Warfarin orion

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT WARFARIN ORION (WARFARIN ORION)

Composition:

Active substance: 1 tablet contains 3 mg or 5 mg of sodium warfarin;

Excipients: lactose monohydrate, corn starch, gelatin, magnesium stearate, indigo carmine E 132 (tablets of 3 mg) or erythrosine E 127 (tablets of 5 mg).

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tablets of 3 mg: round-shaped tablets with a flat surface, beveled edges and a score line, light blue in color, with possible speckles. The surface of the tablets bears the imprint "ORN 17" on one side;

Tablets of 5 mg: round-shaped tablets with a flat surface, beveled edges and a score line, pink in color, with possible speckles. The surface of the tablets bears the imprint "ORN 18" on one side.

Pharmacotherapeutic group. Antithrombotic agents. Vitamin K antagonists.

ATC code B01A A03.

Pharmacological properties.

Pharmacodynamics.

Warfarin, or 4-hydroxycoumarin, is an anticoagulant that inhibits vitamin K-dependent synthesis of blood clotting factors. Among its isomers, S-warfarin is approximately five times more potent than R-warfarin. Its effectiveness is based on warfarin's ability to block the action of vitamin K on the synthesis of clotting factors II, VII, IX, and X. At therapeutic doses, warfarin reduces the rate of clotting factor synthesis by 30–50% and also decreases their biological activity. The full effect occurs on days 2–7 (during this time, clotting factors already circulating in the blood are cleared from the body).

Genetic variation in the VKORC1 gene, which encodes vitamin K epoxide reductase (warfarin's target), has been shown to influence the required dose due to increased sensitivity to warfarin. Studies have reported approximately a two-fold difference between the highest and lowest average doses among different haplotype groups. Individuals of European descent are relatively evenly distributed among these groups, whereas Asians predominantly carry genes requiring lower doses. Genotyping may be considered in the treatment of particularly sensitive patients for whom avoiding excessive anticoagulant effect is especially important.

Pharmacokinetics.

Absorption. After oral administration, warfarin bioavailability exceeds 90%, and maximum plasma concentration is reached within 1.2 hours. Concomitant food intake slows absorption but does not quantitatively reduce overall absorption, due to the presence of enterohepatic circulation.

Distribution. Warfarin is almost completely bound to plasma albumin, with the free fraction ranging from 0.5% to 3%. The volume of distribution is approximately 0.14 L/kg. Warfarin crosses the placenta but does not enter breast milk.

Metabolism and elimination. Warfarin is metabolized in the liver via CYP2C9 (S-warfarin), CYP1A2, and CYP3A (R-warfarin), being converted into inactive metabolites that are excreted in urine. The elimination half-life of S-warfarin is 18–35 hours, and that of R-warfarin is 20–70 hours.

CYP2C9 genotype: The primary enzyme responsible for the metabolism of S-warfarin is CYP2C9. CYP2C9 exhibits genetic polymorphism. Alleles *1, *2, and *3 are the most common among individuals of European descent. Allele *1 confers "normal" enzyme activity. Alleles *2 and *3 result in reduced enzyme activity, thereby decreasing warfarin clearance (and prolonging its half-life). The most pronounced reduction in clearance occurs in patients with two *3 alleles. This genotype is present in 0.5% of the European population. A meta-analysis showed that the average daily warfarin dose was 20% lower in patients carrying CYP2C9*2 alleles and 34% lower in those with CYP2C9*3 alleles. Patients with two such alleles (homozygous) require a dose reduction of 36% (CYP2C9*2) or 78% (CYP2C9*3). It may take longer to reach a steady state and achieve the therapeutic effect with warfarin. Genotyping may be considered in the treatment of particularly sensitive patients for whom avoiding excessive anticoagulant effect is especially important.

Clinical characteristics.

Indications.

