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Pharmaceutical recipes. Warfarin: instructions for use Warfarin indications and contraindications

Various diseases blood vessels are the most common ailments of our time that need urgent correction by serious medicines. In some cases, such medicines are sold strictly by prescription. "Warfarin" (on Latin the name of the drug is spelled Warfarin) is strictly a prescription drug. It can only be used as directed by a doctor. Although pharmacies in our country ask for medication quite often, it is almost impossible to purchase Warfarin without a prescription. This is due to the fact that the drug has an impressive range of side effects and contraindications. However, more on that later. The article will consider in detail the instructions for "Warfarin", analogues and drug reviews.

At the appointment with a specialist

Before prescribing this medication, the doctor must write out a prescription for "Warfarin" in Latin. It is with such a document, certified by a seal, that you should go to the pharmacy and purchase medicine.

However, first you need to carefully listen to the recommendations and warnings of the attending doctor, so that taking the drug does not harm, but benefits. Only strictly adhering to the dosage and other appointments of a specialist, you can achieve success in using this remedy to treat your ailments.

What does the recipe for "Warfarin" look like in tablets in Latin? Most likely, the entry will look like this: Tab. Warfarini 0.0025. What does this mean? This recipe for "Warfarin" (in Latin) indicates the active substance of the drug, its form of release, as well as the dosage. Among other recommendations, the doctor will definitely write out a regimen for taking the medication.

Briefly about the composition of the drug

So, we found out if you need a prescription for Warfarin. What is remarkable this drug? The thing is that the active substance of the drug is warfarin sodium (related to anticoagulants indirect action), which thins the blood and slows down its clotting. We will talk about the pharmacological action of this component in more detail below.

The composition of the tablets, in addition to the active substance, includes other ingredients. One pill, in addition to sodium warfarin in the amount of 2.5 milligrams, contains 50 milligrams of lactose, as well as corn starch, calcium hydrogen phosphate dihydrate, magnesium stearate, indigo carmine, povidone 30.

What is a drug? These are light blue rounded tablets with a cross-shaped line for easy division of the pill.

Pharmacological action of the drug

The medicine "Warfarin", as mentioned above, is used to thin the blood. What slows down the clotting process? First of all, the fact that the active ingredient blocks the synthesis of vitamin K and K-dependent factors necessary for blood clotting. First of all, these are factors II (prothrombin), VII (proconvertin), Christmas and Stuart-Prower factors (IX and X, respectively). As a result of this effect, the concentration of these components decreases, which slows down blood clotting.

Pharmacokinetic features of the drug

According to the instructions for use, the drug "Warfarin" is almost rapidly absorbed from the organs. gastrointestinal tract. Its binding to plasma proteins is almost one hundred percent.

The metabolic process takes place in the liver. It is there that the substance breaks up into two isomers, which are split in different ways.

The drug begins to act already on the second or third day after the first application. The maximum effect on the body is observed on the fifth or sixth day after the start of the drug. A few days after the end of the course (on the fourth or fifth day), the active component is excreted from the body and ceases to have any effect on it. In this case, the half-life of the component is no more than one to three days.

The drug is removed from the body in this way. Metabolized in the liver, "Warfarin" is reabsorbed in the organs of the gastrointestinal tract and excreted along with urine.

Under what ailments is the use of such a serious drug justified?

Indications for the use of the drug

As mentioned above, the drug is used for serious pathologies. blood vessels. Most often, doctors prescribe "Warfarin" for venous thrombosis of recurrent or acute form as well as embolism pulmonary artery. Heart ailments such as myocardial infarction, strokes and ischemic attacks are common indications for the use of the drug.

This medication is also actively used for prophylactic purposes to prevent the above-mentioned diseases. Moreover, it is prescribed to patients diagnosed with valvular heart disease or atrial fibrillation, in order to prevent thromboembolic complications. To prevent such pathologies, tablets are also taken by people who have undergone prosthetic heart valves.

In some cases, the attending physician may consider it appropriate to prescribe "Warfarin" after surgical interventions as a prevention of thrombosis.

As you can see, indications for the use of the drug are serious pathologies and disorders. of cardio-vascular system. In what cases can not take pills?

Medication contraindications

In addition, the manufacturer strictly does not recommend the appointment of "Warfarin" for acute bleeding, as well as severe pathologies of the liver and kidneys. The following serious contraindications to the use of the drug include conditions such as DIC acute nature, thrombocytopenia, deficiency (lack) of proteins S and C.

Moreover, tablets will not be recommended by a specialist if the patient is at risk of bleeding. This may be caused by pathological conditions, as various hemorrhagic disorders, esophageal varices, arterial aneurysm, peptic ulcer duodenum or stomach, lumbar puncture, intracranial hemorrhage, malignant hypertension, severe wounds (including postoperative), bacterial endocarditis, hemorrhagic stroke.

Pregnancy, lactation and medication

Can the drug be used to treat pregnant patients? During the period of gestation, it is best for a woman to refrain from using this drug. It should only be used if the expected benefit to the mother outweighs possible harm for the fetus.

According to the instructions, "Warfarin" is categorically contraindicated in the first three months, as well as in the last four weeks. pregnancy. This is due to the fact that the active substance can provoke bleeding during childbearing and during delivery. Moreover, the active component negatively affects the development of the fetus, causing it to deform the nasal cartilage, spine, and hands. Possible atrophy optic nerve, delay of physical or mental development etc. Paying attention to this information, when treating with “Warfarin”, women of childbearing age should use effective methods contraception.

According to the manufacturer's recommendations, tablets can be used during the period breastfeeding, as therapeutic dose drugs should not have a serious pathological effect on the newborn. And yet, many women decide to interrupt lactation and transfer the baby to artificial feeding during treatment with Warfarin.

Side effects from taking the drug

It is not surprising that such a serious potent agent can provoke the appearance of unwanted reactions. Most often this is due to individual intolerance to the drug or its improper use. For example, when the dosage of the medication was incorrectly prescribed or its prescription turned out to be inappropriate.

What side effects can accompany the intake of the drug of interest to us? First of all, the use of "Warfarin" may be accompanied by bleeding of various organs, as well as vomiting, loose stools, and nausea. According to the data, eight percent of patients taking the drug during the year open different kind bleeding. Most often, these are bleeding from the nose or gums, vaginal or subconjunctival, from the rectum or organs of the gastrointestinal tract. Rarely, intracranial or intracerebral hemorrhages, hematuria. In some cases, the patient's condition may be so severe that urgent hospitalization or even a transfusion of blood or blood substitutes is required. Most often, this state of affairs is observed in elderly people or patients with a history of stroke or gastrointestinal bleeding.

Quite rarely, taking the drug is accompanied by bruising on the skin, rash, itching, urticaria. Sometimes such adverse events can provoke skin necrosis, which most often begins with a darkening of the epidermis and its swelling in the legs and buttocks. Such side effects often bother women five to ten days after starting a course of pills.

In men, there is such an undesirable reaction of the body as the palmar-plantar syndrome, which manifests itself in burning pain and purple lesions of the epidermis on the fingers and feet. This condition worries the representatives of the stronger sex suffering from atherosclerotic diseases.

In some cases, a side effect of taking "Warfarin" may be increased activity of liver enzymes or jaundice, vasculitis or cholestatic hepatitis, eczema or headache.

How should you take pills so that the course of therapy is beneficial, and not harmful?

The doctor will prescribe a detailed regimen and dosage for you, however, the instructions for using Warfarin give general recommendations regarding its use.

Tablets should be taken orally once a day with a small amount of water. It is desirable that exactly 24 hours pass between each dose. The dosage of the drug and the duration of the coagulant course are prescribed by the attending physician. You can cancel the medication immediately.

According to the instructions and recommendations of medical specialists, before starting therapy, as well as during treatment (every four to eight weeks), it is necessary to take an INR test. According to reviews, many patients find it inconvenient and stressful to regularly conduct such blood tests, but this is very important during the period of treatment with Warfarin. Control of INR should be carried out to regulate the required dosage of the drug. What is this analysis and how does it affect the correction of the prescribed dosage? You can read about it below.

Now it is necessary to understand the general recommendations of experts. According to the instructions, those patients who have not previously used the medication are prescribed five milligrams of the active substance per day for the first four days. Then you need to go through the analysis mentioned above. According to the result, the doctor recommends a maintenance dose, which can vary between 2.5-7.5 milligrams per day.

If the patient has already used "Warfarin" before, then he is prescribed the drug in the amount of ten milligrams of the active substance for two days. Then a maintenance dose of the drug is prescribed to the person, after which an analysis for INR is taken and therapy is carried out in accordance with the obtained indicators.

Examination and its influence on dosage

As mentioned above, before and during treatment with Warfarin, it is necessary to take an INR test. What kind of research is this?

This abbreviation stands for international normalized ratio. talking plain language, is an indicator of the health of the hemostasis system, which shows whether a person has a tendency to increase the occurrence of blood clots. Or, conversely, the patient is prone to a decrease in clotting and frequent bleeding. INR norm for healthy person(regardless of gender) varies between 0.7 and 1.3.

For the prevention or treatment of venous thrombosis, pulmonary embolism, dilated cardiomyopathy, atrial fibrillation, serious illnesses heart valves or their prosthetics with bioprostheses, it is necessary to maintain INR values at the level of 2-3 units. If the patient has undergone prosthetics with mechanical prostheses or diagnosed with acute myocardial infarction of a complicated form, then the INR indicators should be slightly higher - 2.5-3.5.

Treatment of young patients

"Warfarin" for the treatment of children is used extremely rarely, however, in some cases, a specialist may consider it justified to prescribe such a serious drug to a child. For children, the dosage of the drug is calculated based on the body weight of a small patient. The recommended INR values are the same as for adults.

How to calculate the required dosage? Of course, the attending physician will recommend a more accurate appointment, but there is a general formula by which a drug can be prescribed. In that case, the initial daily dose"Warfarin" should be 0.2 mg per 1 kg of the child's weight. The maintenance dose is selected by the doctor based on the indicators of the INR analysis.

Below is a table that will show how to correctly calculate the dosage of the medication for the treatment of young children.

How to carry out maintenance therapy for young patients? In this case, everything will depend on the parameters of the blood test for INR. The table below lists possible dosage options.

