Warfarin Nycomed tablets 2.5 mg bottle No. 100

Instructions for Warfarin Nycomed tablets 2.5 mg bottle No. 100

Composition

active ingredient: warfarin sodium;

1 tablet contains 2.5 mg of warfarin sodium;

excipients: indigotine dye (E 132); lactose monohydrate; corn starch; povidone 30; calcium hydrogen phosphate; magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: light blue biconvex tablets with a cross-shaped score.

Pharmacotherapeutic group

Antithrombotic agents. Vitamin K antagonists.

ATX code B01A A03.

Pharmacological properties

Pharmacodynamics.

Warfarin is an anticoagulant that blocks the synthesis of vitamin K-dependent clotting factors. Vitamin K is essential for the synthesis of clotting factors in the liver, namely factors II, VII, IX, and X. Clotting factors are formed by carboxylation of their protein precursors, and in this process, vitamin K is oxidized to vitamin K 2,3-epoxide. Oral anticoagulants prevent the conversion of vitamin K 2,3-epoxide to vitamin K, thus leading to the accumulation of vitamin K 2,3-epoxide. This means that less vitamin K is available, which inhibits the synthesis of clotting factors. The concentration of these components in the blood decreases and the clotting process slows down.

The onset of anticoagulant action is observed 32-72 hours after the start of taking the drug, with the maximum effect developing on the 5-7th day from the start of using the drug. After stopping using the drug, the activity of vitamin K-dependent blood clotting factors is restored within 4-5 days.

The S-enantiomer of warfarin has 2-5 times greater anticoagulant activity than the R-enantiomer of warfarin.

Pharmacokinetics.

Absorption. The drug is rapidly absorbed from the digestive tract. The rate of absorption depends on the individual characteristics of the patient.

Distribution: Binding to plasma proteins is 97-99%.

Metabolism. In humans, warfarin is found as a racemic compound, with the levorotatory form being more active than the dextrorotatory form. Warfarin is metabolized in the liver, and the metabolites formed are either inactive or of low activity. The R- and S-isomers are metabolized in the liver by different pathways. Each isomer is converted into two separate 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-enantiomer) has 2-5 times greater anticoagulant activity than the dextrorotatory isomer (R-enantiomer), but the half-life of the latter is longer. Patients with CYP2C9 enzyme polymorphisms, including CYP2C9*2 and CYP2C9*3 alleles, may have increased sensitivity to warfarin, increased anticoagulant effects, and an increased risk of bleeding.

Elimination. Warfarin metabolites are excreted in the bile, reabsorbed in the gastrointestinal tract, and excreted in the urine. The half-life is 20 to 60 hours. For the R-enantiomer, the half-life is 37 to 89 hours, and for the S-enantiomer, it is 21 to 43 hours. Warfarin is excreted in breast milk in an inactive form.

Indication

Treatment and prevention of deep vein thrombosis and pulmonary embolism. Secondary prevention of myocardial infarction and prevention of thromboembolic complications (stroke or systemic embolism) after myocardial infarction. Prevention of thromboembolic complications in patients with atrial fibrillation, heart valve disease or prosthetic heart valves. Prevention of transient ischemic attacks and stroke.

Contraindication

Hypersensitivity to the components of the drug; clinically established bleeding; to avoid the risk of severe bleeding within 72 hours after major surgical interventions, within 48 hours in the postpartum period, bleeding tendency (hemophilia, von Willebrand disease; thrombocytopenia and platelet dysfunction); tendency to fall; severe renal failure; severe hepatic failure, cirrhosis of the liver; untreated or uncontrolled arterial hypertension; recent hemorrhagic stroke; conditions predisposing to intracranial hemorrhage, such as cerebral aneurysm, aortic aneurysm; central nervous system or eye surgery; gastrointestinal or renal bleeding and their complications, diverticulosis or malignant tumors; pericarditis (including exudative). A condition in which therapy cannot be carried out safely enough (e.g. psychosis, dementia, alcoholism).

The drug is contraindicated for use in women in the first trimester of pregnancy and during the last four weeks of pregnancy (see section "Use during pregnancy or breastfeeding").

