indication

For the treatment and prevention of thromboembolic diseases. More specifically, it is indicated for the for the prevention of cerebral embolism, deep vein thrombosis, pulmonary embolism, thromboembolism in infarction and transient ischemic attacks. It is used for the treatment of deep vein thrombosis and myocardial infarction.

pharmacology

Acenocoumarol inhibits the reduction of vitamin K by vitamin K reductase. This prevents carboxylation of certain glutamic acid residues near the N-terminals of clotting factors II, VII, IX and X, the vitamin K-dependent clotting factors. Glutamic acid carboxylation is important for the interaction between these clotting factors and calcium. Without this interaction, clotting cannot occur. Both the extrinsic (via factors VII, X and II) and intrinsic (via factors IX, X and II) are affected by acenocoumarol.

mechanism of action

Acenocoumarol inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent clotting factors, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited resulting in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

toxicity

The onset and severity of the symptoms are dependent on the individual's sensitivity to oral anticoagulants, the severity of the overdosage, and the duration of treatment. Bleeding is the major sign of toxicity with oral anticoagulant drugs. The most frequent symptoms observed are: cutaneous bleeding (80%), haematuria (with renal colic) (52%), haematomas, gastrointestinal bleeding, haematemesis, uterine bleeding, epistaxis, gingival bleeding and bleeding into the joints. Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains.

biotransformation

Extensively metabolized in the liver via oxidation forming two hydroxy metabolites and keto reduction producing two alcohol metabolites. Reduction of the nitro group produces an amino metabolite which is further transformed to an acetoamido metabolite. Metabolites do not appear to be pharmacologically active.

absorption

Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration.

half life

8 to 11 hours.

route of elimination

Mostly via the kidney as metabolites

drug interactions

Acetaminophen: Acetaminophen may increase the anticoagulant effect of acenocoumarol. Monitor for changes in the therapeutic and adverse effects of acenocoumarol if acetaminophen is initiated, discontinued or dose changed.

Acetylsalicylic acid: Acetylsalicylic acid increases the effect of the anticoagulant, acenocoumarol.

Allopurinol: Allopurinol may increase the anticoagulant effect of acenocoumarol.

Aminoglutethimide: Aminoglutethimide may decrease the anticoagulant effect of acenocoumarol.

Amiodarone: Amiodarone may increase the anticoagulant effect of acenocoumarol.

Amprenavir: Amprenavir may increase the anticoagulant effect of acenocoumarol by increasing its serum concentration.

Aprepitant: Aprepitant may decrease the anticoagulant effect of acenocoumarol by decreasing its serum concentration.

Atazanavir: The protease inhibitor, atazanavir, may increase the anticoagulant effect of acenocoumarol.

Azathioprine: Azathioprine may decrease the anticoagulant effect of acenocoumarol.

Azithromycin: Azithromycin may increase the anticoagulant effect of acenocoumarol by increasing its serum concentration.

Betamethasone: The corticosteroid, betamethasone, alters the anticoagulant effect, acenocoumarol.

Bosentan: Bosentan may decrease the anticoagulant effect of acenocoumarol by increasing its metabolism.

Butabarbital: Barbiturates like butabarbital may increase the metabolism of Vitamin K Antagonists like acenocoumarol. onitor for decreased therapeutic effects of oral anticoagulants if a barbiturate is initiated/dose increased (anticoagulant dosage increases of 30% to 60% may be needed based on monitored PT), or increased effects if a barbiturate is discontinued/dose decreased. An increased frequency of PT monitoring should be considered for the period immediately following barbiturate initiation/dosage changes.

Butalbital: Barbiturates such as butalbital may increase the metabolism of Vitamin K Antagonists such as acenocoumarol. Monitor for decreased therapeutic effects of oral anticoagulants if a barbiturate is initiated/dose increased (anticoagulant dosage increases of 30% to 60% may be needed based on monitored PT), or increased effects if a barbiturate is discontinued/dose decreased. An increased frequency of PT monitoring should be considered for the period immediately following barbiturate initiation/dosage changes.

Capecitabine: Capecitabine may increase the anticoagulant effect of acenocoumarol by increasing its serum concentration.

Carbamazepine: Carbamazepine may decrease the anticoagulant effect of acenocoumarol by decreasing its serum concentration.

Cefotetan: The cephalosporin, cefotetan, may increase the anticoagulant effect of acenocoumarol.

Cefoxitin: The cephalosporin, cefoxitin, may increase the anticoagulant effect of acenocoumarol.

Ceftriaxone: The cephalosporin, ceftriaxone, may increase the anticoagulant effect of acenocoumarol.

Celecoxib: Celecoxib may increase the anticoagulant effect of acenocoumarol.

Cholestyramine: The bile acid sequestrant, cholestyramine, may decrease the anticoagulant effect of acenocoumarol by decreasing its absorption.

Cimetidine: Cimetidine may increase the anticoagulant effect of acenocoumarol.

Ciprofloxacin: The quinolone antibiotic, ciprofloxacin, may increase the anticoagulant effect of acenocoumarol.

Cisapride: Cisapride may increase the anticoagulant effect of acenocoumarol.

