Warfarin


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Treatment and prophylaxis of venous thrombosis; Treatment and prophylaxis of pulmonary embolism; Prophylaxis of thromboembolism following cardiac valve replacement; Prophylaxis of systemic embolism in patients with rheumatic heart disease or atrial fibrillation; Transient ischaemic attacks Dosage is tailored to individual requirements. Usual dose: Initial: 5-10 mg/day for 1 or 2 days. Maintenance: 3-9 mg/day, depending on the prothrombin time or other appropriate coagulation tests. IV Treatment and prophylaxis of venous thrombosis; Treatment and prophylaxis of pulmonary embolism; Prophylaxis of thromboembolism following cardiac valve replacement; Prophylaxis of systemic embolism in patients with atrial fibrillation Dosage is tailored to individual requirements. Usual dose: Initial: 5-10 mg daily for 1 or 2 days. Maintenance: 2-10 mg/day, depending on the prothrombin time or other appropriate coagulation tests.
Dosage Details
Intravenous
Prophylaxis of pulmonary embolism, Prophylaxis of systemic embolism in patients with atrial fibrillation, Prophylaxis of thromboembolism following cardiac valve replacement, Prophylaxis of venous thrombosis, Pulmonary embolism, Venous thrombosis
Adult: Dosage is tailored to individual requirements. Usual dose: Initially, 5-10 mg daily for 1 or 2 days. Maintenance: 2-10 mg daily, depending on the prothrombin time or other appropriate coagulation tests.
Elderly: Dose reduction may be needed.

Oral
Prophylaxis of pulmonary embolism, Prophylaxis of systemic embolism in patients with atrial fibrillation, Prophylaxis of systemic embolism in patients with rheumatic heart disease, Prophylaxis of thromboembolism following cardiac valve replacement, Prophylaxis of venous thrombosis, Pulmonary embolism, Transient ischaemic attack, Venous thrombosis
Adult: Dosage is tailored to individual requirements. Usual dose: Initially, 5-10 mg daily for 1 or 2 days. Maintenance: 3-9 mg daily, depending on the prothrombin time or other appropriate coagulation tests.
Elderly: Dose reduction may be needed.
Special Patient Group
Pharmacogenomics:

Warfarin is administered as a racemic mixture of the R- and S-stereoisomers. S-warfarin is 3-5 times more potent than R-warfarin and metabolised predominantly by CYP2C9. Interindividual differences in pharmacokinetic parameter values and treatment outcomes with warfarin are associated with CYP2C9 polymorphisms. In addition, pharmacodynamic mechanism is involved in the association between VKORC1 and warfarin’s anticoagulant effect. VKORC1 encodes the vit K epoxide reductase protein, and catalyses the conversion of vit K epoxide to vit K. The anticoagulant effect of warfarin is due to the inhibition of VKORC1, which limits the availability of reduced vit K leading to decreased formation of clotting factors. The reduced vit K is metabolised by CYP4F2. CYP4F2 is a primary hepatic vit K oxidase that catalyses the metabolism of vit K to hydroxy-vit K1 and removes vit K from the vit K cycle. It acts as an important counterpart to VKORC1 in limiting excessive accumulation of vit K. CYP2C9, VKORC1, CYP4F2 and rs12777823 genotype-guided warfarin dosing may be useful to achieve target INR of 2-3.

Genetic testing for CYP2C9 and VKORC1 prior to initiation of therapy should be considered. Although not as commonly tested for as CYP2C9 and VKORC1, some clinical laboratories may also test for CYP4F2 to detect CYP4F2*3 variant. The inclusion of the CYP4F2 in warfarin dosing models that included CYP2C9, VKORC1 and clinical factors improved the accuracy of dose prediction.

CYP2C9
CYP2C9*2 and *3 impair metabolism of S-warfarin by 30-40% and 80-90%, respectively. Individuals who inherit 1 or 2 copies of CYP2C9*2 or *3 are at greater risk of bleeding during warfarin therapy, compared to patients homozygous for CYP2C9*1. These patients require lower doses to achieve similar levels of anticoagulation and require more time to achieve a stable INR.

The prevalence of CYP2C9 *2 and *3 variant allele is estimated in 11% and 7% of Caucasians, respectively. CYP2C9*2 is virtually absent in Asians. CYP2C9*5, *6, *8, and *11 are associated with decreased function of the CYP2C9 enzyme and contribute to dose variability. These alleles are found with the highest frequency among those of African ancestry, and generally, are more common than CYP2C9*2 and *3 in that group. Allele variants in VKORC1 accounts for up to 18% of variance among patients of European ancestry.

VKORC1
A common variant upstream of VKORC1 (c.-1639G>A; rs9923231) is significantly associated with warfarin sensitivity. 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 VKORC1 protein expression.

Allele variants in VKORC1 account for up to 30% of variance among patients of European ancestry.

