Warfarin-fs

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT WARFARIN-PS (WARFARIN-PS)

Composition:

Active substance: warfarin sodium clathrate;

One tablet contains warfarin sodium clathrate equivalent to 2.5 mg warfarin sodium or 3 mg warfarin sodium;

Excipients: lactose monohydrate, maize starch, gelatin, indigocarmine (E 132), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

2.5 mg tablets: blue tablets with speckles, flat-surfaced, round-shaped, bevelled tablets with a cross-shaped notch on one side;

3 mg tablets: blue tablets with ‎ speckles, biconvex-surfaced, ‎ round-shaped, with a single line on one side.‎

Pharmacotherapeutic group. Antithrombotic agents. Vitamin K antagonists.

ATC code B01AA03.

Pharmacological properties.

Pharmacodynamics.

Warfarin, or 4-hydroxycoumarin, is an anticoagulant that inhibits vitamin K-dependent synthesis of blood clotting factors. The S-warfarin isomer is approximately five times more potent than R-warfarin. The efficacy of warfarin is based on its 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 eliminated from the body).

Studies have shown that the VKORC1 gene variant, which encodes the vitamin K epoxide reductase complex (the target of warfarin), is associated with increased sensitivity to warfarin.

A difference of approximately two-fold has been reported 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 beneficial when treating particularly sensitive patients, for whom avoiding excessive anticoagulant effect is critically important.

Pharmacokinetics.

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

Distribution. Warfarin is almost completely bound to plasma albumin; the free fraction varies 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). It is converted into inactive metabolites, which are excreted in urine. The elimination half-life of S-warfarin ranges from 18 to 35 hours, and that of R-warfarin from 20 to 70 hours.

Genotype CYP2C9: CYP2C9 is the main enzyme catalyzing the metabolism of S-warfarin and is characterized by 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 confer reduced enzyme activity, resulting in decreased warfarin clearance (and prolonged half-life). The most pronounced reduction in clearance occurs in patients with two *3 alleles. Among individuals of European descent, this genotype occurs in 0.5% of the population. A meta-analysis showed that the mean daily warfarin dose was 20% lower in patients with CYP2C9*2 alleles and 34% lower in patients with CYP2C9*3 alleles. For patients with two such alleles (homozygosity), the dose should be reduced by 36% (CYP2C9*2) or by 78% (CYP2C9*3). It may take longer to reach a steady state and achieve the therapeutic effect of warfarin. Genotyping may be beneficial when treating particularly sensitive patients, for whom avoiding excessive anticoagulant effect is critically important.

Clinical characteristics.

Indications.

For the prevention and treatment of deep vein thrombosis and pulmonary artery embolism. For secondary prevention of myocardial infarction and prevention of thromboembolic complications (cerebral embolism or systemic embolism) following myocardial infarction. For prevention of thromboembolic complications (cerebral embolism or systemic embolism) in patients with atrial fibrillation, heart valve disorders, or prosthetic heart valves.

Contraindications.

Hypersensitivity to warfarin or any of the excipients; tendency to bleeding (hemophilia, von Willebrand disease, thrombocytopenia, or platelet function disorders); active bleeding; to avoid the development of severe bleeding, do not use within 72 hours after major surgical procedures or within 48 hours in the postpartum period; pregnancy; severe renal or hepatic insufficiency and liver cirrhosis; uncontrolled or untreated hypertension; recent intracranial stroke; conditions predisposing to intracranial hemorrhage, such as cerebral artery aneurysm or aortic aneurysm; tendency to fall; lumbar puncture; central nervous system surgery or eye surgery; gastrointestinal or urinary tract bleeding and its complications; diverticulosis; malignant tumors; esophageal varices; infectious endocarditis or pericarditis (including exudative forms); dementia, psychoses, alcoholism, and other situations where patient compliance may be inadequate, making anticoagulant therapy insufficiently safe.

Interaction with other medicinal products and other forms of interaction.

Warfarin has a narrow therapeutic index, and other medicinal products may influence its effect. Consult a physician before initiating treatment, changing dosage, or 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 numerous other medicinal products.

Concomitant use with antithrombotic or hemostatic agents may potentiate the pharmacological effects 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 cautiously with intensified clinical and laboratory monitoring.

