Warfarex®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VAREX® (VARFAREX)

Composition:

Active substance: warfarin;

1 tablet contains 3 mg or 5 mg of sodium warfarin (as sodium warfarin clathrate);

Excipients: lactose monohydrate; microcrystalline cellulose; crospovidone; magnesium stearate; indigo carmine (E 132) (for 3 mg tablets) and Ponceau 4R (E 124) (for 5 mg tablets).

Pharmaceutical form. Tablets.

Main physico-chemical properties:

3 mg tablets – round, flat-cylindrical, blue tablets with darker specks, with a bevel and a score line on one side;

5 mg tablets – round, flat-cylindrical, pink tablets with darker specks, with a bevel and a quadrisected score line on one side.

Pharmacotherapeutic group. Antithrombotic agents. Vitamin K antagonists.

ATC code B01A A03.

Pharmacological properties.

Pharmacodynamics.

Warfarin belongs to the group of anticoagulants – coumarin derivatives. Drugs of this group inhibit the formation in the liver of the reduced form of vitamin K, which is necessary for the final stage of synthesis of several factors involved in the regulation of blood coagulation: prothrombin (factor II), proconvertin (factor VII), antihemophilic globulin B (factor IX), Stuart-Prower factor (factor X), as well as proteins C and S, resulting in prolonged blood clotting time. Warfarin does not exert a direct effect on already formed coagulation factors in systemic circulation; therefore, 8–12 hours elapse from the moment of drug intake to the onset of effect. Maximum effectiveness of the drug occurs on days 2–7 (during this period, coagulation factors already circulating in the blood are eliminated from the body). After a single dose, the duration of action lasts for 5 days. Among warfarin isomers, S-warfarin is approximately 5 times more potent than R-warfarin.

Pharmacokinetics.

The bioavailability of orally administered warfarin is at least 90%, and the maximum plasma concentration is achieved within 1.2 hours. Concomitant food intake slows absorption but does not reduce its extent due to the presence of enterohepatic circulation. Enterohepatic recirculation occurs. Warfarin is highly bound to plasma proteins, with the unbound fraction ranging from 0.5% to 3%. The volume of distribution is approximately 0.14 L/kg. Warfarin crosses the placental barrier and is excreted in milk in trace amounts. Warfarin is metabolized in the liver. By the action of enzymes CYP2C9 (S-warfarin), CYP1A2, and CYP3A (R-warfarin), it is converted into inactive metabolites, which are excreted in the urine. The elimination half-life of S-warfarin is 18–35 hours, and that of R-warfarin is 20–70 hours.

Clinical characteristics.

Indications.

• Prophylaxis and treatment of deep vein thrombosis and pulmonary artery embolism;
• secondary prevention of myocardial infarction and prevention of thromboembolic complications (stroke or systemic embolism) following myocardial infarction;
• prevention of thromboembolic complications in patients with atrial fibrillation, heart valve disease, or prosthetic heart valves;
• prevention of transient ischemic attacks and stroke.

Contraindications.

• Hypersensitivity to warfarin and/or any excipient of the medicinal product;
• clinically evident bleeding;
• tendency to bleeding (von Willebrand disease, hemophilia, thrombocytopenia, and platelet function disorders);
• to avoid the risk of severe bleeding, within 72 hours after major surgical procedures, within 48 hours in the postpartum period;
• severe renal and hepatic insufficiency or hepatic cirrhosis;
• untreated or uncontrolled arterial hypertension;
• recent intracranial hemorrhage; conditions predisposing to intracranial hemorrhage, such as cerebral artery aneurysm, aortic aneurysm;
• tendency to syncope (falls);
• surgery on the central nervous system or eyes;
• gastrointestinal or renal bleeding and their complications;
• diverticulosis;
• malignant tumors;
• esophageal varices;
• infectious endocarditis, pericarditis, or exudative pericarditis;
• conditions where therapy cannot be conducted safely enough (e.g., dementia, psychoses, alcoholism);
• lumbar puncture.

Interaction with other medicinal products and other types of interactions.

Warfarin interacts with many other drugs.