Treatment and prevention of deep vein thrombosis and pulmonary embolism. Secondary prevention of myocardial infarction and prevention of thromboembolic complications (cerebral embolism or systemic embolism) following myocardial infarction. Prevention of thromboembolic complications (cerebral embolism or systemic embolism) in patients with atrial fibrillation, valvular heart disease, or prosthetic heart valves.

Contraindications.

Tendency to bleeding (von Willebrand disease, hemophilia, thrombocytopenia, and platelet function disorders), acute bleeding, to avoid the risk of severe bleeding within 72 hours after major surgical procedures, within 48 hours in the postpartum period, pregnancy, severe renal insufficiency, severe hepatic insufficiency and liver cirrhosis, uncontrolled or untreated arterial hypertension, recent intracranial hemorrhage, conditions predisposing to intracranial hemorrhage (e.g., cerebral artery aneurysm, aortic aneurysm), tendency to fall, lumbar puncture, central nervous system surgery or eye surgery, gastrointestinal or renal bleeding and their complications, diverticulosis or malignant tumors, esophageal varices, infectious endocarditis or exudative pericarditis, dementia, psychoses, alcoholism, and other situations where patient compliance may be inadequate and anticoagulant therapy cannot be safely administered, hypersensitivity to warfarin or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Warfarin has a narrow therapeutic index, and other medicinal products may affect its action. It is essential to consult a physician before starting treatment, when changing dosage, or when discontinuing therapy. The influence of other medicinal products is determined by their pharmacodynamic and/or pharmacokinetic properties.

In the liver, warfarin is metabolized via CYP2C9 (S-warfarin), and CYP1A2 and CYP3A4 (R-warfarin).

Warfarin interacts with many other medicinal products.

When used concomitantly with antithrombotic or hemostatic agents, these may potentiate the pharmacological effect of warfarin, increasing the risk of bleeding. Streptokinase and alteplase are contraindicated in patients taking warfarin.

When using warfarin, avoid concomitant use of thrombin inhibitors, unfractionated heparins and their derivatives, low-molecular-weight heparins, fondaparinux, rivaroxaban, glycoprotein IIb/IIIa receptor antagonists, prostacyclin, serotonin reuptake inhibitors, erlotinib, methylphenidate, and oral contraceptives. If concomitant use is unavoidable, these medicinal products should be administered with caution under intensified clinical and laboratory monitoring.

Warfarin interacts with many other medicinal products.

The absorption and enterohepatic circulation of warfarin may be altered by certain medicinal products, such as cholestyramine. Both induction (antiepileptic or antituberculosis drugs) and inhibition (amiodarone or metronidazole) of warfarin's effect are possible. In some cases, discontinuation of induction or inhibition of hepatic enzymes may also alter the balance of warfarin therapy. Some medicinal products may displace warfarin from plasma protein binding, increasing the free fraction and consequently enhancing its metabolism and elimination, leading to reduced effect (except in patients with liver disease). Pharmacodynamic interaction occurs when co-administered with drugs affecting platelets (acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, tirofiban, direct oral anticoagulants such as dabigatran and apixaban, and most nonsteroidal anti-inflammatory drugs). Primary and secondary hemostasis may predispose patients to severe bleeding. High-dose penicillins have a similar effect. Anabolic steroids, azapropazone, erythromycin, and certain cephalosporins directly reduce vitamin K-dependent synthesis of clotting factors and enhance the effect of warfarin. Vitamin K intake with food reduces the effect of warfarin. Reduced absorption of vitamin K due to, for example, diarrhea, may potentiate the action of warfarin. Patients receiving inadequate dietary intake of vitamin K become dependent on vitamin K2 produced by gut microflora. In such patients, most antibiotics may reduce the ability of gut flora to produce vitamin K2, leading to enhanced warfarin effect. In alcoholism with associated liver damage, the effect of warfarin is potentiated. Quinine, present in tonic water, may also enhance the effect of warfarin. Long-term use of lactulose may potentiate the effect of warfarin.

Protease inhibitors (e.g., ritonavir, lopinavir) may alter warfarin plasma concentrations. Regular monitoring of INR (International Normalized Ratio) is required when co-administered with warfarin.

