Method of action:
Medically reviewed by Oliinyk Elizabeth Ivanovna, PharmD. Last updated on 2020-03-28
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Top 20 medicines with the same components:
Marevan 0.5mg Tablets
Warfarin 0.5mg Tablets
Each tablet contains 0.5mg Warfarin Sodium.
Excipients with known effect:
Lactose: contains 48.350 mg lactose per tablet
White, flat, circular, bevel-edged uncoated tablets having 'M' breakline '0.5' on one side and plain on other side.
The score line is not intended for breaking the tablet.
Prophylaxis of systemic embolism in patients with rheumatic heart disease and atrial fibrillation.
Prophylaxis after insertion of prosthetic heart valves.
Prophylaxis and treatment of venous thrombosis and pulmonary embolism.
Transient attacks of cerebral ischaemia.
Adults: The typical induction dose is 10mg daily for 2 days but this should be tailored to individual requirements. The daily maintenance dose is usually 3 to 9mg taken at the same time each day. The exact maintenance dose depends on the prothrombin time or other appropriate coagulation tests.
Control tests should be made at regular intervals and the maintenance dose should be adjusted according to the results obtained. Once the maintenance dose is established, it is rarely necessary to alter it.
In emergencies, anticoagulant therapy should be initiated with heparin and warfarin together.
Concomitant therapy with heparin affects the results of control tests, and should be discontinued at least six hours before the first test is carried out.
Elderly: As for adults, but dosage may need to be lowered.
Paediatric population: No data are available.
Method of administration
- Haemorrhagic stroke
- Clinically significant bleeding
- Within 72 hours of major surgery with risk of severe bleeding
- Within 48 hours postpartum
- Drugs where interactions may lead to a significantly increased risk of bleeding
Most adverse events reported with warfarin are a result of over anticoagulation therefore it is important that the need for therapy is reviewed on a regular basis and therapy discontinued when no longer required.
Patients should be given a patient-held information booklet ('warfarin card') and informed of symptoms for which they should seek medical attention.
Commencement of therapy
When warfarin is started using a standard dosing regimen the INR should be determined daily or on alternate days in the early days of treatment. Once the INR has stabilised in the target range the INR can be determined at longer intervals.
INR should be monitored more frequently in patients at an increased risk of over coagulation e.g. patients with severe hypertension, liver or renal disease.
Patients for whom adherence may be difficult should be monitored more frequently.
Patients with protein C deficiency are at risk of developing skin necrosis when starting warfarin treatment. In patients with protein C deficiency, therapy should be introduced without a loading dose of warfarin even if heparin is given. Patients with protein S deficiency may also be at risk and it is advisable to introduce warfarin therapy slowly in these circumstances.
Risk of haemorrhage
The most frequently reported adverse effect of all oral anticoagulants is haemorrhage. Warfarin should be given with caution to patients where there is a risk of serious haemorrhage (e.g. concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastrointestinal bleeding).
Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age >65, highly variable INRs, history of gastrointestinal bleeding, uncontrolled hypertension, cerebrovascular disease, serious heart disease, risk of falling, anaemia, malignancy, trauma, renal insufficiency, concomitant drugs. All patients treated with warfarin should have INR monitored regularly. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed on measures to minimise risk of bleeding and to report immediately to physicians signs and symptoms of bleeding.
Checking the INR and reducing or omitting doses depending on INR level is essential, following consultation with anticoagulation services if necessary. If the INR is found to be too high, reduce dose or stop warfarin treatment; sometimes it will be necessary to reverse anticoagulation. INR should be checked within 2-3 days to ensure that it is falling.
Any concomitant anti-platelet drugs should be used with caution due to an increased risk of bleeding.
Haemorrhage can indicate an overdose of warfarin has been taken.
Unexpected bleeding at therapeutic levels should always be investigated and INR monitored.
Anticoagulation following an ischaemic stroke increases the risk of secondary haemorrhage into the infarcted brain. In patients with atrial fibrillation long term treatment with warfarin is beneficial, but the risk of early recurrent embolism is low and therefore a break in treatment after ischaemic stroke is justified. Warfarin treatment should be re-started 2-14 days following ischaemic stroke, depending on the size of the infarct and blood pressure. In patients with large embolic strokes, or uncontrolled hypertension, warfarin treatment should be stopped for 14 days.
Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with high mortality. The condition is mainly observed in patients with end-stage renal disease on dialysis or in patients with known risk factors such as protein C or S deficiency, hyperphosphataemia, hypercalcaemia or hypoalbuminaemia. Rare cases of calciphylaxis have been reported in patients taking warfarin, also in the absence of renal disease. In case calciphylaxis is diagnosed, appropriate treatment should be started and consideration should be given to stopping treatment with warfarin.
For surgery where there is no risk of severe bleeding, surgery can be performed with an INR of <2.5.
For surgery where there is a risk of severe bleeding, warfarin should be stopped 3 days prior to surgery.
Where it is necessary to continue anticoagulation e.g. risk of life-threatening thromboembolism, the INR should be reduced to <2.5 and heparin therapy should be started.
If surgery is required and warfarin cannot be stopped 3 days beforehand, anticoagulation should be reversed with low-dose vitamin K.
The timing for re-instating warfarin therapy depends on the risk of post-operative haemorrhage. In most instances warfarin treatment can be re-started as soon as the patient has an oral intake.
Warfarin need not be stopped before routine dental surgery, eg, tooth extraction.
Active peptic ulceration
Due to a high risk of bleeding, patients with active peptic ulcers should be treated with caution. Such patients should be reviewed regularly and informed of how to recognise bleeding and what to do in the event of bleeding occurring.
Many drugs and foods interact with warfarin and affect the prothrombin time. Any change to medication, including self-medication with OTC products, warrants increased monitoring of the INR. Patients should be instructed to inform their doctor before they start to take any additional medications including over the counter medicines, herbal remedies or vitamin preparations.
The rate of warfarin metabolism depends on thyroid status. Therefore patients with hyper- or hypo-thyroidism should be closely monitored on starting warfarin therapy.
Additional circumstances where changes in dose may be required
The following also may exaggerate the effect of warfarin tablets, and necessitate a reduction of dosage:
- Loss of weight
- Acute illness
- Cessation of smoking
The following may reduce the effect of warfarin tablets, and require the dosage to be increased:
- Weight gain
Acquired or inherited warfarin resistance should be suspected if larger than usual daily doses of warfarin are required to achieve the desired anticoagulant effect.
Genetic variability particularly in relation to CYP2C9 and VKORC1 can significantly affect dose requirements for warfarin. If a family association with these polymorphisms is known extra care is warranted.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Warfarin has a narrow therapeutic range and care is required with all concomitant therapy. The individual product information for any new concomitant therapy should be consulted for specific guidance on warfarin dose adjustment and therapeutic monitoring. If no information is provided the possibility of an interaction should be considered. Increased monitoring should be considered when commencing any new therapy if there is any doubt as to the extent of interaction.
Drugs which are contraindicated
Concomitant use of drugs used in the treatment or prophylaxis of thrombosis, or other drugs with adverse effects on haemostasis may increase the pharmacological effect of warfarin, increasing the risk of bleeding.
Fibrinolytic drugs such as streptokinase and alteplase are contraindicated in patients receiving warfarin.
Drugs which should be avoided if possible
The following examples should be avoided, or administered with caution with increased clinical and laboratory monitoring:
- NSAIDs (including aspirin and cox-2 specific NSAIDS)
- Thrombin inhibitors such as bivalirudin, dabigatran
- Unfractionated heparins and heparin derivatives, low molecular weight heparins
- Fondaparinux, rivaroxaban
- Glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and abciximab
- SSRI and SNRI antidepressants
- Other drugs which inhibit haemostasis, clotting or platelet action
Low-dose aspirin with warfarin may have a role in some patients but the risk of gastrointestinal bleeding is increased. Warfarin may initially be given with a heparin in the initial treatment of thrombosis, until the INR is in the correct range.
Warfarin is a mixture of enantiomers which are metabolised by different CYPP450 cytochromes. R-warfarin is metabolised primarily by CYP1A2 and CYP3A4. S-warfarin is metabolised primarily by CYP2C9. The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered.
Drugs that compete as substrates for these cytochromes or inhibit their activity may increase warfarin plasma concentrations and INR, potentially increasing the risk of bleeding. When these drugs are co-administered, warfarin dosage may need to be reduced and the level of monitoring increased.