Fibrinolytics such as streptokinase and alteplase are contraindicated in patients receiving warfarin.

Concomitant use of warfarin should be avoided or used with caution under careful clinical and laboratory monitoring when administered with thrombin inhibitors, unfractionated heparins and their derivatives, low-molecular-weight heparins, fondaparinux, rivaroxaban, glycoprotein IIb/IIIa receptor antagonists, prostacyclin, and serotonin reuptake inhibitors.

Some drugs, for example cholestyramine, may affect the absorption or enterohepatic recirculation of warfarin. The metabolism of warfarin in the liver may be increased (e.g., antiepileptic and antituberculosis agents) or decreased (e.g., amiodarone or metronidazole). The free fraction of warfarin in blood may increase, and in the absence of hepatic insufficiency, metabolism and excretion of warfarin are enhanced, leading to reduced effect. Drugs affecting platelets and primary hemostasis (acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, and most nonsteroidal anti-inflammatory drugs, but not coxibs) may cause pharmacodynamic interaction and increase the patient's susceptibility to severe bleeding. High-dose penicillins have a similar effect on primary hemostasis.

Anabolic steroids, azapropazone, erythromycin, and other cephalosporins reduce vitamin K-dependent synthesis of clotting factors and potentiate the effect of warfarin. Excessive intake of vitamin K in food reduces the effect of warfarin. Impaired absorption of vitamin K, for example in cases of diarrhea, may enhance the effect of warfarin. Patients whose diet is low in vitamin K depend on vitamin K2 produced by intestinal bacteria. In such patients, various antibiotics may reduce the synthesis of vitamin K2, leading to an increased effect of warfarin.

Excessive alcohol consumption in the presence of hepatic insufficiency potentiates the effect of warfarin. Quinine, contained in tonic water, may also enhance the effect of warfarin.

For pain relief during warfarin therapy, paracetamol or opioids are recommended.

Warfarin may enhance the effect of oral antidiabetic agents that are sulfonylurea derivatives.

During warfarin therapy, the use of erlotinib, methylphenidate, and oral contraceptives should be avoided.

Anticoagulant effect of warfarin is enhanced by: acetylsalicylic acid, allopurinol, amiodarone, amoxicillin, argatroban, azapropazone, azithromycin, bezafibrate, bicalutamide, cephalexin, cefamandole, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, celecoxib, cyclophosphamide, cimetidine, ciprofloxacin, danazol, dextropropoxyphene, (dextro)thyroxine, diflunisal, digoxin, disulfiram, diclofenac (risk of bleeding is increased, including with intravenous diclofenac), doxycycline, entacapone, erythromycin, esomeprazole, etodolac, etoposide, etoricoxib, phenylbutazone, fenofibrate, feprazone, fluconazole, fluorouracil, flurbiprofen, flutamide, fluvastatin, fluvoxamine, gatifloxacin, gemfibrozil, grepafloxacin, typhoid vaccine, quinidine, quinine, chloramphenicol, chloral hydrate, ibuprofen, ifosfamide, indomethacin, alpha- and beta-interferons, itraconazole, isoniazid, carboxyuridine, ketoconazole, ketoprofen, ketorolac, clarithromycin, clofibrate, codeine, latamoxef, leflunomide, lepirudin, levofloxacin, lovastatin, mefenamic acid, meloxicam, methylphenidate, metolazone, methotrexate, metronidazole, miconazole (including oral cavity gel), mirtazapine, moxifloxacin, nalidixic acid, naproxen, neomycin, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol (effect appears after 1–2 weeks of continuous use), parecoxib, piroxicam, proguanil, propafenone, propranolol, ritonavir, rofecoxib, roxithromycin, rosuvastatin, selective serotonin reuptake inhibitors, simvastatin, sulfaphenazole, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfinpyrazone, sulfophenuron, sulindac, (anabolic and androgenic) steroid hormones, tamoxifen, tegafur, tetracycline, thioglycolic acid, tolmetin, toremifene, tramadol, trastuzumab, troglitazone, valdecoxib, valproic acid, venlafaxine, vitamin A, vitamin E, zafirlukast. Lactulose may potentiate the effect of warfarin with prolonged use.