Citalopram: The SSRI, citalopram, increases the effect of anticoagulant, acenocoumarol.

Clarithromycin: The macrolide, clarithromycin, may increase the anticoagulant effect of acenocoumarol.

Clofibrate: The fibrate increases the anticoagulant effect

Colestipol: The bile acid sequestrant, colestipol, may decrease the anticoagulant effect of acenocoumarol by decreasing its absorption.

Cyclophosphamide: The antineoplastic agent, cyclophosphamide may alter the anticoagulant effect of acenocoumarol.

Danazol: The androgen, danazol, may increase the anticoagulant effect of acenocoumarol.

Demeclocycline: The tetracycline, demeclocycline, may increase the anticoagulant effect of acenocoumarol.

Dexamethasone: The corticosteroid, dexamethasone, alters the anticoagulant effect, acenocoumarol.

Dextrothyroxine: The thyroid hormone, dextrothyroxine, increase the anticoagulant effect of acenocoumarol.

Dicloxacillin: Dicloxacillin may decrease the anticoagulant effect of acenocoumarol.

Diflunisal: The NSAID, diflunisal, may increase the anticoagulant effect of acenocoumarol.

Disulfiram: Disulfiram may increase the anticoagulant effect of acenocoumarol.

Doxycycline: The tetracycline, doxycycline, may increase the anticoagulant effect of acenocoumarol.

Erythromycin: The macrolide, erythromycin, may increase the anticoagulant effect of acenocoumarol.

Ethchlorvynol: Ethchlorvynol may decrease the anticoagulant effect of acenocoumarol.

Ethinyl Estradiol: Increased thrombotic risk due to estrogen

Etodolac: The NSAID, etodolac, may increase the anticoagulant effect or acenocoumarol.

Etoricoxib: Etoricoxib may increase the anticoagulant effect of acenocoumarol.

Fenofibrate: Fenofibrate may increase the anticoagulant effect of acenocoumarol.

Fenoprofen: The NSAID, fenoprofen, may increase the anticoagulant effect of acenocoumarol.

Fluconazole: Fluconazole may increase the serum concentration of acenocoumarol by decreasing its metabolism.

Fludrocortisone: The corticosteroid, fludrocortisone, alters the anticoagulant effect, acenocoumarol.

Fluorouracil: The antineoplasic agent, fluorouracil, may increase the anticoagulant effect of acenocoumarol.

Fluoxetine: The SSRI, fluoxetine, increases the effect of anticoagulant, acenocoumarol.

Fluoxymesterone: The androgen, fluoxymesterone, may increase the anticoagulant effect of acenocoumarol.

Flurbiprofen: The NSAID, flurbiprofen, may increase the anticoagulant effect of acenocoumarol.

Fluvastatin: Fluvastatin may increase the anticoagulant effect of acenocoumarol. Monitor for changes in the therapeutic and adverse effects of acenocoumarol if fluvastatin is initiated, discontinued or dose changed.

Fluvoxamine: Fluvoxamine may increase the anticoagulant effect of acenocoumarol by increasing its serum concentration.

Fosamprenavir: The protease inhibitor, fosamprenavir, may increase the anticoagulant effect of acenocoumarol.

Fosphenytoin: Increased hydantoin levels and risk of bleeding

Gefitinib: Gefitinib may increase the anticoagulant effect of acenocoumarol.

Gemcitabine: Gemcitabine may increase the anticoagulant effect of acenocoumarol.

Gemfibrozil: Gemfibrozil may increase the anticoagulant effect of acenocoumarol.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Glutethimide: Glutethimide may decrease the anticoagulant effect of acenocoumarol.

Griseofulvin: Griseofulvin may decrease the anticoagulant effect of acenocoumarol.

Hydrocortisone: The corticosteroid, hydrocortisone, alters the anticoagulant effect, acenocoumarol.

Ibuprofen: The NSAID, ibuprofen, may increase the anticoagulant effect of acenocoumarol.

Imatinib: Imatinib may increase the anticoagulant effect of acenocoumarol.

Indinavir: The protease inhibitor, indinavir, may increase the anticoagulant effect of acenocoumarol.

Indomethacin: The NSAID, indomethacin, may increase the anticoagulant effect of acenocoumarol.

Isoniazid: Isoniazid may increase the anticoagulant effect of acenocoumarol.

Itraconazole: Itraconazole may increase the anticoagulant effect of acenocoumarol.

Ketoconazole: Ketoconazole may increase the anticoagulant effect of acenocoumarol.

Ketoprofen: The NSAID, ketoprofen, may increase the anticoagulant effect of acenocoumarol.

Ketorolac: The NSAID, ketorolac, may increase the anticoagulant effect of acenocoumarol.

Leflunomide: Leflunomide may increase the anticoagulant effect of acenocoumarol.

Levamisole: Levamisole may increase the anticoagulant effect of acenocoumarol.

Levofloxacin: The quinolone antibiotic, levofloxacin, may increase the anticoagulant effect of acenocoumarol.

Levothyroxine: The thyroid hormone, levothyroxine, increase the anticoagulant effect of acenocoumarol.

