling. Warfarin almost completely binds to serum albumin, the content of the free fraction varies from 0.5 to 3%. The distribution volume is approximately 0.14 l / kg. Warfarin penetrates the placenta, but does not excrete with breast milk. Warfarin is metabolized in the liver. By catalysing CYP2C9 (S isomer) and CYP1A2 and CYP1A3 (R isomer) warfarin is converted into inactive metabolites, which are excreted in the urine. The half-life of the S-isomer of warfarin is 18-35 hours, the R-isomer of warfarin is 20-70 hours. 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.

Indications:

- Treatment and prevention of deep vein thrombosis and 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 prosthetic heart valves.

- Treatment and prevention of transient ischemic attacks and strokes.

Contraindications:

- Hypersensitivity to the components of the drug,

- tendency to bleeding (von Willebrand's disease, hemophilia, thrombocytopenia, platelet function disorders, hemorrhagic diathesis),

- acute DVS-syndrome, deficiency of proteins C and S;

- condition with a tendency to bleeding or obvious bleeding (including gastrointestinal hemorrhages in the anamnesis, peptic ulcer of the stomach and duodenal ulcer in the acute stage, as well as bleeding from the urinary, genital, respiratory tract, diverticulosis, malignant tumors, varicose veins expansion of the veins of the esophagus, aneurysm of the arteries, lumbar puncture,);

- eclampsia and preeclampsia,

- threatening abortion;

- recently suffered intracranial hemorrhage (incl.aneurysm of cerebral arteries, hemorrhagic stroke),

- recently transferred or suspected complex operations of the central nervous system,

- ophthalmic operations and diagnostic procedures;

- dementia, psychosis, alcoholism and other conditions, due to the impossibility of contact with the patient;

- severe arterial hypertension.

- severe renal and / or hepatic impairment, severe liver or kidney disease;

- mechanical jaundice;

- infectious endocarditis or exudative pericarditis;

- diabetes; propensity to fall;

- pregnancy (I and III trimester),

- lack of appropriate equipment to determine blood coagulation indicators.

Lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

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

Pregnancy and lactation:Warfarin quickly penetrates the placenta, has a teratogenic effect (nasal hypoplasia and chondrodysplasia) at 6 to 12 weeks of gestation. The drug can cause bleeding in the fetus at the end of pregnancy and during labor. Warfarin categorically contraindicated in the I and III trimester of pregnancy. The use of warfarin is not recommended in the remaining periods of pregnancy, except in cases of extreme necessity. Warfarin is not excreted in breast milk and can be used during lactation, however it is advisable to refrain from breast-feeding for the first time 3 days of therapy with the drug.

Dosing and Administration:

Warfarin is prescribed once a day, preferably at the same time. The duration of treatment is determined by the doctor in accordance with the indicators for use.

Before the start of therapy, the International Normalized Ratio (MHO) is determined. 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 weight and spontaneous International Normalized Ratio (MHO) less than 1/2 warfarin for four consecutive days.On the 5th day of treatment, MHO is determined, and in accordance with this indicator, a maintenance dose is prescribed.

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

For elderly patients, patients with a small body weight, with spontaneous MHO greater than 1.2 or having concomitant diseases (see section "Special instructions"), or receiving any medications that affect the effectiveness of anticoagulant therapy, the recommended initial dose of warfarin is 4.5 mg for two consecutive days. The dose is then calculated according to the table below, based on the measurement of MHO on the third day of therapy.

Day	MHO	Dose of warfarin, mg / day
1	-	10
2	-	10
3	<2,0	10
	from 2.0 to 2.4	6
	from 2.5 to 2.9	3
	from 3.0 to 3.4	1,5
	>4,0	miss one day
4-6	< 1,4	10
	from 1.4 to 1.9	7,5
	from 2.0 to 2.4	6
	from 2.5 to 2.9 from 3.0 to 3.9 from 4.0 to 4.5> 4.5	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 from 2.0 to 3.0 from 3.1 to 4.0> 4.5	weekly dose of warfarin rises by 20% weekly dose of warfarin rises by 10%, the dose remains reduced by 10% skip until MHO drops to <4.5, then continue treatment with a dose reduced by 20%.

Note: * the initial doses for patients with hereditary deficiency of protein S or C are indicated.

Measurement of MHO is performed daily until a stable target level is reached, which is usually set for 5 to 6 days of treatment. In the case of large abnormalities in the MHO level or in patients with liver disease or diseases affecting 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 MHO. 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 MHO measurement should be performed 1 or 2 weeks after the adjustment. After this, the measurements are continued until the 4-week intervals are reached.

Children:

Therapy with anticoagulants in children is conducted under the supervision of pediatricians.Doses are selected in accordance with the table below.

I. Day 1

If the base value MHO 1.0 - 1.3, the initial 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 from 2.0 to 3.0 from 3.1 to 3.5> 3.5

Actions:

Repeat the initial dose;

50% of the initial dose;

50% of the previous dose;

25% of the previous dose;

stop the drug before reaching

MHO <3.5, then resume treatment with a dose,

which is 50% of the previous dose.