Patients receiving warfarin treatment should not use herbal preparations/preparations containing hypericum perforatum (St. John's wort), as their concomitant use causes a decrease in warfarin plasma concentrations, which leads to a decrease in the clinical effect (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Warfarin has a narrow therapeutic index, other drugs may affect the action of warfarin. Before starting treatment, when changing the dosage or when ending the course of treatment, it is necessary to consult a doctor. The effect of other drugs is determined by pharmacodynamic and/or pharmacokinetic properties.

It is not recommended to start or stop taking other medications, as well as change the doses of medications used, without consulting a doctor.

This also applies to non-prescription medicines, herbal medicines, food supplements and vitamins used in doses exceeding the recommended ones. The intervals between treatment monitoring can be gradually increased during the course of treatment. However, intensive monitoring is necessary at the beginning and end of the intake of other medicines.

Pharmacokinetic interactions.

Warfarin is metabolized by hepatic enzymes. Other drugs that are metabolized by the above enzymes may inhibit or enhance the action of these enzymes. This may lead to increased or decreased warfarin levels.

Warfarin is highly protein bound. Interactions may occur due to mechanisms of competition for binding.

A significant number of drugs interact with oral anticoagulants.

The most important of these are: broad-spectrum antibiotics, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), clofibrate, barbiturates, phenytoin, and oral antidiabetic drugs.

Warfarin in combination with NSAIDs significantly increases the risk of bleeding. This also applies to other platelet aggregation inhibitors such as dipyridamole and valproic acid. Such combinations should be avoided.

This may also apply to compounds with a pronounced inhibitory effect on the cytochrome P450 system, such as cimetidine and chloramphenicol, the use of which for several days increases the risk of bleeding. In such cases, cimetidine can be replaced by ranitidine or famotidine. If treatment with chloramphenicol is necessary, anticoagulant therapy should be temporarily suspended. The use of diuretics in case of pronounced hypovolemic effect may lead to an increase in the concentration of coagulation factors, which reduces the effect of anticoagulants.

If warfarin is to be used in combination with other drugs listed below, it is recommended to monitor treatment (international normalized ratio) (INR) at the beginning and end of treatment, 2-3 weeks after the start of therapy. This applies to drugs that induce liver enzymes (barbiturates, phenytoin, carbamazepine) and thereby reduce the anticoagulant effect of warfarin. When using drugs that can increase bleeding either by reducing the normal coagulation process or by inhibiting clotting factors, or by incomplete inhibition of liver enzymes (e.g. laxatives, the strategy of anticoagulant therapy will depend on the possibility of laboratory monitoring). If possible, frequent laboratory monitoring of therapy is necessary, which will allow at the beginning of additional treatment to adjust the dose of warfarin, for example, to reduce or increase it by 5-10%. With limited possibilities for laboratory monitoring of therapy, the appointment of these drugs should be avoided. The list of drugs below, interactions with which must be considered, is far from complete.

The effect of warfarin is enhanced when used concomitantly with allopurinol, amiodarone, anabolic steroids (testosterone and other C-17 alkylated steroids), acetylsalicylic acid, paracetamol, NSAIDs, heparin, glucagon, danazol, diazoxide, disapyramide, disulfiram, isoniazid, ketoconazole, clofibrate, levamisole, metronidazole, miconazole, nalidixic acid, flutamide, omeprazole, serotonin reuptake inhibitors (fluoxetine, fluvoxamine, paroxetine, sertraline), proguanil, antidiabetic agents - sulfonylurea derivatives (glibenclamide), sulfonamide, tamoxifen, thyroxine, quinine, quinidine, antifungal drugs (fluconazole, itraconazole, ketoconazole, voriconazole), anti-inflammatory drugs (prednisolone, prednisolone), fluorouracil, capecitabine, imatinib, ifosfamide, quinolones, chloral hydrate, chloramphenicol, cephalosporins, cimetidine, erythromycin, ethacrynic acid, penicillin antibiotics (cloxacillin, amoxicillin), macrolides (clarithromycin, azithromycin), sulfamethoxazole, clopidogrel, eptifibatide, tirofiban, abciximab, lipid-modifying agents (simvastatin, rosuvastatin, fluvastatin, gemfibrozil), propafenone, ethacrynic acid, quinolones (ciprofloxacin, norfloxacin), leflunomide, phenylbutazone, tramadol, antiepileptic drugs (fosphenytoin, phenytoin) and disulfiram, glucosamine. Ethanol may enhance the effect of warfarin.