CYP4F2
The nonsynonymous variant CYP4F2*3 (c.1297G>A; p.Val433Met; rs2108622) affects enzyme activity and is associated with warfarin dose variability. Carriers of this nonsynonymous variant allele may have a reduced capacity to metabolise vit K and are likely to have elevated hepatic levels of vit K, requiring a higher warfarin dose to achieve therapeutic anticoagulation.

Allele variants in VKORC1 account for up to 11% of variance among patients of European ancestry.

Recommendations for warfarin based on genotype:

Non-African ancestry
Patients carrying CYP2C9*2 and *3 alleles and VKORC1-1639G>A variant alleles: Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends calculation of warfarin dose based on validated published pharmacogenetic algorithms. For loading dose, may consider the use of a pharmacogenetics-based warfarin initiation dose algorithm. Consider an alternative agent in individuals with CYP2C9 poor metabolism (carriers of CYP2C9*2/*3, *3/*3) or both increased sensitivity (VKORC1 A/G or A/A) and CYP2C9 poor metabolism.

Patients carrying CYP2C9*5, *6, *8 or *11 variant alleles (e.g. *1/*8, *1/*11, *8/*11): CPIC recommends decreasing the calculated warfarin dose by 15-30%.

Patients carrying CYP4F2 rs2108622 T allele: CPIC recommends increasing warfarin dose by 5-10%.

African ancestry
Patients carrying CYP2C9*2 and *3 allele and VKORC1-1639G>A variant alleles who were tested for CYP2C9*5, *6, *8, and *11 variant alleles: CPIC recommends calculation of warfarin dose based on validated published pharmacogenetic algorithms. Consider an alternative agent in individuals with CYP2C9 poor metabolism (carriers of CYP2C9*2/*3, *3/*3) or both increased sensitivity (VKORC1 A/G or A/A) and CYP2C9 poor metabolism. If CYP2C9*5, *6, *8, and *11 who were not tested, CPIC recommends dosing warfarin clinically (without genetic information, which may include use of clinical dosing algorithm or standard dose approach).

Patients carrying CYP2C9*5, *6, *8 or *11 variant alleles: CPIC recommends decreasing the calculated warfarin dose by 15-30%.

African-Americans who are tested positive for rs12777823 A/G or A/A genotype: Decrease dose by 10-25%.

