Warfarin Orion tablets 5 mg No. 100

Instructions for Warfarin Orion tablets 5 mg No. 100

Composition

active ingredient: 1 tablet contains warfarin sodium 3 mg or 5 mg;

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

Dosage form

Pills.

Main physicochemical properties:

3 mg tablets: round tablets with a flat surface with beveled edges and a score, light blue in color, with possible inclusions. The surface of the tablets contains an imprint of "ORN 17" on one side;

5 mg tablets: round, flat tablets with beveled edges and a score, pink in color, with possible inclusions. The surface of the tablets contains an imprint of "ORN 18" on one side.

Pharmacotherapeutic group

Antithrombotic agents. Vitamin K antagonists.

ATX code B01A A03.

Pharmacological properties

Pharmacodynamics.

Warfarin or 4-hydroxycoumarin is an anticoagulant that blocks the vitamin K-dependent synthesis of blood clotting factors. Of its isomers, S-warfarin is approximately 5 times more potent than R-warfarin. Its effectiveness is based on the ability of warfarin to block the action of vitamin K on the synthesis of blood clotting factors II, VII, IX and X. In therapeutic doses, warfarin reduces the rate of synthesis of clotting factors by 30-50% and also reduces their biological activity. The full effect occurs on the 2nd-7th day (during this time, clotting factors already circulating in the blood are excreted from the body).

Genetic variation in the VKORC1 gene, which encodes vitamin K epoxide reductase (a warfarin target), has been shown to influence the required dose by increasing sensitivity to warfarin. Studies have reported an approximately two-fold difference between the highest and lowest mean doses for different haplotype groups. Caucasians are relatively evenly distributed across the groups, while Asians predominantly carry genes that require dose reduction. Genotyping may be considered in the management of particularly sensitive patients for whom it is particularly important to avoid excessive anticoagulant effects.

Pharmacokinetics.

Absorption: After oral administration, the bioavailability of warfarin is greater than 90% and peak plasma concentrations are reached after 1.2 hours. Concomitant food intake slows down absorption but does not reduce the extent of absorption due to the presence of enterohepatic circulation.

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

Metabolism and Elimination: Warfarin is metabolized in the liver by CYP2C9 (S-warfarin), CYP1A2, and CYP3A (R-warfarin) to inactive metabolites that are excreted in the urine. The half-life of S-warfarin is 18-35 hours and that of R-warfarin is 20-70 hours.

CYP2C9 genotype: The main metabolic catalyst for S-(warfarin) is the CYP2C9 enzyme. CYP2C9 represents a genetic polymorphism. The *1, *2 and *3 alleles are most common in Caucasians. The *1 allele provides “normal” enzyme activity. The *2 and *3 alleles provide reduced enzyme activity and thus reduce clearance (and increase half-life) of warfarin. The most pronounced reduction in clearance is achieved in patients with two *3 alleles. Among Caucasians, this genotype is present in 0.5% of the population. A meta-analysis showed that the average daily dose of warfarin was 20% lower in patients with CYP2C9*2 alleles and 34% lower in patients with CYP2C9*3 alleles. Patients with two such genes (homozygosity) require a 36% (CYP2C9*2) or 78% (CYP2C9*3) dose reduction. It may take longer to achieve steady state and therapeutic effect for warfarin. Genotyping may be considered in the treatment of particularly sensitive patients for whom it is particularly important to avoid excessive anticoagulant effect.

Indication

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) after myocardial infarction. Prevention of thromboembolic complications (cerebral embolism or systemic embolism) in patients with atrial fibrillation, heart valve disease or prosthetic heart valves.