III. Maintain if the value MHO: from 1 to 1.3 from 1.4 to 1.9 from 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 drug before reaching MHO <3.5, then resume treatment with a 20% less dose than the previous one.

Elective surgery:

Pre-, post- and postoperative anticoagulant therapy is performed as indicated below (if immediate cessation of anticoagulant effect is required - see the section "Overdose").

Identify MHO one week prior to the scheduled operation.

Stop taking warfarin 1 to 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 pause in taking warfarin depends on the value of MHO. Acceptance of warfarin is discontinued:

- for 5 days before surgery, if MHO> 4.0

- 3 days before surgery, if the MHO is from 3.0 to 4.0

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

Determine MHO in the evening before surgery and administer 0.5-1.0 mg of vitamin K] 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.

Treatment of elderly patients should be carried out with special precautions. the synthesis of clotting factors and hepatic metabolism in such patients is reduced, as a result of which the effect of warfarin may be excessive.

Side effects:

Very 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 (> 1/10 000, <1/1000) - eosinophilia, increased activity of liver enzymes, jaundice, rash, hives, itching, eczema, skin necrosis, vasculitis, hair loss, nephritis, urolithiasis, tubular necrosis.

During the year, bleeding is observed in approximately 8% of cases among patients receiving warfarin. Of these, 1.0% is classified as severe (intracranial, retroperitoneal) leading to hospitalization or blood transfusion, and 0.25% as fatal. The most frequent risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension. The probability of bleeding increases if MHO well above the target level. If the bleeding started at MHO, which is within the target level, then there are other related conditions that need to be investigated. Independent risk factors for serious bleeding during treatment with warfarin are: old age, high intensity of concomitant anticoagulant and antiplatelet therapy, history of strokes and gastrointestinal bleeding.The risk of bleeding is increased in patients with gene polymorphism CYP2C9.

From the digestive system: vomiting, nausea, diarrhea.

From the skin: Coumarin necrosis is a rare complication in the treatment with warfarin. Necrosis usually begins with swelling and darkening of the skin of lower extremities and buttocks or (less often) in other places. Later, the lesions become necrotic. In 90% of cases, necrosis develops in women. The lesions are observed from the 3rd to the 10th day of the drug administration and the etiology assumes the deficiency of antithrombotic protein C or S. Congenital insufficiency of these proteins can be the cause of complications, therefore, taking warfarin should begin simultaneously 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 very rare complication in warfarin therapy, its development is characteristic among men with atherosclerotic diseases. Presumably warfarin causes hemorrhages of atheromatous plaques, leading to microemboli.There are symmetrical purple lesions of the skin of the fingers and the soles of the feet, accompanied by burning pains.

After discontinuation of taking warfarin, these symptoms gradually disappear.

Other: reactions of hypersensitivity, manifested as skin rashes, and characterized by a reversible increase in the concentration of liver enzymes, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and calcification of the trachea.

Overdose:

Symptoms: the indicator of the effectiveness of treatment is on the border of development of bleeding, so the patient may have minor bleeding (including microhematuria, bleeding gums).

Treatment: With minor bleeding, it is sufficient to stop taking the drug until the target MHO value is reached. In case of severe bleeding, introduction of vitamin K (intravenously) and activated charcoal, a concentrate of coagulation factors or freshly frozen plasma.

If oral anticoagulants are indicated for the purpose in the future, large doses of vitamin K should be avoided. resistance to warfarin develops within 2 weeks.

Interaction:

It is not recommended to start or stop taking other medicines, to change the doses of the medications taken without consulting the attending physician. At simultaneous appointment, it is also necessary to take into account the effects of cessation of induction and / or inhibition of the action 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), antibiotics of the penicillin group in large doses.

Also, the combined use of warfarin with drugs that have a pronounced inhibitory effect on the isoenzymes of the cytochrome P450 system should be avoided (incl. cimetidine, chloramphenicol), the reception of which within a few days increases the risk of bleeding. In such cases cimetidine can be replaced, for example, ranitidine or famotidine.

The effect of warfarin can be enhanced with simultaneous use with the following medicines: acetylsalicylic acid, allopurinol, amiodarone, azapresene, azithromycin, alpha and beta interferon, amitriptyline, bezafibrate, vitamin A, vitamin E, glibenclamide, glucagon, gemfibrozil, heparin, grapafloxacin, danazol, dextropropoxyphene, diazoxide ,. digoxin, disopyramide, disulfiram, zafirlukast, indomethacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, levamisole, lovastatin, metolazone, methotrexate, metronidazole, miconazole (including in the form of a gel for the oral cavity), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol (especially after 1-2 weeks of continuous admission), paroxetine, piroxicam, proguanil, propafenone, propranolol, influenza vaccine, roxithromycin, sertraline, simvastatin, sulfafurazole, sulfamethisole, sulfamethoxazole / trimethoprim, sulfafenazole, sulfinpyrazone, sulindac, steroid hormones (anabolic and / or androgenic), tamoxifen, tegafur, testosterone, 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, cefmetazole, cefoperazone, cefuroxime, cimetidine, ciprofloxacin, cyclophosphamide, erythromycin, etoposide, ethanol.

