Oral Prophylaxis of systemic embolism after myocardial infarction
Adult: As adjunctive therapy: Appropriate initial dosage varies widely among different patients and may be influenced by clinical factors (e.g. age, race, body weight, sex, genotype, concomitant medications, comorbidities). Initially, 2-5 mg once daily. Alternatively, 5-10 mg to be taken on day 1. Usual maintenance: 2-10 mg once daily. Dosage must be individualised according to the patient's INR and the condition being treated. Treatment duration must also be individualised for each patient. Dosage and treatment recommendations may vary among countries (refer to latest local guidelines). Elderly: Lower doses may be required.
Oral Pulmonary embolism, Thromboembolic complications associated with atrial fibrillation, Thromboembolic complications associated with cardiac valve replacement, Venous thrombosis
Adult: For prophylaxis and treatment: Appropriate initial dosage varies widely among different patients and may be influenced by clinical factors (e.g. age, race, body weight, sex, genotype, concomitant medications, comorbidities). Initially, 2-5 mg once daily. Alternatively, 5-10 mg to be taken on day 1. Usual maintenance: 2-10 mg once daily. Dosage must be individualised according to the patient's INR and the condition being treated. Treatment duration must also be individualised for each patient. Dosage and treatment recommendations may vary among countries (refer to latest local guidelines). Elderly: Lower doses may be required.
What are the brands available for Warfarin in Hong Kong?
Debilitated patients: Lower doses may be required.
Pharmacogenomics:
Dosage requirements for warfarin may be affected by variations in the genes responsible for warfarin metabolism or pharmacodynamic response. Warfarin is administered as a racemic mixture of R- and S-enantiomers. The S-enantiomer of warfarin is 2-5 times more potent than the R-enantiomer and is metabolised predominantly by CYP2C9, a polymorphic enzyme. Vitamin K epoxide reductase complex subunit 1 (VKORC1) is the gene that encodes vitamin K epoxide reductase protein, the target enzyme of warfarin, and catalyses the conversion of vitamin K epoxide to vitamin K.
Additionally, CYP4F2 is a liver vitamin K oxidase that catalyses the metabolism of vitamin K to hydroxy-vitamin K1 which acts as an important counterpart to VKORC1 in limiting the excessive accumulation of vitamin K. Although the exact mechanism remains unknown, it has been found that the rs12777823 genotype is associated with the oral clearance of S-warfarin.
Genetic testing for CYP2C9 and VKORC1 prior to initiation of therapy should be considered. Although not as commonly tested for as CYP2C9 and VKORC1, genetic testing for CYP4F2 and rs12777823 may also be considered.
CYP2C9
Studies suggest that CYP2C9*2 and CYP2C9*3 alleles impair the metabolism of S-warfarin by approx 30-40% and 80-90%, respectively. Patients who inherit 1 or 2 copies of CYP2C9*2 or CYP2C9*3 are at greater risk of bleeding during warfarin therapy as compared to patients homozygous for CYP2C9*1 (normal or extensive metabolisers). These patients need lower doses to achieve similar levels of anticoagulation and need more time to achieve a stable INR.
The prevalence of CYP2C9*2 and CYP2C9*3 variant alleles is estimated to be 11% and 7% in Caucasians, respectively. CYP2C9*2 is virtually absent in Asians. Other variant alleles associated with decreased function of the CYP2C9 enzyme include CYP2C9*5, *6, *8, and *11, these alleles are most prevalent among patients of African ancestry, and as a group, are more common than CYP2C9*2 and CYP2C9*3 in that population.
VKORC1
A single nucleotide polymorphism in the VKORC1 gene (c.-1639G>A; rs9923231) is significantly associated with variable warfarin sensitivity and dosage requirements. Patients with 1 or 2 -1639A require progressively lower warfarin doses than -1639G/G homozygotes. The -1639G>A polymorphism is present on a haplotype that affects the expression of VKORC1 protein.
Frequency of the c.-1639G>A allele differs across various ancestral populations, largely accounting for the differences in average dosage requirements among whites, blacks, and Asians.
CYP4F2
Studies showed that the nonsynonymous variant CYP4F2*3 (rs2108622) is associated with reduced CYP4F2 activity and reduced metabolism of vitamin K, which may lead to increased warfarin dosage requirement.
CYP2C
The CYP2C rs12777823 is a single nucleotide polymorphism situated in the CYP2C cluster near the CYP2C18 gene on chromosome 10. It is associated with significant changes in warfarin clearance, independently of CYP2C9*2 and CYP2C9*3. Based on a study, African Americans who are heterozygous or homozygous for the rs12777823 A allele require a decrease in warfarin dose of approx 7 mg or 9 mg per week, respectively.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of September 2017:
If CYP2C9*2, CYP2C9*3 and VKORC1 genotypes are available, follow the recommendations below according to the patient's self-identified ancestry. If these genotypes are not available, dose warfarin clinically without consideration for the genotype, which may include the use of a clinical dosing algorithm or standard dose approach.