Other situations

Are there any restrictions when using the drug for the treatment of elderly patients? According to the instructions for the medication, in this case there is no need to reduce the dosage of the active substance. However, patients over 65 years of age who take Warfarin should be closely monitored by specialists, as they are at an increased risk of side effects.

And what about patients who suffer from various serious disorders in the liver? They also do not need to lower the dosage. However, treatment should be carried out under close monitoring of INR levels.

Regular testing is also necessary for people suffering from various kidney dysfunctions. However, in this case, it is also recommended to lower the dosage of the active substance of the drug. An individual treatment regimen should be prescribed by the attending physician.

But what if a person who regularly takes Warfarin needs to surgical intervention? In such cases, it is recommended to stop taking the drug a few days before surgery. When to do it? Everything will depend on the indicators of INR:

If the level of the analysis we are interested in is more than four units, then the anticoagulant is stopped five days before the operation.
If the INR indicators vary within three to four, then it is best to stop taking the medication three days before the manipulation.
If the level of the analysis we are interested in fluctuates between 2 and 3, then the doctor will recommend giving up the pills two days before surgery.

It is also necessary to conduct a blood test before the operation. If the INR level is greater than 1.8, then the patient should take 0.5 or 1 milligram of vitamin K 1 (the dosage is determined by the attending physician). medicinal substance can be administered intravenously or taken orally.

If a person is at risk of developing thrombosis, then for prophylactic purposes it is necessary to introduce low molecular weight heparin. This should be done on the day of the operation. In some cases, doctors recommend further administration for five to seven days after surgery.

You can resume taking Warfarin a few hours after a minor operation. If the surgical intervention was more serious, then anticoagulant treatment should be resumed as soon as the patient begins to receive enteral nutrition.

Influence of other diseases

According to the instructions for use, the absorption of the active substance can be affected general state patient and his associated ailments. For example, it has been clinically proven that diseases such as fever, decompensated heart failure, hyperthyroidism, alcoholism (provoking various liver damage) enhance the effect of warfarin sodium. On the other hand, with hypothyroidism, a decrease in the effect of taking the medication is possible.

It should also be taken into account that kidney failure or nephrotic syndrome can provoke an inadequate response of the body to active substance drug. In this case, the effect of its use can either increase sharply or decrease sharply.

If a patient has a history of a mutation in the gene encoding a specific CYP2C9 enzyme, then a lower dosage of the drug should be prescribed to him, since the half-life of warfarin sodium in such a person will last much longer.

If the patient suffers from protein C or S deficiency, then he should not be given a loading dose of the drug. The course of treatment should begin with small doses of the active substance. This is necessary in order to avoid possible development skin necrosis.

There are situations when you need to quickly achieve the desired therapeutic effect. In this case, it is necessary to start treatment with the introduction of a certain dose of heparin, and only then combine the intake of this drug and Warfarin.

In rare cases, the patient may have individual resistance to warfarin sodium. Then the attending physician may consider it appropriate to increase the loading dose of the drug by five or even twenty times.

What to do with an overdose

Symptoms of such an unpleasant condition may be slight bleeding from the gums or the detection of blood in the urine. In this case, you must either lower the dosage of the drug, or completely stop taking it. In severe overdose, the doctor may consider it appropriate to give intravenous vitamin K, clotting factor concentrate, or even plasma. Admission required activated carbon inside.

Interaction with other drugs

Many patients are interested in the compatibility of Warfarin with painkillers. According to the instructions, tramadol, paracetamol or opiates should be used in the treatment with this drug.

It is important to remember that the combined use of "Warfarin" and drugs that affect hemostasis and platelet levels can cause severe bleeding. Such prohibited drugs include acetylsalicylic acid, clopidogrel, dipyridamole, ticlopidine, NSAIDs (excluding COX-2 inhibitors), antibiotics of the penicillin group in large doses.

You should know that such medicines reduce the therapeutic effect of the agent of interest to us: Colestyramine, Bosentan, Aprepitant, Mesalazine, Sucralfate, Griseofulvin, Dicloxacillin, Rifampicin, Nafcillin, “ Colestyramine”, “Cyclosporine”, “Aminoglutethimide” and others. This group of medicines also includes some antiviral, antidepressants, antiepileptic drugs, St. John's wort, ginseng, as well as foods rich in vitamin K (green vegetables and fruits, mint, olive oil, mustard, etc.).

However, there are substances that can enhance the effect of "Warfarin", which may also be undesirable. These include medicines such as Abciximab, Cimetidine, Glibenclamide, Omerpazole, Amiodarone, Digoxin, Dipyridamole, Sulfinpyrazone and many others. To this list it is also necessary to add some hypolipidemic and antifungals, steroid hormones and macrolide antibiotics.

Medication Substitutes

Among the analogues of the drug of interest to us in terms of the active component, Warfarin Nycomed occupies the first place. The instructions for these tools are almost identical.

Below is a short list of substitutes for "Warfarin", according to the pharmacological effects:

"Phenilin". The active ingredient is phenindione. The drug is available in tablets and is used to treat thrombosis, thrombophlebitis and complications caused by strokes, heart attacks, etc.
"Sincumar". Active ingredient tablets is acenocoumarol. This anticoagulant is used in the conditions described above.
"Paradax". One capsule of the drug contains dabigatran etexilate in the amount of 150 milligrams. Most often, the medication is prescribed as a venous and systemic character, as well as a stroke. Can be used in atrial fibrillation.

What people say about the drug

We examined in detail the instructions for the use of "Warfarin" and analogues. Feedback from real patients about this tool are of interest to many.

Most people note that they are very satisfied with the drug. Most often, "Warfarin" is prescribed for various thrombosis, less often - for the prevention of strokes. Many patients take pills for life to prevent relapse, and according to their feedback, the disease no longer progresses.

However, many admit that taking the medication is accompanied by some side effects, such as severe itching epidermis, baldness. Often people have slight bleeding, headaches.

Yet most thrombotic patients agree that Warfarin is inexpensive and effective drug, which helps well if taken strictly in accordance with the doctor's recommendations. He saved many lives, and also improved the quality of life and health.

We dismantled the instructions for "Warfarin". Reviews and analogues were also considered in the review.

The active substance is warfarin

Pharmacological group - anticoagulants

Indications for use -

Treatment and prevention of thrombosis and embolism of blood vessels:

acute and recurrent venous thrombosis, pulmonary embolism;

transient ischemic attacks and strokes;

secondary prevention 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 prosthetic heart valves;

prevention of postoperative thrombosis.

pharmachologic effect- indirect anticoagulant

Release forms - Tablets, 2.5 mg

Prescription warfarin

Rp:Tab.Warfarini 0.0025

Ds. inside 1 time per day, preferably at the same time.

Dosage and administration

inside.

1 time per day, preferably at the same time.

The duration of treatment is determined by the doctor in accordance with the indications for use.

control during treatment. Before starting therapy, MHO is determined. In the future, laboratory control is carried out regularly every 4-8 weeks.

The duration of treatment depends on clinical condition patient. Treatment can be canceled immediately.

Patients who have not previously taken warfarin: the initial dose is 5 mg / day (2 tablets per day) for the first 4 days. On the 5th day of treatment, the MHO is determined and, in accordance with this indicator, a maintenance dose of the drug is prescribed. Usually the maintenance dose of the drug is 2.5-7.5 mg / day (1-3 tablets per day).

Patients who have previously taken warfarin: the recommended starting dose is twice the known maintenance dose of the drug and is administered during the first 2 days. The treatment is then continued with a known maintenance dose. On the 5th day of treatment, MHO is monitored and the dose is adjusted in accordance with this indicator. It is recommended to maintain the MHO value from 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve disease, prosthetic heart valves with bioprostheses. Higher MHO values from 2.5 to 3.5 are recommended for prosthetic heart valves with mechanical prostheses and complicated acute infarction myocardium.

Children: data on the use of warfarin in children are limited. The initial dose is usually 0.2 mg/kg/day for normal liver function and 0.1 mg/kg/day for impaired liver function. The maintenance dose is selected in accordance with the MHO. Recommended MHO levels are the same as for adults. The decision to prescribe warfarin and monitor treatment in children should be made by an experienced pediatrician. Doses are selected in accordance with Table. 1.

Table 1

Selection of a maintenance dose of warfarin in accordance with the MHO indicators

Day 1	If the base value of MHO is from 1 to 1.3, then the loading dose is 0.2 mg / kg
Days 2 to 4 if MHO value:	Actions:
1 to 1.3	Repeat loading dose
from 1.4 to 1.9	50% of the loading dose
2 to 3	50% of the loading dose
3.1 to 3.5	25% of the loading dose
>3,5	<3,5, затем возобновить лечение дозой, составляющей 50% от предыдущей
Maintain if MHO value:	Actions (weekly dose):
1 to 1.3	Increase dose by 20%
from 1.4 to 1.9	Increase dose by 10%
2 to 3	Without changes
3.1 to 3.5	Reduce dose by 10%
>3,5	Stop the drug before reaching the MHO<3,5, затем возобновить лечение дозой на 20% меньшей, чем предыдущая

Elderly patients: There are no specific recommendations for the use of warfarin in the elderly. However, elderly patients should be carefully monitored, because. they have a higher risk of side effects.

Patients with liver failure: Liver dysfunction increases warfarin sensitivity because the liver produces clotting factors and also metabolizes warfarin. In this group of patients, careful monitoring of MHO parameters is necessary.

Patients with renal insufficiency: in patients with impaired renal function, a reduction in the dose of warfarin and careful monitoring is required.

Planned (elective) surgical interventions: pre-, peri- and postoperative anticoagulant therapy is carried out as indicated below (if urgent withdrawal of oral anticoagulant treatment is necessary.

1. Determine the MHO one week before the scheduled operation.

2. Stop taking warfarin 1-5 days before surgery. In the case of a high risk of thrombosis, a low molecular weight drug is administered to the patient for the prevention of s / c. The duration of the pause in taking warfarin depends on the MHO. Stop taking warfarin:

- 5 days before surgery, if MHO > 4;

- 3 days before surgery, if MHO is from 3 to 4;

- 2 days before surgery, if MHO is from 2 to 3.

3. Determine the MNR in the evening before the operation and administer 0.5–1 mg of vitamin K 1 orally or intravenously if the INR > 1.8.

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

5. Continue subcutaneous low molecular weight heparin for 5–7 days postoperatively with concomitant reinstatement of warfarin.

