Warfarin Nycomed (Tablets) Instructions for Use

Marketing Authorization Holder

Takeda Pharma A/S (Denmark)

Manufactured By

Takeda Pharma Sp. z o.o. (Poland)

ATC Code

B01AA03 (Warfarin)

Active Substance

Warfarin (Rec.INN registered by WHO)

Dosage Form

Warfarin Nycomed

Tablets 2.5 mg: 50 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are light blue, round, biconvex, with a cross-shaped score.

Excipients: lactose – 50 mg, corn starch – 34.6 mg, calcium hydrogen phosphate dihydrate – 32.2 mg, indigo carmine – 6.4 mcg, povidone 30 – 1.0 mg, magnesium stearate – 600 mcg.

50 pcs. – plastic bottles.
100 pcs. – plastic bottles.

Clinical-Pharmacological Group

Indirect-acting anticoagulant

Pharmacotherapeutic Group

Indirect-acting anticoagulant agent

Pharmacological Action

An indirect-acting anticoagulant. It blocks the synthesis of vitamin K-dependent blood clotting factors in the liver, namely II, VII, IX, and X. The concentration of these components in the blood decreases, and the blood clotting process slows down.

The onset of the anticoagulant effect is observed 36-72 hours after starting the drug, with the maximum effect developing on the 5th-7th day from the start of use. After discontinuation of the drug, the activity of vitamin K-dependent blood clotting factors is restored within 4-5 days.

Pharmacokinetics

Absorption and Distribution

The drug is rapidly absorbed from the gastrointestinal tract. Plasma protein binding is 97-99%.

Metabolism

It is metabolized in the liver. Warfarin is a racemic mixture, with the R- and S-isomers being metabolized in the liver via different pathways. Each isomer is converted into 2 main metabolites. The primary catalyst for the metabolism of the S-enantiomer of warfarin is the enzyme CYP2C9, while for the R-enantiomer of warfarin, it is CYP1A2 and CYP3A4. The levorotatory isomer of warfarin (S-Warfarin) has 2-5 times greater anticoagulant activity than the dextrorotatory isomer (R-enantiomer), but the T_1/2 of the latter is longer. Patients with polymorphism of the CYP2C9 enzyme, including the CYP2C9*2 and CYP2C9*3 alleles, may have increased sensitivity to warfarin and an increased risk of bleeding.

Excretion

Warfarin is eliminated from the body as inactive metabolites with bile, which are reabsorbed in the gastrointestinal tract and excreted in the urine. T_1/2 ranges from 20 to 60 hours. For the R-enantiomer, T_1/2 ranges from 37 to 89 hours, and for the S-enantiomer, from 21 to 43 hours.

Indications

• Treatment and prevention of thrombosis and embolism of blood vessels: acute and recurrent venous thrombosis, pulmonary embolism;
• Secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction;
• Prevention of thromboembolic complications in patients with atrial fibrillation, heart valve lesions, or with prosthetic heart valves;
• Treatment and prevention of transient ischemic attacks and strokes, prevention of postoperative thrombosis.

ICD codes

Dosage Regimen

Warfarin is prescribed once a day at the same time. The duration of treatment is determined by the doctor in accordance with the indications for use.

Before starting therapy, the INR is determined. Subsequently, laboratory control is performed regularly every 4-8 weeks.

The duration of treatment depends on the patient’s clinical condition; treatment can be discontinued immediately.

The initial dose for patients who have not previously used Warfarin is 5 mg/day (2 tablets) for the first 4 days. On the 5th day of treatment, the INR is determined, and, according to this indicator, a maintenance dose of the drug is prescribed. Usually, the maintenance dose of the drug is 2.5-7.5 mg/day (1-3 tablets).

For patients who have previously used Warfarin, the recommended starting dose is double the known maintenance dose of the drug and is prescribed for the first 2 days. Then, treatment is continued with the known maintenance dose. On the 5th day of treatment, INR control is performed and the dose is adjusted according to this indicator.

It is recommended to maintain an INR value from 2 to 3 for the prevention and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve diseases, and bioprosthetic heart valve replacement. Higher INR values from 2.5 to 3.5 are recommended for mechanical heart valve replacement and complicated acute myocardial infarction.

Data on the use of warfarin in children are limited. The initial dose is usually 0.2 mg/kg/day with normal liver function and 0.1 mg/kg/day with impaired liver function. The maintenance dose is selected according to the INR values. The recommended INR levels are the same as for adults. The decision to prescribe warfarin in children should be made by an experienced specialist. Treatment should be carried out under the supervision of an experienced specialist – a pediatrician. Doses are selected according to the table below.

