Adult: As prophylaxis and treatment of thromboembolic disorders, including venous thrombosis and pulmonary embolism: Initially, 2-4 mg daily for 2 days. Alternatively, a loading dose of 6 mg may be given on the 1st day, followed by 4 mg on the 2nd day. Maintenance: 1-8 mg daily. Adjust doses based on the patient's response and prothrombin time/INR results. Dosage must be individualised based on the underlying condition and desired intensity of anticoagulation. Elderly: Dose reduction may be needed.
Special Patient Group
Pharmacogenomics:
Acenocoumarol is a racemic mixture of 2 enantiomers, the S- and R-enantiomers. Both enantiomers are metabolised in the liver via oxidation primarily by CYP2C9 isoenzyme. The S-enantiomer has a higher potency than the R-enantiomer; however, the S-enantiomer is rapidly excreted, leading to the R-enantiomer being mainly responsible for the pharmacological effect. Additionally, the vitamin K epoxide reductase complex subunit 1 (VKORC1) is a gene that encodes for the vitamin K epoxide reductase complex, the target enzyme of acenocoumarol involved in the reactivation of the inactive form of vitamin K during the process of hepatic synthesis of coagulation factors II, VII, IX, and X. Variants of CYP2C9 and VKORC1 genes are associated with interindividual variability in response or dosing requirements.
Genetic testing for CYP2C9 and VKORC1 genotypes plus non-genetic covariables of vitamin K antagonist (VKA) exposure may be considered before treatment initiation to determine the optimal dose or guide the prescription to an alternative therapeutic option. If previous genetic testing has not been performed, testing after starting the treatment is also suggested to explain haemorrhagic events or VKA resistance.
CYP2C9
According to studies, patients who are carriers of CYP2C9*2 and CYP2C9*3 have reduced S-acenocoumarol clearance and may have an increased risk for major bleeding complications compared with normal metabolisers. These individuals were shown to have more difficulty in reaching stable anticoagulation compared with non-carriers and they require lower daily doses to maintain the targeted therapeutic INR.
The prevalence of CYP2C9*2 and CYP2C9*3 alleles among Caucasians occur at 12% and 8%, respectively. In African patients, CYP2C9*2 and CYP2C9*3 allele frequencies are significantly lower from 1-4% and 0.5-2.3%, respectively, compared to Caucasians. Additionally, Japanese patients also exhibited lower allele frequencies of 0.1% for CYP2C9*2 and 1-6% for CYP2C9*3 compared to Caucasians.
VKORC1
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:
Genotype
Description
Recommendations
VKORC1 rs9923231 TT genotype (-1639 AA genotype)
May cause an INR of ≥6, resulting in an increased risk of bleeding (occurs in 8-12% of patients during the 1st weeks of therapy with standard regulation).
Use 50% of the standard initial dose and monitor INR more frequently.
VKORC1 rs9923231 CT genotype (-1639 AG genotype)
Little or no increased risk of bleeding or excessive anticoagulation.
No action is required.
Recommendations for genetic testing and dosing may vary between countries (refer to the latest local guidelines).
Renal Impairment
Severe: Contraindicated.
Hepatic Impairment
Severe: Contraindicated.
Contraindications
Haemorrhagic diathesis and/or haemorrhagic blood dyscrasia (e.g. haemophilia, leukaemia, thrombocytopenic purpura); peptic ulceration and gastrointestinal, urogenital, or respiratory tract haemorrhage; cerebrovascular haemorrhage, cerebral or dissecting aortic aneurysm, acute pericarditis, pericardial effusion, infective endocarditis, severe hypertension; ascorbic acid deficiency, polyarthritis, severe kidney or liver parenchymal lesions; threatened abortion, eclampsia or pre-eclampsia. Uncooperative patients (e.g. alcoholics, unsupervised senile, patient with psychiatric disorder). Recent or potential surgery of the CNS or eyes; major regional lumbar block anaesthesia, traumatising surgery involving extensive tissue exposure; recent surgery resulting in increased fibrinolytic activity (e.g. surgery of the lung, prostate or uterus). Severe renal and hepatic impairment. Pregnancy.
Special Precautions
Patient with severe heart failure, risk factors for bleeding (e.g. high intensity of anticoagulation [INR >4], variable INRs, history of gastrointestinal bleeding, cerebrovascular disease, hypertension, malignancy, anaemia, trauma); prolonged dietary insufficiencies (e.g. vitamin K deficiency), known or suspected protein C or S deficiency; acute infection or active TB, thyroid disease, anaphylactic disorders. Patients undergoing dental and minor surgery (with no undue risk of haemorrhage). Patients with certain genetic variations in CYP2C9 and VKORC1. Mild to moderate renal and hepatic impairment. Elderly. Lactation.