Antidepressants—norepinephrine reuptake inhibitors (e.g., venlafaxine, duloxetine) and serotonin reuptake inhibitors (e.g., fluoxetine, sertraline)—may increase the risk of bleeding when used concomitantly with warfarin.

Concomitant use with cranberry juice and other cranberry-containing products should be avoided, as they significantly enhance the effect of warfarin.

For temporary pain relief in patients receiving warfarin, paracetamol or opioids are recommended.

Warfarin may potentiate the effect of oral hypoglycemic sulfonylurea agents.

The following medicinal products are known to alter the effect of warfarin

Enhancement of effect: allopurinol, amiodarone, amoxicillin, argatroban, acetylsalicylic acid, azapropazone, azithromycin, vitamin A, bezafibrate, dextropropoxyphene, digoxin, disulfiram, doxycycline, erythromycin, etoposide, vitamin E, fenofibrate, phenylbutazone, fepirazone, fluconazole, fluorouracil, flutamide, fluvastatin, fluvoxamine, gatifloxacin, gemfibrozil, grepafloxacin, ifosfamide, rubella vaccine, alpha- and beta-interferon, isoniazid, itraconazole, capecitabine, carboplatin, cefamandole, cephalexin, cefmetazole, cefmenoxime, cefoperazone, cefuroxime, ketoconazole, quinidine, quinine, clarithromycin, clindamycin, clofibrate, chloral hydrate, codeine, latamoxef, leflunomide, lepirudin, levofloxacin, lovastatin, metolazone, methotrexate, metronidazole, miconazole (including oral gel), moxalactam, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxyphenbutazone, cimetidine, proton pump inhibitors (e.g., omeprazole), proguanil, propafenone, propranolol, rofecoxib, roxithromycin, celecoxib, cimetidine, simvastatin, ciprofloxacin, sulfaphenazole, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfipirazone, sulfophenur, sulindac, (anabolic or androgenic) steroid hormones, cyclophosphamide, tamoxifen, tegafur, tetracycline, tolmetin, tramadol, EGFR inhibitors (e.g., gefitinib), monoclonal antibodies (e.g., trastuzumab), troglitazone, zafirlukast, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen, ketoprofen, naproxen, diclofenac, indomethacin, and piroxicam), (dextro)thyroxine, valproate.

Increased INR levels have been reported when warfarin is used concomitantly with noscapine or chondroitin sulfate.

Increased INR levels have been reported in patients taking glucosamine and oral vitamin K antagonists. Therefore, patients taking oral vitamin K antagonists should be closely monitored before initiating and discontinuing glucosamine therapy.

Concomitant use of melatonin and warfarin may lead to increased anticoagulation; therefore, INR monitoring is recommended. A reduction in warfarin dose may be necessary.

Reduction of effect: azathioprine, (barbiturates), aprepitant, bosentan, vitamin C, dicloxacillin, disopyramide, phenobarbital, griseofulvin, carbamazepine, cloxacillin, chlorthalidone, chlordiazepoxide, mercaptopurine, mesalazine, mitotane, nafcillin, nevirapine, primidone, rifampicin, cyclosporine, spironolactone, trazodone.

Treatment with herbal medicinal products may also enhance the effect of warfarin, e.g., Ginkgo biloba extract, garlic (Allium sativum) extract, dong quai (Angelica sinensis, contains coumarins), papaya (Carica papaya) extract, or danshen (Salvia miltiorrhiza), or reduce its effect, e.g., ginseng (Panax spp.) or St. John’s wort (Hypericum perforatum) extract. This is due to the enzyme-inducing properties of St. John’s wort. Therefore, herbal products containing St. John’s wort are not recommended for concomitant use with warfarin. The effect may persist for up to 2 weeks after discontinuation of herbal products. If a patient is already taking St. John’s wort extract, INR levels should be measured and the extract discontinued. Since INR may increase after stopping St. John’s wort, close monitoring is required. Warfarin dose adjustment may be necessary.