Increased INR has been reported in patients taking glucosamine and an oral vitamin K antagonist. Therefore, patients receiving an oral vitamin K antagonist should be closely monitored when initiating or discontinuing glucosamine therapy.

Some herbal preparations can also either enhance the effect of warfarin (e.g., ginkgo biloba, garlic, angelica, papaya, sage, cranberry) or reduce it (e.g., ginseng, St. John's wort).

Quinine, which is found in tonic drinks, can also enhance the effects of warfarin.

Foods high in vitamin K (such as green vegetables) reduce the effects of warfarin. Because the chemical structures of coenzyme Q10 and vitamin K2 are similar, their combined use may increase or decrease the effects of warfarin.

When warfarin is used concomitantly with acetylsalicylic acid preparations, the INR should be within 2.0-2.5.

When used together with antithrombotic or hemostatic agents, the pharmacological effects of warfarin may be enhanced, increasing the risk of bleeding. Streptokinase and alteplase are contraindicated in patients taking warfarin. When using warfarin, thrombin inhibitors, unfractionated heparins and their derivatives, low molecular weight heparins, fondaparinux, rivaroxaban, glycoprotein IIb/IIIa receptor antagonists, prostacyclin, serotonin reuptake inhibitors, erlotinib, methylphenidate, oral contraceptives should be avoided. If this is not possible, these drugs should be prescribed with caution under increased clinical and laboratory monitoring. Alcohol abuse can slow down the metabolism of warfarin and increase the INR.

Chronic alcohol use may accelerate the metabolism of warfarin. Lactulose may potentiate the effects of warfarin with long-term use.

If temporary pain relief is required, it is recommended that patients receiving warfarin be prescribed paracetamol or opiates.

Application features

Calciphylaxis is a rare syndrome of vascular calcification with skin necrosis associated with a high fatality rate. This condition occurs predominantly in patients with end-stage renal disease on dialysis or in patients with risk factors such as protein C and S deficiency, hyperphosphatemia, hypercalcemia, or hypoalbuminemia. Rare cases of calciphylaxis have also been reported in patients taking warfarin without renal impairment. If calciphylaxis is diagnosed, appropriate treatment should be initiated and warfarin discontinuation should be considered.

After assessing the benefit of thromboembolic prevention over the risk of bleeding, an important condition of warfarin therapy is mandatory adherence to the prescribed dose of the drug. Patients suffering from alcoholism, as well as patients with dementia, may be unable to adhere to the required warfarin regimen.

At the beginning of warfarin treatment, after the end of treatment, or when changing the course of treatment with other medications, it is necessary to conduct intensive monitoring of the patient's condition, since other medications may change the effect of warfarin.

Physicians and patients should be informed about the risk of bleeding, especially from the digestive tract, which is increased when warfarin is used concomitantly with acetylsalicylic acid and NSAIDs.

Special caution and careful monitoring of the INR level are necessary when prescribing warfarin to patients at risk of serious bleeding. The most likely risk factors for bleeding are high levels of anticoagulation (A > 4); age from 65 years; unstable INR; recent gastrointestinal bleeding, ischemic stroke, bacterial endocarditis; peptic ulcer of the stomach; cerebrovascular disease; serious heart disease; anemia; trauma; renal failure; concomitant use of other drugs. All patients taking warfarin must have regular INR measurements. Patients at increased risk of bleeding require more frequent INR measurements, more careful dose selection to achieve the desired INR, and a shorter duration of therapy. If the INR is high, reduce the dose or stop warfarin. Sometimes reversal therapy with anticoagulants is necessary. The INR should be measured within 2-3 days to ensure that it has decreased. Other antiplatelet drugs should be used with extreme caution due to the increased risk of bleeding.

In patients with compromised renal glomerular integrity or a history of renal disease, acute kidney injury may occur, possibly in association with episodes of excessive anticoagulation and haematuria. A few cases have been reported in patients without a history of renal disease. Close monitoring, including assessment of renal function, is recommended in patients with supratherapeutic international normalised ratio (INR) and haematuria (including microscopic).

