Warfarin sodium clathrate

This medicine is indicated in adults for:

- Prophylaxis of systemic embolism in patients with rheumatic heart disease and atrial fibrillation.

- Prophylaxis after insertion of prosthetic heart valves.

- Prophylaxis of venous thrombosis and pulmonary embolism and for use in the treatment of these conditions to prevent their extension.

Posology:

A baseline coagulation screen and liver function tests should be performed before initiating warfarin therapy.

Adults: The typical induction dose is 10 mg daily for 2 days but this should be tailored to individual requirements.

The daily maintenance dose is usually 3 to 9 mg taken at the same time each day. The exact maintenance dose depends on the prothrombin time, usually reported as the INR (international normalised ratio), 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.).

In emergencies, anticoagulant therapy should be initiated with heparin and warfarin together.

Elderly: As for adults, but dosage may need to be lowered. The elderly are generally more sensitive to the effects of warfarin and often require a smaller dose.

Paediatric population:

Dosage for children has not been established. Warfarin 1mg/ml Oral Suspension is not recommended for use in children.

Method of administration:

For oral administration only.

Haemorrhagic stroke

Clinically significant bleeding

Use within 72 hours of surgery with risk of severe bleeding

Use within 48 hours postpartum.

Warfarin is contraindicated in pregnancy.

Drugs where interactions 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

If this preparation replaces or is replaced by another warfarin product, the patient should be monitored closely in the period immediately following the change.

Monitoring

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.

For patients with any impairments that may influence their ability to take the correct dosage safely, the assistance of a carer to administer the dose may be required.

Thrombophilia

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.

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 including congestive cardiac failure, risk of falling, anaemia, malignancy, trauma, renal insufficiency, impaired hepatic function, haemorrhagic blood dyscrasias, hypermetabolic states e.g. hyperthyroidism, or fever, acute illness, vitamin K deficiency state, diarrhoea concomitant drugs.

Genetic factors: genetic polymorphisms in the cytochrome P450 CYP2C9 gene result in impaired metabolism of S-warfarin. Affected individuals have an increased sensitivity to warfarin, manifesting as low dose requirements and an increased risk of bleeding. The variant alleles occur at a higher frequency in white populations than in other ethnic groups studies.

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

Haemorrhage can indicate an overdose of warfarin has been taken.

If haemorrhage occurs overdose should be suspected. Bleeding may occur at therapeutic INR values, in which case the possibility of an underlying condition that predisposes the haemorrhage should be investigated.

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 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.

Surgery

Minor surgical procedures with low risk of bleeding can be performed in general with an INR of <2.5. However the local recommendation should be considered.

For surgery, other surgical procedures, where there is a risk of severe bleeding, warfarin should be stopped 3-5 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.

Dental Surgery

In most cases warfarin need not be stopped before routine dental surgery, e.g. tooth extraction.

Calciphylaxis

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.

Peptic ulceration

Due to a high risk of bleeding, patients with history of 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.

Interactions

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 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.

Thyroid disorders

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 suspension, and necessitate a reduction of dosage:

- Loss of weight

- Acute illness

- Cessation of smoking

The following may reduce the effect of warfarin suspension, and require the dosage to be increased:

- Weight gain

- Diarrhoea

- Vomiting

Other warnings

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

Ingredients in the formulation

The product contains liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Warfarin has no influence on the ability to drive and use machines.

Frequency categories are unknown for the following reported adverse reactions and therefore have not been included.

^a MedDRA is a dictionary of medical terminology used by the MHRA to enter data into the Yellow Card database. The dictionary is organized by system organ class

Skin necrosis is a rare but serious side effect of warfarin. It occurs mainly in obese, female patients, usually within 3 to 10 days of starting therapy, and is associated with the use of high induction doses. Patients with protein C or protein S deficiency are at particular risk. Initially, the lesions consist of painful, indurated, reddened areas, which progress through a stage of blood-filled blisters into well-demarcated blackened necrotic patches. Areas of skin with underlying fatty tissue, such as breasts, flanks and buttocks are most often affected. Pain in a particular area of skin is a premonitory symptom, and withdrawal of the oral anticoagulant at this stage, reversal of its effects with vitamin k or fresh frozen plasma, and the use of heparin may limit the extent of tissue damage.

'Purple toes' which is a rare complication of warfarin therapy. Typically, the syndrome presents 3 to 8 weeks after initiation of warfarin therapy as a sometimespainful blue-tinged discoloration of the plantar aspects and sides of the toes. Cholesterol emboli released from atheromatous plaques have been implicated as the cause. If the syndrome occurs, it is recommended that warfarin therapy be withdrawn, if possible, as the affected tissue may undergo ischaemic necrosis

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 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.

In cases of life-threatening haemorrhage

Stop warfarin treatment, give prothrombin complex concentrate* (factors II, VII, IX, and X) or (if no concentrate available) fresh frozen plasma. 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).

Where rapid re-anticoagulation is desirable (e.g., valve replacements) give prothrombin complex concentrate* (factors II, VII, IX, and X) or (if no concentrate available) fresh frozen plasma.

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) by slow intravenous injection or by mouth (for partial reversal of anticoagulation give smaller oral doses of phytomenadione 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 6·0-8·0, no bleeding or minor bleeding—stop warfarin, restart when INR <5·0

- INR <6·0 but more than 0·5 units above target value—reduce dose or stop warfarin, restart when INR <5·0

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 0·25 mg/kg;

OR

b) the prothrombin time is already significantly prolonged (INR >4·0).

*For the dosages to be used for phytomenadione or prothrombin complex concentrate* (factors II, VII, IX, and X, please refer to the relevant product SPC.

The degree of reversal of anticoagulation must be decided on an individual basis. Full reversal with vitamin K may result in prolonged resistance to warfarin, giving rise to the possibility of valve thrombosis and thrombo-embolism in patients with prosthetic heart valves.

Pharmacotherapeutic Category: Antithrombotic agent (Vitamin K Antagonist)

ATC Code: BO1 AA03

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, and is excreted in the urine mainly as metabolites.

Warfarin has been shown to be teratogenic in animal studies and may cause abnormalities and foetal death when administered during pregnancy in humans.

Not applicable.

Any unused product or waste material should be disposed of in accordance with local requirements.