During warfarin therapy, vitamin K intake from food should remain constant. The highest vitamin K content is found in green vegetables and greens such as: tea leaves (but not brewed tea), amaranth greens, avocado, endive, peas, chayote, cabbage, green onion, kiwi fruit, coriander, cucumber peel (but not peeled cucumber), kale, lettuce, turnip, mint leaves, olive oil, broccoli, parsley, spinach, pistachios, red seaweed, onion, Brussels sprouts, rapeseed oil, mustard greens, soybeans, soybean oil, watercress.

Smoking may enhance warfarin elimination; therefore, smokers may require higher warfarin doses. Conversely, smoking cessation may increase warfarin effect. Thus, patients who quit smoking after prolonged use require careful INR monitoring.

Special precautions for use.

If rapid antithrombotic effect is required, treatment should be initiated with heparin administration. Heparin administration should then be continued concurrently with warfarin for 5–7 days until the INR remains within the target range for at least two consecutive days.

During treatment with oral anticoagulants, the most commonly reported adverse reaction is bleeding. Warfarin should be administered with caution in patients at risk of serious bleeding (e.g., when used concomitantly with NSAIDs, after recent ischemic stroke, in bacterial endocarditis, or gastrointestinal bleeding).

The most likely risk factors for bleeding include a high level of anticoagulation (INR > 4.0), age over 65 years, unstable INR, recent gastrointestinal bleeding, uncontrolled arterial hypertension, cerebrovascular disease, severe heart disease, tendency to fall, anemia, malignancy, trauma, renal insufficiency, and concomitant use of other medications. All patients taking warfarin must regularly monitor their INR. Patients at increased risk of bleeding require more frequent INR monitoring, careful dose adjustment to achieve the desired INR, and possibly shorter treatment duration. Patients should be informed about measures to minimize the risk of bleeding and must report any signs or symptoms of bleeding to their physician immediately.

INR monitoring, physician consultation, and dose reduction or discontinuation of the drug are critically important. If INR is elevated, warfarin dosage should be reduced or therapy discontinued. Sometimes continued anticoagulant therapy is necessary. INR should be monitored over 2–3 days to ensure that it has decreased.

Other antiplatelet agents should be used with particular caution due to the increased risk of bleeding.

Strict adherence to the prescribed warfarin dosage is mandatory.

Bleeding may indicate warfarin overdose. Unexpected bleeding during therapeutic dosing should be investigated, and INR must be monitored.

Anticoagulant therapy after ischemic stroke increases the risk of secondary intracerebral hemorrhage. In patients with atrial fibrillation, long-term warfarin therapy is beneficial; however, the risk of early recurrent embolism is low, thus a temporary interruption of treatment after ischemic stroke may be justified. Warfarin therapy should be restarted 2–14 days after ischemic stroke, depending on the size of the infarct and blood pressure. In patients with embolic stroke or uncontrolled hypertension, warfarin therapy should be discontinued for 14 days.

Before surgical procedures, if there is no risk of serious bleeding, surgery may be performed with INR < 2.5. Before surgical procedures associated with a risk of significant bleeding, warfarin should be discontinued 3 days prior to surgery.

If anticoagulant therapy must be continued, e.g., in life-threatening thromboembolism, INR should be reduced to < 2.5 and heparin therapy initiated.

If surgery is required and warfarin cannot be discontinued 3 days prior, reversal of anticoagulation should be achieved using low doses of vitamin K.

Resumption of warfarin therapy depends on the risk of postoperative bleeding.

Warfarin should not be discontinued prior to routine dental procedures such as tooth extraction.

Treatment of patients with peptic ulcer disease should be conducted with particular caution due to the high risk of bleeding. Such patients should be regularly monitored and informed about how to recognize bleeding and what actions to take if bleeding occurs.

Patients with alcoholism or dementia may be unable to adhere to the required warfarin regimen. Heavy alcohol consumption increases the risk of hypoprothrombinemia and bleeding.