Contraindication

Bleeding tendency (von Willebrand's disease, hemophilia, thrombocytopenia and platelet dysfunction), acute bleeding, to avoid the risk of severe bleeding within 72 hours after major surgery, within 48 hours in the postpartum period, pregnancy, severe renal failure, severe hepatic failure and cirrhosis, untreated or uncontrolled arterial hypertension, recent intracranial hemorrhage, medical conditions predisposing to intracranial hemorrhage, such as cerebral aneurysm, aortic aneurysm, tendency to fall, lumbar puncture, central nervous system or eye surgery, gastrointestinal or renal bleeding and their complications, diverticulosis or malignant tumors, esophageal varices, infective endocarditis or exudative pericarditis, dementia, psychoses, alcoholism and other situations where compliance is compromised may be insufficient and anticoagulant therapy cannot be carried out safely enough, hypersensitivity to warfarin or to any of the excipients.

Interaction with other medicinal products and other types of interactions

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

Warfarin interacts with many other medications.

When used concomitantly with antithrombotic or hemostatic agents, the latter may enhance the pharmacological effect of warfarin, 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.

Warfarin interacts with many other medications.

Absorption and enterohepatic circulation of warfarin may be altered by certain drugs, such as cholestyramine. Both induction (antiepileptic or antituberculosis drugs) and inhibition (amiodarone or metronidazole) of the effect of warfarin are possible. In some cases, cessation of induction or inhibition of hepatic enzymes may also alter the balance of warfarin therapy. Some drugs may displace warfarin from plasma protein binding, which increases the free fraction and, as a result, the metabolism and excretion of warfarin are enhanced, leading to a decrease in effect (except in patients with liver disease). Pharmacodynamic interactions are observed with concomitant administration with drugs that affect platelets (acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole and most nonsteroidal anti-inflammatory drugs). Primary and secondary hemostasis may predispose the patient to severe bleeding. Penicillins in large doses have the same effect. Anabolic steroids, azapropazone, erythromycin and some cephalosporins directly reduce the level of vitamin K-dependent synthesis of coagulation factors and enhance the effect of warfarin. Taking vitamin K with food reduces the effect of warfarin. Reduced absorption of vitamin K, caused, for example, by diarrhea, can potentiate the effect of warfarin. Patients who receive inadequate amounts of food containing vitamin K are dependent on vitamin K2 produced by intestinal microflora. In such patients, most antibiotics can reduce the ability of intestinal microflora to produce vitamin K2, which leads to an increase in the effect of warfarin. In alcoholism with concomitant liver damage, the effect of warfarin is potentiated. Quinine, which is contained in Tonic water, can also enhance the effect of warfarin. Lactulose may potentiate the effect of warfarin with long-term use.

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

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

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

Enhancement of the effect: allopurinol, amiodarone, amoxicillin, argatroban, acetylsalicylic acid, azapropazone, azithromycin, vitamin A, bezafibrate, dextropropoxyphene, digoxin, disulfiram, doxycycline, erythromycin, etoposide, vitamin E, fenofibrate, phenylbutazone, feprazone, fluconazole, fluorouracil, flutamide, fluvastatin, fluvoxamine, gatifloxacin, gemfibrozil, grepafloxacin, ifosfamide, influenza vaccine, alpha and beta interferon, isoniazid, itraconazole, capecitabine, carboxyuridine, cefamandole, cephalexin, cefmetazole, cefmenoxime, cefperazone, cefuroxime, ketoconazole, quinidine, quinine, clarithromycin, clindamycin, clofibrate, chloral hydrate, codeine, latamoxef, leflunomide, lepirudin, levofloxacin, lovastatin, metolazone, methotrexate, metronidazole, miconazole (also oral gel), moxalatam, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxyphenbutazone, omeprazole, paracetamol (the effect is evident after 1-2 weeks of continuous administration), proguanil, propafenone, propranolol, rofecoxib, roxithromycin, celecoxib, cimetidine, simvastatin, ciprofloxacin, sulfafenazole, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfinpyrazone, sulfofenur, sulindac (anabolic or androgenic) steroid hormones, cyclophosphamide, tamoxifen, tegafur, tetracycline, tolmentin, tramadol, trastuzumab, troglitazone, zafirlukast, non-steroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen, ketoprofen, naproxen, diclofenac, indomethacin and piroxicam), (dextro)thyroxine, valproate.

