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Drugs List
Therapeutic Indications
Dosage
Administration
Contraindications
Precautions and Warnings
Pregnancy and Lactation
Side Effects
Monograph

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)
Cardiac failure
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.

Thrombophilia
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
uncontrolled hypertension
cerebrovascular disease
serious heart disease including congestive cardiac failure
risk of falling
anaemia
malignancy
trauma
renal insufficiency
hepatic impairment
haemorrhagic blood dyscrasias
hypermetabolic states
fever
acute illness
vitamin K deficiency state
diarrhoea

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.

Ischaemic stroke
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.

Surgery
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

Pregnancy

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 ).

Lactation

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

Presentation

Oral formulations of warfarin sodium.

Drugs List

warfarin 1mg tablets

warfarin 1mg/ml oral suspension sugar-free

warfarin 3mg tablets

warfarin 500microgram tablets

warfarin 5mg tablets

Therapeutic Indications

Uses

Anticoagulant for:
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

Dosage

Adults

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.

Children

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.

Neonates

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.

Administration

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.

Contraindications

Pregnancy - (see Pregnancy)

Within 48 hours postpartum

Within 72 hours of surgery where there is a severe risk of bleeding

Haemorrhagic stroke

Clinically significant bleeding

Severe renal impairment

Severe hepatic impairment