Warfarin resistance is very rare. Such patients may require 5 to 20 times the usual warfarin dose to achieve a therapeutic effect. If warfarin appears ineffective, other more likely causes should be investigated: non-compliance, drug or food interactions, or laboratory errors.

Patients with hereditary deficiency of antithrombotic protein C are at risk of developing skin necrosis at the beginning of warfarin therapy. For such patients, treatment should be initiated without a loading dose of warfarin, even if heparin is being administered. Patients with hereditary deficiency of antithrombotic protein S are also advised to start warfarin therapy gradually.

The risk of bleeding and hemorrhagic complications increases when INR rises significantly above the target therapeutic range. If hemorrhagic complications occur while INR is within the target therapeutic range, this usually indicates another underlying condition, and the cause of bleeding should be identified.

To prevent coumarin-induced skin necrosis in patients with congenital deficiency of antithrombotic protein C or S, initial treatment should begin with heparin. The initial warfarin maintenance dose should not exceed 5 mg daily. Heparin therapy should be continued for 5–7 days.

Treatment of elderly patients should be conducted with particular caution. The patient's ability to adhere strictly to the dosing regimen must be ensured. Hepatic metabolism and synthesis of coagulation factors are reduced in elderly patients, increasing the risk of excessive warfarin effect. Treatment should be initiated cautiously. Concomitant medication use must be considered to avoid undesirable interactions.

Many drugs and food products interact with warfarin and affect prothrombin time. The use of any medication, including over-the-counter (OTC) products, warrants intensified INR monitoring. Patients should be advised to inform their physician before starting any medication, including herbal remedies and vitamin supplements.

Many conditions and factors—such as fever, diarrhea, vomiting, hyper-/hypothyroidism, heart failure, malabsorption, and significant changes in dietary vitamin K intake—can affect the efficacy of warfarin therapy.

Initiating or discontinuing other medications or changing doses of concomitant drugs without consulting a physician is not recommended.

Hyperthyroidism, fever, and decompensated heart failure may enhance the effect of warfarin. Hypothyroidism may reduce warfarin's effect. The effect of warfarin is enhanced in patients with moderate liver insufficiency. In renal insufficiency or nephrotic syndrome, the free fraction of warfarin in plasma increases, which may lead to either enhanced or reduced anticoagulant effect depending on concomitant conditions. In all these cases, clinical monitoring and INR assessment are essential.

Factors such as weight loss, acute illness, or smoking cessation may enhance warfarin's effect, possibly requiring dose reduction.

Conversely, weight gain, diarrhea, and vomiting may reduce warfarin's effect, possibly requiring dose increase.

Warfarin elimination is slower in patients with a specific genetic variant of the CYP2C9 enzyme, which metabolizes (S)-warfarin. These patients require only low maintenance doses and are at risk of excessive bleeding if given a high initial dose. Additionally, more time may be needed to reach a new therapeutic level after dose adjustment. Patients with genetic variations in the VKOR enzyme may also require lower doses due to increased sensitivity to warfarin.

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

Anticoagulant-related nephropathy

Acute kidney injury may occur in patients with altered glomerular integrity or a history of kidney disease, possibly related to episodes of excessive anticoagulation and hematuria. Cases have also been reported in patients without prior kidney disease. Close monitoring, including assessment of renal function, is recommended in patients with supratherapeutic international normalized ratio (INR) and hematuria (including microscopic).

The product contains lactose. It is contraindicated in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Warfarin crosses the placenta. Warfarin therapy during pregnancy may cause warfarin embryopathy (nasal hypoplasia and chondrodysplasia) if administered during organogenesis (weeks 6–12), and may even later cause central nervous system developmental abnormalities. Warfarin may cause fetal hemorrhage, especially at the end of pregnancy and during delivery. Warfarin embryopathy, as described, occurs in 4%–6% of cases when warfarin is used during pregnancy, and the risk increases with daily doses exceeding 5 mg. Therefore, warfarin is contraindicated during pregnancy. The risk of warfarin to the fetus must be carefully weighed against the risk to the mother if anticoagulation is not used. Antithrombotic therapy during pregnancy should be individualized and closely supervised by appropriate specialists.