There are no specific recommendations for the use of warfarin in elderly patients. However, elderly patients should be carefully monitored as they have a higher risk of developing side effects.

Impaired liver function increases sensitivity to warfarin because the liver produces blood clotting factors and also metabolizes Warfarin. In this group of patients, careful monitoring of INR values is necessary.

In patients with impaired renal function, a reduction in the warfarin dose and careful monitoring are required.

Planned (elective) surgical interventions: pre-, peri-, and postoperative anticoagulant therapy is carried out as indicated below (if urgent discontinuation of the oral anticoagulant is necessary, see the “Overdose” section). Determine INR one week before the scheduled surgery. Discontinue warfarin 1-5 days before surgery. In case of high risk of thrombosis, the patient is administered low molecular weight heparin subcutaneously for prophylaxis. The duration of the pause in warfarin intake depends on the INR. Warfarin intake is discontinued

• 5 days before surgery if INR >4;
• 3 days before surgery if INR is from 3 to 4;
• 2 days before surgery if INR is from 2 to 3.

INR should be determined on the evening before surgery and 0.5-1 mg of vitamin K₁ should be administered 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. Subcutaneous administration of low molecular weight heparin should be continued for 5-7 days after surgery with concomitant resumed intake of warfarin.

Resume warfarin intake with the usual maintenance dose on the same evening after minor surgeries, and on the day when the patient starts enteral nutrition after major surgeries.

Adverse Reactions

Adverse reactions to the drug are ordered by system-organ class and are consistent with preferred terms (according to MedDRA). Within the system-organ class category, reactions are distributed by frequency of occurrence according to the following scheme: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

From the hematopoietic system very common – bleeding (in various organs); common – increased sensitivity to warfarin after prolonged use.

From the digestive system common – vomiting, nausea, diarrhea; very rare – melena.

From the skin and subcutaneous tissues rare – vasculitis, skin necrosis, alopecia, rash, urticaria, itching.

From the cardiovascular system rare – purple toe syndrome; very rare – cholesterol embolism.

From the immune system common – hypersensitivity.

From the liver rare – increased activity of liver enzymes, jaundice.

Over the course of a year, bleeding is observed in approximately 8% of cases among patients receiving Warfarin. Of these, 1.0% are classified as severe (intracranial, retroperitoneal), leading to hospitalization or blood transfusion, and 0.25% as fatal. The most common risk factor for intracranial hemorrhage is untreated or uncontrolled arterial hypertension. The likelihood of bleeding increases if the INR is significantly above the target level. If bleeding starts with an INR within the target range, then there are other underlying conditions that should be investigated.

Examples of such complications include nosebleeds, hemoptysis, hematuria, gum bleeding, skin bruising, vaginal bleeding, subconjunctival bleeding, bleeding from the rectum and other parts of the gastrointestinal tract, intracerebral bleeding, prolonged or heavy bleeding after injuries or surgeries. Bleeding, including severe bleeding, can be expected to develop in any organ. In patients receiving long-term anticoagulant treatment, bleeding events leading to death, hospitalization, or the need for blood transfusion have been reported.

Independent risk factors for significant bleeding during warfarin use include: elderly age, high level of anticoagulation, history of stroke, history of gastrointestinal bleeding, concomitant diseases, and atrial fibrillation. Patients with CYP2C9 polymorphism may have an increased risk of excessive anticoagulant effect and bleeding episodes. In such patients, careful monitoring of hemoglobin level and INR should be performed.

From the digestive system vomiting, nausea, diarrhea.

From the skin: coumarin necrosis is a rare complication during warfarin treatment. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks or (less commonly) in other places. Later, the lesions become necrotic. In 90% of cases, necrosis develops in women. Lesions are observed from the 3rd to the 10th day of drug use, and the etiology suggests a deficiency of antithrombotic protein C or S. Congenital deficiency of these proteins may be the cause of complications, so warfarin intake should be started simultaneously with heparin administration and with small initial doses of the drug. If a complication occurs, warfarin intake is discontinued and heparin administration is continued until the lesions heal or scar.

Palmar-plantar syndrome is a very rare complication during warfarin therapy; its development is characteristic among men with atherosclerotic diseases. Presumably, Warfarin causes hemorrhages in atheromatous plaques, leading to microembolisms. Symmetrical purple skin lesions on the fingers and soles of the feet are observed, accompanied by burning pain.

