Warfarin

Registered South African indications:

• Prevention and management of deep venous thrombosis and pulmonary embolism
• Prevention of thromboembolism
  - In atrial fibrillation
  - In prosthetic heart valves
  - In post myocardial infarction
• Transient ischaemic attacks

Contraindications 

South Africa recommendations

• Hypersensitivity to warfarin sodium or to any of the excipients 
• Haemorrhagic states 
• Haemorrhagic stroke 
• Clinically significant bleeding 
• Peptic ulcers or other gastrointestinal disease involving bleeding 
• Conditions involving bleeding from respiratory or genito-urinary tract 
• Severe wounds (including surgical) 
• Prosthetic heart valves 
• Infective endocarditis 
• Impaired liver function 
• Impaired kidney function 
• Hypertension 
• Cerebrovascular haemorrhage 
• Aneurysm (cerebral or aortic) 
• Pericarditis or pericardial effusion 
• Neuro- or ophthalmic surgery (recent or contemplated) 
• Surgery involving large exposed raw surfaces 
• Within 72 hours of major surgery with risk of severe bleeding 
• Polyarthritis 
• Vitamin C deficiency 
• Major regional block anaesthesia 
• Inadequate laboratory facilities or lack of patient cooperation 
• Pregnancy 
• Breastfeeding mothers 
• Within 48 hours postpartum 
• Threatened abortion 
• Medicines where interactions may lead to a significantly increased risk of bleeding (e.g. fibrinolytic agents such as streptokinase and alteplase are contraindicated in patients receiving warfarin) 

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients 
• Haemorrhagic stroke 
• Clinically significant bleeding 
• Within 72hrs of major surgery with risk of severe bleeding 
• Within 48hrs postpartum
• Pregnancy (first and third trimesters)
• Drugs where interactions may lead to a significantly increased risk of bleeding 

Cautions

• Second trimester of pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Renal impairment (Recommendations in other jurisdictions)
• Hepatic impairment (Recommendations in other jurisdictions)
• Elderly
• Hypertension
• History of gastrointestinal bleeding
• Peptic ulcer disease  
• Cerebrovascular disease  
• Ischaemic stroke
• Risk of falling
• Anaemia
• Malignancy
• Trauma
• Protein C and S deficiency
• Surgery
• Thyroid disorders
• Dietary changes
• Weight loss
• Weight gain
• Acute illness
• Cessation of smoking
• Diarrhoea 
• Vomiting
• Infection
• Acquired or inherited warren resistance
• Patients with genomic variants in CYP2C9 and/or VKORC1
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption 

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Prevention and management of deep venous thrombosis and pulmonary embolism
Prevention of thromboembolism
- In atrial fibrillation
- In prosthetic heart valves
- In post myocardial infarction
Transient ischaemic attacks

• Oral (tab): Initial dose range: 10-15mg, dly; Treatment duration: 3 days; Maintenance dose range: 2.5-10mg, dly

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The administration and dosage of warfarin must be individualised for each patient according to the patient's sensitivity as indicated by the prothrombin time (PT) or international normalised ratio (INR)

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PT measurements should be carried out before treatment, on the 2nd and 3rd day of treatment and then on alternate days until the maintenance dose is established. Thereafter the patient should be monitored monthly

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Satisfactory levels of PT or INR for maintenance vary with the condition treated and the risk of thromboembolism. Currently recommended ranges of therapeutic anticoagulation are the following:

INR 2.0-2.5 (PT ratio 1.3-1.5)
Prophylaxis of deep vein thrombosis (DVT) including surgery in high risk patients

INR 2.0-3.0 (PT ratio 1.3-1.5)
Prophylaxis of DVT in hip surgery and fractured femur operations
Prevention of thromboembolism in myocardial infarction, mitral stenosis with embolism, atrial fibrillation and tissue prosthetic heart valves
Treatment of DVT, pulmonary embolism, transient ischaemic attacks and systemic embolism

INR 3.0-4.5 (PT ratio 1.5-2.0)
Recurrent DVT and pulmonary embolism
Arterial disease including myocardial infarction
Mechanical prosthetic heart valves

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The correlation between the INR and the PT ratio is based on thromboplastin with an international sensitivity index of 2.3

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Warfarin should be taken at the same time each day, preferably on an empty stomach

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Indications and dosages registered in other jurisdictions

Prophylaxis of systemic embolism in patients with rheumatic heart disease and atrial fibrillation
Prophylaxis after insertion of prosthetic heart valves
Prophylaxis and treatment of venous thrombosis and pulmonary embolism
Transient attack of cerebral ischaemia

• Oral (tab): Elective and sub-acute prophylactic loading dose: 10mg, dly for 2 days (tailored to individual requirements); Maintenance: 3-9mg, dly

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Monitoring: Baseline prothrombin (PT) or INR measurements should be made before beginning therapy with warfarin tablets

