Drug Description

Presentation

Indications

Adult Dosage

Warfarin tablets are for oral administration.

An initial daily dose of 10mg on the first two days. Subsequent daily doses should be adjusted according to the results of the prothrombin time or other appropriate coagulation tests. The single daily maintenance requirement is usually between 5mg and 12mg, but can vary between 2mg and 30mg.

The maintenance dose is omitted if the prothrombin time is excessively prolonged.

Use in elderly patients: The elderly are generally more sensitive to the effects of warfarin and often require a smaller dose on a weight for weight basis than younger patients.

Contra Indications

Animal studies have shown warfarin to be teratogenic and there have been reports of foetal death and embryopathy associated with its administration during human pregnancy. Warfarin should not be prescribed for pregnant women.

Warfarin should not be given to patients within three days of surgery.

The use in patients known to be hypersensitive to warfarin is contra-indicated.

Special Precautions

There is some evidence that abrupt conclusion or interruption of anticoagulation therapy leads to complications in the form of relapses or exacerbations of the underlying disease and it is probably wiser to taper off oral anticoagulants when therapy has to be concluded.

Prothrombin times should be determined at least twice weekly for the first two weeks until the results stabilise in the therapeutic range. Subsequent measurements may be made at appropriate intervals, such as every two to three weeks. When warfarin therapy is first introduced, patients should be told what to do if bleeding occurs.

Warfarin should be given with caution to patients with impaired liver or kidney function or in severe hypertension.

Warfarin should be given with caution to patients where there is a risk of serious haemorrhage such as aortic or cerebral aneurysms, haemorrhagic blood dyscrasias, haemophilia, ulcerative disorders, threatened abortion, subacute bacterial endocarditis, in the presence of extensive surgical wounds and after recent surgery to the eye and central nervous system.

Acquired or inherited warfarin resistance should be suspected if larger than usual daily doses of warfarin are required to achieve the desired anticoagulant effect.

The anticoagulant effect of warfarin may be increased or decreased by concomitant use of herbal medicines. One such example is the interaction between warfarin and St. John's Wort.

Patients should be advised to avoid excessive intake of vitamin K, as may occur with ingestion of certain vitamin supplements or of large amounts of food rich in vitamin K (examples include liver, broccoli, cauliflower, cabbage, spinach, green leafy vegetables, and green tea).

Some validation studies to compare coagulation results obtained by laboratory and portable instruments showed discrepancies in results. Check with hospital/local laboratory for verification of the results prior to adjusting the dose.

Interactions

Care is required with all concomitant therapy. Known interactions include the following, but in the case of other medicines, including newly available ones, the prescriber should refer to the manufacturer's information or to the appropriate monograph.

Many factors potentiate the effect of warfarin:

1. Warfarin in the circulation is firmly bound to plasma protein and will have an increased effect if displaced by other drugs such as diuretics, oral anti-diabetic agents, anti-inflammatory agents and amiodarone.

2. Certain drugs, for example D-thyroxine, potentiate the effects of warfarin by increasing the affinity for the hepatic receptor site.

3. Alcohol may inhibit liver enzymes, leading to a reduced dosage requirement of warfarin.

4. Other drugs which may potentiate the effect of warfarin include anabolic steroids; cimetidine; aspirin and other non-steroidal anti-inflammatory drugs; lipid-regulating drugs, including the fibrates, such as clofibrate, and statins, such as simvastatin; sulphinpyrazone; chloral hydrate; some aminoglycoside antibiotics; chloramphenicol; macrolide antibacterials such as erythromycin, clarithromycin or azithromycin; quinolone antibacterials such as ciprofloxacin or nalidixic acid; some antifungal drugs, including miconazole; some anti-retroviral agents, such as indinavir or ritonavir (although the effect of the latter on the INR may be variable); antineoplastic drugs, including 5-fluorouracil; selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine and fluoxetine; disulfiram; paracetamol.

The effect of warfarin may be enhanced by certain herbal medicines such as dong quai and ginkgo.

5. Renal damage may reduce the rate of excretion of warfarin and thus decrease the dose requirement.

6. Acute illness, weight loss and a decreased intake of vitamin K will exaggerate the response.

Other factors may decrease the effect of warfarin:

1. Warfarin is metabolised in the liver by microsomal enzymes. These enzymes are induced by drugs such as barbiturates and phenytoin leading to rapid metabolism of warfarin and necessitating an increased dose.

2. Oestrogens and oral contraceptives increase the concentration of Vitamin K- dependent factors. Increased doses of warfarin may therefore be required.

3. Cholestyramine may absorb warfarin and thus reduce its effect.

4. Weight gain, gastro-intestinal upset and increased intake in Vitamin K will necessitate an increase in maintenance dosage of warfarin.

5. Carbamazepine, glutethimide, phenazone, griseofulvin and rifampicin also diminish the effect of warfarin.

6. The effect of warfarin can be reduced by concomitant use of the herbal remedy St. John's Wort (hypericum perforatum) and ginseng.

Individual case reports suggest a possible interaction between warfarin and cranberry juice, in most cases leading to an increase in INR or bleeding event. It is not possible to define a safe quantity or brand of cranberry juice, therefore patients taking warfarin should be advised to avoid this drink unless the health benefits are considered to outweigh any risks. Increased medical supervision and INR monitoring should be considered for any patient taking warfarin and a regular intake of cranberry juice.

It is not known whether other cranberry products, such as capsules or concentrates, might also interact with warfarin. Therefore similar caution should be observed with these products.

Adverse Reactions

External or internal bleeding is the most common adverse effect of warfarin therapy. Internal haemorrhage can occur in any tissue or organ. This may be due to over-anticoagulation due to poorly controlled treatment or drug interaction. Bleeding may also occur at therapeutic INR values, in which case the possibility of an underlying condition predisposing to haemorrhage should be investigated. Management of bleeding whilst taking warfarin is discussed in 'Overdose'.

Skin reactions: Purpura and ecchymosis are common in over-anticoagulated patients. Pruritic lesions (macular, papular, vesicular and urticarial) have also been reported. Skin necrosis is a rare but potentially serious effect. It is associated with loading doses of over 10mg, and occurs mainly in obese elderly women, usually within 3 - 5 days of starting treatment. It may be associated with a Protein C or Protein S deficiency. It usually affects fatty tissues (breast, thighs, buttocks) and starts as a localised, painful, erythematous or haemorrhagic lesion which becomes bullous and eventually necrotic. Advice on management usually includes discontinuing the warfarin and administration of vitamin K or fresh frozen plasma, and heparinising the patient. The 'purple toes' syndrome is also rarely reported.

Other adverse effects that have been reported: Alopecia, diarrhoea, an unexplained fall in the haematocrit, jaundice and hepatic dysfunction, fever, nausea, vomiting and pancreatitis. Hypersensitivity reactions occur extremely rarely. If any of these effects occur, warfarin treatment should normally be stopped immediately.

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