After discontinuation of warfarin, these symptoms gradually disappear.

Other hypersensitivity reactions, manifested as skin rash, and characterized by reversible increase in liver enzyme concentration, cholestatic hepatitis, vasculitis, priapism, reversible alopecia, and tracheal calcification.

Independent risk factors for the development of serious bleeding during warfarin treatment are: elderly age, high intensity of concomitant anticoagulant and antiplatelet therapy, history of strokes and gastrointestinal bleeding. The risk of bleeding is increased in patients with CYP2C9 gene polymorphism.

Contraindications

• Acute bleeding;
• Severe liver diseases;
• Severe kidney diseases;
• Acute DIC syndrome;
• Deficiency of proteins C and S;
• Thrombocytopenia;
• Patients with a high risk of bleeding, including patients with hemorrhagic disorders, esophageal varices, arterial aneurysm, lumbar puncture, peptic ulcer of the stomach and duodenum, with severe wounds (including surgical ones), bacterial endocarditis, malignant arterial hypertension, hemorrhagic stroke, intracranial hemorrhage;
• Pregnancy (first trimester and last 4 weeks);
• Established or suspected hypersensitivity to the components of the drug.

Use in Pregnancy and Lactation

Warfarin rapidly crosses the placental barrier, has a teratogenic effect on the fetus, leading to the development of warfarin syndrome in the fetus at 6-12 weeks of pregnancy. Manifestations of this syndrome: nasal hypoplasia (saddle nose deformity and other cartilage changes) and stippled chondrodysplasia on X-ray (especially in the spine and long tubular bones), short hands and fingers, optic nerve atrophy, cataract leading to complete blindness, mental and physical development delay, microcephaly. The drug can cause bleeding at the end of pregnancy and during childbirth.

Taking the drug during pregnancy can cause congenital malformations and lead to fetal death. The drug should not be prescribed in the first trimester of pregnancy and during the last 4 weeks. The use of warfarin is not recommended during the remaining periods of pregnancy, except in cases of extreme necessity.

Women of reproductive age should use an effective method of contraception during the period of warfarin use.

Warfarin is excreted in breast milk, but when warfarin is taken in therapeutic doses, no effect on the breastfed infant is expected. The drug can be used during lactation (breastfeeding).

Data on the effect of warfarin on fertility are absent.

Use in Hepatic Impairment

Contraindicated in severe liver diseases.

Impaired liver function increases sensitivity to warfarin because the liver produces blood clotting factors and also metabolizes Warfarin. In this group of patients, careful monitoring of INR values is necessary.

Use in Renal Impairment

Contraindicated in severe kidney diseases.

Patients with renal failure do not require any specific recommendations for warfarin dose selection. Patients on peritoneal dialysis do not require an additional increase in the warfarin dose.

Pediatric Use

Data on the use of warfarin in children are limited. The initial dose is usually 0.2 mg/kg/day with normal liver function and 0.1 mg/kg/day with impaired liver function. The maintenance dose is selected according to the INR values. The recommended INR levels are the same as for adults. The decision to prescribe warfarin in children should be made by an experienced specialist. Treatment should be carried out under the supervision of an experienced specialist – a pediatrician.

Geriatric Use

There are no specific recommendations for taking warfarin in elderly patients. However, elderly patients should be carefully monitored as they have a higher risk of developing side effects.

Special Precautions

A mandatory condition for warfarin therapy is the patient’s strict adherence to the prescribed dose of the drug. Patients suffering from alcoholism, as well as patients with dementia, may be unable to adhere to the prescribed warfarin regimen.

Fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage, can enhance the effect of warfarin.

In hypothyroidism, the effect of warfarin may be reduced.

In case of renal failure or nephrotic syndrome, the level of the free fraction of warfarin in the blood plasma increases, which, depending on concomitant diseases, can lead to either an enhancement or a reduction of the effect. In case of moderate hepatic insufficiency, the effect of warfarin is enhanced. In all the above conditions, careful monitoring of INR should be carried out.

For patients receiving Warfarin, it is recommended to prescribe paracetamol, tramadol, or opiates as painkillers.

Patients with a mutation of the gene encoding the CYP2C9 enzyme have a longer T_1/2 of warfarin. These patients require lower doses of the drug, since when taking usual therapeutic doses, the risk of bleeding increases.

Warfarin should not be taken by patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome due to the presence of lactose in the drug (as an excipient).

If a rapid antithrombotic effect is necessary, it is recommended to initiate treatment with heparin administration; then, combined therapy with heparin and warfarin should be conducted for 5-7 days until the target INR value is maintained for 2 days.