6. Continue warfarin at the usual maintenance dose on the same day in the evening after minor surgery and on the day the patient starts enteral nutrition after major surgery.

Warfarin Nycomed
Latin name: Warfarin Nycomed
Pharmacological groups: Anticoagulants
I25.9 Chronic ischemic disease heart, unspecified. I48 Atrial fibrillation and flutter. I74 Embolism and thrombosis of arteries. I82 Embolism and thrombosis of other veins. Z100 CLASS XXII Surgical practice
Composition and form of release:
in polypropylene containers of 50 or 100 pcs.

Characteristic: Anticoagulant of indirect action in the form of a racemic compound, while the levorotatory isomer has a greater pharmacological activity.

Pharmachologic effect:Anticoagulant. Inhibits the synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X) in the liver, reduces their concentration in plasma and slows down the process of blood coagulation.

Pharmacokinetics: Absorbed from the gastrointestinal tract almost completely. Plasma protein binding 97-99%, therapeutic plasma concentration 1-5 μg / ml. It is metabolized in the liver to form inactive or inactive compounds that are reabsorbed from the bile. Excreted by the kidneys, T1 / 2 40 hours.

Pharmacodynamics: The action appears on the 3-5th day from the start of use and stops 3-5 days after cancellation.

Indications: Prevention of thrombosis and thromboembolism. Short term - at acute thrombosis veins and pulmonary embolism (in combination with heparin), postoperative thrombosis, acute myocardial infarction, surgical and thrombolytic treatment of thrombosis, cardioversion in case of atrial flutter. Long-term - with recurrent vein thrombosis and pulmonary embolism, prosthetic heart valves and blood vessels (possibly in combination with acetylsalicylic acid), coronary artery disease, transient ischemic attacks, secondary prevention of a heart attack, chronic atrial fibrillation, thrombosis of peripheral arteries.

Contraindications: Acute bleeding, pronounced violations of the liver and kidneys, severe arterial hypertension, pregnancy.

Contraindicated. For safety reasons, breastfeeding should be stopped for the first 3 days of treatment.

Side effects: Hemorrhages (> 1%), rarely - vasculitis, diarrhea, increased activity of liver enzymes, eczema, skin necrosis, hair loss.

Interaction: The anticoagulant effect is enhanced acetylsalicylic acid and other NSAIDs, allopurinol, amiodarone, anabolic agents (with alkyl at the C17 position), oral hypoglycemic sulfonamides, cephalosporins, cimetidine, danazol, diazoxide, disopyramide, disulfiram, erythromycin, ethacrynic acid, fluconazole, fluorouracil, levamisole, dipyramole, chloramphenicol , fluvoxamine, glucagon, heparin, isoniazid, ketoconazole, quinine, quinidine, quinolones, clarithromycin, clofibrate, chloral hydrate, chloramphenicol, metronidazole, miconazole, nalidixic acid, nilutamide, omeprazole, paroxetine, proguanil, simvastatin, sulfonamides, tamoxifen, thyroxine; weaken - oral laxatives, barbiturates, dicloxacillin, phenazone, griseofulvin, carbamazepine, coenzyme Q 10, cholestyramine, mianserin, paracetamol (in high doses), retinoids, rifampicin, sucralfate, phenytoin, vitamin K (antagonist).

Overdose:Symptoms: increased bleeding, bleeding.
Treatment: with significant bleeding - in / in the slow introduction of small doses of phytomenadione, blood transfusion is possible.

Dosage and administration:inside, once, at the same time of day.
Initial doses - 2.5–5 mg / day.
Further dosing regimen is set individually, depending on the results of determining the prothrombin time (should be increased by 2-4 times from the original) or the international normalized ratio (should reach 2.2-4.4 depending on the disease, the risk of thrombosis, the risk of bleeding and individual characteristics patient).

Precautionary measures: Special care should be taken in patients with endogenous bleeding disorders, thrombocytopenia, severe hypertension, peptic ulcer stomach and duodenum in the acute stage, impaired liver and kidney function, cerebral hemorrhages, alcoholism. Alcohol consumption increases the risk of hypoprothrombinemia and bleeding.

Special instructions: At the beginning of treatment and every 4-8 weeks, blood coagulation should be monitored in terms of INR. When combined with other drugs, continuous monitoring (as often as possible) is necessary to allow the dose to be adjusted. warfarin and within 10–

Warfarin Nycomed (Warfarin Nycomed)

Active ingredient (INN) Tamsulosin (Tamsulosin)
Application:

Contraindications:

Side effects:

Others:

Interaction: warfarin

Overdose:Symptoms: possible severe hypotension.
Treatment:

Dosage and administration:

Precautionary measures:

Tamsulosin (-)

Active ingredient (INN) Testosterone (Testosterone)
Application:

Contraindications:

Side effects:

Interaction:warfarin

Dosage and administration:

Precautionary measures:

Testosterone (Testosterone) (-)

omnic
Latin name: Omnic
Pharmacological groups: Alpha blockers. Drugs that affect the metabolism in the prostate gland and correctors of urodynamics
Nosological classification (ICD-10): N40 Prostatic hyperplasia
pharmachologic effect

Active ingredient (INN) Tamsulosin (Tamsulosin)
Application: Functional symptoms, incl. violation of urination, with benign prostatic hyperplasia.

Contraindications: Hypersensitivity, history of orthostatic hypotension, severe hepatic and / or renal insufficiency.

Side effects:From the side nervous system and sense organs: 5–20% - dizziness, headache, asthenia; less than 5% - drowsiness / insomnia.
From the side of the cardiovascular system and blood (hematopoiesis, hemostasis): less than 5% - orthostatic hypotension.
From the side genitourinary system: retrograde ejaculation (8.4%); less than 5% - a decrease in libido.
Others: 5–20% - back pain, rhinitis, diarrhea; less than 5% - chest pain, nausea.

Interaction: Simultaneous use with other alpha1-blockers may lead to an increase in the hypotensive effect. Cimetidine increases, and furosemide lowers the concentration in the blood, diclofenac and warfarin increase the release rate.

Overdose:Symptoms: possible severe hypotension.
Treatment: giving the patient lying position, the introduction of plasma-substituting solutions or vasoconstrictor drugs; to stop absorption - gastric lavage, taking activated charcoal or an osmotic laxative.

Dosage and administration: Inside (after breakfast, drinking plenty of water), 0.4 mg / day.

Precautionary measures: Before starting treatment, it is necessary to verify the diagnosis (to exclude prostate carcinoma).
Use with caution with a predisposition to orthostatic hypotension, severe liver dysfunction and Cl creatinine below 10 ml / min. If signs of orthostatic hypotension (dizziness, weakness) appear, the patient is recommended to be seated or laid down.
Use with caution during work for drivers of vehicles and people whose profession is associated with increased concentration of attention.

Omnic

Gelarium Hypericum
Latin name: Helarium Hypericum
Pharmacological groups: Antidepressants. Sedatives
Nosological classification (ICD-10): F32.0 Depressive episode mild degree. F32.1 Depressive episode medium degree. F34.1 Dysthymia. F41.2 Mixed anxiety and depressive disorder R45.1 Restlessness and agitation
Composition and form of release: in a blister 15 or 20 pieces; in a carton box 2 or 3 packs respectively.

Pharmachologic effect:Antidepressant. Eliminates anxiety and tension, improves mood.

Indications: Psycho-vegetative disorders (depressed mood, apathy, etc.), neurotic reactions, depressive states of mild and moderate severity.

Contraindications: Hypersensitivity, photosensitivity.
Co-administration of indinavir or other protease inhibitors, childhood up to 12 years old.

Use during pregnancy and lactation: Should not be used during pregnancy and during breastfeeding due to lack of data.

Side effects: Allergic reactions, fatigue, anxiety, gastrointestinal disorders (rarely), manifestation of photosensitivity (especially in people with fair skin).

Interaction: May reduce the effect of indirect anticoagulants ( warfarin, phenprocoumon), cyclosporine, digoxin, indinavir, amitriptyline, nortriptyline, theophylline (simultaneous administration is possible only on prescription with mandatory monitoring of blood parameters and prothrombin time at the beginning and end of treatment). Simultaneous reception with oral contraceptives can weaken their effect and lead to intermenstrual bleeding.

Dosage and administration:inside, during meals, without chewing, drinking liquid, adults and children over 12 years old, 1 tablet 3 times a day for 4 weeks (at least).

Special instructions: Does not affect the speed of reaction when driving vehicles and mechanisms. It should not be taken simultaneously with antidepressants - MAO inhibitors, the interval between doses should be at least 2 weeks.
During treatment, intense exposure to ultraviolet rays (prolonged sunbathing, UV lamp exposure, solarium) should be avoided.
Consultation required if symptoms persist for more than 4 weeks

Gelarium Hypericum (Helarium Hypericum)

Omnadren 250
Latin name: Omnadren 250
Pharmacological groups:
Nosological classification (ICD-10):
pharmachologic effect

Application: Androgen deficiency in men: delayed puberty, oligospermia, post-castration syndrome, underdevelopment of the genital organs, hypopituitrism, infertility in violation of spermatogenesis, menopausal syndrome, impotence, osteoporosis.
In women: hyperestrogenism, uterine fibroids, endometriosis, menopause (in combination with estrogens), premenstrual tension syndrome, breast cancer, osteoporosis.

Contraindications: Hypersensitivity, established or suspected carcinoma of the prostate and / or mammary glands, nephrosis or nephrotic phase of nephritis, hypercalcemia, edema, impaired liver and kidney function, diabetes, prostatic hypertrophy with symptoms of urination disorders, cardiac and coronary insufficiency, history of myocardial infarction, atherosclerosis in older men, pregnancy, breastfeeding.

Side effects: Precocious puberty, anomalies and prostate cancer, increased sexual arousal and increased erection, penis enlargement, priapism, oligospermia, decreased ejaculate volume, sodium and water retention, premature closure of bone growth zones; headache, depression, anxiety, sleep disturbance, paresthesia, bleeding in the gastrointestinal tract, nausea, cholestatic jaundice, etc. androgenic effects(hirsutism, seborrhea, acne, etc.).

Interaction: Increases the effect of indirect anticoagulants ( warfarin, nikumalon, phenylin) and hypoglycemic agents, inhibits the excretion of cyclosporine. Barbiturates and alcohol reduce the effect.

