- Drugs List
- Therapeutic Indications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
Oral formulations of warfarin sodium.
prophylaxis and treatment of pulmonary embolism
prophylaxis of systemic embolism in rheumatic heart disease
prophylaxis of systemic embolism in atrial fibrillation
prophylaxis and treatment of venous thrombosis
prophylaxis after insertion of prosthetic heart valves
transient ischaemic attack
Initial dose: 10mg daily, for 2 days. Dose should be adjusted according to individual patient requirements.
Maintenance dose: 3mg to 9mg daily, to be taken at the same time each day. The exact maintenance dose depends on prothrombin time usually reported as International Normalised Ratio (INR), or other appropriate coagulation tests.
Dosage for children has not been established.
The following unlicensed doses may be suitable:
Initial dose: 200 micrograms/kg as a single dose, for 1 day. Maximum dose should not exceed 10mg.
Maintenance dose: 100 micrograms/kg once a day for 3 days, maximum of 5mg per dose. Adjust dose based on individual patient response and INR levels. Doses of 50 micrograms/kg to 300 micrograms/kg once a day, up to 400 micrograms/kg once a day may be required.
The following unlicensed doses may be suitable:
Initial dose: 200 micrograms/kg as a single dose, for 1 day.
Maintenance dose: 100 micrograms/kg once a day for 3 days. Adjust dose based on individual patient response and INR levels. Doses of 50 micrograms/kg to 300 micrograms/kg once a day, up to 400 micrograms/kg once a day may be required.
Patients with Renal Impairment
Use with caution in renal impairment.
There is an increased risk of over coagulation in patients with renal disease.
Avoid in severe renal impairment.
The Renal Drug Handbook states that the dose is as given to patients with normal renal function.
Patients with Hepatic Impairment
Use with caution in hepatic impairment.
There is an increased risk of over coagulation is patients with hepatic disease.
Avoid in severe hepatic impairment if prothrombin time is already prolonged.
For oral administration, usually once daily.
It is recommended that the doses are taken at the same time each day.
If the oral formation is replaced by or replaces another warfarin product then patients should be closely monitored in the period following the change.
Therapeutic Drug Monitoring
If possible, the base-line prothrombin time should be determined but the first dose should not be delayed while the result is obtained.
In the early stages of treatment, the INR should be determined daily, or every other day then at less frequent intervals depending on the patient's response, but not less frequently than once every 12 weeks. Any change in the clinical condition of the patient, particularly any change due to liver disease, intercurrent illness, patients at risk from bleeding or addition or removal of concurrent medication, requires more frequent testing. Major changes in diet or alcohol consumption may effect warfarin control.
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) and in patients for whom adherence may be difficult.
Pregnancy - (see Pregnancy)
Within 48 hours postpartum
Within 72 hours of surgery where there is a severe risk of bleeding
Clinically significant bleeding
Severe renal impairment
Severe hepatic impairment
Precautions and Warnings
Not all formulations are licensed for all indications.
The MHRA has advised that most adverse events reported with warfarin are due to over anticoagulation so the need for continued therapy should be reviewed regularly and discontinued when no longer required.
Patients should be given a patient-held information booklet (warfarin card) and informed of the need for regular blood tests and of symptoms for which they should seek medical attention. Patients should be advised to carry the alert card at all times.
Monitor prothrombin times regularly.
The INR should be monitored more frequently in patients at an increased risk of over coagulation (e.g. patients with severe hypertension, hepatic or renal disease) and in patients for whom adherence to the dosage regimen may be difficult. Changes to patient's clinical condition may necessitate more frequent measurement of INR and dose adjustment. Such changes include:
Changes in weight
Acute illness (including diarrhoea or vomiting)
Alteration or introduction of concurrent medication.
Tobacco smoke induces the cytochrome P450 isoenzyme CYP1A2, by which warfarin is partially metabolised. This may result in reduced plasma level of warfarin. Dosage adjustment may be required if smoking started or stopped during treatment with warfarin.
Alcohol and NSAIDs may potentiate the effect of warfarin. Patients should be advised to avoid these unless under the guidance of a clinician.
Limited evidence suggests that grapefruit juice may cause a modest rise in some patients taking warfarin.
Patients should be advised to avoid simvastatin unless under the guidance of a clinician.
Advise patient to avoid large quantities of pomegranate juice whilst taking warfarin, as this may result in an increase in the INR.
Increased INR has been reported in patients taking glucosamine and warfarin. This combination is not recommended.
Major changes to the diet, especially changes of intake of vitamin K, increase or decrease in the intake of salads, vegetables (broccoli, sprouts and leafy green vegetables), liver, fats and oils, and changes in alcohol consumption may affect the INR. Dose adjustment may be necessary in these situations. Advise patients to avoid cranberry juice or cranberry extract.
Patients should generally avoid herbal remedies or food supplements whilst taking warfarin. Advise patient to inform their doctor before making any major changes to their diet or starting additional medicinal medication including over-the-counter medicines, herbal remedies or vitamin supplements.