Conversely, drugs which induce these metabolic pathways may decrease warfarin plasma concentrations and INR, potentially leading to reduced efficacy. When these drugs are co-administered, warfarin dosage may need to be increased and the level of monitoring increased.
There is a small subset of drugs for which interactions are known; however the clinical effect on the INR is variable, in these cases increased monitoring on starting and stopping therapy is advised.
Care should also be taken when stopping or reducing the dose of a metabolic inhibitor or inducer, once patients are stable on this combination (offset effect).
Listed below are drugs which are known to interact with warfarin in a clinically significant way.
Examples of drugs which potentiate the effect of warfarin
allopurinol, capecitabine, erlotinib, disulfiram, azole antifungals (ketoconazole, fluconazole etc)
omeprazole, paracetamol (prolonged regular use), propafenone, amiodarone, tamoxifen, methylphenidate
zafirlukast, fibrates, statins (not pravastatin; predominantly associated with fluvastatin)
erythromycin, sulfamethoxazole, metronidazole
Examples of drugs which antagonise the effect of warfarin
Barbiturates, primidone, carbamazepine, griseofulvin, oral contraceptives, rifampicin, azathioprine, phenytoin
Examples of drugs with variable effect
Corticosteroids, nevirapine, ritonavir
Other drug interactions
Broad spectrum antibiotics may potentiate the effect of warfarin by reducing the gut flora which produce vitamin K. Similarly, orlistat may reduce absorption of vitamin K. Cholestyamine and sucralfate potentially decrease absorption of warfarin.
Increased INR has been reported in patients taking glucosamine and warfarin. This combination is not recommended.
Interactions with herbal products
Herbal preparations containing St John's Wort (Hypericum perforatum) must not be used whilst taking warfarin due to a proven risk of decreased plasma concentrations and reduced clinical effects of warfarin.
Many other herbal products have a theoretical effect on warfarin; however most of these interactions are not proven. Patients should generally avoid taking any herbal medicines or food supplements whilst taking warfarin, and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.
Acute ingestion of a large amount of alcohol may inhibit the metabolism of warfarin and increase INR. Conversely, chronic heavy alcohol intake may induce the metabolism of warfarin. Moderate alcohol intake can be permitted.
Interactions with food and food supplements
Individual case reports suggest a possible interaction between warfarin and cranberry juice, in most cases leading to an increase in INR or bleeding event. Patients should be advised to avoid cranberry products. Increased supervision and INR monitoring should be considered for any patient taking warfarin and regular cranberry juice.
Limited evidence suggests that grapefruit juice may cause a modest rise in INR in some patients taking warfarin.
Certain foods such as liver, broccoli, Brussels sprouts and green leafy vegetables contain large amounts of vitamin K. Sudden changes in diet can potentially affect control of anticoagulation. Patients should be informed of the need to seek medical advice before undertaking any major changes in diet.
There are limited data on possible drug interactions with glucosamine, but increments in the INR parameter have been reported with oral vitamin K antagonists. Patients treated with oral vitamin K antagonists should therefore be closely monitored at the time of initiation or termination of glucosamine therapy.
Many other food supplements have a theoretical effect on warfarin; however most of these interactions are not proven. Patients should generally avoid taking any food supplements whilst taking warfarin, and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.
Heparins and danaparoid may prolong the prothrombin time, therefore a sufficient time interval should be allowed after administration before performing the test.
Based on human experience warfarin causes congenital malformations and foetal death when administered during pregnancy.
Warfarin is contraindicated in pregnancy in the first and third trimester.
Women of child-bearing age who are taking warfarin tablets should use effective contraception during treatment.
Warfarin is excreted in breast milk in small amounts. However, at therapeutic dose of warfarin no effects on the breast-feeding child are anticipated. Warfarin can be used during breast-feeding.
Warfarin has no influence on the ability to drive and use machines.
The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100) ; rare (>1/10,000 to <1/1,000); very rare (<1/10,000) and not known - cannot be estimated from the available data.