The absorption and enterohepatic circulation of warfarin may be altered by certain medicinal products, such as cholestyramine.

Both potentiation (e.g., by antiepileptic or antituberculosis drugs) and inhibition (e.g., by amiodarone or metronidazole) of warfarin's effect are possible. In some cases, discontinuation of enzyme induction or inhibition may also alter the balance of warfarin therapy. Some medicinal products may displace warfarin from plasma protein binding, increasing the free fraction and thereby enhancing metabolism and elimination, leading to reduced effect (except in patients with liver disease). Pharmacodynamic interactions occur when warfarin is taken concomitantly with agents affecting platelets (acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, tirofiban, direct oral anticoagulants such as dabigatran and apixaban, and 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. Dietary intake of vitamin K reduces the effect of warfarin. Reduced absorption of vitamin K due to, for example, diarrhea, may potentiate warfarin's action. Patients receiving inadequate dietary vitamin K depend on vitamin K2 produced by intestinal 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, warfarin's effect is intensified. Quinine, present in tonic drinks, may also enhance warfarin's effect. Long-term use of lactulose may potentiate warfarin's effect.

Protease inhibitors (e.g., ritonavir, lopinavir) may alter warfarin plasma concentrations. When coadministered with warfarin, monitoring of INR (International Normalized Ratio) is required.

Antidepressants—norepinephrine reuptake inhibitors (e.g., venlafaxine, duloxetine) and serotonin reuptake inhibitors (e.g., fluoxetine, sertraline)—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 warfarin's effect.

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

Warfarin may potentiate the effect of oral hypoglycemic agents—sulfonylurea derivatives.

Medicinal products that alter the effect of warfarin

Enhancement of warfarin effect occurs with concomitant use of the following agents: 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-interferons, isoniazid, itraconazole, capecitabine, carboxyuridine, 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), paracetamol (effect evident after 1–2 weeks of continuous use), proguanil, propafenone, propranolol, rofecoxib, roxithromycin, celecoxib, cimetidine, simvastatin, ciprofloxacin, sulfaphenazole, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfinpyrazone, sulfophenur, sulindac, steroid hormones (anabolic or androgenic), cyclophosphamide, tamoxifen, tegafur, tetracycline, tolmetin, tramadol, EGFR inhibitors (e.g., gefitinib), monoclonal antibodies (e.g., trastuzumab), troglitazone, zafirlukast, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, ketoprofen, naproxen, diclofenac, indomethacin, piroxicam), (dextro)thyroxine, valproate.

Increased INR levels have been reported with concomitant use of 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; thus, INR monitoring is recommended. Warfarin dose reduction may be necessary.

Reduction of warfarin effect occurs with concomitant use of the following agents: azathioprine, barbiturates, aprepitant, bosentan, vitamin C, dicloxacillin, disopyramide, phenobarbital, griseofulvin, carbamazepine, cloxacillin, chlorthalidone, chlordiazepoxide, mercaptopurine, mesalazine, mitotane, nafcillin, nevirapine, primidone, rifampicin, cyclosporine, spironolactone, trazodone.

Herbal products may also enhance the effect of warfarin, e.g.: Ginkgo biloba extract, garlic (Allium sativum) extract, Chinese angelica (Angelica sinensis, contains coumarins), papaya (Carica papaya) extract, Salvia miltiorrhiza extract—or reduce it, e.g.: ginseng (Panax spp.), St. John’s wort (Hypericum perforatum) extract. St. John’s wort induces enzymes involved in drug metabolism. 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 should be measured and the extract discontinued. Since INR may increase after stopping St. John’s wort, this parameter should be closely monitored. Warfarin dose adjustment may be required.

During warfarin therapy, vitamin K intake from food should remain constant. The highest vitamin K content is found in green vegetables and leafy greens such as: tea leaves (but not brewed tea), sorrel leaves, 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 leaves, soybeans, soybean oil, watercress.

Smoking may enhance warfarin elimination, so smokers may require higher warfarin doses. Conversely, smoking cessation may increase warfarin's effect. Therefore, patients who quit smoking after prolonged use require careful INR monitoring.