Anticoagulant therapy after a recent ischemic stroke increases the risk of secondary cerebral hemorrhage. A break in treatment after ischemic stroke and in patients with long-term warfarin therapy with atrial fibrillation is justified, given the low risk of early recurrent embolism. Warfarin treatment should be restarted 2-14 days after ischemic stroke, depending on the size of the infarct and blood pressure. In patients with embolic strokes, warfarin should be discontinued for 14 days.

Mandatory consultation with a doctor and observation when planning surgical interventions. It should be noted that warfarin should be discontinued several days before elective surgical procedures. Careful monitoring and adjustment of the INR level should be carried out as a minimum safety measure before surgical interventions (including dental surgery). Surgical operations are possible in cases with an INR < 2.5, if there is no risk of serious bleeding. Before surgical operations, if there is a risk of serious bleeding, warfarin should be discontinued 3 days before surgery. If it is necessary to continue anticoagulant therapy, for example, in case of life-threatening thromboembolism, the INR should be reduced to < 2.5 and heparin therapy should be initiated. If surgery is necessary and warfarin cannot be discontinued 3 days before surgery, anticoagulant therapy should be discontinued using low doses of vitamin K. Resumption of warfarin depends on the risk of postoperative bleeding.

Patients with hereditary antithrombotic protein C deficiency are at risk of developing skin necrosis when initiating warfarin therapy. In such patients, therapy should be initiated without a loading dose of warfarin, even if the patient is receiving heparin. It is also recommended that warfarin therapy be initiated slowly in patients with hereditary antithrombotic protein S deficiency.

During treatment, it is necessary to refrain from using ethanol (risk of hypoprothrombinemia and bleeding).

Elderly patients should be treated with special caution due to reduced hepatic metabolism and reduced synthesis of blood clotting factors. As a result, excessive warfarin effects may easily occur. It is also necessary to ensure the patient's ability to adhere to strict rules when taking the drug.

Hyperthyroidism, fever and decompensated heart failure may enhance the effect of warfarin. In hypothyroidism, the effect of warfarin may be reduced. In patients with moderate hepatic insufficiency, the effect of warfarin is enhanced. In renal insufficiency or nephrotic syndrome, the level of the free fraction of warfarin in the blood plasma increases, which, depending on concomitant diseases, may lead to an increase or decrease in the effect of warfarin. More frequent monitoring of the INR level is necessary in patients with an increased risk of hypercoagulability, for example, in patients with severe arterial hypertension, liver or kidney disease.

Patients with a mutation in the gene encoding the CYP2C9 enzyme have a longer half-life of warfarin. Such patients require lower doses of the drug, as the risk of bleeding is increased when taking conventional therapeutic doses.

Patients with VKORC1 gene mutations have increased sensitivity to warfarin, therefore, such patients should use a maintenance dose of the drug (see section "Adverse reactions").

The drug contains lactose, so it should not be used in patients with hereditary galactose intolerance, lactase enzyme deficiency, or glucose/galactose malabsorption.

Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients taking warfarin-containing medicinal products. Patients should be informed of the signs and symptoms of these skin reactions. If symptoms occur, the drug should be discontinued immediately, and the patient should be provided with appropriate treatment and closely monitored.

Use during pregnancy or breastfeeding

Pregnancy: Warfarin can cause birth defects and fetal death when used during pregnancy. Women of childbearing potential should use effective contraception during treatment.

Warfarin crosses the placenta rapidly. Use of warfarin during pregnancy may result in fetal warfarin syndrome. Warfarin administration in pregnant women may cause warfarin embryopathy (nasal hypoplasia (saddle nose and other cartilaginous deformities) and chondrodysplasia) if warfarin is administered during the period of organogenesis (weeks 6 to 12), and even thereafter it may cause central nervous system abnormalities. These abnormalities are characterized by striated cartilage on X-rays (particularly in the spine and long bones), small fingers and hands, optic atrophy, microcephaly, oligophrenia and growth retardation, and cataracts, which may lead to complete or partial blindness. Fetal death may also occur.