Increased INR (International Normalized Ratio) levels have been reported with concomitant use with Nosparin or glucosamine (with or without chondroitin sulfate).

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

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

Herbal treatment may also increase the effect of warfarin, e.g. ginkgo biloba extract, garlic extract (Allium sativum), dong quai (Angelica sinensis, containing coumarins), papaya extract (Carica papaya) or danshen (Salvia miltiorrhiza), or decrease it, e.g. ginseng (Panax spp.) or St. John's wort (Hypericum perforatum) extract. This is due to the ability of St. John's wort to induce drug-metabolizing enzymes. Therefore, herbal preparations containing St. John's wort are not recommended to be taken concomitantly with warfarin. The effect may persist for 2 weeks after discontinuation of the herbal preparation. If the patient is already taking St. John's wort extract, the INR level should be measured and the St. John's wort extract should be discontinued. Since the INR may increase when St. John's wort extract is discontinued, it should be carefully monitored. The dose of warfarin may need to be adjusted.

During warfarin therapy, the level of vitamin K intake with food should remain unchanged. The highest levels of vitamin K are found in green vegetables and herbs, such as: tea leaves (but not brewed tea), amaranth greens, avocado, endive, peas, chayote, collard greens, green onions, kiwi fruit, coriander, cucumber skin (but not cucumber without skin), kale, lettuce, turnips, mint leaves, olive oil, broccoli, parsley, spinach, pistachios, red seaweed, onions, Brussels sprouts, turnip oil, mustard greens, soybeans, soybean oil, watercress.

Smoking may increase the elimination of warfarin, so patients who smoke may require an increase in the dose of warfarin. On the other hand, smoking cessation may increase the effect of warfarin. Therefore, a patient who quits smoking after a long-term smoking period should have their INR levels monitored closely.

Application features

If a rapid antithrombotic effect is required, it is recommended to start treatment with heparin. Then continue heparin with concomitant warfarin for 5-7 days until the INR is maintained at the target level for at least two days.

Bleeding is the most commonly reported adverse reaction with oral anticoagulants. Warfarin should be used with caution in patients at risk of serious bleeding (e.g., concomitant use of NSAIDs, recent ischemic stroke, bacterial endocarditis, gastrointestinal bleeding).

It is extremely important to measure the INR, consult a doctor and reduce the dose or discontinue the drug. If the INR is high, the dose should be reduced or warfarin therapy should be discontinued. Sometimes it is necessary to continue anticoagulant therapy. The INR should be measured for 2-3 days to make sure that it has decreased.

Other antiplatelet drugs should be used with extreme caution due to an increased risk of bleeding.

A mandatory condition of warfarin therapy is strict adherence to the prescribed dose of the drug.

The occurrence of bleeding may indicate an overdose of warfarin. Unexpected bleeding at therapeutic doses should be investigated and the INR should be monitored.

Anticoagulation after ischemic stroke increases the risk of secondary cerebral hemorrhage. In patients with atrial fibrillation, long-term warfarin therapy is beneficial, but the risk of early re-embolism is low and therefore a break in treatment after ischemic stroke is justified. 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 or uncontrolled hypertension, warfarin treatment should be stopped for 14 days.

Before surgery, if there is no risk of serious bleeding, surgery can be performed with an INR < 2.5. Before surgery, if there is a risk of serious bleeding, warfarin should be discontinued 3 days before surgery.

If continued anticoagulant therapy is necessary, for example, in 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, anticoagulation should be discontinued with low doses of vitamin K.

Resumption of warfarin therapy depends on the risk of post-operative bleeding.

Warfarin should not be stopped before routine dental procedures, such as tooth extraction.

Patients with peptic ulcer disease should be treated with particular caution due to the high risk of bleeding. Such patients should be monitored regularly and informed about how to recognise bleeding and, if bleeding occurs, what action to take.

Patients with alcoholism and dementia may be unable to adhere to the required warfarin regimen. In the case of heavy alcohol consumption, the risk of hypothrombinemia and bleeding increases.