System organ class
Infections and infestations
Immune system disorders
Nervous system disorders
Cerebral haemorrhage; Cerebral subdural haematoma
Respiratory, thoracic and mediastinal disorders
Gastrointestinal haemorrhage, rectal haemorrhage, haematemesis; pancreatitis; diarrhoea; nausea; vomiting; melaena
Jaundice; hepatic dysfunction
Skin and subcutaneous disorders
Rash; alopecia; purpura; 'purple toes' syndrome; erythematous swollen skin patches leading to ecchymosis, infarction and skin necrosis; calciphylaxis
Renal and Urinary disorders
Unexplained drop in haematocrit; haemoglobin decreased
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
The benefit of gastric decontamination is uncertain. If the patient presents within 1 hour of ingestion of more than 0.25 mg/kg or more than the patient's therapeutic dose, consider activated charcoal (50 g for adults; 1 g/kg for children)
In cases of life-threatening haemorrhage
Stop warfarin treatment, give prothrombin complex concentrate (factors II, VII, IX, and X) 30-50 units/kg or (if no concentrate available) fresh frozen plasma 15 mL/kg. Discuss with local haematologist or National Poisons Information Service, or both.
Non-life threatening haemorrhage
Where anticoagulation can be suspended, give slow intravenous injection of phytomenadione (vitamin K1) 10-20 mg for adults (250 micrograms/kg for a child)
Where rapid re-anticoagulation is desirable (eg, valve replacements) give prothrombin complex concentrate (factors II, VII, IX, and X) 30-50 units/kg or (if no concentrate available) fresh frozen plasma 15 mL/kg.
Monitor INR to determine when to restart normal therapy. Monitor INR for at least 48 hours post overdose.
For patients on long-term warfarin therapy without major haemorrhage
- INR >8Â·0, no bleeding or minor bleedingâ€”stop warfarin, and give phytomenadione (vitamin K1) 0Â·5-1 mg for adults, 0Â·015-0Â·030 mg/kg (15-30 micrograms/kg) for children by slow intravenous injection or 5 mg by mouth (for partial reversal of anticoagulation give smaller oral doses of phytomenadione eg, 0Â·5-2Â·5 mg using the intravenous preparation orally); repeat dose of phytomenadione if INR still too high after 24 hours. Large doses of phytomenadione may completely reverse the effects of warfarin and make re-establishment of anticoagulation difficult.
- INR 6Â·0-8Â·0, no bleeding or minor bleedingâ€”stop warfarin, restart when INR <5Â·0
- INR <6Â·0 but more than 0Â·5 units above target valueâ€”reduce dose or stop warfarin, restart when INR <5Â·0
For patients NOT on long-term anticoagulants without major haemorrhage
Measure the INR (prothrombin time) at presentation and sequentially every 24-48 hours after ingestion depending on the initial dose and initial INR.
- If the INR remains normal for 24-48 hours and there is no evidence of bleeding, there should be no further monitoring necessary.
- Give vitamin K1 (phytomenadione) if:
a) there is no active bleeding and the patient has ingested more than 0Â·25 mg/kg;
b) the prothrombin time is already significantly prolonged (INR >4Â·0).
The adult dose of vitamin K1 is 10-20 mg orally (250 micrograms/kg body weight for a child). Delay oral vitamin K1 at least 4 hours after any activated charcoal has been given. Repeat INR at 24 hours and consider further vitamin K1.
Pharmacotherapeutic group: Antithrombotic agents,Vitamin K antagonists
ATC code: B01AA03
Mechanism of action
Warfarin is a synthetic anticoagulant of the coumarin series. It acts by inhibiting the formation of active clotting factors II, VII, IX and X.
Warfarin is readily absorbed from the gastro-intestinal tract.
Its plasma half-life is about 40 hours.
It is metabolised in the liver.
It is excreted in the urine mainly as metabolites.
No further data of relevance.
Maize starch pregelatinised
Sodium starch glycollate
36 months for securitainers
24 months for blister packs
Do not store above 25°C. Protect from light.
Polypropylene container with tamper evident polyethylene lid containing 28, 56, 100, 112 or 500 tablets.
Aluminium foil with PVC/PVdC film blisters containing 28, 56 or 112 tablets.
Not all pack sizes may be marketed.
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Mercury Pharmaceuticals Ltd
85 King William Street,
London EC4N 7BL, UK
19th November 1998