Warfarin

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.

Examples of drugs which antagonise the effect of warfarin:

• barbiturates
• primidone
• carbamazepine
• griseofulvin
• oral contraceptives
• rifampicin
• azathioprine
• phenytoin

Warfarin is a mixture of enantiomers which are metabolized by different CYP P450 cytochromes. R-warfarin is metabolized primarily by CYP1A2 and CYP3A4. Swarfarin is metabolized primarily by CYP2C9. The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered.

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.

Warfarin is a mixture of enantiomers which are metabolized by different CYP P450 cytochromes. R-warfarin is metabolized primarily by CYP1A2 and CYP3A4. S-warfarin is metabolized 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.

Surgery

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.

Dental Surgery

Warfarin need not be stopped before routine dental surgery e.g. tooth extraction.

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.

Limited evidence suggests that grapefruit juice may cause a modest rise in INR in some patients taking warfarin.

Warfarin may initially be given with a heparin in the initial treatment of thrombosis, until the INR is in the correct range.

Any concomitant anti-platelet drugs should be used with caution with warfarin due an increased risk of bleeding.

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 minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding.

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

Cholestyamine and sucralfate potentially decrease absorption of warfarin.

The following examples should be avoided, or administered with caution with increased clinical and laboratory monitoring:

• Clopidogrel.
• NSAIDs (including aspirin and cox-2 specific NSAIDS).
• Sulfinpyrazone.
• Thrombin inhibitors such as bivalirudin, dabigatran.
• Dipyridamole.
• Fondaparinux, rivaroxaban.

The following examples should be avoided in co-administration with warfarin, or administered with caution with increased clinical and laboratory monitoring:

• Glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and abciximab.
• Prostacyclin.
• SSRI and SNRI antidepressants.
• Other drugs which inhibit haemostasis, clotting or platelet action.

Increased INR has been reported in patients taking glucosamine and warfarin. This combination is not recommended.

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.

The rate of warfarin metabolism depends on thyroid status. Therefore patients with hyper- or hypo-thyroidism should be closely monitored on starting warfarin therapy.

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.

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.

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.

Not relevant.

Infections and infestations: Fever

Immune system disorders: Hypersensitivity

Nervous system disorders: Cerebral haemorrhage; Cerebral subdural haematoma

Vascular disorders: Haemorrhage

Respiratory, thoracic and mediastinal disorders: Haemothorax, epistaxis

Gastrointestinal disorders: Gastroinestinal haemorrhage, rectal haemorrhage, haematemesis; pancreatitis; diarrhoea; nausea; vomiting; melaena

Hepatobiliary disorders: 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: Haematuria

Investigations: Unexplained drop in haematocrit; haemoglobin decreased