Anticoagulant effect of warfarin is reduced by: acitretin, aminoglutethimide, azathioprine, barbiturates, cyclosporine, dicloxacillin, disopyramide, phenobarbital, phenytoin, griseofulvin, chlordiazepoxide, chlorthalidone, carbamazepine, cloxacillin, mercaptopurine, mesalazine, mitotane, nafcillin, primidone, rifampicin, spironolactone, sucralfate, trazodone, vitamin C.

Anticoagulant effect of warfarin may be enhanced or reduced by: atazanavir, estrogens, fosamprenavir, cholestyramine, corticosteroids (high doses of corticosteroids increase anticoagulant effect), nevirapine, progesterone, tricyclic antidepressants, sulfonilurea agents (coumarins may enhance their hypoglycemic effect).

Herbal products may either enhance the effect of warfarin, for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis, contains coumarins), papaya (Carica papaya, mechanism unknown), and salvia (Salvia miltiorrhiza, slows elimination of warfarin), or reduce its effect, for example, ginseng (Panax ginseng). The effect of warfarin may be reduced when used concomitantly with St. John's wort (Hypericum perforatum). This interaction is due to enzymes contained in St. John's wort that degrade warfarin. Therefore, St. John's wort-containing products must not be combined with warfarin. The weakening effect may persist for 2 weeks after discontinuation of St. John's wort. If a patient is using St. John's wort-containing products, INR must be determined and their use discontinued. INR must be carefully monitored, as INR may increase after stopping St. John's wort. Warfarin dose adjustment may be required.

During warfarin therapy, vitamin K intake from food should be as constant as possible. Foods and plants rich in vitamin K (e.g., green vegetables) reduce the effect of warfarin.

Concomitant use of warfarin with cranberry juice should be avoided, as the anticoagulant effect is enhanced.

After application of chamomile lotion, bruising on the face may occur during warfarin therapy.

Since the effect of warfarin may be altered by a significant number of medicinal products, additional laboratory monitoring of the patient's coagulation system is required with any change in concomitant therapy.

Special precautions.

A mandatory condition for Warfarin® therapy is strict adherence to the prescribed dose of the drug.

To achieve a rapid antithrombotic effect, treatment should be initiated with heparin. Heparin should then be combined with warfarin for 5–7 days before and 2 days after reaching the target International Normalized Ratio (INR) level.

Particular caution and careful monitoring of INR levels are required when prescribing to patients at risk of serious bleeding (e.g., when used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), after recent ischemic stroke, 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 impairment, and concomitant use of other medications. All patients taking warfarin should have their INR measured regularly. 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 and should immediately report any signs or symptoms of bleeding to their physician.

Measuring INR, consulting a physician, and reducing or discontinuing the drug are extremely important. If INR is elevated, reduce the dose or discontinue warfarin therapy. Sometimes anticoagulant therapy must be continued. INR should be measured over 2–3 days to ensure that it has decreased.

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

Anticoagulation after ischemic stroke increases the risk of secondary intracranial hemorrhage. In patients with atrial fibrillation, long-term warfarin therapy is indicated, but since the risk of early recurrent embolism is low, 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 arterial 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 continuation of anticoagulant therapy is necessary (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 examined and informed about how to recognize bleeding and what measures should be taken 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 a rare phenomenon. Resistant patients may require 5–20 times higher warfarin doses to achieve a therapeutic effect. In cases of poor patient response to warfarin, other more likely causes should be ruled out: noncompliance, drug or food interactions, and laboratory errors.

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

Patients with a mutation in the gene encoding the CYP2C9 enzyme have a prolonged warfarin half-life. These patients require lower doses of the drug, as standard therapeutic doses increase the risk of bleeding.

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.

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. Patients with supratherapeutic International Normalized Ratio (INR) and hematuria (including microscopic) should be closely monitored, including assessment of renal function.

Elderly patients: treatment should be initiated with particular caution. Patient compliance and ability to follow strict medical instructions must be ensured. Hepatic metabolism of warfarin and synthesis of clotting factors are slowed in elderly patients, which may easily lead to an excessive warfarin effect.

