Orion warfarin

General characteristics. Structure:

Active ingredient: 3,0 mg or 5,0 mg of warfarin of sodium.

Excipients: lactoses monohydrate, starch corn, gelatin, magnesium stearate; dyes: indigo carmine (E132), erythrosine (E127).

Drug with pronounced anticoagulating action.

Pharmacological properties:

Pharmacodynamics. Warfarin or 4 hydroxycoumarin — anticoagulant which blocks vitamin K-dependent synthesis of blood-coagulation factors. From its S-warfarin isomers is about 5 times stronger, than R-warfarin. Its efficiency is based on ability of warfarin to block effect of vitamin K on synthesis of blood-coagulation factors of II, VII, IX and X. In therapeutic doses warfarin reduces the speed of synthesis of factors of coagulation by 30–50% and their biological activity. The full effect occurs for the 2-7th day (during this time coagulation factors which already circulate in blood, are brought out of an organism).

Pharmacokinetics. After oral administration bioavailability of warfarin is higher than 90% and Cmax in a blood plasma is reached in 1–2 h. The concomitant use of food slows down absorption, but does not reduce absorption quantitatively, due to existence of enterogepatichesky circulation. Warfarin almost completely contacts a seralbumin, the free fraction varies in the range of 0,5-3%. The volume of distribution makes about 0,14 l/kg of body weight. Warfarin gets through a placenta, but does not get into breast milk. Warfarin is metabolized in a liver by means of a catalysis of CYP 2C9 (S-warfarin), CYP 1A2 and CYP 3A (R-warfarin) it turns into inactive metabolites which are removed with urine. T½ S-warfarin makes 18–35 h, and R-warfarin — 20–70 h.

Indications to use:

Treatment and prevention of a deep vein thrombosis and embolism of a pulmonary artery. Secondary prevention of a myocardial infarction and prevention of tromboembolic episodes (a stroke or a system embolism) after a myocardial infarction. Prevention of tromboembolic episodes at patients with fibrillation of auricles, damages of heart valves or with the fitted a prosthesis heart valves. Prevention of the fast-taking place ischemic attacks and a stroke.

Route of administration and doses:

The target objective INR (the international normalized relation) for peroral anticoagulating therapy:

• prevention of tromboembolic episodes at patients with the fitted a prosthesis heart valves — MHO=2,5-3,5;
• other indications — MHO=2,0-3,0.

Adults: to patients with the normal body weight and spontaneous MNO <1,2 appoint 10 mg of warfarin within 3 consecutive days. Then the dose is calculated according to the table below based on measurement of MNO for the 4th day.

In out-patient conditions and at patients with hereditary insufficiency of a protein of C or S recommended initial dose makes 5 mg of warfarin within 3 consecutive days. Then the dose is calculated according to the table given below based on measurement of MNO for the 4th day.
For patients of advanced age, with small body weight, with spontaneous MNO> 1,2 either having the associated diseases or receiving any medicines influencing efficiency of anticoagulating therapy, the recommended initial dose makes 5 mg of warfarin within 2 consecutive days. Then the dose is calculated according to the table given below based on measurement of MNO for the 3rd day.

 

Day	MHO	Dose of warfarin, mg/days
The 1st	—	10 (5 *)
The 2nd	—	10 (5 *)
The 3rd	<2	10 (5 *)
	2–2,4	5
	2,5–2,9	3
	3–3,4	2,5
	3,5–4	1,5
	> 4,0	To miss 1 day of reception
The 4-6th	<1,4	10
	1,4–1,9	7,5
	2–2,4	5
	2,5–2,9	4,5
	3–3,9	3
	4–4,5	To pass 1 day, then MHO=1,5
	> 4,5	To pass 2 days, then MHO=1,5
The 7th		Week dose of warfarin
	1,1–1,4	Increases by 20%
	1,5–1,9	Increases by 10%
	2–3	Remains
	3,1–4	Decreases by 10%
	> 4,5	To pass until MNO reaches <4,5, then to continue treatment in the dose lowered by 20%

Measurement of MNO is taken daily before achievement of the stable target objective which usually is established for the 5-6th day of treatment. Then measurement of MNO is taken weekly, reaching a 4 weeks interval. In case of big deviations in the MNO level or patients with the abnormal liver functions or diseases influencing vitamin K absorption, intervals of measurements can have less than 4 weeks. Appointment new or cancellation of earlier accepted medicines demands carrying out additional measurements of MNO. At long therapy correction is carried out to a week dose of warfarin according to the stated above table. If dose adjustment is required, then the following measurement of MNO needs to be taken in 1 or 2 weeks after correction. After this measurement proceed before achievement of 4 weeks intervals.