Warfarin can cause birth defects and fetal hemorrhage, especially late in pregnancy and during labor. Warfarin embryopathy occurs in 4-6% of cases when warfarin is used during pregnancy, and the likelihood of its occurrence increases with daily doses exceeding 5 mg. Therefore, warfarin is contraindicated in the first trimester and during the last four weeks of pregnancy (see section "Contraindications"). The risk of warfarin administration to the fetus should be carefully weighed against the risk to the mother if warfarin is not used. Antithrombotic therapy during pregnancy should be carried out individually under close medical supervision.

Breastfeeding. Warfarin can be used during breastfeeding. Warfarin is excreted in breast milk, but if the drug is taken in therapeutic doses, no adverse reactions in the newborn are expected.

Ability to influence reaction speed when driving vehicles or other mechanisms

Not detected. The drug has no or negligible influence on the ability to drive and use machines.

Method of administration and doses

Target INR (international normalized ratio) level for oral anticoagulant therapy.

Prevention of thromboembolic complications in patients with prosthetic heart valves: INR 2.5-3.5.

Other indications: MNI 2-3.

Adults: Patients of normal weight with a spontaneous INR below 1.2 should be given 10 mg of warfarin for three consecutive days. The dose is then calculated according to Table 1, based on the INR measurement on the 4th day.

In outpatients and in patients with hereditary protein C or S deficiency, the recommended initial dose is 5 mg of warfarin for three consecutive days. The dose is then calculated according to Table 1, based on the INR measurement on day 4.

Patients with hereditary antithrombotic protein C deficiency are at risk of developing skin necrosis when warfarin therapy is initiated. In such patients, warfarin should be initiated without a loading dose, even if the patient is receiving heparin.

In case of skin necrosis, warfarin should be discontinued.

For elderly patients, patients with low body weight, with a spontaneous INR above 1.2, or those with comorbidities or receiving any medications that affect the effectiveness of anticoagulant therapy, the recommended initial dose is 5 mg of warfarin for the next two days. The dose is then calculated according to Table 1, based on the INR measurement on day 3.

Table 1.

INR measurements are performed daily until a stable target level is reached, which is usually established on the 5th-6th day of treatment. INR measurements should then be performed weekly, reaching a 4-week interval. In the case of large deviations in INR levels or in patients with liver disease or diseases affecting the absorption of vitamin K, measurement intervals may be less than 4 weeks. The appointment of new drugs or the withdrawal of those previously used requires additional INR measurements. With long-term therapy, adjustment is made to the weekly dose of warfarin (see Table 1). If the dose requires adjustment, the next INR measurement should be performed 1 or 2 weeks after the adjustment. After this, measurements continue until 4-week intervals are reached.

Children: Anticoagulant therapy in children is carried out under the supervision of pediatricians. Doses are selected according to Table 2.

Table 2.

Elective surgeries: pre-, peri-, and postoperative anticoagulant therapy is performed as indicated below.

Determine the MNI one week before the scheduled surgery.

Stop warfarin 1-5 days before surgery. In case of high risk of thrombosis, the patient should be given low molecular weight heparin subcutaneously for prophylaxis.

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

5 days before surgery if INR > 4;

3 days before surgery if INI = 3 to 4;

2 days before surgery if INI = 2 to 3.

Determine the INR the evening before surgery and administer 0.5-1 mg of vitamin K1 orally or intravenously if the INR is > 1.8.

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

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

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

Children.

Anticoagulant therapy in children is carried out under the supervision of pediatricians.

Overdose

Elevated INR is a major indicator of warfarin overdose, which increases the risk of bleeding. Elevated INR correlates with the half-life of coagulation factor VII. Elevated INR is evident within 24 hours and reaches a maximum value within 36-72 hours after taking the drug.

Clinical manifestations occur several days or weeks after taking the drug and are characterized by nosebleeds, bleeding gums, pallor, hematomas around the joints and buttocks, and blood in the urine and feces. Other symptoms may include back pain, bleeding lips, bleeding mucous membranes, abdominal pain, vomiting, and petechiae. Central paralysis due to bleeding, profuse bleeding, and death may occur later.

Treatment. Symptomatic and supportive therapy. Activated charcoal can be used within 1 hour after taking the drug. In case of serious bleeding, intravenous vitamin K, transfusion of coagulation factor concentrate, fresh frozen plasma or blood are prescribed. Since the half-life of warfarin is 20-60 hours, it is necessary to monitor the patient for a long time.