In particular, patients should be advised that they should not take St John's Wort while on warfarin treatment.
Absorption may be reduced by diarrhoea and vomiting - the dose may need to be increased.
In patients with protein C deficiency therapy should be introduced without a loading dose of warfarin even if heparin is given. It is advised to introduce warfarin therapy slowly in patients with protein S deficiency. Patients with these conditions are at risk of skin necrosis when starting warfarin treatment.
Risk of haemorrhage
Use with caution in patients where there is a risk of severe haemorrhage (e.g. concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastro-intestinal bleeding).
Patients with these conditions may benefit from more frequent INR monitoring; carefully adjust dose to desired INR and consider a shorter duration of therapy. Risk factors for bleeding include:
high intensity of anticoagulation (INR greater than 4),
age greater than 65 years
history of gastrointestinal bleeding
serious heart disease including congestive cardiac failure
risk of falling
haemorrhagic blood dyscrasias
vitamin K deficiency state
Advise patient to report any signs of bleeding to their clinician. Advise patients on measures to minimise risk of bleeding.
Investigate unexpected bleeding at therapeutic levels for underlying causes. If haemorrhage occurs an overdose should be suspected. Checking the INR and reducing or omitting doses when appropriate is essential and in some cases reversal of anticoagulation may be necessary. Recheck the INR within 2 to 3 days to ensure it is falling.
Haemorrhage can indicate an overdose of warfarin has been taken. For treatment of haemorrhage see - Overdosage.
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 in 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 to 14 days following ischaemic stroke, depending on the size of infarction and blood pressure. In patients with large embolic strokes, or uncontrolled hypertension warfarin treatment should be stopped for 14 days.
For surgery where there is no risk of severe bleeding, surgery can be preformed with an INR of less than 2.5.
Warfarin is contraindicated within 3 days of surgery where there is a severe risk of bleeding. Where it is necessary to continue anticoagulation (e.g. risk of life-threatening thromboembolism) the INR should be reduced to below 2.5 and heparin therapy started. If surgery is required and warfarin cannot be stopped three days beforehand, anticoagulation should be reversed with low-dose vitamin K. The timing for reinstating warfarin therapy depends on the risk of post-operative haemorrhage. In most instances warfarin treatment can be re-instated as soon as the patient has oral intake.
Warfarin need not be stopped before routine dental surgery (e.g. tooth extraction).
Use with caution in patients with active peptic ulcers. Review such patients regularly and inform them of how to recognise bleeding and what to do if bleeding occurs.
Monitor patients with hyper- or hypo- thyroidism closely when treated with warfarin; the rate of warfarin metabolism depends on thyroid status
Hepatic impairment - (see Dosage - Hepatic impairment). Liver function tests should be preformed before starting warfarin treatment.
Renal impairment - (see Dosage - Renal impairment)
Breastfeeding - (see Lactation)
Elderly - (see Dosage - Elderly)
Children under 18 years - (see Dosage - Children)
Acquired or inherited warfarin resistance should be suspected if larger than usual daily doses of warfarin are required to achieve the desired anticoagulant effect.
Use with care in patients with a family association to CYP2C9 and VKORC1 polymorphisms
Inform patient of concerning risk to foetus if pregnancy occurs during treatment. Advise women of child-bearing age to use adequate contraception.
Reversal of the anticoagulation effects of warfarin by vitamin K. In emergency situations fresh frozen plasma should be administered.
Concurrent heparin should be discontinued 6 hours before any control tests are carried out.
Warfarin should be discontinued if purple toe syndrome, purpura, fever, nausea, vomiting, pancreatitis, haemothorax or epistaxis occurs.
Calciphylaxis is a very rare condition that is most commonly observed in patients with known risk factors such as end stage renal failure.
If calciphylaxis is diagnosed, appropriate treatment should be started and consideration should be given to stopping treatment with warfarin.
Some formations contains lactose and should be used with caution in patients with galactosaemia, glucose-galactose malabsorption syndrome or in those who are lactose intolerant.
Some formations contain maltitol. These should not be used in patients with hereditary fructose intolerance.
Pregnancy and Lactation
The use of warfarin is contraindicated throughout pregnancy. Women of child-bearing age should use effective contraception.
Based on human experience, warfarin causes congenital malformations and foetal death when administered during pregnancy. Use in the first trimester carries a significant risk to the foetus. A characteristic pattern of abnormalities called Foetal Warfarin syndrome has been seen in infants exposed during the sensitive period believed to be in the 6th to 9th week of gestation (Briggs, 2011) (Schaefer (2007) clarifies this as week 8 after last menstrual period (LMP) or week 6 post conception). Features of foetal warfarin syndrome include low birth weight, eye defects, hypoplasia of extremities, developmental retardation, seizures, scoliosis, hearing loss and congenital heart disease. Other risks to the foetus noted include central nervous system defects (possibly linked to haemorrhage and subsequent scarring), spontaneous abortion, mid-face and lung hypoplasia, still birth, prematurity and neonatal death (Briggs, 2011). In addition, use near term carries the risk of foetal/neonatal haemorrhage (Briggs, 2011).