Children: therapy by anticoagulants at children is carried out under observation of pediatricians. Doses are selected according to the table given below.

MHO	Actions
1st day, if spontaneous MHO=1-1,3	Initial dose — 0,2 mg/kg of body weight, at an abnormal liver function — 0,1 mg/kg of body weight
Days from the 2nd for the 4th
1,1–1,3	To repeat an initial dose
1,4–1,9	50% of an initial dose
2–3	50% of an initial dose
3,1–3,5	25% of an initial dose
> 3,5	To stop administration of drug before achievement of MHO <3,5, then to resume treatment in the dose making 50% of the previous dose
The supporting treatment
1,1–1,4	To raise a week dose for 20%
1,5–1,9	To raise a week dose for 10%
2–3	Without changes
3,1–3,5	To lower a week dose by 10%
> 3,5	To stop administration of drug before achievement of MHO <3,5, then to resume treatment in a dose 20% lower previous

Planned operations: pre-, peri-and post-operational anticoagulating therapy is carried out, as shown below. To define MNO for 1 week before the appointed operation.

To stop reception of warfarin in 1–5 days prior to operation. In case of high risk of thrombosis to the patient for prevention п / to enter low-molecular heparin.

Pause duration in reception of warfarin depends on MNO. Reception of warfarin is stopped:

• in 5 days prior to operation, if MNO> 4,0;
• in 3 days prior to operation, if MNO = 3,0–4,0;
• in 2 days prior to operation, if MHO=2,0-3,0.
To define MNO in the evening before operation and to enter 0,5–1,0 mg of K1 vitamin orally or in/in if MNO> 1,8.

To take into account need of infusion of unfractionated heparin or preventive administration of low-molecular heparin in day of operation.

To continue п / to administration of low-molecular heparin within 5–7 days after operation with the accompanying resumed warfarin reception.
To continue reception of warfarin in a usual maintenance dose on the same day in the evening after small operations and in day when the patient begins to receive an enteroalimentation after extensive operations. 

Features of use:

 In case of need bystry antitrombotichesky effect it is recommended to begin treatment with administration of heparin. Then administration of heparin is continued with a concomitant use of warfarin within 5–7 days until MNO remains at the target objective within at least 2 days.

During reception of oral anticoagulants messages on such side reaction as bleeding most often arrive. Should appoint warfarin with care patients who have a risk of developing of serious bleedings (for example at simultaneous use of NPVP, after recently had ischemic stroke, a bacterial endocarditis, gastrointestinal bleeding).

The greatest risk factors of developing of bleedings are the high level of anti-coagulation (MNO> 4,0), the age is more senior than 65 years, unstable MNO, recently postponed gastrointestinal bleeding, uncontrollable AG, cerebrovascular diseases, serious heart troubles, a tendency to falling, anemia, a malignant tumor, an injury, a renal failure, the accompanying reception of other medicines. All patients accepting warfarin have to measure MNO regularly. More frequent measurement of MNO, more careful selection of a dose for achievement of desirable MNO and shorter duration of therapy are required for patients with the increased risk of developing of bleedings. Patients have to be warned about measures of minimization of risk of developing of bleeding, and also immediately report to the doctor about emergence and symptoms of bleeding.

Measurement of MNO, consultation of the doctor and dose decline or drug withdrawal are extremely important. At high MNO reduce a dose or stop therapy by warfarin. Sometimes it is necessary to continue therapy by anticoagulants. It is necessary to measure MNO within 2–3 days to make sure that it decreased.

Other antithrombocytic medicines should be applied with extra care because of the increased risk of developing of bleeding.
Indispensable condition of therapy by warfarin is strict observance of the appointed drug dose.

Developing of bleeding can demonstrate warfarin overdose. Unexpected bleeding at reception in therapeutic doses has to be investigated and MNO needs to be controlled.

Anti-coagulation after an ischemic stroke increases risk of a secondary hematencephalon. At patients with fibrillation of auricles long therapy by warfarin is useful, but the risk of an early repeated embolism low therefore having rummaged in treatment after an ischemic stroke is justified. Treatment by warfarin needs to be resumed in 2–14 days after an ischemic stroke, depending on the size of a heart attack and the ABP. At patients with embolic strokes or not controlled AG treatment by warfarin should be stopped for 14 days.