Special precautions for use.

Calciphylaxis is a rare syndrome of vascular wall calcification with skin necrosis, associated with a high number of fatal cases. 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 receiving warfarin without renal impairment. If calciphylaxis is diagnosed, appropriate treatment should be initiated and discontinuation of warfarin should be considered.

Anticoagulant-related nephropathy

Acute kidney injury may occur in patients with glomerular integrity impairment or with a history of kidney disease, possibly related to episodes of excessive anticoagulation and hematuria. Several cases of kidney injury have been reported in patients without prior kidney disease. Patients with supratherapeutic International Normalized Ratio (INR) and hematuria (including microscopic) should be closely monitored, including assessment of kidney function.

Strict adherence to the prescribed dose of Warfarin-FS is mandatory. Patients suffering from alcoholism, as well as patients with dementia, may be unable to comply with the required warfarin dosing regimen. Consumption of large amounts of alcohol increases the risk of hypoprothrombinemia and bleeding.

Resistance to warfarin is very rare. In such cases, the patient may require 5 to 20 times the usual warfarin dose to achieve a therapeutic effect. If warfarin treatment is insufficiently effective, more likely causes include non-adherence to medication, interactions with other drugs or food products, or laboratory errors.

If a rapid antithrombotic effect is required, treatment should be initiated with heparin. 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 oral anticoagulant therapy, bleeding is the most commonly occurring adverse reaction. Warfarin should be administered with caution in patients at risk of serious bleeding (e.g., when used concomitantly with NSAIDs, after recent ischemic stroke, bacterial endocarditis, or gastrointestinal bleeding).

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

Determining the INR, consulting a physician, and reducing the dose or discontinuing the drug are extremely important. If the INR is elevated, the warfarin dose should be reduced or therapy discontinued. Sometimes reversal therapy with anticoagulants is necessary. The INR should be rechecked within 2–3 days to confirm its reduction. Other antiplatelet drugs should be used with particular caution due to the increased risk of bleeding.

Bleeding may indicate warfarin overdose. In case of unexpected bleeding during therapeutic dosing, investigation is required and INR should be monitored.

Anticoagulant therapy after a recent ischemic stroke increases the risk of secondary intracerebral hemorrhage. A temporary interruption of treatment after ischemic stroke is justified, especially in patients on long-term warfarin therapy for atrial fibrillation, considering 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 therapy should be discontinued for 14 days.

Surgical procedures are possible when INR < 2.5, provided there is no risk of serious bleeding. Before surgical procedures associated with a risk of serious 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 requires special caution due to the high risk of bleeding. Such patients should be regularly examined and informed about how to recognize bleeding and what actions to take if bleeding occurs.

In patients with hereditary deficiency of antithrombotic protein C, there is a risk of skin necrosis at the beginning of warfarin therapy.

In such patients, treatment should be initiated without a loading dose of warfarin, even if the patient is receiving heparin. Patients with hereditary deficiency of antithrombotic protein S are also advised to initiate warfarin therapy slowly.

The likelihood of bleeding and hemorrhagic complications increases if the INR rises significantly above the target therapeutic level. If hemorrhagic complications occur when the INR is within the target therapeutic range, this is usually indicative of another condition, and the cause of bleeding should be identified.

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

Treatment of elderly patients should be conducted with special caution. The patient's ability to adhere strictly to dosing instructions must be ensured. Hepatic metabolism, as well as coagulation factor synthesis, is reduced in elderly individuals, which may easily result in an excessive warfarin effect.

Many drugs and food products interact with warfarin and affect prothrombin time. The use of any medication, including over-the-counter drugs, necessitates intensified INR monitoring. The patient must inform the 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 very low or very high vitamin K intake due to dietary changes—can affect the efficacy of warfarin therapy.

It is not recommended to start or discontinue other medications or to change the doses of concomitant drugs without consulting a physician.

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 hepatic insufficiency. In renal insufficiency or nephrotic syndrome, the free fraction of warfarin in plasma increases, which, depending on concomitant diseases, may lead to either enhanced or reduced warfarin effect. In all these cases, monitoring of the patient's clinical status and INR levels is required.