Adverse Reactions
Significant: Hypersensitivity reactions, including anaphylaxis; purple toe syndrome. Rarely, skin necrosis or gangrene (patients with protein C or S deficiency are at higher risk), calciphylaxis. Gastrointestinal disorders: Rarely, nausea, vomiting. Hepatobiliary disorders: Very rarely, liver injury. Metabolism and nutrition disorders: Rarely, decreased appetite. Skin and subcutaneous tissue disorders: Rarely, alopecia. Vascular disorders: Very rarely, vasculitis. Potentially Fatal: Major haemorrhage.
Patient Counseling Information
Women of childbearing potential must use effective contraception during treatment.
Monitoring Parameters
Obtain prothrombin time and INR at baseline and regularly during therapy; INR measurement may be closely monitored daily or on alternate days in the early days of treatment, then at longer intervals based on response. Monitor hepatic function and CBC; signs and symptoms of bleeding and neurological impairment.
Overdosage
Symptoms: Nosebleed, haematemesis, haemoptysis, haematoma, haematuria (with renal colic), gastrointestinal or cutaneous haemorrhage, gingival bleeding, bleeding into the joints, vaginal bleeding, or menorrhagia. Hypotension, tachycardia, peripheral circulatory disorders due to blood loss, nausea, vomiting, abdominal pain, and diarrhoea may also occur. Management: For minor bleeding (e.g. brief nosebleeds, small isolated haematomas), may temporarily reduce or discontinue the acenocoumarol dose. Oral phytomenadione may be given for moderate haemorrhage. In life-threatening cases, administer IV fresh frozen plasma or whole blood, complex concentrate, or recombinant factor VIIa supplemented with phytomenadione.
Drug Interactions
May potentiate the anticoagulant effect with certain antibiotics (e.g. clarithromycin, ciprofloxacin, amoxicillin), imidazole derivatives (e.g. ketoconazole, fluconazole), antiarrhythmic agents (e.g. amiodarone, quinidine), fibrates and its derivatives (e.g. clofibric acid, fenofibrate), statins (e.g. atorvastatin, fluvastatin), and SSRIs (e.g. citalopram, sertraline). May decrease the anticoagulant effect with azathioprine, mercaptopurine, barbiturates (e.g. phenobarbital), ritonavir, carbamazepine, colestyramine, rifampicin, oral contraceptives, and other CYP2C9, CYP2C19 or CYP3A4 inducers. May increase the serum concentration of hydantoin derivatives (e.g. phenytoin). May potentiate the hypoglycaemic effect of sulfonylurea derivatives (e.g. glibenclamide, glimepiride). Potentially Fatal: Increased risk of haemorrhage with heparin (including LMWH), platelet aggregation inhibitors (e.g. clopidogrel, dipyridamole, ticlopidine), salicylic acid derivatives (e.g. aspirin, diflunisal), certain antibiotics (e.g. clindamycin), NSAIDs (e.g. celecoxib, phenylbutazone), and high dose IV methylprednisolone.
Food Interaction
May result in increased prothrombin time/INR with acute alcohol ingestion; in contrast, may decrease prothrombin time/INR with chronic alcohol consumption. May increase INR and cause severe bleeding with cranberry juice or other cranberry products. Reduced anticoagulant effect when taken with food high in vitamin K (e.g. green leafy vegetables, beef or pork liver, green tea). May decrease the anticoagulant effect with St. John's wort.
Action
Description: Mechanism of Action: Acenocoumarol, a coumarin derivative, is a vitamin K antagonist oral anticoagulant. It inhibits vitamin K epoxide reductase complex subunit 1 (VKORC1) enzyme, subsequently decreasing the γ-carboxylation of certain glutamic acid molecules near the terminal end both of coagulation factors II, VII, IX, and X, as well as proteins C and cofactor protein S. This activity causes a depletion of functional vitamin K reserves, thereby reducing the synthesis of active clotting factors. Pharmacokinetics: Absorption: Rapidly absorbed from the gastrointestinal tract. Bioavailability: 60%. Time to peak plasma concentration: 1-3 hours. Distribution: Crosses the placenta; enters breast milk (small quantities). Volume of distribution: 0.16-0.34 L.kg. Plasma protein binding: 99%. Metabolism: Both S- and R-enantiomers are metabolised in the liver via oxidation by CYP2C9 isoenzyme; additionally, the R-enantiomer is also metabolised by CYP1A2 and CYP2C19. Undergoes nitro-reduction by gut flora. Excretion: Via urine (60% as metabolites; small amounts as unchanged drug); faeces (29% as metabolites). Elimination half-life: 8-11 hours.
Chemical Structure
Acenocoumarol Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 54676537, Acenocoumarol. https://pubchem.ncbi.nlm.nih.gov/compound/Acenocoumarol. Accessed July 26, 2024.
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