Concomitant use of other drugs: potential harmful interactions should be considered.

Hyperthyroidism, fever, and uncompensated heart failure may enhance the effect of warfarin. Hypothyroidism may reduce warfarin's effect. Hyperthyroidism may reduce warfarin's effect.

Hepatic impairment: moderate liver dysfunction enhances the effect of warfarin.

Renal impairment and nephrotic syndrome increase the concentration of free warfarin fraction in plasma, which may either increase or decrease warfarin's effect depending on the patient's comorbidities.

In all cases, careful monitoring of the patient's clinical status and INR values is required.

Bleeding is the main adverse effect of warfarin therapy; therefore, a continuous assessment of the balance between bleeding risk and potential benefit is necessary.

Warfarin® 3 mg and 5 mg tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Warfarin® 5 mg tablets contain the dye Ponceau 4R (E 124), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy due to its teratogenic effects, risk of fetal bleeding, and potential fetal death. 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 individually managed under close supervision by appropriate specialists.

Warfarin passes into breast milk in small amounts and has almost no effect on blood coagulation in the infant; therefore, the drug may be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Warfarin® 3 mg and 5 mg tablets do not affect the ability to drive or operate machinery.

Method of Administration and Dosage

Warfarex® should be taken at the same time each day.

The dosage of Warfarex® is determined individually by a physician based on the patient's prothrombin time expressed as the International Normalized Ratio (INR).

Target INR range 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 an initial INR below 1.2 should receive 10 mg/day of warfarin (2 tablets of 5 mg) for 3 days. Subsequent doses, based on the INR level on day 4, are shown in Table 1.

The recommended initial dose for outpatients and patients with congenital protein C or S deficiency is 5 mg/day of warfarin (*) for 3 days. Subsequent doses, based on the INR level on day 4, are shown in Table 1.

Elderly patients, patients with reduced body weight.

The recommended initial dose is 5 mg/day of warfarin (*) for 2 days. Subsequent doses, based on the INR level on day 3, are shown in Table 1.

Patients with an initial INR above 1.2, patients with diseases or who are taking drugs affecting anticoagulant therapy efficacy.

The recommended initial dose is 5 mg/day of warfarin (*) for 2 days. Subsequent doses, based on the INR level on day 3, are shown in Table 1.

Table 1

The duration of treatment is determined individually (from 6 weeks to lifelong use). In case of developing tolerance to the effect of Warfarex®, the dose may be increased 2–10 times. Strict adherence to the physician's recommendations regarding drug use and careful laboratory monitoring of blood coagulation parameters are absolutely essential.

INR should be measured daily until a stable target INR level is achieved, which usually occurs within 5–6 days after starting treatment. Then, the interval between INR measurements may be gradually extended by one week until reaching a 4-week interval. The interval between measurements should be less than 4 weeks if INR results vary significantly or in patients with liver disease or any other condition affecting vitamin K absorption. Starting a new medication or discontinuing a previous one requires more frequent INR monitoring. During long-term treatment, adjust the weekly warfarin dose (the total amount of warfarin the patient receives over a week) according to Table 1. If a dose adjustment is needed, the next INR measurement should be performed after 1 or 2 weeks. Afterwards, the interval may again be gradually extended up to 4 weeks.

If a 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 2 consecutive days.

Planned surgeries. Perioperative anticoagulant therapy should be managed as follows:

Measure INR one week before the scheduled surgery.

Discontinue warfarin 1–5 days before surgery. If the patient has a high risk of thrombosis, administer prophylactic low-molecular-weight heparin subcutaneously. The timing of warfarin discontinuation depends on the INR value. Discontinue warfarin:

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

Measure INR on the evening before surgery. If INR >1.8, administer 0.5–1.0 mg of vitamin K1 orally or intravenously. On the day of surgery, consider infusion of unfractionated heparin or prophylactic administration of low-molecular-weight heparin.

For 5–7 days after surgery, continue subcutaneous administration of low-molecular-weight heparin concurrently with resumption of warfarin therapy.

After minor surgeries, resume warfarin at the usual maintenance dose on the evening of the surgical day; after major surgeries – on the day when enteral feeding is resumed.