Factors such as weight loss, acute illness, or cessation of smoking may enhance the effect of warfarin and require a reduction in warfarin dose. Conversely, weight gain, diarrhea, and vomiting may reduce warfarin's effect and require dose increases.

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

The product contains lactose; therefore, Warfarin-FS is contraindicated in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy.

When used during pregnancy, warfarin may cause congenital defects and fetal death. Women of reproductive age should use effective contraceptive methods during treatment.

Warfarin crosses the placenta. Warfarin therapy in pregnant women may cause warfarin embryopathy (nasal hypoplasia and chondrodysplasia) if warfarin is taken during organogenesis (weeks 6–12), and even thereafter it may cause developmental disorders of the central nervous system. These disorders are characterized by stippled cartilage on X-rays (particularly in the spine and long tubular bones), small fingers and hands, optic nerve atrophy, microcephaly, oligophrenia and growth retardation, cataracts, which may lead to complete or partial blindness. Fetal death may also occur.

Warfarin may cause fetal hemorrhage, especially toward 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 likelihood increases with daily doses exceeding 5 mg. Therefore, warfarin is contraindicated during pregnancy. The risk of warfarin use to the fetus must be carefully weighed against the risk to the mother if warfarin is not used.

Antithrombotic therapy during pregnancy should be individualized and closely supervised by appropriate specialists.

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

Ability to affect reaction speed when driving or operating machinery.

The drug does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

Target INR level for oral anticoagulant therapy

Prevention of thromboembolic complications in patients with prosthetic heart valves: 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 the dose should be adjusted according to the table below based on the INR measured 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 the dose should be adjusted according to the table below based on the INR measured on day four.

In patients with hereditary deficiency of antithrombotic protein C, initiation of warfarin therapy carries a risk of skin necrosis. In such patients, treatment should be started without a loading dose of warfarin, even if the patient is receiving heparin.

If skin necrosis develops, warfarin should be discontinued.

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

Table 1

Measure INR daily until a stable target level is achieved, which is usually established by day 5–6 of treatment. Thereafter, 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 monitoring intervals may be less than 4 weeks. The initiation or discontinuation of concomitant medications requires additional INR measurements. During long-term therapy, dose adjustments are made based on the 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. After this, monitoring continues until 4-week intervals are achieved.

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

Determine INR one week before the scheduled surgery.

Discontinue warfarin 1–5 days before surgery. In patients at high risk of thrombosis, administer low molecular weight heparin subcutaneously 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 is between 3.0 and 4.0;
• 2 days before surgery if INR is between 2.0 and 3.0.

Measure INR on 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 resumption of warfarin therapy.

Resume warfarin at the usual maintenance dose on the same day in the evening after minor surgery, or during the day when the patient begins enteral feeding after major surgery.

Children: anticoagulant therapy in children must be conducted under the supervision of a pediatrician. Doses should be adjusted according to the Table 2 below.

Table 2

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

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

Patients with genetic enzyme variations: Significant deviations in INR response may be associated with genetic factors, particularly reduced activity of the CYP2C9 enzyme and increased sensitivity of the VKOR enzyme (the pharmacological target of warfarin).

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

Children. The decision to prescribe the drug to children should be made by a pediatrician, under whose supervision the treatment is conducted.

Overdose.

Elevated INR is the primary indicator of warfarin overdose, leading to an increased risk of bleeding. The degree of INR elevation correlates with the half-life of blood coagulation factor VII. Increased INR levels appear within 24 hours and reach maximum levels within 36–72 hours after drug administration.

Clinical manifestations occur several days or weeks after drug intake and are characterized by nosebleeds, gum bleeding, pallor, hematomas around joints and buttocks, and presence of blood in urine and stool. Other symptoms may include back pain, lip bleeding, mucosal bleeding, abdominal pain, vomiting, and petechiae. Later complications may include central paralysis due to hemorrhage, severe bleeding, and fatal outcome.

Treatment. In cases of gradual overdose, discontinuation of therapy is sufficient. In acute overdose, gastric lavage is not recommended due to the risk of bleeding; administration of activated charcoal is advisable to prevent absorption and enterohepatic recirculation of warfarin.