Before surgeries if there is no risk of development of serious bleedings, operation can be performed at MNO <2,5. Before surgeries if there is a risk of serious bleeding, reception of warfarin should be stopped in 3 days prior to operation.

In need of continuation of anticoagulating therapy, for example, at a thromboembolism, life-threatening, MNO has to be lowered to <2,5 and therapy is begun with heparin.

If operation is necessary and reception of warfarin cannot be stopped in 3 days prior to operation, cancellation of anti-coagulation has to be carried out by means of low doses of vitamin K.

Therapy resuming by warfarin depends on risk of developing of post-operational bleeding.

Reception of warfarin should not be stopped before routine dental operations, such as an odontectomy.

Treatment of patients with a round ulcer of a stomach needs to be carried out with extra care, considering high risk of developing of bleeding. Such patients need to be inspected and informed on how to distinguish bleeding and, in case of its emergence what it is necessary to take measures regularly.

Patients with alcoholism, and also patients with dementia can be incapable to adhere to the necessary mode of reception of warfarin. In case of the use of a large amount of alcohol danger of a gipotrombinemiya and development of bleedings increases.

Resistance to warfarin is noted very seldom. Such patients for achievement of therapeutic effect need from 5 to 20 usual doses of warfarin. If reception of warfarin is insufficiently effective, it is necessary to establish other more reliable reasons: lack of administration of drug, interaction with other medicines or foodstuff, and also laboratory mistakes.

Patients with hereditary insufficiency of an antitrombotichesky protein of C at the beginning of therapy by warfarin have a risk of development of a necrosis of skin. At such patients therapy has to begin without warfarin saturation dose even if to the patient enter heparin. With hereditary insufficiency of an antitrombotichesky protein of S it is also recommended to patients to begin therapy with warfarin slowly.

Treatment of patients of advanced age should be carried out with extra care. It is necessary to make sure of ability of the patient to follow the strict rules at administration of drug. Hepatic metabolism, as well as synthesis of factors of coagulation at elderly people, decreases. Thereof the overshot effect of warfarin can easily occur. Treatment should be begun with care. It is necessary to take into consideration the accompanying reception of medicines in order to avoid undesirable interactions.

Many medicines and food stuffs interact with warfarin and influence a prothrombin time. Reception of any medicines, including OTS-drugs, is the basis for strengthening of control of the MNO level. It is necessary to warn patients about need to inform the attending physician before reception of any medicines, including herbal remedies and vitamin drugs.

The hyperthyroidism, fever and noncompensated heart failure can strengthen effect of warfarin. In case of a hypothyroidism the effect of warfarin can be reduced. At patients with a moderate liver failure the effect of warfarin amplifies. In case of a renal failure or a nephrotic syndrome the level of free fraction of warfarin in a blood plasma which depending on associated diseases can lead to strengthening or decrease in effect of warfarin increases. In all these cases it is necessary to carry out monitoring of a clinical condition of the patient and the MNO level.

Patients with a mutation of a gene which codes CYP 2C9 enzyme have longer T½ of warfarin. Lower doses of drug as at reception of usual therapeutic doses the risk of bleeding increases are required for such patients.

Influence of such factors as body degrowth, acute disease and smoking cessation, can strengthen effect of warfarin therefore the dose decline can be required.

Increase in body weight, diarrhea and vomiting, on the contrary, reduce effect of warfarin therefore increase in a dose can be necessary.

Drug contains lactose. At rare hereditary intolerance of a galactose, a lactose intolerance of Lapp or malabsorption of a glucose/galactose use of drug is not shown.

It is necessary to avoid simultaneous use with juice from a cranberry and other products which contain a cranberry as they considerably strengthen effect of warfarin.

During therapy by warfarin level of consumption of vitamin K with food has to remain invariable.

Most of all vitamin K contains in green vegetables and greens, such as tea leaves (but not brewing tea), greens of an amaranth, avocado, endiviya, peas, a chayot, headed cabbage, green onions, kiwi fruits, a coriander, a cucumber peel (but not a cucumber without peel), sheet cabbage, a lettuce, turnip, mint leaves, olive oil, broccoli, parsley, spinach, pistachios, red algas, onions, a Brussels sprout, burdock oil, mustard leaves, soybeans, soy oil, water cress.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Does not influence.