Non-African ancestry:
Calculate warfarin dose using published pharmacogenetic algorithms (e.g. Gage or International Warfarin Pharmacogenetics Consortium [IWPC] algorithm), including genotype information for VKORC1-1639 G>A, CYP2C9*2 and CYP2C9*3. Consider an alternative oral anticoagulant in CYP2C9 poor metabolisers (e.g. CYP2C9*2/*3, *3/*3) or in patients with both increased sensitivity (VKORC1-1639 A/A) and CYP2C9 poor metabolism. For loading dose, may consider the use of a pharmacogenetics-based warfarin loading dose algorithm.
Patients carrying CYP2C9*5, *6, *8 or *11 variant alleles (e.g. *1/*8, *1/*11, *8/*11): May reduce calculated warfarin dose by 15-30% or consider an alternative agent. Large dose reductions may be necessary in patients homozygous for variant alleles (i.e. 20-40%).
Patients carrying CYP4F2*3 (rs2108622 T): May increase warfarin dose by 5-10%.
African ancestry:
If CYP2C9*5, *6, *8 and *11 are also tested, calculate warfarin dose using a validated pharmacogenetic algorithm, including genotype information for VKORC1-1639 G>A, CYP2C9*2 and CYP2C9*3. Consider an alternative oral anticoagulant in CYP2C9 poor metabolisers (e.g. CYP2C9*2/*3, *3/*3) or in patients with both increased sensitivity (VKORC1-1639 A/A) and CYP2C9 poor metabolism. For loading dose, may consider the use of a pharmacogenetics-based warfarin loading dose algorithm.
If CYP2C9*5, *6, *8 and *11 are not tested, dose warfarin clinically without consideration for the genotype.
Patients carrying CYP2C9*5, *6, *8 or *11 variant alleles (e.g. *1/*8, *1/*11, *8/*11): Reduce calculated warfarin dose by 15-30%. Large dose reductions may be necessary in patients carrying 2 variant alleles (i.e. 20-40%).
African Americans (primarily originating from West Africa) who tested positive for rs12777823 A/G or A/A genotype: Reduce warfarin dose by 10-25%.
Recommendations on pharmacogenetic testing and dosing may vary among countries. Refer to the latest local guidelines.
Hepatic Impairment
Severe: Contraindicated.
Administration
Warfarin May be taken with or without food.
Contraindications
Haemorrhagic stroke, clinically significant bleeding, blood dyscrasias, bleeding tendencies (e.g. bacterial endocarditis, pericarditis, pericardial effusion, cerebral aneurysm, dissecting aortic aneurysm; active gastrointestinal ulceration or overt bleeding of gastrointestinal, respiratory or genitourinary tract; CNS haemorrhage; spinal puncture and other diagnostic or therapeutic procedures with potential for significant bleeding); major regional or lumbar block anaesthesia; recent or contemplated surgery of the CNS or eye, traumatic surgery resulting in large open surfaces; threatened abortion, eclampsia or pre-eclampsia; malignant hypertension. Unsupervised patients with conditions associated with possible high level of non-compliance with treatment (e.g. dementia or senility). Use within 48 hours postpartum or within 72 hours of major surgery with risk of severe bleeding. Severe hepatic impairment. Pregnancy (excluding pregnant women with mechanical heart valves who are at high risk for thromboembolism). Concomitant use with fibrinolytic agents (e.g. streptokinase, alteplase).
Special Precautions
Patient with vitamin K deficiency, protein C or protein S deficiency, risk factors for bleeding (e.g. higher dosages, high intensity of anticoagulation [INR >4.0], highly variable INRs, history of gastrointestinal bleeding, recent ischaemic stroke, uncontrolled hypertension, serious heart disease, cerebrovascular disease, malignancy, anaemia, trauma), hyperthyroidism or hypothyroidism, acute illness or infection, any disruption of normal intestinal flora, polycythaemia vera, diabetes mellitus, vasculitis, changes in weight. Patient undergoing dental surgery or minor surgery with no risk of severe bleeding. Patient with certain genetic variations in CYP2C9, VKORC1, and CYP4F2 genes or with rs12777823 genotype. Not to be used as initial treatment in patients with heparin-induced thrombocytopenia or heparin-induced thrombocytopenia with thrombosis syndrome. Smoking (including cessation). Renal and mild to moderate hepatic impairment. Elderly and debilitated patient. Lactation.
Adverse Reactions
Significant: Acute kidney injury. Rarely, purple toes syndrome. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, pancreatitis, dysgeusia, abdominal pain, flatulence, bloating. General disorders and administration site conditions: Fever, chills. Hepatobiliary disorders: Jaundice, hepatic dysfunction. Immune system disorders: Hypersensitivity reactions (including urticaria and anaphylactic reactions). Skin and subcutaneous tissue disorders: Rash, alopecia, dermatitis (including bullous eruptions), pruritus. Potentially Fatal: Major haemorrhage. Rarely, atheroemboli or cholesterol microemboli, calciphylaxis, skin necrosis or gangrene.