Drugs of some medicinal plants (officinal or non-formal) can also enhance the effect of warfarin: for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica officinalis (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza); and reduce: for example, ginseng (Panax ginseng), St. John's Wort (Hypericum perforatum).

You can not simultaneously take warfarin and any preparations of St. John's Wort, it should be borne in mind that the effect of inducing the effects of warfarin may persist for another 2 weeks after discontinuation of St. John's wort. In the event that the patient is taking St. John's wort preparations, one should measure MHO and stop receiving. Monitoring MHO must be careful, because its level can increase when the St. John's wort is canceled. After that, you can assign warfarin.

Also, the action of warfarin can be enhanced by quinine, which is contained in tonic beverages.

Warfarin can enhance the effect of oral hypoglycemic agents of sulfonylurea derivatives.

The effect of warfarin may be weakened when used simultaneously with azathioprine, aminoglutethimide, barbiturates, valproic acid, vitamin C, vitamin K, glutetimide, griseofulvin, dicloxacillin, disopyramide, carbamazepine, colestyramine, coenzyme Q10, mercaptopurine, mesalazine, mianserin, mitotane, nafcillin, primidone, retinoids, ritonavir, rifampicin, rofecoxib, spironolactone, sucralfate, trazodone, phenazone, chlordiazepoxide, chlorthalidone, cyclosporine.

The use of diuretics in the case of pronounced hypovolemic effects may lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants.

In the case of concomitant use of warfarin with other drugs listed in the list below, it is necessary to monitor MHO at the beginning and at the end of treatment, and, if possible, 2-3 weeks after the start 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, potentiates 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 fruit, lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red algae, spinach greens, spring onions, soybeans, tea leaves (but not tea-drink), greens turnips, watercress.

Special instructions:

A mandatory condition for therapy with warfarin is strict adherence to the patient's intake of the prescribed dose of the drug. Patients suffering from alcoholism, as well as patients with dementia, may not be able to comply with the prescribed mode of taking warfarin.

Fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage, may increase the effect of warfarin. With hypothyroidism, the effect of warfarin can be reduced.

In the case of renal failure or nephrotic syndrome, the level of free fraction of warfarin in the blood plasma increases, which, depending on the concomitant diseases, can lead to both intensification and reduction of the effect.In the case of moderate hepatic insufficiency, the effect of warfarin is enhanced. In all of the above conditions, careful monitoring of the MHO level should be carried out.

Patients receiving warfarin, it is recommended to prescribe as an anesthetic paracetamol, tramadol or opiates.

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, since the usual therapeutic doses increase the risk of bleeding. Do not take warfarin patients with hereditary intolerance to galactose, a deficiency of the enzyme lactase, a violation of absorption of glucose and galactose. If it is necessary to achieve a rapid antithrombotic effect, it is recommended to begin treatment with the administration of heparin; then for 5-7 days, combined therapy with heparin and warfarin should be carried out until the target MHO level is maintained for 2 days.

To avoid coumarin necrosis, patients with hereditary deficiency of antithrombotic protein C or S should first be treated with heparin.The concomitant initial loading dose should not exceed 5 mg. The administration of heparin should continue for 5-7 days.

In the case of individual resistance to warfarin (it is rare) to achieve a therapeutic effect, 5 to 20 shock doses of warfarin are necessary. If the use of warfarin in such patients is ineffective, other possible causes should be established: simultaneous administration of warfarin with other drugs, inadequate diet, laboratory errors. Treatment of elderly patients should be carried out with special precautions, as synthesis of coagulation factors and hepatic metabolism in such patients is reduced, resulting in an excessive effect of warfarin.

Effect on the ability to drive transp. cf. and fur:Data on the adverse impact of Marevana on the ability to drive vehicles and serve other mechanisms are not present.

Form release / dosage:Tablets 3 mg.

Packaging:For 30 or 100 tablets in a plastic bottle of high-density polyethylene (HDPE) with a plastic cover, equipped with a ring of the first opening. For 1 bottle with instructions for use in a cardboard bundle.

Storage conditions:At a temperature not higher than + 25 ° С. Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LS-002606

Date of registration:01.03.2012

Expiration Date:Unlimited

Date of cancellation:2017-09-26

The owner of the registration certificate:Orion Corporation Orion Pharma Orion Corporation Orion Pharma Finland

Manufacturer: & nbsp

ORION CORPORATION ORION PHARMA Finland

Representation: & nbspORION CORPORATION ORION PHARMA ORION CORPORATION ORION PHARMA Finland

Information update date: & nbsp27.03.2018

Illustrated instructions

Instructions

Marewan (Marevan)