Women on warfarin who are planning a pregnancy should be transferred to heparin or low molecular weight heparin pre-conception or at the very latest before the sixth week post conception (information from Clinical Knowledge Summaries states week 7 after conception). Schaefer (2007) states that elective termination of pregnancy is not recommended if unplanned exposure occurs in early pregnancy. Close follow up is recommended for all exposures. High risk patients will present prescribing dilemmas and may require overruling of the contraindication during some periods of the pregnancy, despite the known risks. Information published on the Clinical Knowledge Summaries suggests that all women with venous thromboembolism taking warfarin and who are planning a pregnancy are referred to a specialist. If the woman continues to take warfarin in the pre-conception period, adequate pregnancy planning must be undertaken so that warfarin can be stopped prior to the seventh week after conception.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Use with caution. There is a consensus that maternal therapy with warfarin carries little risk for the normal, full-term breast fed infant.
Warfarin is highly protein bound and therefore very little warfarin would be expected to appear in the milk. In the small number of cases followed, insignificant amounts of warfarin have been detected in breast milk. Some authorities take the cautious approach of advising observation of the infant for signs of bleeding e.g. bruising, petechiae, and the use of oral vitamin K supplements in the infant. Consideration may be given to determining the coagulation status of the infant, especially if born pre-term (Schaefer, 2007).
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Effects on Ability to Drive and Operate Machinery
Advise patients to take doses at the same time each day.
Ensure patients receive an anticoagulant card and inform them of the need for regular blood tests.
Advise patient to report any sign of bleeding to their clinician.
Warn patients that sudden changes to their diet, for example a marked increase or decrease in the amount of salads, vegetables, fats or oils could affect their condition. Supplements containing Vitamin K should not be taken.
Advise patients to limit or avoid cranberry juice or cranberry extract.
Advise women of child-bearing age to use adequate contraception. Inform patient concerning risk to foetus if pregnancy occurs during treatment. Advise patient to consult her doctor before conception as a planned transfer to alternative medication may be possible to minimise risk.
Advise patient that many medicines, including those purchased over the counter (e.g. NSAIDs and simvastatin) and herbal medicines may affect their medicine and alter their bleeding times. The patient should consult their doctor or pharmacists before any new medication is used.
Advise patient that alcohol can potentiate the effects of warfarin.
Advise patient not to take St. John's Wort concurrently with this medication.
Advise patient to avoid large quantities of pomegranate juice concurrently with this medication.
Advise patient not to take glucosamine concurrently with warfarin.
Advise patient to avoid grapefruit juice concurrently with warfarin.
"Purple toes" syndrome
Decrease in haematocrit
Decrease in haemoglobin
The MHRA has issued the following standard guidance for warfarin overdose.
The benefit of gastric decontamination is uncertain. If the patient presents within 1 hour of ingestion of more than 0.25mg/kg or more than the patient's therapeutic dose, consider activated charcoal (50g for adults, 1g/kg for children).
In cases of life-threatening haemorrhage
Stop warfarin treatment, give prothrombin complex concentration (factors II, VII, IX and X) 30units/kg to 50units/kg or (if no concentrate available) fresh frozen plasma 15ml/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) 10mg to 20mg for adults (250micrograms/kg for a child).
Where rapid re-anticoagulation is desirable (e.g. valve replacements) give prothrombin complex concentrate (factor II, VII, IX and X) 30units/kg to 50units/kg or (if no concentrate available) fresh frozen plasma 15ml/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 > 8.0, no bleeding or minor bleeding - stop warfarin, and give phytomenadione (vitamin K1) 0.5mg to 1mg for adults, 15microgram/kg to 30 micrograms/kg for children by slow intravenous injection or 5mg by mouth (for partial reversal of anticoagulation give smaller oral doses of phytomenadione e.g., 0.5mg to 2.5mg 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 6.0 to 8.0, no bleeding or minor bleeding - stop warfarin, restart when INR less than 5.0.
- INR less than 6.0 but more than 0.5 units above target value - reduce dose or stop warfarin, restart when INR less than 5.0.
For patients NOT on long-term anticoagulants without major haemorrhage
Measure the INR (prothrombin time) at presentation and sequentially every 24 to 48 hours after ingestion depending on the initial dose and initial INR.
- If the INR remains normal for 24 to 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 0.25mg/kg;
b) the prothrombin time is already significantly prolonged (INR greater than 4.0)
The adult dose of vitamin K1 is 10mg to 20mg orally (250micrograms/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.
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Shelf Life and Storage
Store at or below 25 degrees C.
Protect from light.
Last Full Review Date: January 2012
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