IV/Parenteral/PO: X, D (For high-risk mechanical heart valve)
Patient Counseling Information
Women of childbearing potential must use effective birth control method during treatment and for at least 1 month after the final dose.
Monitoring Parameters
Confirm pregnancy status before treatment in women of childbearing potential. Perform INR assessments at baseline, daily or on alternate days in the early stages of therapy, then at longer intervals once the dose has been established and patient is well stabilised. Monitor CBC (regularly) and for signs and symptoms of bleeding. Consider genetic testing for CYP2C9 and VKORC1 before treatment initiation, if possible.
Overdosage
Symptoms: Abnormal bleeding such as blood in urine and stools, melaena, petechiae, excessive menstrual bleeding, excessive bruising or persistent oozing from superficial injuries. Management: Activated charcoal may be considered if patient presents within 1 hour of ingestion of >0.25 mg/kg or more than the patient's therapeutic dose. Oral phytomenadione may be given in doses of 10-20 mg in adults (250 mcg/kg for children); delay oral phytomenadione at least 4 hours after administering activated charcoal. Repeat INR after 24 hours and consider further phytomenadione dose. In case of life-threatening haemorrhage, discontinue warfarin and administer prothrombin complex concentrate (factors II, VII, IX, and X) 30-50 units/kg or fresh-frozen plasma 15 mL/kg if the concentrate is unavailable. For non-life-threatening haemorrhage, give phytomenadione 10-20 mg for adults (250 mcg/kg for children) via slow IV inj. If rapid re-anticoagulation is desirable (e.g. valve replacements), give prothrombin complex concentrate or fresh frozen plasma. Monitor INR for at least 48 hours post-overdose and determine when to restart normal therapy. Refer to specific product or local guidelines for further information.
Drug Interactions
Increased risk of bleeding with other anticoagulants (e.g. heparin), antiplatelet agents (e.g. aspirin, clopidogrel), SSRIs (e.g. fluoxetine, fluvoxamine, paroxetine, sertraline) and NSAIDs (e.g. celecoxib, ibuprofen). Increased plasma concentration and effect with inhibitors of CYP2C9 (e.g. phenylbutazone, fluvastatin, amiodarone, fluconazole, voriconazole, capecitabine, metronidazole, zafirlukast), CYP1A2 (e.g. ciprofloxacin), or CYP3A4 (e.g. atazanavir, fosamprenavir, imatinib, itraconazole, ketoconazole, clarithromycin). Reduced plasma concentration and effect with inducers of CYP2C9 (e.g. aprepitant, nevirapine), CYP1A2 (e.g. omeprazole), or CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, bosentan). Decreased absorption with azathioprine, mercaptopurine, colestyramine and sucralfate. Reduced anticoagulant effect with phytomenadione. Aprepitant may decrease the plasma concentration of S-enantiomer of warfarin and decrease INR. Potentially Fatal: May enhance anticoagulant effect with fibrinolytic agents (e.g. alteplase, streptokinase).
Food Interaction
Increased metabolism with St. John's wort. May reduce anticoagulant effect with foods high in vitamin K content (e.g. spinach, broccoli, cabbage, and other green leafy vegetables). May increase effect with cranberry and vitamin E. Acute ingestion of alcohol may decrease the metabolism of warfarin, while chronic alcohol consumption may increase the metabolism of warfarin.
Action
Description: Mechanism of Action: Warfarin, a coumarin anticoagulant, inhibits the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X, as well as the anticoagulant protein C and its cofactor protein S. It is believed to inhibit the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, leading to a decrease in vitamin K1 epoxide regeneration and subsequently reducing clotting factor synthesis. Onset: Initial anticoagulant effect on INR: 24-72 hours. Duration: 2-5 days. Pharmacokinetics: Absorption: Rapidly and completely absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 4 hours. Distribution: Crosses the placenta; enters breast milk (small amounts). Volume of distribution: Approx 0.14 L/kg. Plasma protein binding: Approx 99%, mainly to albumin. Metabolism: Metabolised in the liver mainly by CYP2C9 and with minor pathways including CYP1A2, CYP3A4, CYP2C8, CYP2C18, and CYP2C19; S-enantiomer of warfarin is metabolised mainly via CYP2C9 while the R-enantiomer is metabolised primarily by CYP1A2 and CYP3A4. Excretion: Via urine (up to 92%, mainly as metabolites and small amounts as unchanged drug). Elimination half-life: 20-60 hours (mean: 40 hours).
Chemical Structure
Warfarin Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 54678486, Warfarin. https://pubchem.ncbi.nlm.nih.gov/compound/Warfarin. Accessed Sept. 25, 2024.
Storage
Store between 15-30°C. Protect from moisture and light.
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