Children. Anticoagulant therapy in children should be conducted under the prescription and supervision of pediatricians. The dose can be selected according to Table 2.

Table 2

Overdose.

Symptoms: bleeding, hemorrhage.

Treatment: in mild cases of gradual overdose, reducing the dose or discontinuing warfarin therapy until the INR returns to the target range is usually sufficient. Gastric lavage is not recommended in acute overdose due to the risk of bleeding. Repeated administration of activated charcoal is advised to prevent absorption and enterohepatic recirculation of warfarin. When administering activated charcoal parenterally (IV), vitamin K should be given. If bleeding occurs, warfarin should be discontinued and vitamin K administered intravenously (5–10 mg), along with coagulation factor concentrate or fresh frozen plasma. If further anticoagulation is required, vitamin K doses exceeding 10 mg should be avoided. Otherwise, the patient may become resistant to warfarin therapy for up to 2 weeks.

Recommendations for the management of overdose are presented in Table 3.

Table 3

Adverse reactions.

The following undesirable adverse reactions have been reported:

Nervous system disorders: subdural hematoma, fever.

Blood and lymphatic system disorders: hemorrhage, coumarin necrosis, purple discoloration of the toes, purpura, eosinophilia, vasculitis, anemia, decreased hematocrit.

Respiratory, thoracic and mediastinal disorders: tracheal calcification, hemothorax.

Gastrointestinal disorders: nausea, vomiting, vomiting of blood, diarrhea, abdominal pain, gastrointestinal bleeding, rectal bleeding, melena.

Hepatobiliary disorders: reversible increase in liver enzyme activity, cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue disorders: reversible alopecia, rash, urticaria, pruritus, eczema, erythematous skin swelling leading to ecchymosis, infarction and skin necrosis.

Renal and urinary disorders: hematuria, priapism, anticoagulant nephropathy (see section "Special precautions").

General disorders: allergic reactions (usually manifested as skin rashes), nephritis, urolithiasis, tubular necrosis.

The most common adverse effects of warfarin are bleeding and hemorrhages, including: minor nosebleeds and bleeding gums, subcutaneous hemorrhages; rarely – intracranial and gastrointestinal bleeding. The most significant risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension. The risk of bleeding increases if the INR is significantly above the target level. If bleeding occurs while the INR is within the desired therapeutic range, an underlying disease or condition usually exists and requires investigation. Even minor bleeding should be reported to a physician.

Coumarin necrosis is a rare complication of warfarin therapy. Necrosis typically begins as skin swelling with darkening of the lower extremities or buttocks, and may also occur in other areas. Subsequently, the lesions become necrotic. In 90% of cases, necrosis occurs in women; lesions typically appear between the 3rd and 10th day of treatment. The etiology is associated with protein C or S deficiency. Congenital deficiency of these proteins may predispose to complications; therefore, warfarin therapy should be initiated concomitantly with heparin and using low initial doses. If this complication occurs, warfarin should be discontinued and heparin therapy continued until lesion healing and scar formation.

Purple discoloration of the toes is an even rarer complication of warfarin therapy. Affected patients are usually men with atherosclerosis. Warfarin causes hemorrhage into atheromatous plaques, leading to microembolism. Symmetrical purpuric skin lesions of the toes and soles develop, accompanied by burning pain. These symptoms gradually resolve upon discontinuation of warfarin. Rarely, the following adverse effects have been reported: systemic cholesterol microembolization, abdominal pain, pancreatitis, taste disturbances, lethargy, weakness, headache, dizziness, paresthesia, pruritus, edema, fever, leukopenia.

Adverse effects in children are similar to those in adults. Moderate bleeding is a significant adverse effect. Skin rash, alopecia, and skin necrosis occur rarely. Osteopenia may develop with long-term use.

Shelf life. 5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in a light-protected place at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

30 or 100 tablets in a container; 1 container in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

JSC "Grindeks".

Manufacturer's address and place of business.

53 Krustpils Street, Riga, LV-1057, Latvia.

Tel./fax: +371 67083205 / +371 67083505.

E-mail: [email protected]