Warfarin

ADMINISTRATION ROUTES:

PO, NG

ALTERNATIVE NAMES:

Coumadin, Marevan

ICU INDICATIONS:

1. Anticoagulation for prophylaxis and/or treatment of venous thrombosis, pulmonary embolism, thromboembolism associated with atrial fibrillation or prosthetic valve insertion

PRESENTATION AND ADMINISTRATION:

PO/NG:

Coumadin tablets:

• 1 mg (beige)
• 2 mg (lavender)
• 5 mg (green)

Marevan tablets:

• 1 mg (brown)
• 3 mg (blue)
• 5 mg (pink)

Tablets can be crushed for administration through an NG/NJ tube. Warfarin is teratogenic - do not crush tablets if pregnant.

DOSAGE:

The dosage is individualised according to the patient's sensitivity which is determined by measurement of INR. Most patients are satisfactorily maintained with a single daily dose of 2 - 10 mg.

Loading doses are dependent on the indication for warfarin.

After valve replacement surgery:

3 mg OD for 2 days

Adjust third & subsequent doses if INR < 1.5 or > 3.0

For all other patients:

5 mg OD for 3 days

Adjust fourth & subsequent doses according to INR

Recommended INR ranges:

An INR > 4.0 provides no additional therapeutic benefit in most patients but is associated with a higher risk of bleeding.

Duration of therapy is individualised. In general warfarin should be continued until the danger of thrombosis or embolism has passed.

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

Dose in renal impairment:

Dose in renal replacement therapy

DOSAGE IN PAEDIATRICS:

PO / NG:

Day 1: 0.2 mg/kg (maximum 5 mg) OD

Day 2 & ongoing: 0.05 - 0.2 mg/kg (maximum 5 mg) OD titrated to INR

CLINICAL PHARMACOLOGY:

Warfarin acts by inhibiting the synthesis of vitamin K dependent clotting factors which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Therapeutic warfarin doses decrease the total amount of the active form of each vitamin K dependent factor made by the liver by approximately 30 - 50%.

An anticoagulant effect generally occurs within 24 hours after drug administration, however peak anticoagulant effect may be delayed by 72-96 hours. The duration of action of a single dose of warfarin is 2-5 days.

Warfarin may potentiate a more hypercoagulable state in the first 24 - 48 hours due to the more rapid depletion of the anticoagulant proteins C & S when compared to the clotting factors with longer half-lives. Due to this, any preceding anticoagulant therapy, such as unfractionated heparin or enoxaparin, should be continued as a bridge until the desired therapeutic INR is reached. This initial pro-coagulant effect is increased with the use of higher loading doses.

Warfarin may increase the APTT test even in the absence of heparin. Heparin therapy may also affect the INR.

Anticoagulants have no direct effect on established thrombus but prevent further extension of the formed clot.

CONTRAINDICATIONS:

Any condition in which the hazard of haemorrhage is greater than the potential clinical benefits of anticoagulation, such as:

1. Pregnancy, threatened abortion, eclampsia and pre-eclampsia
2. Haemorrhagic tendencies or blood dyscrasias
3. Severe to moderate hepatic or renal insufficiency
4. Recent or contemplated surgery of the central nervous system, eye, or traumatic surgery resulting in large open surfaces
5. Bleeding tendencies associated with active ulceration or overt bleeding of gastrointestinal / genitourinary or respiratory tracts, cerebrovascular haemorrhage, cerebral aneurysms, dissecting aorta
6. Pericarditis and pericardial effusions
7. Bacterial endocarditis
8. Discharge to an area with Inadequate laboratory facilities for ongoing INR monitoring
9. Unsupervised senility, alcoholism, psychosis or lack of patient co-operation
10. Spinal puncture
11. Malignant hypertension
12. Known or suspected deficiency in protein C
13. Known hypersensitivity to warfarin

WARNINGS:

Therapy in each patient is highly individualised and regular INR monitoring is required due to the narrow therapeutic index of warfarin, which may be easily affected by other drugs and dietary vitamin K.

The risk of haemorrhage in any tissue or organ is related to level of intensity and duration of anticoagulant therapy.

Use with caution in patients with venous thromboembolism, who have developed heparin-induced thrombocytopenia. Limb ischaemia, necrosis and gangrene have occurred when warfarin was started or continued after heparin was stopped in these cases.

Atheroemboli / cholesterol microemboli have rarely been reported with warfarin with the most common sites as the kidneys, pancreas, liver, and spleen. Onset varies between 2 weeks to 6 months from initiation.

Serious and fatal calciphylaxis has rarely been reported in patients with and without end-stage kidney disease on warfarin. Onset is delayed and can present between 1 month to 14 years from initiation.

Skin necrosis is a very rare condition associated with warfarin. Onset is rapid and usually appears within the first 5 days of therapy.

PRECAUTIONS:

General:

An increased INR response can be seen in patients > 60 years old, patients with active infection, cancer, congestive heart failure, hyperthermia, hyperthyroidism, hepatic and renal impairment, and in patients with a poor nutritional state (especially in vitamin K defficiency).

A decreased INR response may be seen with oedema, hyperlipidaemia and hypothyroidism.

Laboratory Tests:

Therapeutic effect is monitored by regular measurement of the INR.

Drug/Laboratory Test Interactions:

None

IMPORTANT DRUG INTERACTIONS FOR THE ICU:

Drugs that may cause an increased INR when used with warfarin include:

• Alcohol
• Allopurinol
• Amiodarone,
• Aspirin
• Azithromycin
• Amitriptyline
• Carbimazole
• Cephazolin
• Ceftriaxone
• Chloramphenicol
• Chloral hydrate
• Ciprofloxacin
• Clarithromycin
• Dexamethasone
• Defibrotide
• Diclofenac
• Doxycycline
• Erythromycin
• Fluconazole
• Fluoxetine
• Glucagon
• Hydrocortisone
• Ibuprofen
• Indomethacin
• Influenza vaccine
• Itraconazole
• Ketorolac
• Linezolid
• Methyldopa
• Miconazole
• Metronidazole
• Naproxen
• Omeprazole
• Paracetamol
• Paroxetine
• Benzylpenicillin
• Phenytoin
• Prednisone
• Propranolol
• Quinine
• Ranitidine
• Simvastatin
• Tamoxifen
• Tetracycline
• Tramadol
• Valproate

Drugs that may cause a decreased INR when used with warfarin include:

• Atorvastatin
• Azathioprine
• Carbamazepine
• Chloral hydrate
• Clozapine
• Flucloxacillin
• Haloperidol
• Phenobarbitone
• Prednisone
• Rifampicin
• Spironolactone
• Sucralfate
• Thiopentone
• Vitamin C (high dose)
• Vitamin K

ADVERSE REACTIONS:

Nervous system:

Headache, dizziness. Haemorrhagic complications may present as headache, paralysis, paraesthesia or altered consciousness & need to be excluded.

Cardiovascular:

Vasculitis, atheromatous embolism, calciphylaxis

Gastrointestinal:

Abdominal pain, nausea, vomiting, diarrhoea, flatulence, bloating, pancreatitis

Hepatic:

Hepatitis, increased liver enzymes

Genitourinary:

Haematuria

Skin:

Necrosis, bullous eruptions, urticaria, dermatitis, pruritus, alopecia