Warfarin does not pass into breast milk; therefore, breastfeeding can be continued during warfarin therapy.

Ability to influence reaction rate when driving or operating machinery.

No effect.

Method of Administration and Dosage.

Target INR (International Normalized Ratio) for oral anticoagulant therapy:

Prevention of thromboembolic complications in patients with heart valve prostheses: INR 2.5–3.5.

Other indications: INR 2.0–3.0.

Adults: Patients with normal body weight and spontaneous INR below 1.2 should be given 10 mg of warfarin for three consecutive days. Then adjust the dose according to the table below, based on INR measurement on day four.

For outpatients and patients with hereditary protein C or S deficiency, the recommended initial dose is 5 mg of warfarin for three consecutive days. Then adjust the dose according to the table below, based on INR measurement on day four.

For elderly patients, patients with low body weight, spontaneous INR above 1.2, or those with concomitant diseases or receiving any drugs affecting the efficacy of anticoagulant therapy, the recommended initial dose is 5 mg of warfarin for two consecutive days. Then adjust the dose according to the table below, based on INR measurement on day three.

Measure INR daily until a stable target level is achieved, which is usually established on day 5–6 of treatment. Then measure INR weekly, progressing to a 4-week interval. In cases of significant INR fluctuations or in patients with liver disease or conditions affecting vitamin K absorption, the measurement intervals may be less than 4 weeks. Starting or discontinuing concomitant medications requires additional INR measurements. During long-term therapy, dosage adjustments are made to achieve a weekly warfarin dose according to the table above. If a dose adjustment is required, the next INR measurement should be performed 1 or 2 weeks after the adjustment. Thereafter, measurements continue until 4-week intervals are achieved.

Planned surgery: pre-, peri-, and postoperative anticoagulant therapy should be conducted as described below.

Determine INR one week before the scheduled surgery.

Discontinue warfarin 1–5 days before surgery. In patients at high risk of thrombosis, subcutaneous administration of low-molecular-weight heparin should be initiated for prophylaxis.

The duration of warfarin interruption depends on the INR level. Discontinue warfarin:

• 5 days before surgery if INR > 4.0;
• 3 days before surgery if INR = 3.0–4.0;
• 2 days before surgery if INR = 2.0–3.0.

Determine INR the evening before surgery and administer 0.5–1.0 mg of vitamin K1 orally or intravenously if INR > 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, along with resumed warfarin therapy.

Resume warfarin therapy on the same day in the evening after minor surgeries, or on the day the patient resumes enteral feeding after major surgeries, using the usual maintenance dose.

Children: anticoagulant therapy in children should be administered under the direction and supervision of pediatricians. Doses should be selected according to the table below.

Hepatic impairment: The effect of warfarin is enhanced in moderate hepatic impairment. The patient's clinical status and INR values should be closely monitored. Warfarin is contraindicated in patients with severe hepatic impairment.

Renal impairment: The plasma free warfarin level may be increased in renal impairment and nephrotic syndrome (depending on other underlying conditions, these findings may lead to increased or decreased effect). The patient's clinical status and INR values should be closely monitored.

Patients with genetic enzyme variations: Significant variation in INR response may be related to genetic factors, particularly genetically reduced activity of the enzyme CYP2C9 and increased sensitivity of the enzyme VKOR (warfarin's pharmacological target).

In patients with CYP2C9*2 or CYP2C9*3 alleles, metabolism of (S)-warfarin is reduced in the CYP2C9 enzyme, and therefore lower initial and maintenance doses may be required.

Children.

Anticoagulant therapy in children should be administered under the prescription and supervision of pediatricians.

Overdose.

In cases of gradual overdose, discontinuation of the drug is usually sufficient.