Use during pregnancy or feeding by a breast. Warfarin gets through a placenta. Therapy by warfarin can cause a varfarinovy embryopathy (a nasal hypoplasia and a chondrodysplasia) in pregnant women if to accept warfarin in the period of an organogenesis (from the 6th to the 12th week), and even after that it can be the cause of disturbances in development of TsNS. Warfarin can cause fruit hemorrhages, especially at the end of pregnancy and at the time of delivery. The Varfarinovy embryopathy as it is described, noted in 4–6% of cases if to apply warfarin during pregnancy, probability of its emergence raises at reception of a daily dose more than 5 mg. Thus, warfarin is contraindicated during pregnancy. Danger of reception of warfarin to a fruit should be estimated carefully concerning risk for mother in case of warfarin non-use. Antitrombotichesky therapy during pregnancy has to be carried out individually under careful observation of the corresponding specialists.

Warfarin does not get into breast milk therefore feeding by a breast can be continued during therapy by warfarin.

Children. Therapy by anticoagulants at children is carried out under observation of pediatricians.

Side effects:

frequency of emergence of side reactions has the following classification: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); seldom (≥1/10 000 <1/1000); extremely seldom (<1/10 000), frequency is unknown (it is impossible to determine by the available data).

Disturbances from system of a kroveobrazovaniye and lymphatic system: often — a hemorrhage; infrequently — anemia; seldom — a coumarinic necrosis, a syndrome of purple fingers, an eosinophilia; extremely seldom — a vasculitis.

Disturbances from respiratory system, thoracic and mediastinal frustration: extremely seldom — trachea calcification.

Disturbances from a digestive tract: often — nausea, vomiting, diarrhea, pain in a stomach.

Disturbances from gepatobiliarny system: extremely seldom — reversible increase in level of liver enzymes, cholestatic hepatitis, jaundice.

Disturbances from skin and hypodermic cellulose: extremely seldom — a reversible alopecia, rash, eczema, a small tortoiseshell, a skin necrosis.

Disturbances from a reproductive and urinary system: extremely seldom — a priapism, nephrite, an urolithiasis, a tubular necrosis.

The general disturbances and reactions in an injection site: extremely seldom — allergic reactions (usually rash), an itch.

During the post-marketing period noted the following side reactions: fever, a subdural hematoma, a hemothorax, nasal bleeding, gastrointestinal bleeding, a proctorrhagia, vomiting blood, pancreatitis, a melena, a purpura, the erythematic cutaneous dropsy leading to an ecchymoma, a heart attack and a necrosis of skin, a hamaturia, decrease in a hematocrit.

Most often messages (1–10%) on such side reaction as bleeding which develops at about 8% of the patients who are annually accepting warfarin arrive. Moderate bleedings arise annually at 6%, heavy bleedings — at 1% and fatal — at 0,25% of patients. The most frequent risk factor for emergence of intracraneal hemorrhage — not treated or uncontrollable AG. The probability of bleeding increases if MNO is much higher than the target objective. If bleeding began at MNO which is in limits of the target objective it means existence of other accompanying conditions which need to be investigated.

Coumarinic necrosis — rare (<0,1%) a complication at therapy by warfarin. The necrosis usually begins with the darkened cutaneous swelling of the lower extremities or buttocks, but can appear also in other places. Later such defeats become necrotic.

90% of such patients — women. Defeats note from the 3rd to the 10th day of reception and the etiology allows insufficiency of an antitrombotichesky protein of C or S. Inherent insufficiency of these proteins can be the cause of complications. For this reason reception of warfarin should be begun along with administration of heparin and in low initial doses. If there is a complication, then reception of warfarin is stopped and continue administration of heparin before healing or scarring of defeats.

Syndrome of purple fingers — very rare complication at warfarin reception. It is characteristic of male patients with atherosclerotic diseases. Assume that warfarin causes the hemorrhages of atheromatous plaques leading to a microembolism. Reveal symmetric purple damages of skin of fingers and a sole of feet, such defeats are followed by a thermalgia. Reception of warfarin should be stopped, damages of skin usually gradually disappear.