Warfarin resistance is very rare. Such patients require 5 to 20 standard doses of warfarin to achieve a therapeutic effect. If warfarin is not effective, other more likely causes should be identified: failure to take the drug, interactions with other drugs or foods, and laboratory errors.

Patients with hereditary antithrombotic protein C deficiency are at risk of 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. In patients with hereditary antithrombotic protein S deficiency, it is also recommended that warfarin therapy be initiated 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 at the target therapeutic level, this is usually a sign of another condition, and the cause of the bleeding should be determined.

To prevent coumarin necrosis, patients with congenital antithrombotic protein C or S deficiency should be initially treated with heparin. The subsequent initial loading dose of warfarin should not exceed 5 mg/day. Heparin should be continued for 5-7 days.

Elderly patients should be treated with special caution. It is necessary to ensure the patient's ability to adhere to strict rules when taking the drug. Hepatic metabolism, as well as the synthesis of clotting factors, is reduced in the elderly. As a result, an excessive effect of warfarin can easily occur. Treatment should be initiated with caution. Concomitant medication should be taken into account to avoid undesirable interactions.

Many drugs and foods interact with warfarin and affect prothrombin time. Taking any drug, including OTC drugs, is a reason for increased monitoring of INR levels. Patients should be warned about the need to inform their doctor before starting any medication, including herbal medicines 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 effectiveness of warfarin therapy.

Hyperthyroidism, fever and uncompensated 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. In all these cases, the patient's clinical condition and the level of INR should be monitored.

The influence of factors such as weight loss, acute illness, and smoking cessation can enhance the effect of warfarin, so a dose reduction may be necessary.

Weight gain, diarrhea, and vomiting, on the other hand, reduce the effect of warfarin, so an increase in dose may be necessary.

Warfarin is eliminated more slowly in patients with a certain genetic variation in the CYP2C9 enzyme, which metabolizes (S)-warfarin. Such patients require only a low maintenance dose and are at risk of excessive bleeding if they receive a high initial dose. In addition, it takes longer to reach a new therapeutic level after dose adjustments. Patients with a genetic variation in the VKOR enzyme may also require lower doses because of increased sensitivity to warfarin.

The drug contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/galactose malabsorption should not take this drug.

Use during pregnancy or breastfeeding

Warfarin crosses the placenta. Warfarin therapy in pregnant women can cause warfarin embryopathy (nasal hypoplasia and chondrodysplasia) if warfarin is administered during the period of organogenesis (6 to 12 weeks), and even after that it can cause disorders in the development of the central nervous system. Warfarin can cause fetal hemorrhage, especially in late pregnancy and during labor. Warfarin embryopathy, as described, occurs in 4% to 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 during pregnancy. 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 the close supervision of appropriate specialists.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

Does not affect.

Method of administration and doses

Target INR (International Normalization Index) 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: For patients of normal weight with a spontaneous INR below 1.2, administer 10 mg of warfarin for three consecutive days. Then calculate the dose according to the table below, based on the INR measurement on the fourth day.

In outpatient treatment 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 should then be calculated according to the table below, based on the INR measurement on the fourth day.

For elderly patients, patients with low body weight, with a spontaneous INR above 1.2, or those who have concomitant diseases or are receiving any drugs that affect the effectiveness of anticoagulant therapy, the recommended initial dose is 5 mg of warfarin for the next two days. The dose should then be calculated according to the table below, based on the INR measurement on the third day.

INR measurements should be 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 that affect the absorption of vitamin K, measurement intervals may be less than 4 weeks. The appointment of new or withdrawal of previously taken drugs requires additional INR measurements. With long-term therapy, adjustments are made to the weekly dose of warfarin according to the table above. 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.

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. If the patient is at high risk of thrombosis, low molecular weight heparin should be administered subcutaneously for prophylaxis.

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

5 days before surgery if INI > 4.0;

3 days before surgery, if INI = 3.0 to 4.0;

2 days before surgery if INI = 2.0 to 3.0.