If activated charcoal is administered, vitamin K, which may be required later, should be given parenterally (intravenously). In case of bleeding, the effect of warfarin 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:

Adverse Reactions

Adverse effects are classified by frequency of occurrence into the following categories: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1,000), very rare (<1/10,000), and not known frequency.

Blood and lymphatic system disorders:
Common — bleeding; uncommon — anemia; rare — coumarin necrosis, purple toe syndrome, eosinophilia; very rare — vasculitis.

Metabolism and nutrition disorders:
Frequency not known — calciphylaxis.

Gastrointestinal disorders:
Common — vomiting, abdominal pain, nausea, diarrhea.

Respiratory, thoracic and mediastinal disorders:
Very rare — tracheal calcification.

Hepatobiliary disorders:
Very rare — increased liver enzymes, cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue disorders:
Very rare — skin necrosis, reversible alopecia, rash, urticaria.

Renal and urinary disorders:
Very rare — nephritis, urolithiasis, tubular necrosis, priapism; frequency not known — anticoagulant nephropathy (see section "Special precautions for use").

Vascular disorders:
Frequency not known — cholesterol embolism.

General disorders and administration site conditions:
Very rare — allergic reactions (usually rash), pruritus.

In the post-marketing period, the following adverse reactions have been reported with warfarin use: decreased hematocrit; fever, pancreatitis, purpura, subdural hematoma, hemothorax, epistaxis, gastrointestinal bleeding, rectal bleeding, hematemesis, melena, erythematous skin swelling leading to ecchymosis, skin infarction and necrosis, hematuria. The most common manifestations of warfarin adverse reactions are hemorrhages and bleeding, including: epistaxis, hemoptysis, hematuria, gingival bleeding, bruising, vaginal bleeding, conjunctival hemorrhage, gastrointestinal bleeding, prolonged and profuse bleeding after surgery or trauma. Bleeding may be severe and can lead to fatal outcomes, hospitalization, or blood transfusions in patients undergoing long-term anticoagulant therapy.

The following factors influence the risk of bleeding during warfarin therapy: advanced age, high intensity of concomitant anticoagulant therapy, history of stroke or gastrointestinal bleeding, comorbid conditions, atrial fibrillation, and patients with CYP2C9 gene polymorphism.

The most significant risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension. The likelihood of bleeding increases when the INR is significantly above the target range. If bleeding occurs while the INR is within the therapeutic range, this suggests the presence of other underlying conditions that require investigation.

Acute kidney injury. Acute kidney injury may occur after oral anticoagulant administration. Cases of acute kidney injury have been reported following warfarin use, particularly when hematuria and/or supratherapeutic INR values were observed, and kidney biopsy revealed numerous red blood cell casts in renal tubules.

Coumarin necrosis — a rare complication of warfarin therapy. Necrosis typically begins as swelling and darkening of the skin on the lower extremities or buttocks, but may also appear in other areas. Later, these lesions become necrotic. Approximately 90% of such cases occur in women. Lesions typically appear between the 3rd and 10th day of treatment. The etiology is thought to involve deficiency of antithrombotic protein C or S. Congenital deficiency of these proteins may predispose to such complications. Therefore, warfarin therapy should be initiated concomitantly with heparin at low initial doses. If this complication occurs, warfarin should be discontinued and heparin continued until lesions heal or scar.

Purple toe syndrome — a rare complication of warfarin therapy. It typically occurs in male patients with atherosclerotic disease. It is believed that warfarin causes hemorrhage from atheromatous plaques, leading to microembolism.

Symmetrical purpuric skin lesions on toes and soles may also occur, accompanied by burning pain. Warfarin should be discontinued; skin lesions usually resolve gradually.

Patients with genetic polymorphisms of CYP2C9 and VKOR enzymes, which increase sensitivity to warfarin, are at higher risk of excessive anticoagulant effect and, consequently, hemorrhagic complications. In such patients, hemoglobin levels and INR should be closely monitored.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children, in the original packaging, at a temperature not exceeding 25 °C.

Packaging. 10 tablets per blister; 1, 3, or 10 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. LLC "Pharma Start".

Manufacturer's address and place of business.
8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse reactions or questions regarding the safety and efficacy of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333.