Interaction with other medicines:

Warfarin interacts with many medicines. At the combined use with antitrombotichesky or hemostatics the last can strengthen pharmacological effect of warfarin that increases risk of developing of bleedings. Streptokinasa and an alteplaza are contraindicated to the patients accepting warfarin.

At use of warfarin it is necessary to avoid reception of inhibitors of thrombin, unfractionated heparins and their derivatives, heparins with a low molecular weight, a fondaparina, a rivaroksabana, antagonists of receptors of a glycoprotein of IIb/IIIa, prostacyclin, inhibitors of the return serotonin reuptake, an erlotinib, methylphenidate, oral contraceptives. If it is impossible, it is necessary to appoint these medicines with care under the strengthened clinical and laboratory control.

Absorption and enterogepatichesky circulation of warfarin can change under the influence of some medicines, for example Colestyraminum. It is possible as induction (antiepileptic or antitubercular drugs), and inhibition (Amiodaronum or metronidazole) of effect of warfarin. In certain cases the termination of induction or inhibition of liver enzymes can also change balance of therapy by warfarin. Some medicines can force out warfarin from connections with proteins of a blood plasma that raises free fraction, and, as a result, metabolism and removal of warfarin amplify, leading to decrease in effect (except patients with liver diseases).

Pharmakodinamichesky interaction is noted at a concomitant use with drugs which influence thrombocytes (acetylsalicylic acid, klopidogret, тиклопидин, Dipiridamolum and the majority of NPVP). Primary and secondary hemostasis can cause tendency to severe bleedings in the patient. Penicillin in high doses renders the same effect. Anabolic steroids, азапропазон, erythromycin and some cephalosporins directly reduce level vitamin of K-dependent synthesis of factors of coagulation and strengthen effect of warfarin. Reception of vitamin K with food reduces effect of warfarin. The vitamin K absorption reduction caused, for example, by diarrhea can exponentiate effect of warfarin. Patients who use inadequate amount of the foodstuff containing vitamin K are dependent on K2 vitamin which is produced by intestinal microflora. At such patients the majority of antibiotics can reduce ability of intestinal microflora to produce K2 vitamin that leads to strengthening of effect of warfarin. At alcoholism with the accompanying damages of a liver effect of warfarin is exponentiated. The quinine which is contained in Tonic water can also strengthen effect of warfarin.

Lactulose can exponentiate effect of warfarin at prolonged use.

In case of need temporary anesthesia the patients receiving warfarin are recommended to appoint paracetamol or opiates.

Warfarin can strengthen action of peroral hypoglycemic means — sulphonylurea derivatives.

The following medicines, as we know, change effect of warfarin. Strengthening of effect: Allopyrinolum, Amiodaronum, amoxicillin, аргатробан, acetylsalicylic acid, азапропазон, azithromycin, vitamin A, безафибрат, dextropropoxyphene, digoxin, Disulfiramum, doxycycline, erythromycin, этопозид, vitamin E, фенофибрат, phenylbutazone, фепразон, флуконазол, fluorouratsit, флутамид, флувастатин, флувоксамин, гатифлоксацин, gemfibrozit, грепафлоксацин, ифосфамид, an anti-influenza vaccine, alpha and beta interferon, an isoniazid, итраконазол, капецитабин, carboxyuridine, цефамандол, cefalexin, цефметазол, tsefmenoksy, цефперазон, tsefuroksy, кетоконазол, quinidine, quinine, кларитромицин, Clofibratum, Chlorali hydras, codeine, латамоксеф, лефлуномид, лепирудин, levofloxacin, ловастатин, метолазон, a methotrexate, metronidazole, Miconazolum (also gel oral), to moksalata, moxifloxacin, Acidum nalidixicum, norfloxacin, ofloxacin, оксифенбутазон, омепразол, paracetamol (the effect is obvious after 1–2 weeks of constant reception), proguanil, пропафенон, propranolol, рофекоксиб, рокситромицин, целекоксиб, Cimetidinum, симвастатин, ciprofloxacin, сульфафеназол, сульфафуразол, сульфаметизол, sulfamethoxazole Trimethoprimum, Sulfinpyrazonum, сульфофенур, сулиндак, steroid (anabolic or androgenic) hormones, cyclophosphamide, Tamoxifenum, Tegafurum, tetracycline, толментин, трамадол, трастузумаб, троглитазон, зафирлукаст, NPVP (such as ibuprofen, ketoprofen, Naproxenum, diclofenac, indometacin and piroxicam), dextrothyroxine, Valproatum.