Non-African Americans: may consider the use of a pharmacogenetics-based warfarin initiation dose algorithm for the loading dose.
Administration
May be taken with or without food.
Reconstitution
IV: Reconstitute with 2.7 mL of sterile water for inj.
Incompatibility
Incompatible with adrenaline, amikacin, metaraminol, oxytocin, promazine, tetracycline. Solutions of warfarin Na mixed with aminophylline, bretylium tosilate, ceftazidime, cimetidine, ciprofloxacin, dobutamine, esmolol, gentamicin, labetalol, metronidazole, vancomycin may result in visual incompatibility. Haze may occur after 24 hours with NaCl 0.9%.
Contraindications
Haemorrhagic stroke, clinically significant bleeding, haemorrhagic tendencies (e.g. active gastrointestinal ulceration, patient bleeding from gastrointestinal, respiratory and genitourinary tracts, cerebral aneurysm, CNS haemorrhage), blood dyscrasias, malignant hypertension, alcoholism, psychosis. Within 72 hours of surgery at risk of severe bleeding. Spinal puncture and other diagnostic or therapeutic procedures with potential uncontrollable bleeding. Major regional or lumbar block anaesthesia. Within 48 hours postpartum. Unsupervised patients with potential high levels of non-compliance. Pregnancy (except in women with mechanical heart valves at high risk for thromboembolism). Concomitant use with fibrinolytic drugs (e.g. streptokinase, alteplase).
Special Precautions
Patient with heparin-induced thrombocytopenia and DVT, thyroid disease, acute infection, active TB, disruption of normal gastrointestinal flora.  Protein C or protein S deficiency, dietary insufficiency (e.g. vitamin K deficiency). Surgical patients. Patients with CYP2C9, VKORC1, CYP4F2 and rs12777823 gene polymorphism. Hepatic and renal impairment. Elderly. Lactation.
Adverse Reactions
Significant: Acute kidney injury. Rarely, skin necrosis or gangrene, hypersensitivity reactions.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, flatulence, pancreatitis, melaena, taste perversion.
General disorders and administration site conditions: Fever, chills.
Hepatobiliary disorders: Hepatic dysfunction, jaundice.
Investigations: Decreased Hb and haematocrit.
Renal and urinary disorders: Haematuria.
Skin and subcutaneous tissue disorders: Alopecia, rash, dermatitis, purpura.
Vascular disorders: Vasculitis.
Potentially Fatal: Haemorrhage (e.g. cerebral or gastrointestinal haemorrhage, haemothorax), calciphylaxis (calcium uremic arteriolopathy). Rarely, purple toes resulting from atheroemboli/cholesterol embolism.
IV/Parenteral/PO: X, D (For high-risk mechanical heart valve)
MonitoringParameters
Monitor INR regularly; haematocrit, prothrombin time. Perform pregnancy test prior to use in women of reproductive potential. Consider genotyping of CYP2C9 and VKORC1 prior to initiation of therapy, if available.
Overdosage
Symptoms: Abnormal bleeding manifested by haematuria, blood in the stools, melaena, petechiae, excessive menstrual bleeding, excessive bruising, or persistent oozing from superficial injuries. Management: Discontinue warfarin. 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. If necessary, administer 10-20 mg vitamin K1 (phytomenadione) orally (250 mcg/kg for child). Delay oral vitamin K1 at least 4 hours after administering activated charcoal. Repeat INR after 24 hours and consider further vitamin K1. In life-threatening cases, 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 not available. For non-life-threatening cases, give phytomenadione via slow IV inj. If rapid re-anticoagulation is necessary (e.g. valve replacements), 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 not available. Monitor INR for at least 48 hours post overdose and determine when to restart normal therapy.
Drug Interactions
Direct-acting antivirals (e.g. sofosbuvir, boceprevir) may diminish the anticoagulant effect of vitamin K antagonists. Increased risk of bleeding with other anticoagulants (e.g. argatroban, dabigatran, heparin), antiplatelet agents (e.g. aspirin, cilostazol, clopidogrel), NSAIDs (e.g. celecoxib, diclofenac, ibuprofen), serotonin reuptake inhibitors (e.g. citalopram, paroxetine, venlafaxine). Increased INR with inhibitors of CYP2C9 (e.g. amiodarone, capecitabine, cotrimoxazole), CYP1A2 (e.g. aciclovir, allopurinol, ciprofloxacin) and CYP3A4 (e.g. alprazolam, amlodipine, atorvastatin). Decreased INR with inducers of CYP2C9 (e.g. carbamazepine, rifampicin), CYP1A2 (e.g. montelukast, phenytoin) and CYP3A4 (e.g. efavirenz, etravirine, prednisone). Cholestatic hepatitis may occur when taken concomitantly with ticlopidine.
Potentially Fatal: Increased risk of bleeding with fibrinolytic drugs (e.g. alteplase, streptokinase).
Food Interaction
May reduce the effects of warfarin with St. John’s wort and chronic alcohol intake. Reduced anticoagulant effect with foods rich in vitamin K (e.g. green leafy vegetables, liver, broccoli, brussels sprouts). Cranberry juice may increase INR and risk of bleeding.
Action
Description: Warfarin inhibits synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X as well as the anticoagulant protein C and its cofactor protein S. These clotting factors are biologically activated by the addition of carboxyl groups to key glutamic acid residues within the proteins' structure. Warfarin competitively inhibits the C1 subunit of the multi-unit vitamin K epoxide reductase (VKORC1) enzyme complex, thus depleting functional vitamin K reserves and subsequently reducing synthesis of active clotting factors.
Onset: Initial anticoagulant effect: 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. Volume of distribution: 0.14 L/kg. Plasma protein binding: 99%.
Metabolism: Metabolised in the liver, mainly by CYP2C9 (CYP2C8, 2C18, 2C19, 1A2, and 3A4 as minor pathways).
Excretion: Via urine (92%, mainly as metabolites and small amounts as unchanged drug). Elimination half-life: 20-60 hours (mean: 40 hours).
Chemical Structure

Chemical Structure Image
Warfarin

Source: National Center for Biotechnology Information. PubChem Database. Warfarin, CID=54678486, https://pubchem.ncbi.nlm.nih.gov/compound/Warfarin (accessed on Jan. 24, 2020)

Storage
Store between 15-30°C. Protect from light.
ATC Classification
B01AA03 - warfarin ; Belongs to the class of vitamin K antagonists. Used in the treatment of thrombosis.
References
Danese E, Montagnana M, Johnson JA et al. Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis. Clin Pharmacol Ther. 2012 Dec;92(6):746-756. Accessed 18/11/2019. PMID: 23132553

Johnson JA, Caudle KE, Gong L et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clinical Pharmacogenetics Implementation Consortium. 2017 Sep;102(3):397-404. doi: 10.1002/cpt.668. Accessed 18/11/2019

Annotation of CPIC Guideline for Warfarin and CYP2C9, CYP4F2, VKORC1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 19/11/2019 .

Anon. CYP2C9 - Warfarin (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 18/11/2019.

Anon. VKORC1 - Warfarin (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 18/11/2019.

Anon. Warfarin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 07/11/2019.

Buckingham R (ed). Warfarin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. http://www.medicinescomplete.com. Accessed 07/11/2019.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 18/11/2019.

Coumadin Tablets; Coumadin for Injection (Bristol-Myers Squibb Company). U.S. FDA. https://www.fda.gov/. Accessed 08/11/2019.

Joint Formulary Committee. Warfarin Sodium. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/11/2019.

Warfarin Pathway, Pharmacodynamics. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 07/11/2019.

Warfarin Pathway, Pharmacokinetics. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 19/11/2019.

Warfarin Sodium Tablet (Exelan Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 07/11/2019.

Disclaimer: This information is independently developed by MIMS based on Warfarin from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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