Patients with protein C deficiency are at risk of developing skin necrosis without using a loading dose of warfarin. Such therapy should be initiated without using a loading dose of warfarin, even when heparin is used. Patients with protein S deficiency may also be at risk; under these circumstances, a slower initiation of warfarin therapy is recommended.

In cases of individual resistance to warfarin (rarely encountered), achieving a therapeutic effect requires from 5 to 20 loading doses of warfarin. If warfarin administration is ineffective in such patients, other possible causes should be identified: concurrent use of warfarin with other drugs, inadequate diet, laboratory errors.

Treatment of elderly patients should be conducted with special precautions, since the synthesis of clotting factors and hepatic metabolism are reduced in such patients, which may lead to an excessive effect of warfarin.

Caution is recommended in patients with impaired renal function, necessitating more frequent monitoring of INR levels in patients at risk of hypercoagulation, for example, with severe arterial hypertension or kidney disease.

Overdose

Symptoms the treatment efficacy indicator is on the verge of bleeding development, so the patient may have minor bleeding (including microhematuria, gum bleeding).

Treatment in mild cases, it is sufficient to reduce the drug dose or discontinue treatment for a short period. For minor bleeding, it is sufficient to stop taking the drug until the target INR level is reached. In case of severe bleeding development, intravenous administration of vitamin K, clotting factor concentrate, or fresh frozen plasma, and oral intake of activated charcoal are recommended.

If oral anticoagulants are indicated for further use, large doses of vitamin K should be avoided, as resistance to warfarin develops within 2 weeks.

Treatment regimens for drug overdose

After treatment, long-term patient observation is necessary, considering that the T_1/2 of warfarin is 20-60 hours.

Drug Interactions

It is not recommended to start or stop taking other medicines, or change the doses of medications being taken without consulting the attending physician.

When co-administering, the effects of cessation of induction and/or inhibition of warfarin action by other drugs should also be considered.

The risk of severe bleeding increases with the simultaneous use of warfarin with drugs affecting platelet levels and primary hemostasis: acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most NSAIDs (except for COX-2 inhibitors), penicillin group antibiotics in high doses.

Combined use of warfarin with drugs having a pronounced inhibitory effect on cytochrome P450 system isoenzymes (for example, cimetidine, chloramphenicol) should also be avoided, as their use for several days increases the risk of bleeding. In such cases, cimetidine can be replaced, for example, with ranitidine or famotidine.

Agents reducing the effect of warfarin

Cholestyramine reduced absorption of warfarin and effect on enterohepatic recirculation.

Bosentan induction of warfarin transformation in CYP2C9/CYP3A4 in the liver.

Aprepitant induction of warfarin transformation in CYP2C9.

Mesalazine possible reduction of the anticoagulant effect of warfarin.

Sucralfate possibility of reduced warfarin absorption.

Griseofulvin reduction of the anticoagulant effect of coumarins.

Retinoids possibility of reduced warfarin activity.

Dicloxacillin increased metabolism of warfarin.

Rifampicin increased metabolism of warfarin; concurrent use of these drugs should be avoided.

Antiviral agents (nevirapine, ritonavir) increased metabolism of warfarin mediated by CYP2C9.

Nafcillin reduction of the anticoagulant effect of warfarin.

Phenazone induction of enzyme metabolism, reduction of warfarin concentration in blood plasma; an increase in warfarin dose may be required.

Rofecoxib mechanism of interaction is unknown.

Barbiturates (e.g., phenobarbital) increased metabolism of warfarin.

Antiepileptic drugs (carbamazepine, valproic acid, primidone) increased metabolism of warfarin.

Antidepressants (trazodone, mianserin) in four cases of clinical use, interaction of trazodone and warfarin was found to cause a decrease in prothrombin time and INR, but the mechanism of this interaction is unknown. The mechanism of interaction between warfarin and mianserin is also unknown.

Glutethimide reduction of the anticoagulant effect of warfarin due to increased metabolism.

Chlordiazepoxide reduction of the anticoagulant effect of warfarin.

Aminoglutethimide increased metabolism of warfarin.

Azathioprine reduced absorption of warfarin and increased metabolism of warfarin.

Mercaptopurine reduction of the anticoagulant effect of warfarin.

Mitotane possible reduction of the anticoagulant effect of warfarin.

Cyclosporine Warfarin increases the concentration of cyclosporine or enhances its effect by influencing the metabolism of cyclosporine.

