Warfalan^® (Tablets) Instructions for Use

Marketing Authorization Holder

Argumentum, LLC (Russia)

Manufactured By

Agio Pharmaceuticals, Ltd. (India)

ATC Code

B01AA03 (Warfarin)

Active Substance

Warfarin (Rec.INN registered by WHO)

Dosage Form

Warfalan®

Tablets 2.5 mg: 50 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to almost white, round in shape, with a biconvex surface, smooth on both sides.

Excipients: lactose – 51 mg, pregelatinized starch – 30 mg, sodium lauryl sulfate – 2.5 mg, sodium carboxymethyl starch – 10 mg, colloidal silicon dioxide – 2 mg, magnesium stearate – 2 mg.

10 pcs. – blister packs (5) – cardboard boxes.
10 pcs. – blister packs (10) – cardboard boxes.

Clinical-Pharmacological Group

Indirect-acting anticoagulant

Pharmacotherapeutic Group

Indirect-acting anticoagulant agent

Pharmacological Action

An indirect-acting anticoagulant, a coumarin derivative. Inhibits the synthesis of vitamin K-dependent blood clotting factors (II, VII, IX, and X) and anticoagulant proteins C and S in the liver.

Pharmacokinetics

After oral administration, Warfarin is rapidly absorbed from the gastrointestinal tract. It is also absorbed through the skin.

Plasma protein binding is high. It crosses the placenta. It is excreted in breast milk in small amounts.

The active substance Warfarin is a racemic mixture of isomers that are metabolized in the liver. The S-isomer is more active and is metabolized faster than the R-isomer. Metabolism occurs with the participation of cytochrome P450 system isoenzymes – 2C9, 2C19, 2C8, 2C18, 1A2 and 3A4, 2C9.

T_1/2 averages 40 hours, in the terminal phase – approximately 1 week. The clearance of the R-isomer is usually half that of the S-isomer, with similar V_d values, the T_1/2 of the R-isomer (37-89 hours) is greater than that of the S-isomer (21-43 hours).

Radioactive labeling studies have shown that after a single oral dose, about 92% of warfarin is excreted in the urine as metabolites and only a small amount is excreted unchanged.

Indications

Treatment and prevention of thrombosis and embolism of blood vessels: acute venous thrombosis and pulmonary embolism; postoperative thrombosis; recurrent myocardial infarction; as an adjunct in surgical or medical (thrombolytic) treatment of thrombosis, as well as during electrical cardioversion of atrial fibrillation; recurrent venous thrombosis; recurrent pulmonary embolism; prosthetic heart valves and blood vessels (a combination with acetylsalicylic acid is possible); thrombosis of peripheral, coronary, and cerebral arteries; secondary prevention of thrombosis and thromboembolism after myocardial infarction and in atrial fibrillation.

ICD codes

Dosage Regimen

Determine the dosage individually for each patient based on regular monitoring of the International Normalized Ratio (INR) or prothrombin time.

Initiate therapy with a single daily dose of 2 mg to 10 mg. Administer the total daily dose orally once a day, preferably at the same time.

For most indications, maintain the INR within the therapeutic range of 2.0 to 3.0. For patients with mechanical heart valves, target a higher INR range of 2.5 to 3.5.

Monitor INR levels daily at the beginning of treatment until a stable dose is established. Thereafter, perform monitoring at longer intervals, typically every 4 to 6 weeks.

Adjust the dose based on the INR result. For an INR below the target range, increase the dose. For an INR above the target range, decrease the dose. Omit a dose for significantly elevated INR levels and consult a physician.

Consider factors that may potentiate the anticoagulant effect, such as advanced age, liver impairment, congestive heart failure, and concomitant medications. Use a lower initial dose in these patients.

Do not use in children and adolescents under 18 years of age due to unestablished safety and efficacy.

Adverse Reactions

From the blood coagulation system: bleeding, hematomas, anemia; rarely – necrosis of the skin and other tissues due to local thromboses.

Dermatological reactions: dermatitis, bullous rash, alopecia.

From the digestive system: nausea, vomiting, diarrhea, abdominal pain, hepatitis, cholestasis, jaundice, increased activity of liver enzymes.

From the cardiovascular system: purple discoloration of the toes, vasculitis, feeling of cold, chills, paresthesia.

From the CNS: fatigue, lethargy, asthenia, headache, dizziness, taste disturbances.

From the respiratory system: rarely – tracheal or tracheobronchial calcification during long-term therapy (clinical significance not established).

Allergic reactions: skin rash, swelling, fever, urticaria, skin itching.

Contraindications

Diseases and conditions with a high risk of bleeding, pathological changes in the blood. Recent cranial surgery, ophthalmic surgery, surgical interventions for trauma with an extensive surgical field. Tendency to bleed in ulcerative lesions of the gastrointestinal tract, in diseases of the genitourinary system, respiratory system; cerebrovascular hemorrhages; aneurysms; pericarditis, exudative pericarditis, bacterial endocarditis. Severe liver or kidney disease, severe arterial hypertension, acute DIC syndrome.

Threatened abortion, pregnancy.

Inadequate laboratory conditions for patient monitoring, lack of monitoring for elderly patients, alcoholism, psychoses, patient disorganization.

Spinal puncture and other diagnostic procedures with a potential threat of uncontrolled bleeding. Extensive regional anesthesia, conduction block. Malignant arterial hypertension.

Use in Pregnancy and Lactation

Warfarin is contraindicated during pregnancy. It easily crosses the placental barrier and can cause hemorrhagic disorders in the fetus, as well as bone development abnormalities.

Warfarin is excreted in breast milk in an inactive form. No changes in prothrombin time have been detected in breastfed infants whose mothers received Warfarin during breastfeeding. The effect of warfarin in premature newborns has not been studied.