Dosage and administration: Inside (capsules, tablets); in / m, s / c (implants, oil solutions of individual esters or their combinations). The dosage regimen is selected individually, depending on the disease, gender, age and dosage forms.

Precautionary measures: With the appearance of androgen-dependent adverse reactions treatment is stopped until they disappear and resume at lower doses.

Omnadren 250 (Omnadren 250)

Nebido
Latin name: Nebido
Pharmacological groups: Androgens, antiandrogens. Antitumor hormonal agents and hormone antagonists
Nosological classification (ICD-10): C50 Malignant neoplasms mammary gland. D26 Other benign neoplasms of uterus. E23.0 Hypopituitarism E25 Adrenogenital disorders. E29 Testicular dysfunction. E29.1 Testicular hypofunction. F52.2 Insufficiency of genital response. M81.9 Osteoporosis, unspecified N46 male infertility. N50 Other diseases of the male genital organs. N80 Endometriosis. N93 Other abnormal bleeding from uterus and vagina. N95.1 Menopausal and climacteric conditions of women
pharmachologic effect

Active ingredient (INN) Testosterone (Testosterone)
Application: Androgen deficiency in men: delayed puberty, oligospermia, post-castration syndrome, underdevelopment of the genital organs, hypopituitrism, infertility in violation of spermatogenesis, menopausal syndrome, impotence, osteoporosis.
In women: hyperestrogenism, uterine fibroids, endometriosis, menopause (in combination with estrogens), premenstrual tension syndrome, breast cancer, osteoporosis.

Contraindications: Hypersensitivity, established or suspected carcinoma of the prostate and / or mammary glands, nephrosis or nephrotic phase of nephritis, hypercalcemia, edema, impaired liver and kidney function, diabetes mellitus, prostatic hypertrophy with symptoms of urination disorders, heart and coronary insufficiency, a history of myocardial infarction, atherosclerosis in older men, pregnancy, breastfeeding.

Side effects: Precocious puberty, anomalies and prostate cancer, increased sexual arousal and increased erection, penis enlargement, priapism, oligospermia, decreased ejaculate volume, sodium and water retention, premature closure of bone growth zones; headache, depression, anxiety, sleep disturbance, paresthesia, bleeding in the gastrointestinal tract, nausea, cholestatic jaundice, other androgenic effects (hirsutism, seborrhea, acne, etc.).

Precautionary measures: With the appearance of androgen-dependent adverse reactions, treatment is stopped until they disappear and resumed at lower doses.

Nebido (Nebido)

Sustanon-250
Latin name: Sustanon-250
Pharmacological groups: Androgens, antiandrogens. Anticancer hormonal agents and hormone antagonists
Nosological classification (ICD-10): C50 Malignant neoplasms of the mammary gland. D26 Other benign neoplasms of uterus. E23.0 Hypopituitarism E25 Adrenogenital disorders. E29 Testicular dysfunction. E29.1 Testicular hypofunction. F52.2 Insufficiency of genital response. M81.9 Osteoporosis, unspecified N46 Male infertility. N50 Other diseases of the male genital organs. N80 Endometriosis. N93 Other abnormal bleeding from uterus and vagina. N95.1 Menopausal and climacteric conditions of women
pharmachologic effect

Contraindications: Hypersensitivity, established or suspected carcinoma of the prostate and / or mammary glands, nephrosis or nephrotic phase of nephritis, hypercalcemia, edema, impaired liver and kidney function, diabetes mellitus, prostatic hypertrophy with symptoms of urination disorders, heart and coronary insufficiency, a history of myocardial infarction, atherosclerosis in older men, pregnancy, breastfeeding.

Side effects: Precocious puberty, anomalies and prostate cancer, increased sexual arousal and increased erection, penis enlargement, priapism, oligospermia, decreased ejaculate volume, sodium and water retention, premature closure of bone growth zones; headache, depression, anxiety, sleep disturbance, paresthesia, bleeding in the gastrointestinal tract, nausea, cholestatic jaundice, other androgenic effects (hirsutism, seborrhea, acne, etc.).

Precautionary measures: With the appearance of androgen-dependent adverse reactions, treatment is stopped until they disappear and resumed at lower doses.

Sustanon-250 (Sustanon-250)

Andriol
Latin name: Andriol
Pharmacological groups: Androgens, antiandrogens. Anticancer hormonal agents and hormone antagonists
Nosological classification (ICD-10): C50 Malignant neoplasms of the mammary gland. D26 Other benign neoplasms of uterus. E23.0 Hypopituitarism E25 Adrenogenital disorders. E29 Testicular dysfunction. E29.1 Testicular hypofunction. F52.2 Insufficiency of genital response. M81.9 Osteoporosis, unspecified N46 Male infertility. N50 Other diseases of the male genital organs. N80 Endometriosis. N93 Other abnormal bleeding from uterus and vagina. N95.1 Menopausal and climacteric conditions of women
pharmachologic effect

Contraindications: Hypersensitivity, established or suspected carcinoma of the prostate and / or mammary glands, nephrosis or nephrotic phase of nephritis, hypercalcemia, edema, impaired liver and kidney function, diabetes mellitus, prostatic hypertrophy with symptoms of urination disorders, heart and coronary insufficiency, a history of myocardial infarction, atherosclerosis in older men, pregnancy, breastfeeding.

Side effects: Precocious puberty, anomalies and prostate cancer, increased sexual arousal and increased erection, penis enlargement, priapism, oligospermia, decreased ejaculate volume, sodium and water retention, premature closure of bone growth zones; headache, depression, anxiety, sleep disturbance, paresthesia, bleeding in the gastrointestinal tract, nausea, cholestatic jaundice, other androgenic effects (hirsutism, seborrhea, acne, etc.).

Precautionary measures: With the appearance of androgen-dependent adverse reactions, treatment is stopped until they disappear and resumed at lower doses.

Andriol (Andriol)

Testosterone Propionate
Latin name: testosteroni propionas
Pharmacological groups: Androgens, antiandrogens. Anticancer hormonal agents and hormone antagonists
Nosological classification (ICD-10): C50 Malignant neoplasms of the mammary gland. D26 Other benign neoplasms of uterus. E23.0 Hypopituitarism E25 Adrenogenital disorders. E29 Testicular dysfunction. E29.1 Testicular hypofunction. F52.2 Insufficiency of genital response. M81.9 Osteoporosis, unspecified N46 Male infertility. N50 Other diseases of the male genital organs. N80 Endometriosis. N93 Other abnormal bleeding from uterus and vagina. N95.1 Menopausal and climacteric conditions of women
pharmachologic effect

Contraindications: Hypersensitivity, established or suspected carcinoma of the prostate and / or mammary glands, nephrosis or nephrotic phase of nephritis, hypercalcemia, edema, impaired liver and kidney function, diabetes mellitus, prostatic hypertrophy with symptoms of urination disorders, heart and coronary insufficiency, a history of myocardial infarction, atherosclerosis in older men, pregnancy, breastfeeding.

Side effects: Precocious puberty, anomalies and prostate cancer, increased sexual arousal and increased erection, penis enlargement, priapism, oligospermia, decreased ejaculate volume, sodium and water retention, premature closure of bone growth zones; headache, depression, anxiety, sleep disturbance, paresthesia, bleeding in the gastrointestinal tract, nausea, cholestatic jaundice, other androgenic effects (hirsutism, seborrhea, acne, etc.).

Precautionary measures: With the appearance of androgen-dependent adverse reactions, treatment is stopped until they disappear and resumed at lower doses.

Testosterone propionate (Testosteroni propionas)

Excipients: lactose - 50 mg, corn starch - 34.6 mg, calcium hydrophosphate dihydrate - 32.2 mg, - 6.4 mcg, povidone 30 - 1.0 mg, magnesium stearate - 600 mcg.

50 pcs. - Plastic vials.
100 pieces. - Plastic vials.

pharmachologic effect

Indirect anticoagulant. It blocks the synthesis of K-dependent blood coagulation factors in the liver, namely II, VII, IX and X. The concentration of these components in the blood decreases, the blood coagulation process slows down.

The onset of anticoagulant action is observed after 36-72 hours from the start of the drug with the development of the maximum effect on the 5-7th day from the start of use. After stopping the drug, the restoration of the activity of vitamin K-dependent blood coagulation factors occurs within 4-5 days.

Pharmacokinetics

Suction and distribution

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

Metabolism

Metabolized in the liver. Warfarin is a racemic mixture, with the R- and S-isomers being metabolized in the liver. different ways. Each of the isomers is converted into 2 main metabolites. The main metabolic catalyst for the S-enantiomer of warfarin is CYP2C9, and for the R-enantiomer of warfarin CYP1A2 and CYP3A4. The levorotatory isomer of warfarin (S-warfarin) has 2-5 times greater anticoagulant activity than the dextrorotatory isomer (R-enantiomer), however, the T 1/2 of the latter is greater. Patients with polymorphisms of the CYP2C9 enzyme, including CYP2C9*2 and CYP2C9*3 alleles, may have increased sensitivity to warfarin and an increased risk of bleeding.

breeding

Warfarin is excreted from the body as inactive metabolites in the bile, which are reabsorbed in the gastrointestinal tract and excreted in the urine. T 1/2 is from 20 to 60 hours. For the R-enantiomer, T 1/2 is from 37 to 89 hours, and for the S-enantiomer, from 21 to 43 hours.

Indications

- 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 prosthetic heart valves;

— treatment and prevention of transient ischemic attacks and strokes, prevention of postoperative thrombosis.

Contraindications

— acute bleeding;

- severe liver disease;

- severe kidney disease;

- acute DIC;

- deficiency of proteins C and S;

- thrombocytopenia;

- patients with a high risk of bleeding, including patients with hemorrhagic disorders, varicose veins esophageal veins, arterial aneurysms, lumbar puncture, gastric and duodenal ulcers, with severe wounds (including surgical wounds), bacterial endocarditis, malignant arterial hypertension, hemorrhagic stroke, intracranial hemorrhage;

- pregnancy (I trimester and last 4 weeks);

- Established or suspected hypersensitivity to the components of the drug.

Dosage

Warfarin is prescribed 1 time / day at the same time. The duration of treatment is determined by the doctor in accordance with the indications for use.

Before starting therapy, MHO is determined. In the future, laboratory control 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.