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A therapeutic range of acceptable coagulation test measurements should be individually established which are then monitored at regular intervals to guide treatment and subsequent dosing. A maintenance dose can be omitted if the prothrombin time is excessively prolonged

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Emergency anticoagulant therapy: Emergency anticoagulation should be initiated with heparin and warfarin together. Where there is less urgency, as in patients predisposed to or at special risk of thromboembolism, anticoagulant therapy may be initiated with warfarin alone

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Warfarin tablets should be taken at the same time each day, preferably on an empty stomach

Recommendations below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Not established for use in children below 18 years

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Indications and dosages registered in other jurisdictions

No information available

Pregnancy

South African recommendations

• Contraindicated
• Warfarin is a recognised teratogen. Treatment with warfarin during pregnancy should be avoided
• Women of childbearing age who are taking warfarin should use effective contraception during treatment

Recommendations in other jurisdictions

• First and third trimester: Contraindicated
• Second trimester: Caution
• Based on human experience warfarin causes congenital malformations and fetal death when administered during pregnancy
• Warfarin is contraindicated in pregnancy in the first and third trimester
• Women of childbearing age who are taking Warfarin tablets should use effective contraception during treatment

Breastfeeding

South African recommendations

• Contraindicated
• Treatment with warfarin during breastfeeding should be avoided

Recommendations in other jurisdictions

• Compatible
• Warfarin is excreted in breast milk in small amounts. However, at therapeutic dose of warfarin no effects on the breastfeeding child are anticipated. Warfarin can be used during breastfeeding

Fertility

• No information available

Renal Impairment

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended

Hepatic Impairment

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended

Elderly

• Caution; dose adjustment recommended 
• May require lower dosages to produce a therapeutic level of anticoagulation

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

•  Permitted - No warnings

Central Nervous System Disorders

• Cerebral haemorrhage
• Cerebral subdural haematoma

Cardiovascular Disorders

• Haemorrhage

Respiratory Disorders

• Haemothorax
• Epistaxis

Gastrointestinal Disorders

• Gastrointestinal haemorrhage
• Rectal haemorrhage
• Haematemesis
• Pancreatitis
• Diarrhoea
• Nausea and vomiting 
• Melaena

Hepatobiliary Disorders

•  Jaundice
•  Hepatic dysfunction

Genitourinary Disorders

• Haematuria

Skin and subcutaneous disorders

• Rash
• Alopecia
• Purpura
• 'Purple toes' syndrome
• Erythematous swollen skin patches leading to ecchymosis 
• Infarction and skin necrosis
• Calciphylaxis

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Fever
• Unexplained drop in haematocrit
• Haemoglobin decreased

Drugs that enhance the anticoagulant effect of warfarin

• Fibrinolytic agents
• Streptokinase
• Alteplase
• Dipyridamole
• Clopidogrel
• Asprin
• Glycoprotein IIb/IIIa receptor antagonists 
• Heparin
• Fondaparinux
• Rivaroxaban
• Dabigatran
• Selective serotonin re-uptake inhibitors
• Non-steroidal anti-inflammatory drugs
• Prostacyclin

Drugs that potentiate the effects of warfarin

• Sulfinpyrazone
• Allopurinol
• Capecitabine
• Erlotinib
• Disulfiram
• Azole antifungals
• Omeprazole
• Paracetamol
• Propafenone
• Amiodarone
• Tamoxifen
• Methylphenidate
• Zafirlukast
• Fibrates
• Statins
• Erythromycin
• Sulfamethoxazole
• Metronidazole
• Broad spectrum antibiotics
• Glucosamine
• Acute alcohol intake
• Cranberry juice
• Grapefruit juice
• Cytochrome P450 enzyme inhibitors

Drugs that decrease the effects of warfarin

• Barbituates
• Primidone
• Carbamazepine
• Griseofulvin
• Oral contraceptives
• Rifampicin 
• Azathioprine
• Phenytoin
• Cholestyramine
• Sucralfate
• St John's wort
• Chronic heavy alcohol intake
• Cytochrome P450 enzyme inducers

Drugs with variable effect

• Corticosteroids
• Nevirapine
• Ritonavir

• INR
• Thyroid function

Warfarin is a synthetic anticoagulant of the coumarin series. It inhibits vitamin K reductase and Vitamin K Epoxide reductase, resulting in inhibition of carboxylation of the vitamin K-dependent coagulant proteins, clotting factors II, VII, IX, and X and anticoagulant proteins C and S. This results in decreased functional levels of vitamin K dependant clotting factors.

Tablet 1mg

• Cipla Warfarin (Cipla Medpro)

Tablet 3mg

• Cipla Warfarin (Cipla Medpro)

Tablet 5mg

• Cipla Warfarin (Cipla Medpro)
• Aspen Warfarin (Pharmacare)