Determine the INR the evening before surgery and administer 0.5-1.0 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 resumed oral 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 should be carried out as prescribed and under the supervision of pediatricians. Doses are 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 insufficiency: Plasma levels of free warfarin may be increased in renal insufficiency and nephrotic syndrome (depending on other underlying conditions, these results in increased or decreased effect). The patient's clinical status and INR values should be closely monitored.

Patients with a genetic enzyme abnormality: a significant deviation in the MNI response may be associated with genetic factors, in particular, a genetic decrease in the activity of the CYP2C9 enzyme and increased sensitivity to the VKOR enzyme (the pharmacological target of warfarin).

Patients with the CYP2C9*2 or CYP2C9*3 alleles in the CYP2C9 enzyme have reduced metabolism of (S)-warfarin and may therefore require lower initial and maintenance doses.

Children.

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

Overdose

In cases of gradual overdose, it is usually sufficient to stop taking the drug.

In acute overdose, gastric emptying is not recommended due to the risk of bleeding. Activated charcoal should be administered again to prevent absorption and enterohepatic circulation of warfarin. If activated charcoal is administered, vitamin K, which may be required later, should be administered parenterally (intravenously). In the event of bleeding, the effect of warfarin can be reversed by the administration of vitamin K, clotting factor concentrate, or fresh frozen plasma. If oral anticoagulants are indicated in the future, large doses of vitamin K exceeding 10 mg should be avoided, as patients become resistant to warfarin within two weeks.

In the treatment of overdose, take the following measures:

Side effects

The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency unknown (cannot be estimated from the available data).

Disorders of the hematopoietic and lymphatic systems.

Common: haemorrhage.

Uncommon: anemia.

Rare: coumarin necrosis, purple finger syndrome, eosinophilia.

Very rare: vasculitis.

Metabolism and eating disorders.

Frequency unknown: calciphylaxis.

Disorders of the vascular system.

Frequency unknown: cholesterol embolism.

Respiratory system disorders, thoracic and mediastinal disorders.

Very rare: tracheal calcification.

Digestive tract disorders.

Common: nausea, vomiting, diarrhea, abdominal pain.

Hepatobiliary system disorders.

Very rare: reversible elevation of liver enzymes, cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue disorders.

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

Disorders of the reproductive and urinary systems.

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

General disorders and administration site reactions.

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

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

The most commonly reported adverse reaction (1% to 10%) is bleeding, which occurs in about 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 likelihood of bleeding increases if the INR is significantly above the target level. If bleeding occurs at an INR within the target level, this indicates the presence of other underlying conditions that should be investigated.

Coumarin necrosis is a rare (<0.1%) complication of warfarin therapy. The necrosis usually begins with swelling of the skin of the lower extremities or buttocks that has darkened, but may also occur elsewhere. Later, such lesions become necrotic. 90% of such patients are women. The lesions are observed from the 3rd to the 10th day of administration and the etiology suggests a deficiency of antithrombotic protein C or S. Congenital deficiency of these proteins can cause complications. For this reason, warfarin should be started simultaneously with heparin administration and in small initial doses. If a complication occurs, warfarin should be discontinued and heparin administration should be continued until the lesions heal or scar.

Purple finger syndrome is a rare complication of warfarin. It occurs in male patients with atherosclerotic disease. Warfarin is thought to cause hemorrhages in atheromatous plaques, leading to microembolism. Symmetrical purpuric skin lesions occur on the fingers and soles of the feet, and these lesions are accompanied by burning pain. Warfarin should be discontinued, and the skin lesions usually resolve gradually.

If the patient has a genetic modification of the polymorphic CYP2C9 and VKOR enzymes that increases sensitivity to warfarin, the risk of excessive anticoagulant effect of warfarin increases. This may increase the risk of hemorrhagic complications. Hemoglobin and INR values should be carefully monitored.

Expiration date

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. Keep out of the reach of children.

Packaging

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

Vacation category

According to the recipe.

Producer

Orion Corporation.

Location of the manufacturer and its business address.

Orionintie 1, 02200 Espoo, Finland.