The initial dose for patients who have not previously used warfarin is 5 mg / day (2 tablets) for the first 4 days. On the 5th day of treatment, the MHO is determined and, in accordance with this indicator, a maintenance dose of the drug is prescribed. Usually the maintenance dose of the drug is 2.5-7.5 mg / day (1-3 tablets).

For patients who have previously used warfarin, the recommended starting dose is twice the dose of a known maintenance dose of the drug and is administered during the first 2 days. The treatment is then continued with a known maintenance dose. On the 5th day of treatment, MHO is monitored and the dose is adjusted in accordance with this indicator.

It is recommended to maintain the MHO value from 2 to 3 in the case of prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve disease, prosthetic heart valves with bioprostheses. Higher MHO values of 2.5 to 3.5 are recommended for prosthetic heart valves with mechanical prostheses and complicated acute myocardial infarction.

children limited. The initial dose is usually 0.2 mg/kg/day for normal liver function and 0.1 mg/kg/day for impaired liver function. The maintenance dose is selected in accordance with the MHO. Recommended MHO levels are the same as for adults. The decision to prescribe warfarin in children should be made by an experienced specialist. Treatment should be carried out under the supervision of an experienced pediatrician. Doses are selected in accordance with the table below.

Day 1	With INR from 1 to 1.3, the loading dose is 0.2 mg / kg of body weight
Days 2 to 4 at INR	Actions
from 1 to 1.3	Repeat loading dose
from 1.4 to 1.9	50% of the loading dose
2 to 3	50% of the loading dose
from 3.1 to 3.5	25% of the loading dose
>3.5	<3.5, затем возобновить лечение дозой, составляющей 50% от предыдущей.
Maintenance therapy with INR value	Actions (weekly dose)
from 1 to 1.3	Increase dose by 20%
from 1.4 to 1.9	Increase dose by 10%
2 to 3	Without changes
from 3.1 to 3.5	Reduce dose by 10%
>3.5	Stop the administration of the drug before reaching the INR<3.5, затем возобновить лечение дозой на 20% меньшей, чем предыдущая.

There are no specific recommendations for the use of warfarin in patients old age

Liver dysfunction increases sensitivity to warfarin because the liver produces clotting factors and also metabolizes warfarin. In this group of patients, careful monitoring of MHO parameters is necessary.

At patients with impaired renal function dose reduction of warfarin and careful monitoring is required.

Elective (elective) surgical interventions: pre-, peri- and postoperative anticoagulant therapy is carried out as indicated below (if urgent withdrawal of oral anticoagulant is necessary, see section "Overdose"). Determine the MHO one week before the scheduled operation. Stop taking warfarin 1-5 days before surgery. In case of a high risk of thrombosis, low molecular weight heparin is administered to the patient for the prevention of s / c. The duration of the pause in taking warfarin depends on the MHO. Stop taking warfarin:

— 5 days before surgery with MHO >4;

— 3 days before surgery with MHO from 3 to 4;

- 2 days before surgery with MHO from 2 to 3.

It is necessary to determine the MHO in the evening before the operation and administer 0.5-1 mg of vitamin K 1 orally or intravenously, with an INR> 1.8.

Consider the need for infusion of unfractionated heparin or prophylactic administration of low molecular weight heparin on the day of surgery. Subcutaneous administration of low molecular weight heparin should be continued for 5-7 days postoperatively with concomitant reinstatement of warfarin.

Continue warfarin at the usual maintenance dose on the same day in the evening after minor surgery and on the day the patient is started on enteral nutrition after major surgery.

Side effects

Adverse reactions to the drug are ordered by system organ class and are consistent with terms of preferred use (according to MedDRA). Within the category of the system organ class, reactions are distributed according to the frequency of occurrence according to the following scheme: very often (≥1/10), often (≥1/100 to<1/10), нечасто (≥1/1000 до <1/100), редко (≥1/10 000 до <1/1000), очень редко (<1/10 000).

From the hematopoietic system: very often - bleeding (in various organs); often - hypersensitivity to warfarin after prolonged use.

often - vomiting, nausea, diarrhea; very rarely - melena.

From the skin and subcutaneous tissues: rarely - vasculitis, skin necrosis, alopecia, rash, urticaria, itching.

From the side of the cardiovascular system: rarely - purple finger syndrome; very rarely - cholesterol embolism.

From the immune system: often - hypersensitivity.

From the side of the liver: rarely - increased activity of liver enzymes, jaundice.

During the year, bleeding occurs in approximately 8% of cases among patients receiving warfarin. Of these, 1.0% are classified as severe (intracranial, retroperitoneal), leading to hospitalization or blood transfusion, and 0.25% as fatal. The most common risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension. The chance of bleeding increases if the MHO is significantly above the target level. If bleeding has started with an MHO within the target range, then there are other concomitant conditions that should be investigated.

Examples of such complications are epistaxis, hemoptysis, hematuria, bleeding from the gums, bruising of the skin, vaginal bleeding, subconjunctival bleeding, bleeding from the rectum and other parts of the gastrointestinal tract, intracerebral bleeding, prolonged or heavy bleeding after injuries or operations. You can expect the development of bleeding, incl. heavy, in any organ. Bleeding leading to death, hospitalization, or the need for blood transfusions has been reported in patients receiving long-term anticoagulant treatment.

Independent risk factors for significant bleeding during warfarin use include older age, high levels of anticoagulation, history of stroke, history of gastrointestinal bleeding, comorbidities, and atrial fibrillation. Patients with CYP2C9 polymorphisms may have an increased risk of excessive anticoagulant activity and bleeding episodes. In such patients, hemoglobin and INR levels should be closely monitored.

From the digestive system: vomiting, nausea, diarrhea.

From the side of the skin: coumarin necrosis is a rare complication of warfarin treatment. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks, or (less commonly) elsewhere. 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 suggests a deficiency of antithrombotic protein C or S. Congenital deficiency of these proteins can cause complications, so warfarin should be started simultaneously with the introduction of heparin and low initial doses of the drug. If a complication occurs, warfarin is discontinued and heparin is continued until the lesions heal or scar.

Palmar and plantar syndrome is a very rare complication of warfarin therapy, its development is typical 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 soles of the feet, accompanied by burning pains.

After discontinuation of warfarin, these symptoms gradually disappear.

Others: hypersensitivity reactions, manifested in the form of a skin rash, and characterized by a reversible increase in the concentration of liver enzymes, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and tracheal calcification.

Independent risk factors for the development of serious bleeding in the treatment of warfarin are: advanced age, high intensity of concomitant anticoagulant and antiplatelet therapy, a history of stroke and gastrointestinal bleeding. The risk of bleeding is increased in patients with CYP2C9 gene polymorphism.

Overdose

Symptoms: the treatment success rate is on the borderline of bleeding, so the patient may have minor bleeding (including microhematuria, bleeding gums).

Treatment: in mild cases, it is sufficient to reduce the dose of the drug or stop treatment for a short time. With minor bleeding, it is sufficient to stop taking the drug until the target MHO level is reached. In case of severe bleeding, intravenous administration of vitamin K, coagulation factor concentrate or fresh frozen plasma, oral administration of activated charcoal is recommended.

If oral anticoagulants are indicated for further administration, large doses of vitamin K should be avoided, as resistance to warfarin develops within 2 weeks.

Treatment regimens for drug overdose

In case of minor bleeding
INR level	Recommendations
< 5	Skip the next dose of warfarin and continue taking lower doses when the therapeutic INR level is reached.
5 to 9	Skip 1-2 doses of warfarin and continue with lower doses when therapeutic INR levels are reached. Or skip 1 dose of warfarin and prescribe vitamin K in doses of 1-2.5 mg orally.
> 9	Stop taking warfarin, prescribe vitamin K in doses of 3-5 mg orally.
Drug withdrawal indicated
INR level	Recommendations
from 5 to 9 - surgery is planned	Stop taking warfarin and prescribe vitamin K in doses of 2-4 mg orally (24 hours before the planned operation).
> 20 or heavy bleeding	Administer vitamin K in doses of 10 mg by slow IV infusion. Transfusion of prothrombin complex factor concentrates or fresh frozen plasma or whole blood. If necessary, vitamin K should be re-introduced every 12 hours.

After treatment, long-term monitoring of the patient is necessary, given that T 1/2 of warfarin is 20-60 hours.

drug interaction

With the simultaneous appointment, it is also necessary to take into account the effects of stopping the induction and / or inhibition of the action of warfarin by other medicines.

The risk of developing severe bleeding increases while taking warfarin with drugs that affect platelet levels and primary hemostasis: clopidogrel, ticlopidine, dipyridamole, most NSAIDs (with the exception of COX-2 inhibitors), antibiotics of the penicillin group in high doses.

You should also avoid the combined use of warfarin with drugs that have a pronounced inhibitory effect on the isoenzymes of the cytochrome P450 system (for example, cimetidine, chloramphenicol), when taken for several days, the risk of bleeding increases. In such cases, cimetidine can be replaced, for example, by ranitidine or famotidine.

Drugs that reduce the effect of warfarin

Colestyramine: decreased absorption of warfarin and effect on enterohepatic recirculation.

Bosentan: induction of conversion of warfarin to CYP2C9/CYP3A4 in the liver.

Aprepitant: induction of conversion of warfarin to CYP2C9.

Mesalazine: Maybe

Sucralfate: the likelihood of reduced absorption of warfarin.

Griseofulvin: decrease in the anticoagulant effect of coumarins.

Retinoids: the possibility of reducing the activity of warfarin.

Dicloxacillin:

Rifampicin: increased metabolism of warfarin; the combined use of these drugs should be avoided.

Antivirals (nevirapine, ritonavir): increased metabolism of warfarin mediated by CYP2C9.

Nafcillin: decreased anticoagulant effect of warfarin.

Phenazone: induction of enzyme metabolism, a decrease in the concentration of warfarin in the blood plasma; the dose of warfarin may need to be increased.

Rofecoxib:

Barbiturates (such as phenobarbital): increased metabolism of warfarin.

Antiepileptic drugs (carbamazepine, primidone): increased metabolism of warfarin.

Antidepressants (trazodone, mianserin): in four cases of clinical use, it was found that the interaction of trazodone and warfarin caused a decrease in prothrombin time and INR, but the mechanism of this interaction is unknown. The mechanism of interaction between warfarin and mianserin is also unknown.