Cholestyramine may reduce the anticoagulant effect of warfarin due to reduced absorption.

Spironolactone, chlorthalidone use of diuretics in case of pronounced hypovolemic effect may lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants.

St. John’s wort (Hypericum perforatum) enhances the metabolism of warfarin carried out by CYP3A4 and CYP1A2 (metabolism of R-warfarin), as well as that carried out by CYP2C9 (metabolism of S-warfarin); the effect of enzyme induction may persist for 2 weeks after discontinuation of St. John’s wort. If the patient is taking St. John’s wort preparations, INR should be measured and intake stopped. Careful monitoring of INR should be carried out, as its level may increase upon discontinuation of St. John’s wort; after that, Warfarin can be prescribed.

Ginseng (Panax ginseng) possible induction of warfarin transformation in the liver; concurrent use of these drugs should be avoided.

Foods containing vitamin K weaken the effect of warfarin. Vitamin K is most abundant in green vegetables (e.g., amaranth greens, avocado, broccoli, Brussels sprouts, cabbage, canola oil, chaya leaf, onion, coriander (cilantro), cucumber peel, chicory, kiwi fruit, lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red seaweed, spinach greens, spring onion, soybeans, tea leaves (but not the drink tea), turnip greens, watercress), so these foods should be consumed with caution during warfarin treatment.

Vitamin C reduction of the anticoagulant effect of warfarin.

Vitamin K Warfarin blocks the synthesis of vitamin K-dependent clotting factors.

Agents enhancing the effect of warfarin

Abciximab, tirofiban, eptifibatide, clopidogrel, heparin additional impact on the hematopoietic system.

Cimetidine pronounced inhibitory effect on the cytochrome P450 system (cimetidine can be replaced by ranitidine or famotidine), leading to reduced metabolism of warfarin.

Glibenclamide enhancement of the anticoagulant effect of warfarin.

Omeprazole enhancement of the anticoagulant effect of warfarin.

Amiodarone reduction of warfarin metabolism after one week of concurrent use; this effect may persist for 1-3 months after discontinuation of amiodarone.

Ethacrynic acid may enhance the effect of warfarin due to displacement of warfarin from protein binding sites.

Hypolipidemic agents (fluvastatin, simvastatin, rosuvastatin, gemfibrozil, bezafibrate, clofibrate, lovastatin, fenofibrate) competition for metabolism mediated by CYP2C9 and CYP3A4.

Propafenone reduction of warfarin metabolism.

Quinidine reduction of clotting factor synthesis.

Diazoxide may displace Warfarin, bilirubin, or another highly protein-bound substance from protein binding sites.

Digoxin enhancement of the anticoagulant effect.

Propranolol enhancement of the anticoagulant effect.

Ticlopidine increased risk of bleeding; INR monitoring is necessary.

Dipyridamole increase in warfarin or dipyridamole concentration due to potentiation of effects; increased risk of bleeding (hemorrhage).

Miconazole (including in oral gel form) reduction of warfarin’s intrinsic clearance and increase in the free fraction of warfarin in blood plasma; reduction of warfarin metabolism mediated by cytochrome P450 system enzymes.

Steroid hormones – anabolic and/or androgens (danazol, testosterone) reduction of warfarin metabolism and/or direct action on coagulation and fibrinolysis systems.

Thyroid-acting agents increased metabolism of vitamin K-dependent clotting factors.

Glucagon enhancement of the anticoagulant effect of warfarin.

Allopurinol enhancement of the anticoagulant effect of warfarin.

Sulfinpyrazone enhancement of the anticoagulant effect due to reduced metabolism and weakened protein binding.

Penicillins in high doses (cloxacillin, amoxicillin) possible increased likelihood of bleeding, including bleeding from gums, nose, appearance of atypical bruising, or dark stools.

Tetracyclines possible enhancement of the anticoagulant effect of warfarin.

Sulfonamides (sulfamethizole, sulfafurazole, sulfaphenazole) possible enhancement of the anticoagulant effect of warfarin.

Quinolones (ciprofloxacin, norfloxacin, ofloxacin, grepafloxacin, nalidixic acid) reduction of warfarin metabolism.

Macrolide antibiotics (azithromycin, clarithromycin, erythromycin, roxithromycin) reduction of warfarin metabolism.

Antifungal agents (fluconazole, itraconazole, ketoconazole) reduction of warfarin metabolism.

Chloramphenicol reduction of warfarin metabolism, pronounced inhibitory effect on the cytochrome P450 system.