Use in Hepatic Impairment

Contraindicated in severe liver diseases.

In case of liver function impairment, the effects of warfarin may be potentiated due to impaired synthesis of clotting factors and reduced metabolism of warfarin.

Use in Renal Impairment

Contraindicated in severe kidney diseases.

Pediatric Use

The safety and efficacy of warfarin in children and adolescents under 18 years of age have not been established.

Geriatric Use

Special monitoring is required for elderly patients when using warfarin.

Special Precautions

The risk of bleeding increases with intensive and long-term anticoagulant therapy.

During treatment, doses should be controlled and prothrombin time or other coagulation parameters should be periodically determined.

When using warfarin simultaneously with other drugs, the high probability of drug interactions should be taken into account.

Anticoagulant therapy with warfarin may increase the risk of embolism by particles of atherosclerotic plaques.

Warfarin should be used with particular caution and after a thorough analysis of the risk-benefit ratio in the following cases: infectious diseases (including sprue) or dysbacteriosis (due to antibiotic therapy); in case of trauma that may cause internal bleeding; surgical intervention or trauma with an extensive bleeding surface; indwelling catheters; severe and moderate arterial hypertension; known or expected protein C deficiency; polycythemia vera, vasculitis, severe diabetes; moderate and severe allergic reactions, anaphylactic reactions.

In patients with congestive heart failure, more frequent laboratory monitoring and dose adjustment of warfarin are required.

Concomitant use of warfarin with urokinase and streptokinase is not recommended.

Special monitoring is required for elderly patients and persons with mental impairments when using warfarin.

It is believed that renal clearance has little effect on the intensity of warfarin’s action.

In case of liver function impairment, the effects of warfarin may be potentiated due to impaired synthesis of clotting factors and reduced metabolism of warfarin.

The safety and efficacy of warfarin in children and adolescents under 18 years of age have not been established.

Drug Interactions

When used concomitantly with anticoagulants and drugs with antiplatelet activity, the risk of bleeding increases.

When used concomitantly with anticholinergic agents, memory and attention impairments are possible in elderly patients.

When used concomitantly with inhibitors of liver microsomal enzymes, the anticoagulant effect of warfarin is enhanced and the risk of bleeding increases.

When used concomitantly with hypoglycemic sulfonylurea derivatives, their hypoglycemic effect may be enhanced.

The anticoagulant effect of warfarin is reduced by: inducers of liver microsomal enzymes (including barbiturates, phenytoin, carbamazepine), glutethimide, griseofulvin, dicloxacillin, coenzyme Q10, mianserin, paracetamol, retinoids, rifampicin, sucralfate, phenazone, cholestyramine, glutethimide, vitamin K, acitretin, diuretics (spironolactone and chlorthalidone), aminoglutethimide, mercaptopurine, mitotane, cisapride, ginseng preparations, glucagon.

Enhancement of the anticoagulant effect of warfarin and an increased risk of bleeding is possible when used concomitantly with heparin, NSAIDs (including acetylsalicylic acid), pyrazolone derivatives (including phenylbutazone, sulfinpyrazone), tramadol, dextropropoxyphene, a combination of paracetamol and codeine, antiarrhythmic agents (including amiodarone, quinidine, propafenone, moracizine), antimicrobial and antifungal agents (including chloramphenicol, metronidazole, cefamandole, cefmetazole, cefoperazone, cefazolin, erythromycin, azithromycin, roxithromycin, clarithromycin, co-trimoxazole, miconazole, ketoconazole, itraconazole, fluconazole, nalidixic acid, ciprofloxacin, norfloxacin, ofloxacin, aminosalicylic acid, benzylpenicillin, doxycycline, isoniazid, neomycin, tetracyclines, aztreonam), glibenclamide, valproic acid, quinine, proguanil, cyclophosphamide, methotrexate, fluorouracil, with combinations of etoposide and vindesine or carboplatin, ifosfamide with mesna, tamoxifen, flutamide, interferon alfa (in chronic hepatitis C), interferon beta, saquinavir, clofibrate, ciprofibrate, fenofibrate, gemfibrozil, cimetidine, lovastatin, fluvastatin, simvastatin, piracetam, danazol, tramadol.

When used concomitantly with tricyclic antidepressants, disopyramide, felbamate, terbinafine, allopurinol, dipyridamole, chloral hydrate, ranitidine, ascorbic acid, tocopherol, data on drug interaction are ambiguous.

In patients with chronic alcoholism taking disulfiram, enhancement of warfarin effects was observed.

When used concomitantly with cholestyramine, the absorption and bioavailability of warfarin are reduced.

Cases of liver damage have been described when used concomitantly with ticlopidine. The anticoagulant effect of warfarin does not change.

When used concomitantly with phenazone, the plasma concentration of warfarin decreases.

When used concomitantly with phenytoin, an initial increase in anticoagulant activity followed by its decrease is reported.

When used concomitantly with fluoxetine, trazodone, vitamin E, there are reports of enhanced warfarin effect.

When used concomitantly with cyclosporine, a mutual decrease in effects is observed.

When used concomitantly with enoxacin, the clearance of the R-isomer decreases, but not the S-isomer, while the prothrombin time does not increase.

When used concomitantly with ethacrynic acid, enhancement of the diuretic effect and hypokalemia is possible, because as a result of competition for plasma protein binding, the concentration of free (active) ethacrynic acid increases.

With regular alcohol consumption, a decrease in the effects of warfarin is possible, apparently due to the induction of liver enzymes. However, in case of liver damage, the effects of warfarin may be enhanced.

With accidental consumption of large amounts of alcohol, the effect of warfarin may be enhanced.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.