Glutethimide: a decrease in the anticoagulant effect of warfarin due to an increase in its metabolism.

Chlordiazepoxide: decreased anticoagulant effect of warfarin.

Aminoglutethimide: increased metabolism of warfarin.

Azathioprine: decreased absorption of warfarin and increased metabolism of warfarin.

Mercaptopurine: decreased anticoagulant effect of warfarin.

Mitotan:

Cyclosporine: warfarin increases the concentration of cyclosporine or enhances its effect, influencing the metabolism of cyclosporine.

Colestyramine: may reduce the anticoagulant effect of warfarin due to a decrease in its absorption.

Spironolactone, chlorthalidone: the use of diuretics in the case of a pronounced hypovolemic effect can lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants.

St. John's wort (Hypericum perforatum): enhances the metabolism of warfarin, carried out by CYP3A4 and CYP1A2 (metabolism of R-warfarin), as well as carried out by CYP2C9 (metabolism of S-warfarin); the effect of enzyme induction may persist for up to 2 weeks after the end of the use of St. John's wort. In the event that the patient is taking preparations of St. John's wort, the INR should be measured and discontinued. Careful monitoring of INR should be carried out, tk. its level may increase with the abolition of St. John's wort; after that, warfarin can be prescribed.

Ginseng (Panax ginseng): it is possible to induce the conversion of warfarin in the liver; the combined use of these drugs should be avoided.

Foods containing vitamin K: weaken the action of warfarin. Most vitamin K is found in green vegetables (for example, amaranth greens, avocado, broccoli, Brussels sprouts, cabbage, canola oil, shayo, onion, coriander (cilantro), cucumber peel, chicory, kiwi fruit, lettuce, mint , green mustard, olive oil, parsley, peas, pistachios, red seaweed, spinach greens, spring onions, soybeans, tea leaves (but not a tea drink), turnip greens, watercress), so when treating with warfarin, you should Be careful when eating these foods.

: decreased anticoagulant effect of warfarin.

Vitamin K: warfarin blocks the synthesis of vitamin K-dependent clotting factors.

Drugs that enhance the effect of warfarin

Abciximab, tirofiban, eptifibatide, clopidogrel, heparin: additional effect on the hematopoietic system.

Cimetidine: a pronounced inhibitory effect on the cytochrome P450 system (cimetidine can be replaced by ranitidine or famotidine), leading to a decrease in the metabolism of warfarin.

Glibenclamide:

Omerpazole: increased anticoagulant effect of warfarin.

Amiodarone: decreased metabolism of warfarin after one week of concomitant use; this effect may persist for 1-3 months after the abolition of amiodarone.

Ethacrynic acid: may enhance the effect of warfarin due to the displacement of warfarin from protein binding.

Lipid-lowering agents (fluvastatin, simvastatin, rosuvastatin, gemfibrozil, bezafibrate, clofibrate, lovastatin, fenofibrate): competition for metabolism mediated by CYP2C9 and CYP3A4.

Propafenone:

Quinidine: decreased synthesis of blood coagulation factors.

Diazoxide: can replace warfarin, bilirubin or other highly protein-bound substance from protein bonds.

Digoxin:

Propranolol: enhancement of the anticoagulant effect.

Ticlopidin: increased risk of bleeding; INR monitoring is required.

Dipyridamole: an increase in the concentration of warfarin or dipyridamole due to potentiation of effects; increased risk of bleeding (hemorrhage).

Miconazole (including in the form of a gel for the oral cavity): a decrease in the intrinsic clearance of warfarin and an increase in the free fraction of warfarin in the blood plasma; a decrease in the metabolism of warfarin mediated by enzymes of the cytochrome P450 system.

Steroid hormones - anabolic and / or androgens (danazol, testosterone): a decrease in the metabolism of warfarin and / or a direct effect on the coagulation and fibrinolysis systems.

Means acting on the thyroid gland: increased metabolism of vitamin K-dependent clotting factors.

Glucagon: increased anticoagulant effect of warfarin.

Allopurinol: increased anticoagulant effect of warfarin.

Sulfinpyrazone: increased anticoagulant effect due to a decrease in its metabolism and a weakening of the connection with proteins.

Penicillins in high doses (cloxacillin, amoxicillin): possible increased chance of bleeding, including bleeding from the gums, nose, unusual bruising or dark stools.

Tetracyclines:

Sulfonamides (sulfamethizole, sulfafurazole, sulfafenazole): may increase the anticoagulant effect of warfarin.

Quinolones (ciprofloxacin, norfloxacin, ofloxacin, grepafloxacin, nalidixic acid): decreased metabolism of warfarin.

Macrolide antibiotics (azithromycin, clarithromycin, erythromycin, roxithromycin): decreased metabolism of warfarin.

Antifungals (fluconazole, itraconazole, ketoconazole): decreased metabolism of warfarin.

Chloramphenicol: a decrease in the metabolism of warfarin, a pronounced inhibitory effect on the cytochrome P450 system.

Cephalosporins (cefamandol, cephalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime): increased effect of warfarin due to suppression of the synthesis of vitamin K-dependent coagulation factors and other mechanisms.

Sulfamethoxazole/trimethoprim: decreased metabolism of warfarin and displacement of warfarin from plasma protein binding sites.

Levamisole: increased anticoagulant effect of warfarin.

Codeine: the combination of codeine and paracetamol enhances the activity of warfarin.

Acetylsalicylic acid: displacing warfarin from albumin binding sites, limiting warfarin metabolism.

NSAIDs (azapropazone, indomethacin, oxyphenbutazone, piroxicam, sulindac, tolmetin, feprazon, celecoxib and others (with the exception of COX-2 inhibitors): competition for metabolism carried out by CYP2C9.

Leflunomide: limitation of warfarin metabolism mediated by CYP2C9.

Paracetamol (acetaminophen) especially after 1-2 weeks of continuous use: restriction of warfarin metabolism or influence on the formation of coagulation factors (this effect does not appear when paracetamol is used at a dose of less than 2 g / day).

Phenylbutazone: decrease in the metabolism of warfarin, displacement of warfarin from the binding sites with plasma proteins; this combination should be avoided.

Narcotic analgesics (dextropropoxyphene): increased anticoagulant effect of warfarin.

Antiepileptic drugs (fosphenytoin, phenytoin): displacement of warfarin from its binding sites with plasma proteins, increased metabolism of warfarin.

Tramadol: competition for metabolism mediated by CYP3A4.

Antidepressants - selective serotonin reuptake inhibitors (SSRIs), incl. fluoxetine, fluvoxamine, paroxetine, sertraline: limitation of warfarin metabolism. SSRIs are believed to limit the CYP2C9 isoenzyme. This enzyme metabolizes the most potent isomer of S-warfarin. In addition, both SSRIs and warfarin bind strongly to albumin, which increases the possibility of displacing one of them from protein binding sites (with simultaneous use).

Chloral hydrate: the mechanism of interaction is unknown.

Fluorouracil: decreased synthesis of CYP2C9, which metabolizes warfarin.

Capecitabine: decreased synthesis of CYP2C9.

Imatinib: competitive suppression of the CYP3A4 isoenzyme and suppression of the metabolism of warfarin mediated by CYP2C9 and CYP2D6.

Ifosfamide: suppression of CYP3A4.

Tamoxifen: is an inhibitor of CYP2C9, may increase the concentration of warfarin in serum due to a decrease in its metabolism.

Methotrexate: increased effect of warfarin due to a decrease in the synthesis of procoagulant factors in the liver.

Tegafur: increased anticoagulant effect of warfarin.

Trastuzumab: increased anticoagulant effect of warfarin.

Flutamide: increased anticoagulant effect of warfarin.

Cyclophosphamide: the likelihood of a change in the anticoagulant effect of warfarin, tk. Cyclophosphamide is an antitumor agent.

Etoposide: it is possible to enhance the anticoagulant effect of coumarins.

Interferon alpha and beta: an increase in the anticoagulant effect and an increase in the serum concentration of warfarin necessitates a reduction in the dose of warfarin.

Disulfiram: decreased metabolism of warfarin.

Metolazone: increased anticoagulant effect of warfarin.

Thienylic acid: increased anticoagulant effect of warfarin.

Zafirlukast: an increase in the concentration or increase in the effect of zafirlukast against the background of the use of warfarin due to changes in the metabolism of zafirlukast.

Troglitazone: decrease in concentration or weakening of the effect of warfarin due to changes in the metabolism of warfarin.

Influenza vaccine: the possibility of enhancing the anticoagulant effect of warfarin.

Proguanil: it is possible to increase the anticoagulant effect of warfarin according to individual reports.

Food (cranberries): reduces the metabolism of warfarin mediated by CYP2C9.

Tonic drinks containing quinine: the use of a large number of tonic drinks containing quinine may necessitate a reduction in the dose of warfarin. This interaction can be explained by the fact that quinine reduces the synthesis of procoagulant factors in the liver.

Ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza): potentiation of the anticoagulant/antiplatelet effect may increase the risk of bleeding.

Drugs that reduce or enhance the effect of warfarin

Disopyramide: may weaken or enhance the anticoagulant effect of warfarin.

Coenzyme-Q10: may enhance or inhibit the effect of warfarin due to the homogeneity of the chemical structure with vitamin K.

Ethanol: inhibition or induction of warfarin metabolism.

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

In the case of the combined use of warfarin with the above drugs, it is necessary to monitor the INR at the beginning and at the end of treatment and, if possible, 2-3 weeks after the start of therapy.

special instructions

A prerequisite for warfarin therapy is strict adherence by the patient to the prescribed dose of the drug. Patients suffering from alcoholism, as well as patients with dementia, may be unable to comply with the prescribed warfarin regimen.

Fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage, may increase the effect of warfarin.

In hypothyroidism, the effect of warfarin may be reduced.

In the case of renal insufficiency or nephrotic syndrome, the level of the free fraction of warfarin in the blood plasma increases, which, depending on concomitant diseases, can lead to either an increase or a decrease in the effect. In the case of moderate liver failure, the effect of warfarin is enhanced. In all of the above conditions, close monitoring of MHO should be carried out.

Paracetamol, tramadol, or opiates are recommended for pain relief in patients receiving warfarin.

Patients with a mutation in the gene encoding the CYP2C9 enzyme have a longer half-life of warfarin. These patients require lower doses of the drug, since the risk of bleeding increases when taking the usual therapeutic doses.