In acute overdose, gastric lavage is not recommended due to the risk of bleeding. Activated charcoal should be administered to prevent absorption.

When treating an overdose, take the following measures:

in the absence of clinically significant bleeding:

INR level < 5: recommendations: skip the next dose of warfarin and resume therapy at a lower dose when the target INR level is reached;

INR level 5-9: recommendations: skip 1-2 doses of warfarin and resume therapy at a lower dose when the target INR level is reached or skip 1 dose of warfarin and prescribe vitamin K1 2.5 mg orally;

INR level > 9: recommendations: stop warfarin, prescribe vitamin K1 3 to 5 mg orally.

INR level 5-9 and elective surgery. Recommendations: Stop warfarin and administer vitamin K1 2 to 4 mg orally. An additional dose of 1 to 2 mg orally may be given approximately 24 hours before surgery.

Very fast cancellation shown:

severe bleeding or severe overdose (e.g. INR > 20). Recommendations: administer vitamin K 10 mg by slow intravenous infusion. Fresh frozen plasma or prothrombin complex concentrate are also indicated, depending on the urgency of the situation. If necessary, vitamin K1 can be repeated every 12 hours.

Side effects

The most common side effects of warfarin are hemorrhages and bleeding, which can occur from any organ, since the desired therapeutic effect is the anticoagulant effect (e.g., nosebleeds, hemoptysis, hematuria, bleeding gums, bruising, vaginal bleeding, conjunctival hemorrhage, rectal, gastrointestinal bleeding, intracerebral hemorrhage, prolonged and profuse bleeding after surgical interventions and after trauma). Bleeding can be serious and lead to hospitalization, blood transfusions in patients who have been on long-term anticoagulant treatment, and death.

The risk of bleeding during warfarin treatment is influenced by the following factors: older age, high intensity of concomitant anticoagulant therapy, history of stroke and gastrointestinal bleeding, comorbid disorders, atrial fibrillation. Patients with CYP2C9 and VKORC1 gene polymorphisms are at increased risk of excessive anticoagulation and bleeding.

Hemoglobin and INR levels should be carefully monitored.

Adverse reactions are classified according to the following frequency: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000), unknown (cannot be determined from the available data).

From the blood and lymphatic system: very often - bleeding from various organs; often - hypersensitivity to warfarin after prolonged treatment; infrequently - anemia; rarely - eosinophilia.

On the part of the digestive tract: infrequently - vomiting, nausea, diarrhea; very rarely - melena; unknown - abdominal pain (secondary to bleeding) and hematemesis.

On the part of the hepatobiliary system: rarely - increased levels of liver enzymes, jaundice.

Skin and subcutaneous tissue disorders: rarely - eczema, vasculitis, skin necrosis, alopecia, rash, urticaria, itching; unknown - calciphylaxis, erythematous edematous areas of the skin with the development of ecchymosis.

From the genitourinary system: rarely - nephritis, urolithiasis, tubular necrosis; unknown - anticoagulant nephropathy (see section "Special instructions").

From the cardiovascular system: very often - bleeding from various organs; rarely - purple finger syndrome; very rarely - cholesterol embolism.

Immune system disorders: common: hypersensitivity reactions; unknown: Stevens-Johnson syndrome, toxic epidermal necrolysis.

General disorders and local reactions: not known - pyrexia.

The following adverse reactions have been reported in the post-marketing setting with warfarin: decreased hematocrit; fever; tracheal calcification; cholestatic hepatitis, pancreatitis; priapism; allergic reactions; purpura; intracranial hemorrhage, subdural hematoma; hemothorax, rectal hemorrhage, hematemesis, melena. The most common risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension. The likelihood of bleeding increases if the INR is significantly above the target level. If bleeding begins with an INR within the target level, this indicates the presence of other concomitant conditions that should be investigated.

Purple finger syndrome is a rare complication of warfarin. It is typical for male patients with atherosclerotic diseases. It is assumed that warfarin causes hemorrhages of atheromatous plaques, which lead to microembolism. Symmetrical purpuric skin lesions of the fingers and lower surface of the foot occur, which are accompanied by burning pain. Warfarin should be discontinued, and the skin lesions will gradually disappear.

Erythematous edema of the skin, leading to ecchymosis, infarction, etc.