Cephalosporins (cefamandole, cephalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime) enhancement of warfarin effect due to suppression of vitamin K-dependent clotting factor synthesis and other mechanisms.

Sulfamethoxazole/trimethoprim reduction of warfarin metabolism and displacement of warfarin from plasma protein binding sites.

Levamisole enhancement of the anticoagulant effect of warfarin.

Codeine the combination of codeine and paracetamol enhances warfarin activity.

Acetylsalicylic acid displacement of warfarin from albumin binding sites, limitation of warfarin metabolism.

NSAIDs (azapropazone, indomethacin, oxyphenbutazone, piroxicam, sulindac, tolmetin, feprazone, celecoxib and others (except for COX-2 inhibitors) competition for metabolism carried out by CYP2C9.

Leflunomide limitation of warfarin metabolism mediated by CYP2C9.

Paracetamol (acetaminophen), especially after 1-2 weeks of continuous use: limitation of warfarin metabolism or influence on clotting factor formation (this effect does not occur when using paracetamol in doses less than 2 g/day).

Phenylbutazone reduction of warfarin metabolism, displacement of warfarin from plasma protein binding sites; use of this combination should be avoided.

Narcotic analgesics (dextropropoxyphene) enhancement of the anticoagulant effect of warfarin.

Antiepileptic drugs (fosphenytoin, phenytoin) displacement of warfarin from plasma protein binding sites, enhancement of warfarin metabolism.

Tramadol competition for metabolism mediated by CYP3A4.

Antidepressants – selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, fluvoxamine, paroxetine, sertraline limitation of warfarin metabolism. It is believed that SSRIs limit the isoenzyme CYP2C9. This enzyme metabolizes the most potent isomer S-Warfarin. Furthermore, both SSRIs and Warfarin are highly bound to albumin, increasing the possibility of displacement of one from protein binding sites (with concurrent use).

Chloral hydrate mechanism of interaction is unknown.

Fluorouracil reduction of CYP2C9 synthesis, which metabolizes Warfarin.

Capecitabine reduction of CYP2C9 synthesis.

Imatinib competitive inhibition of the CYP3A4 isoenzyme and inhibition of warfarin metabolism mediated by CYP2C9 and CYP2D6.

Ifosfamide suppression of CYP3A4.

Tamoxifen is an inhibitor of CYP2C9, may increase warfarin concentration in serum due to reduced metabolism.

Methotrexate enhancement of warfarin effect due to reduced synthesis of procoagulant factors in the liver.

Tegafur enhancement of the anticoagulant effect of warfarin.

Trastuzumab enhancement of the anticoagulant effect of warfarin.

Flutamide enhancement of the anticoagulant effect of warfarin.

Cyclophosphamide possibility of change in the anticoagulant effect of warfarin, as cyclophosphamide is an antineoplastic agent.

Etoposide possible enhancement of the anticoagulant effect of coumarins.

Interferon alfa and beta increase in the anticoagulant effect and increase in warfarin concentration in serum necessitates a reduction in warfarin dose.

Disulfiram reduction of warfarin metabolism.

Metolazone enhancement of the anticoagulant effect of warfarin.

Tienilic acid enhancement of the anticoagulant effect of warfarin.

Zafirlukast increase in concentration or enhancement of zafirlukast effect during warfarin use due to change in zafirlukast metabolism.

Troglitazone reduction in concentration or weakening of warfarin effect due to change in warfarin metabolism.

Influenza vaccine possibility of enhancement of the anticoagulant effect of warfarin.

Proguanil possible enhancement of the anticoagulant effect of warfarin according to individual reports.

Food (cranberry) reduces warfarin metabolism mediated by CYP2C9.

Tonic drinks containing quinine consumption of large amounts of tonic drinks containing quinine may necessitate a reduction in warfarin dose. This interaction may be explained by quinine reducing the synthesis of procoagulant factors in the liver.

Ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza) potentiation of anticoagulant/antiplatelet effect may increase the risk of bleeding.

Agents reducing or enhancing the effect of warfarin

Disopyramide may weaken or enhance the anticoagulant effect of warfarin.

Coenzyme-Q10 may enhance or suppress the effect of warfarin due to chemical structure homogeneity with vitamin K.

Ethanol inhibition or induction of warfarin metabolism.

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

In case of concurrent use of warfarin with the above-mentioned drugs, INR control should be performed at the beginning and end of treatment and, if possible, 2-3 weeks after initiation of therapy.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 5 years.

Dispensing Status

The drug is dispensed by prescription.

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.