Patients with rare hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome should not take warfarin due to the presence of lactose in the preparation (as an excipient).

If it is necessary to achieve a rapid antithrombotic effect, it is recommended to start treatment with the introduction of heparin; then, for 5-7 days, combination therapy with heparin and warfarin should be carried out until the target value of the INR is maintained for 2 days.

In patients with protein C deficiency, there is a risk of skin necrosis without the use of a loading dose of warfarin. Such therapy should be initiated without the use of a loading dose of warfarin, even with heparin. Patients with protein S deficiency may also be at risk; in these circumstances, a slower initiation of warfarin therapy is recommended.

In the case of individual resistance to warfarin (rare), 5 to 20 shock doses of warfarin are needed to achieve a therapeutic effect. If warfarin is not effective in such patients, other possible causes should be established: concomitant use of warfarin with other drugs, inadequate dietary intake, laboratory errors.

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

Caution is advised in patients with impaired renal function, as a result of which INR levels should be monitored more frequently in patients at risk of hypercoagulability, for example, with severe arterial hypertension or kidney disease.

Pregnancy and lactation

Warfarin quickly crosses the placental barrier, has a teratogenic effect on the fetus, leading to the development of warfarin syndrome in the fetus at 6-12 weeks of gestation. Manifestations of this syndrome: nasal hypoplasia (saddle nose deformity and other cartilage changes) and punctate chondrodysplasia on x-ray (especially in the spine and long bones), short hands and fingers, optic nerve atrophy, cataracts leading to complete blindness, mental retardation and physical development, microcephaly. The drug can cause bleeding at the end of pregnancy and during childbirth.

Taking the drug during pregnancy can cause congenital malformations and lead to fetal death. The drug should not be prescribed in the first trimester of pregnancy and during the last 4 weeks. The use of warfarin is not recommended during the remaining stages of pregnancy, except in cases of emergency.

Women of reproductive age should use an effective method of contraception while taking warfarin.

Warfarin is excreted in breast milk, but when taking warfarin in therapeutic doses, no effect on the breastfed child is expected. The drug can be used during lactation (breastfeeding).

Data on the effect of warfarin on fertility are not available.

Application in childhood

Data on the use of warfarin in children limited. The initial dose is usually 0.2 mg/kg/day for normal liver function and 0.1 mg/kg/day for impaired liver function. The maintenance dose is selected in accordance with the MHO. Recommended MHO levels are the same as for adults. The decision to prescribe warfarin in children should be made by an experienced specialist. Treatment should be carried out under the supervision of an experienced pediatrician.

For impaired renal function

Appointment is contraindicated in severe kidney disease.

Patients with renal insufficiency do not need any special recommendations on the selection of the dose of warfarin. Patients on peritoneal dialysis do not need an additional increase in the dose of warfarin.

For impaired liver function

Appointment is contraindicated in severe liver diseases.

Liver dysfunction increases sensitivity to warfarin because the liver produces clotting factors and also metabolizes warfarin. In this group of patients, careful monitoring of MHO parameters is necessary.

Use in the elderly

There are no specific recommendations for the use of warfarin in patients old age. However, elderly patients should be closely monitored as they have a higher risk of side effects.

Terms of dispensing from pharmacies

The drug is dispensed by prescription.

Terms and conditions of storage

The drug should be stored out of the reach of children at a temperature not exceeding 25 ° C. Shelf life - 5 years.

Warfarin Nycomed

International non-proprietary name

warfarin

Dosage form

Tablets 2.5 mg

Cleaving

One tablet contains

active substance- warfarin sodium 2.5 mg,

Excipients: lactose, corn starch, calcium hydrogen phosphate, indigotine (E 132), povidone 30, magnesium stearate.

Description

Pale blue, round, biconvex tablets with a cross-cut notch.

Pharmacotherapeutic group

Anticoagulants. Anticoagulants are indirect. Warfarin.

ATX code B01AA03

Pharmacological properties

Pharmacokinetics

The drug is rapidly absorbed from the gastrointestinal tract. Plasma protein binding is 97 - 99%. Metabolized in the liver. Warfarin is a racemic mixture, with the R- and S-isomers being metabolized in the liver in different ways. Each of the isomers is converted into 2 main metabolites. The main metabolic catalyst for the S-enantiomer of warfarin is the enzyme CYP2C9, and for the R-enantiomer of warfarin CYP1A2 and CYP3A4. The levorotatory isomer of warfarin (S - warfarin) has 2 to 5 times greater anticoagulant activity than the dextrorotatory isomer (R-enantiomer), but the half-life of the latter is longer. Patients with polymorphisms of the CYP2C9 enzyme, including CYP2C9*2 and CYP2C9*3 alleles, may have increased sensitivity to warfarin and an increased risk of bleeding.

Warfarin is excreted in the bile as inactive metabolites, which are reabsorbed in the gastrointestinal tract and excreted in the urine. The half-life is from 20 to 60 hours. For the R-enantiomer, the half-life is from 37 to 89 hours, and for the S-enantiomer from 21 to 43 hours.

Pharmacodynamics

Warfarin is an indirect anticoagulant that blocks the synthesis of vitamin K-dependent blood clotting factors in the liver, namely, factors II, VII, IX and X. These factors are formed as a result of carboxylation of precursor proteins, in which vitamin K is oxidized to 2,3- vitamin K epoxide. Oral anticoagulants prevent the reverse reduction of epoxide to vitamin K and thus cause accumulation of vitamin K 2,3-epoxide. This can lead to depletion of vitamin K stores and slow the production of clotting factors. As a result, the concentration of these components in the blood decreases, which leads to the suppression or reduction of the coagulation process. Anticoagulant effect is observed after 36-72 hours from the start of taking the drug Warfarin Nycomed with the development of the maximum effect on 5-7 days from the start of use. After discontinuation of the drug Warfarin Nycomed, the restoration of the activity of vitamin K-dependent blood coagulation factors occurs within 4-5 days.

Indications for use

Treatment and prevention of thrombosis and embolism of blood vessels, including:

acute venous thrombosis and pulmonary embolism (in combination with heparin)

prevention and treatment of postoperative thrombosis

recurrent myocardial infarction

in prosthetics of blood vessels and valves of the heart (including in combination with athecylsalicylic acid)

prevention of thromboembolic complications in patients with atrial fibrillation

recurrent thrombosis

thrombosis of peripheral, coronary and cerebral arteries

transient ischemic attacks and strokes.

The drug is used for secondary prevention of thrombosis and thromboembolism after myocardial infarction and with atrial fibrillation.

Dosage and administration

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

Control during treatment:

A coagulogram should be performed before starting treatment. Since warfarin has a low therapeutic index, treatment should be regularly monitored. Sensitivity to warfarin varies in different patients and in the same patient. In individuals, sensitivity may be high due to genetic factors, abnormal liver function, congestive heart failure, or drug interactions.

Therapeutic INR levels

In the presence of mechanical heart valves and in acute myocardial infarction with complications, an anticoagulant effect is achieved with an INR of 2.5-3.5.

For the prevention and treatment of venous thrombosis and pulmonary embolism, atrial fibrillation (not associated with valvular defects), severe dilated cardiomyopathy, complicated heart defects and in the presence of biprosthetic heart valves, a moderate anticoagulant effect is achieved with an INR in the range of 2.0 - 3.0.

Patients who have not previously taken warfarin:

The initial dose is 5 mg / day (2 tablets per day) for the first 4 days. On the 5th day of treatment, the INR is determined and, in accordance with this indicator, a maintenance dose of the drug is prescribed. The usual maintenance dose of the drug is 2.5 - 7.5 mg / day (1 - 3 tablets per day).

Patients who have previously taken warfarin:

The recommended starting dose is twice the known maintenance dose of the drug and given for the first 2 days. The treatment is then continued with a known maintenance dose. On the 5th day of treatment, the INR is monitored and the dose is adjusted in accordance with this indicator.

The higher doses described above do not reduce the time to anticoagulant effect, but increase the risk of bleeding.

Aged people:

However, elderly patients should be closely monitored, as they have a higher risk of side effects.

Patients with liver failure:

Patients with renal insufficiency:

In patients with renal insufficiency, it is necessary to reduce the dosage of the drug Warfarin Nycomed and conduct careful monitoring.

Side effects

Examples of side effects are epistaxis, hemoptysis (hemoptysis), hematuria (blood in the urine), bleeding gums, bruising of the skin, vaginal bleeding, subconjunctival bleeding, bleeding from the rectum and other parts of the gastrointestinal tract, bleeding in the brain, prolonged or heavy bleeding after injury or surgery. Bleeding, including severe, can develop in any organ. Bleeding has been reported in patients treated with long-term anticoagulants leading to death, hospitalization, or the need for blood transfusions.

Independent risk factors for significant bleeding during the use of Warfarin Nycomed include: advanced age, high levels of anticoagulation, history of stroke, history of gastrointestinal bleeding, comorbidities, and atrial fibrillation. Patients with CYP2C9 polymorphisms have an increased risk of excessive anticoagulation and bleeding episodes. In such patients, hemoglobin and INR levels should be closely monitored.

Adverse reactions are distributed in the following order, taking into account the frequency of occurrence: very often (≥1 / 10); often (≥1/100 to<1/10); не часто (≥1/1000 до <1/100); редко (≥1/10000 до <1/1,000); очень редко (<1/10000), неизвестные (невозможно оценить на основе имеющихся данных).

Highly often:

bleeding in various organs

Often:

increased sensitivity to warfarin after prolonged use

hypersensitivity

Infrequently:

vomiting, nausea, diarrhea

Seldom:

vasculitis, necrosis, alopecia, hair loss, rash, urticaria, pruritus

eosinophilia

purple finger syndrome

elevated liver enzymes, jaundice

urolithiasis, nephritis, tubular necrosis

Rarely:

melena, cholesterol embolism

palmoplantar syndrome

After starting treatment with the drug, all suspicious side effects should be reported. This allows continuous monitoring of the benefit/risk profile of a given medicinal product.