In acute overdose, gastric emptying is not recommended due to the risk of bleeding. Administer activated charcoal repeatedly to prevent absorption and enterohepatic recirculation of warfarin. When administering activated charcoal, vitamin K, which may be required later, should be given parenterally (intravenously). In case of bleeding, warfarin's effect can be reversed by administration of vitamin K, prothrombin complex concentrate, or fresh frozen plasma. If oral anticoagulants are indicated in the future, vitamin K doses exceeding 10 mg should be avoided, as patients may become resistant to warfarin for up to two weeks.

Measures to be taken in overdose management:

Section "Side Effects"

The frequency of occurrence of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Disorders of the blood and lymphatic system.

Common: hemorrhage.

Uncommon: anemia.

Rare: coumarin necrosis, purple toe syndrome, eosinophilia.

Very rare: vasculitis.

Metabolism and nutrition disorders.

Frequency not known: calciphylaxis.

Vascular disorders.

Frequency not known: cholesterol embolism.

Respiratory, thoracic and mediastinal disorders.

Very rare: tracheal calcification.

Gastrointestinal disorders.

Common: nausea, vomiting, diarrhea, abdominal pain.

Hepatobiliary disorders.

Very rare: reversible increase in liver enzyme levels, cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue disorders.

Very rare: reversible alopecia, rash, eczema, urticaria, skin necrosis.

Renal and urinary disorders.

Very rare: priapism, nephritis, urolithiasis, tubular necrosis.

Frequency not known: anticoagulant nephropathy (see section "Special precautions for use").

General disorders and administration site conditions.

Very rare: allergic reactions (usually rash), pruritus.

In the post-marketing period, the following adverse reactions have been observed: fever, subdural hematoma, hemothorax, epistaxis, gastrointestinal bleeding, rectal bleeding, vomiting blood, pancreatitis, melena, purpura, erythematous skin swelling leading to ecchymosis, infarction and skin necrosis, hematuria, decreased hematocrit.

The most frequently reported adverse reaction (in 1% to 10% of patients) is bleeding, occurring in approximately 8% of patients taking warfarin annually. Moderate bleeding occurs annually in 6%, severe bleeding in 1%, and fatal bleeding in 0.25% of patients. The most common risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension. The risk of bleeding increases if the INR is significantly above the target range. If bleeding occurs while the INR is within the therapeutic range, this indicates the presence of other underlying conditions that need to be investigated.

Coumarin necrosis is a rare (<0.1%) complication of warfarin therapy. Necrosis usually begins with swelling of the skin of the lower limbs or buttocks, which darken, but may also appear in other areas. Later, these lesions become necrotic. Ninety percent of such patients are women. Lesions typically appear between the 3rd and 10th day of treatment, and the etiology is believed to involve deficiency of antithrombotic protein C or S. Congenital deficiency of these proteins may be the cause of complications. For this reason, warfarin therapy should be initiated simultaneously with heparin and at low initial doses. If complications occur, warfarin should be discontinued and heparin continued until lesions heal or scar.

Purple toe syndrome is a rare complication of warfarin therapy. It is typically observed in male patients with atherosclerotic disease. It is believed that warfarin causes hemorrhage from atheromatous plaques, leading to microembolism. Symmetrical purpuric skin lesions of the toes and soles of the feet develop, accompanied by burning pain. Warfarin therapy should be discontinued, and skin lesions usually resolve gradually.

If a patient has a genetic polymorphism of the CYP2C9 and VKOR enzymes, which increases sensitivity to warfarin, the risk of excessive anticoagulant effect is increased. This may increase the risk of hemorrhagic complications. Hemoglobin and INR values should be closely monitored.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Store in a tightly closed bottle. Keep the bottle in the outer carton. Store in a place inaccessible to children.

Packaging. 30 or 100 tablets in a bottle with a moisture-absorbing capsule; 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Orion Corporation.

Manufacturer's address and place of business.

Orionintie 1, 02200 Espoo, Finland / Orionintie 1, 02200 Espoo, Finland.