Warfarin (Tablets) Instructions for Use

ATC Code

B01AA03 (Warfarin)

Active Substance

Warfarin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Indirect-acting anticoagulant

Pharmacotherapeutic Group

Antithrombotic agent, vitamin K antagonists

Pharmacological Action

An indirect-acting anticoagulant, a coumarin derivative. It 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, which 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.

The average T_1/2 is 40 hours, and in the terminal phase it is 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 and vascular valves (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 dose individually based on the patient’s INR (International Normalized Ratio) response. Never use a fixed dose for all patients.

Initiate therapy with a dose of 2-10 mg orally once daily. For most patients, a starting dose of 5 mg is typical. Adjust the dose based on INR results.

Obtain an INR at least prior to initiation, then monitor daily after the initial dose until a stable therapeutic range is achieved. Perform subsequent monitoring every 1 to 4 weeks for stable patients.

Maintain the INR within the target therapeutic range specific to the clinical indication. Common ranges are 2.0-3.0 for most conditions (e.g., atrial fibrillation, venous thrombosis) and 2.5-3.5 for mechanical heart valves.

Take the total daily dose at the same time each day, typically in the evening. If a dose is missed, take it as soon as remembered on the same day. Do not take a double dose the next day to make up for a missed dose.

Make dosage adjustments in small increments, typically by 5-20% of the total weekly dose. Recheck the INR frequently after any dosage change, concomitant medication change, or change in clinical status.

Consider factors that may alter warfarin response, including dietary vitamin K intake, concomitant medications, acute illness, and hepatic function.

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 disorders.

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 operative field. Tendency to bleed in ulcerative lesions of the gastrointestinal tract, in diseases of the genitourinary system, respiratory system; cerebrovascular hemorrhage; 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 were found 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 disease.

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 disease.

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 disorders may occur 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 agents of the 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, the 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.

Data on drug interactions with tricyclic antidepressants, disopyramide, felbamate, terbinafine, allopurinol, dipyridamole, chloral hydrate, ranitidine, ascorbic acid, tocopherol are ambiguous.

In patients with chronic alcoholism taking disulfiram, an 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 with concomitant use 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 has been reported.

There are reports of enhanced warfarin effect with concomitant use with fluoxetine, trazodone, vitamin E.

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, and the prothrombin time does not increase.

When used concomitantly with ethacrynic acid, an 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, an enhancement of the warfarin effect is possible.

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.