Contraindications

hypersensitivity to the components of the drug

pregnancy (first trimester and last 4 weeks of pregnancy)

severe liver and kidney failure

acute bleeding of any localization

high risk of bleeding (including patients with hemorrhagic diathesis, esophageal varices, arterial aneurysms, after spinal puncture, with peptic ulcer, with extensive wounds (including surgical ones), cerebrovascular diseases)

bacterial endocarditis

malignant arterial hypertension

hemorrhagic stroke

rare hereditary disorders - galactose intolerance, lactose deficiency or glucose-galactose malabsorption

children and adolescents up to 18 years of age

Patients taking warfarin should not consume products / traditional medicines containing hypericum perforatum (St.

Drug Interactions

Warfarin is metabolized by liver enzymes. Under the influence of other drugs metabolized by the same enzymes, suppression or enhancement of the activity of these enzymes can occur. This can lead to an increase or decrease in plasma levels of warfarin.

Warfarin is highly protein bound, and one mechanism for drug interactions may be displacement of warfarin from this association.

With simultaneous administration, it is also necessary to take into account the effects of stopping the induction and / or inhibition of the action of the drug Warfarin Nycomed by other drugs.

Medicines that reduce the effect of the drug Warfarin Nycomed(decrease in INR)

	Name	Possible mechanism
The cardiovascular system	Cholesteramine	Decreased absorption of warfarin and effect on enterohepatic recirculation.
The cardiovascular system	Bosentan	Induction of conversion of warfarin to CYP2C9/CYP3A4 in the liver.
Gastrointestinal drugs	Aprepitant	Induction of conversion of warfarin to CYP2C99.
Dermatological preparations	griseowulfin	The mechanism of interaction between griseovulfin and warfarin is unknown.
Anti-infectives	Dicloxacillin
	Rifampicin	Increased metabolism of warfarin.
	Ritonavir	Induces CYP2C9 mediated metabolism of warfarin
	Phenazone	The mechanism of interaction between phenazone and warfarin is unknown.
central nervous system	Barbiturates (eg phenobarbital)	Increased metabolism of warfarin.
central nervous system	Antiepileptics (carbamazepine)	Increased metabolism of warfarin.
Cytostatics	Aminoglutethimide	Increased metabolism of warfarin.
	Azathioprine	Decreased absorption of warfarin and increased metabolism of warfarin.
	Nevirapine	Causes the metabolism of warfarin mediated by CYP2C9.
Traditional medicine	Hypericum perforatum(St. John's wort)	Causes the metabolism of warfarin, carried out by CYP P450-3A4 and -1A2 (metabolism of R-warfarin), as well as carried out by CYP P450-2C9 (metabolism of S-warfarin). The effect of enzyme induction may appear at least 2 weeks after the end of St. John's wort treatment.
Traditional medicine	Ginseng	Possible induction of warfarin conversion in the liver. The combined use of these drugs should be avoided.
Food	Foods containing vitamin K(e.g. kale, avocado, broccoli and spinach)	Counteracting the effect of warfarin.

Medicines that enhance the effect of the drug Warfarin Nycomed(increased INR)

	Name	Possible mechanism
Blood and hematopoietic organs	Abciximab Tirofiban Eptifibatil Clopidogrel Heparin	Inhibition of clotting factors.
Gastrointestinal tract and metabolism	Cimeditin
The cardiovascular system	Amiodarone	Reduces warfarin metabolism after one week of co-administration. This effect may persist for one to three months after the withdrawal of amiodarone.
	Ethacrynic acid	The mechanism of interaction between ethacrynic acid and warfarin is not known.
	Lipid-lowering agents (fluvastatin, simvastatin, rosuvastatin, gemfibrozil)	Competition for metabolism mediated by cytochromes P450 2C9- and 3A4.
	propafenone	Decreased metabolism of warfarin.
	Quinidine	Decreased clotting factors.
Dermatological products	Miconazole	Decrease in own clearance of warfarin and increase in free fraction of warfarin in plasma; restriction of warfarin metabolism mediated by P450 cytochromes.
The genitourinary system and sex hormones	Steroid hormones (danazol, testosterone)	Restriction of warfarin metabolism and/or direct effect on coagulation and fibrinolysis systems
Hormones for systemic use	Agents acting on the thyroid gland	Increased metabolism of vitamin K-dependent coagulation factors.
Anti-infectives	Penicillins (cloxacillin, amoxicillin)	The mechanism of interaction with warfarin is unknown.
	Quinolones (ciprofloxacin, norfloxacin)
	Macrolides ( azithromycin, clarithromycin, erythromycin)	Limitation of warfarin metabolism.
	Antifungals (fluconazole, itraconazole, ketoconazole, metronidazole)	Limitation of warfarin metabolism.
	Chloramphenicol	Limitation of warfarin metabolism.
	Sulfamethoxazole	Restriction of warfarin metabolism and displacement of warfarin from protein binding sites.
Remedies for muscle, joint and bone pain	Acetylsalicylic acid	Displacement of warfarin from plasma albumin, restriction of warfarin metabolism, direct hypothrombinemic effect of aspirin, and gastric erosion
	NSAIDs	Competition for metabolism carried out by cytochrome P450 2C9 enzymes.
	Leflunomide	Limitation of warfarin metabolism mediated by CYP2C9.
	Paracetamol (acetaminophen)	Limitation of warfarin metabolism or influence on the formation of coagulation factors (this effect does not appear when taking less than 2 g of paracetamol per day).
	Phenylbutazone	Decreased metabolism of warfarin, displacement of warfarin from protein binding sites. This combination should be avoided.
central nervous system	Antiepileptic drugs(fosphenytoin, phenytoin)	Displacement of warfarin from protein binding sites, increased metabolism of warfarin.
	Tramadol	Competition for cytochrome P450 3A4 mediated metabolism.
	Antidepressants
	Selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine, sertraline)	Limitation of warfarin metabolism. SSRIs are believed to limit the cytochrome P450 2C9 isoenzyme (CYP2C9). It is the enzyme that metabolizes the most potent isomer of S-warfarin. In addition, both SSRIs and warfarin bind strongly to albumin. In the presence of both, the possibility of displacement of one of the compounds from albumin increases.
Cytostatics	Fluorouracil	Decreased synthesis of cytochrome P450 2C9 enzymes that metabolize warfarin.
	Capecitabine	Decreased CYP2C9 isoenzymes.
	Imatinib	Competitive restriction of CYP3A4 isoenzyme and restriction of CYP2C9 caused by imatinab, as well as CYP2D6 mediated metabolism of warfarin.
	Ifosfamide	Suppression of CYP3A4.
	Tamoxifen	The mechanism of interaction between tamoxifen and warfarin is unknown.
Substance Abuse Treatment Drugs	Disulfiram	Limitation of warfarin metabolism.
Food	Cranberry	Cranberries reduce the metabolism of warfarin mediated by CYP2C9.

Substances that lower or increase INR

special instructions

After assessing the relationship between the benefits of thromboembolic disease prevention and increased risk of bleeding, it is necessary to evaluate the patient's ability to strictly adhere to the prescribed treatment. Patients suffering from drug addiction, alcoholism or dementia may be unable to comply with the prescribed regimen for taking Warfarin Nycomed. Drug interactions may alter the effect of Warfarin Nycomed. Therefore, the control of warfarin intake should be strengthened at the beginning of treatment, at the end or when changing treatment with other drugs.

The anticoagulant effect of warfarin can be affected by various factors, including acute illness, hyperthyroidism, hypothyroidism, vomiting, diarrhea, and congestive heart failure. Significant dietary changes (eg, a vegetarian diet) may affect vitamin K absorption and alter the effect size of warfarin. Accordingly, when these factors change, more careful monitoring of patients should be carried out.

Physicians and patients should be aware of the increased risk of bleeding, especially from the gastrointestinal tract, during concomitant treatment with NSAIDs and acetylsalicylic acid.

In patients with mutations in the gene encoding the CYP2C9 enzyme, the half-life of warfarin is increased. Such patients require a lower maintenance dose and the risk of bleeding may be increased with a higher loading dose.

A few days before surgery, you should consider the possibility of discontinuing warfarin. Before surgery (including dental surgery), at a minimum, INR should be monitored and adjusted.

In patients with antithrombotic protein C deficiency at the beginning of warfarin treatment, there is a risk of developing skin necrosis, as a result, therapy should be started without a loading dose of warfarin (even when heparin is prescribed). Patients with protein S deficiency may also be at risk, in such cases slower initiation of warfarin treatment is recommended.

Particular attention should be paid to patients with renal insufficiency. INR should be monitored more closely in patients at increased risk of hypercoagulability, such as those with severe hypertension, liver or kidney disease.

Pregnancy and lactation

Pregnancy

Based on patient experience, it is known that warfarin given during pregnancy can cause congenital anomalies and fetal death.

Women of childbearing age must use an effective method of contraception during treatment with Warfarin Nycomed.

Warfarin quickly crosses the placenta. The use of the drug Warfarin Nycomed in the first three months and in the last four weeks of pregnancy is contraindicated. Between these periods, warfarin is used only when absolutely necessary.

Warfarin can cause serious malformations, fetal bleeding, and fetal death. The use of warfarin during pregnancy can lead to the development of warfarin syndrome in the fetus, similar to punctate chondrodysplasia. Manifestations of this syndrome: nasal hypoplasia (saddle nose and other cartilaginous formations), pinpoint cartilage dysplasia on x-ray (especially in the spine and long bones), short hands and fingers, optic nerve atrophy, cataracts leading to partial or complete blindness, delayed physical and mental development and microcephaly.

Lactation

Warfarin is excreted in breast milk, but at therapeutic doses no effect of warfarin on a breastfed child is expected, therefore, Warfarin Nycomed can be used during breastfeeding.

Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

The effect of the drug Warfarin Nycomed on the ability to drive vehicles and control other mechanisms is absent or negligible.

Overdose

Symptoms appear a few days or weeks after the start of treatment. These include: nosebleeds, bleeding from the gums, pallor, hematomas in the periarticular and gluteal region, the appearance of blood in the urine and feces. Other possible symptoms include back pain, bleeding from the lips or mucous membranes, abdominal pain, vomiting, and petechiae. Later, paralysis may occur due to cerebral hemorrhage and, finally, hemorrhagic shock and death.

Treatment overdose is mainly supportive and symptomatic. It may be necessary to prescribe the antidote phytomenadione (vitamin K1) and, if necessary, intravenous administration of concentrated clotting factors, fresh frozen plasma, or blood transfusion. Due to the long half-life of warfarin (20-60 hours), patients should be observed for a long time.