Decrease in effect: Azathioprinum, barbiturates, vitamin C, диклоксацилин, Disopyramidum, phenobarbital, griseofulvin, carbamazepine, клоксацилин, Chlortalidonum, chlordiazepoxide, Mercaptopurinum, месалазин, Mitotanum, нафцилин, not Virapinum, Primidonum, rifampicin, cyclosporine, Spironolactonum, Trazodonum.

Treatment by drugs of a plant origin can also strengthen effect of warfarin, for example extract of a ginkgo (Ginkgo biloba), extract of garlic (Allium sativum), drugs dong квай (Angelica sinensis, contains coumarins), extract of a papaya (Carica papaya) or даншен (Salvia miltiorrhiza), or to reduce it, for example a ginseng (Panax spp.) or extract of a St. John's Wort of made a hole (Hypericum perforatum). It is caused by ability of a St. John's Wort to induction of enzymes which metabolize medicines. Therefore drugs of a plant origin which contain a St. John's Wort are not recommended to be accepted along with warfarin. The effect can remain during 2 weeks after the termination of administration of drugs of a plant origin. If the patient already accepts St. John's Wort extract, it is necessary to measure the MNO level and to stop St. John's Wort extract reception. As MNO can raise at St. John's Wort extract cancellation, it should be controlled carefully. There can be a need for warfarin dose adjustment.

Contraindications:

Hypersensitivity to warfarin or any of excipients, acute bleeding, tendency to bleedings (an angiohemophilia, hemophilia, thrombocytopenia and dysfunctions of thrombocytes), in order to avoid risk of development of heavy bleedings for 72 h after extensive operative measures, during 48 h in a puerperal period, a heavy renal failure, a heavy liver failure and cirrhosis, not treated or uncontrollable AG, recent intracraneal hemorrhage, the state of health contributing to intracraneal hemorrhage, for example aneurism of brain arteries, an aortic aneurysm, a tendency to falling, a lumbar puncture, operations on TsNS or eye operations, gastrointestinal or renal bleedings and their complications, a divertuculosis or malignant tumors, a gullet varicosity, an infectious endocarditis or an exudative pericardis, dementia, psychoses, alcoholism and other situations when the komplayentnost can be insufficient and therapy by anticoagulants cannot be carried out rather safely.

Overdose:

In cases of gradual overdose it is usually enough to stop administration of drug for achievement of the target objective of MNO. At acute overdose gastric emptying because of danger of bleeding is not recommended. Repeatedly appoint absorbent carbon for prevention of absorption and enterogepatichesky circulation of warfarin. At purpose of absorbent carbon vitamin K which can be necessary later should be entered parenterally (in/in). In case of bleeding warfarin it can be terminated by administration of vitamin K, a concentrate of a factor of coagulation or freshly frozen plasma. If peroral anticoagulants are shown in the future, it is necessary to avoid the high doses of vitamin K exceeding 10 mg as patients become resistant to warfarin during 2 weeks.

At therapy of overdose take such measures:

In the absence of clinically significant bleeding
MNO level	Recommendations
<5,0	To pass the following dose of warfarin and to resume therapy in lower dose at achievement of the target objective of MNO
5,0–9,0	To pass 1–2 doses of warfarin and to resume therapy in lower dose at achievement of the target objective of MNO or to pass 1 dose of warfarin and to appoint mg K1 2,5 vitamin orally
> 9,0	To stop warfarin reception, to appoint K1 vitamin in a dose of 3-5 mg orally
Bystry cancellation is shown (for example before operation)
MNO level	Recommendations
5,0–9,0 and operation planned	To stop reception of warfarin and to appoint  mg K1 2-4 vitamin orally. Approximately for 24 h before operation it is possible to give an additional dose of 1-2 mg orally
Very bystry cancellation is shown
MNO level	Recommendations
Severe bleeding or strong overdose (for example MNO> 20,0)	To appoint vitamin K in a dose of 10 mg in the way slow in/in infusion. Also depending on urgency of a situation freshly frozen plasma or a concentrate of a prothrombin complex are shown. If necessary it is possible to repeat administration of K1 vitamin each 12 h

Storage conditions:

To store at the room temperature (15–25 °C) in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets on 3,0 mg of blue color, on 5,0 mg - pink. On 30 or 100 tablets in a bottle; in a cardboard box.