Lovastatin: Lovastatin may increase the anticoagulant effect of acenocoumarol. Monitor for changes in the therapeutic and adverse effects of acenocoumarol if lovastatin is initiated, discontinued or dose changed.

Lumiracoxib: Lumiracoxib may increase the anticoagulant effect of acenocoumarol.

Medroxyprogesterone: Medroxyprogesterone may increase the anticoagulant effect of acenocoumarol.

Mefenamic acid: The NSAID, mefanamic acid, may increase the anticoagulant effect of acenocoumarol.

Mefloquine: Mefloquine may increase the anticoagulant effect of acenocoumarol.

Meloxicam: Meloxicam may increase the anticoagulant effect of acenocoumarol.

Mercaptopurine: Mercaptopurine may decrease the anticoagulant effect of acenocoumarol.

Methimazole: The antithyroid agent, methimazole, may decrease the anticoagulant effect of acenocoumarol.

Metronidazole: Metronidazole may increase the anticoagulant effect of acenocoumarol.

Miconazole: Miconazole may increase the serum concentration of acenocoumarol by decreasing its metabolism.

Minocycline: The tetracycline, minocycline, may increase the anticoagulant effect of acenocoumarol.

Mitotane: Mitotane may decrease the anticoagulant effect of acenocoumarol.

Moxifloxacin: The quinolone antibiotic, moxifloxacin, may increase the anticoagulant effect of acenocoumarol.

Nabumetone: The NSAID, nabumetone, may increase the anticoagulant effect of acenocoumarol.

Nalidixic Acid: The quinolone antibiotic, nalidixic acid, may increase the anticoagulant effect of acenocoumarol.

Naproxen: The NSAID, naproxen, may increase the anticoagulant effect of acenocoumarol.

Nelfinavir: The protease inhibitor, nelfinavir, may increase the anticoagulant effect of acenocoumarol.

Nevirapine: Nevirapine may decrease the anticoagulant effect of acenocoumarol.

Norfloxacin: The quinolone antibiotic, norfloxacin, may increase the anticoagulant effect of acenocoumarol.

Ofloxacin: The quinolone antibiotic, ofloxacin, may increase the anticoagulant effect of acenocoumarol.

Orlistat: Orlistat may increase the anticoagulant effect of acenocoumarol.

Oxaprozin: The NSAID, oxaprozin, may increase the anticoagulant effect of acenocoumarol.

Oxyphenbutazone: The NSAID, oxyphenbutazone, may increase the anticoagulant effect of acenocoumarol.

Paroxetine: The SSRI, paroxetine, increases the effect of the anticoagulant, acenocoumarol.

Pentoxifylline: Pentoxifylline may increase the anticoagulant effect of acenocoumarol.

Phenobarbital: The barbiturate, phenobarbital, decreases the anticoagulant effect of acenocoumarol.

Phenylbutazone: The NSAID, phenylbutazone, may increase the anticoagulant effect of acenocoumarol.

Phenytoin: Increased hydantoin levels and risk of bleeding

Piroxicam: The NSAID, piroxicam, may increase the anticoagulant effect of acenocoumarol.

Prednisolone: The corticosteroid, prednisolone, alters the anticoagulant effect, acenocoumarol.

Prednisone: The corticosteroid, prednisone, alters the anticoagulant effect, acenocoumarol.

Primidone: The barbiturate, primidone, decreases the anticoagulant effect of acenocoumarol.

Propafenone: Propafenone may increase the anticoagulant effect of acenocoumarol.

Propoxyphene: Propoxyphene may increase the anticoagulant effect of acenocoumarol.

Propylthiouracil: The anti-thyroid agent, propylthiouracil, may decrease the anticoagulant effect of acenocoumarol.

Quinidine: Quinidine may increase the anticoagulant effect of acenocoumarol.

Quinine: Quinine, a moderate CYP2C9 inhibitor, may increase the serum concentration of acenocoumarol by decreasing its metabolism via CYP2C9.

Ranitidine: Ranitidine may increase the anticoagulant effect of acenocoumarol. (Conflicting evidence)

Rifabutin: Rifabutin may decrease the anticoagulant effect of acenocoumarol by increasing its metabolism.

Rifampin: Rifampin may decrease the anticoagulant effect of acenocoumarol by increasing its metabolism.

Sulindac: The NSAID, sulindac, may increase the anticoagulant effect of acenocoumarol. Consider alternate therapy or monitor for signs and symptoms of bleeding during concomitant therapy.

Tamoxifen: Tamoxifen may increase the serum concentration of Acenocoumarol increasing the risk of bleeding. Concomitant therapy should be avoided.

Telithromycin: Telithromycin may increase the anticoagulant effect of acenocoumarol.

Tenoxicam: The NSAID, tenoxicam, may increase the anticoagulant effect of acenocoumarol.

Testolactone: The androgen, Testolactone, may incrase the anticoagulant effect of the Vitamin K antagonist, Acenocoumarol. Monitor for changes in the therapeutic effect of Acenocoumarol if Testolactone is initiated, discontinued or dose changed.

Testosterone: The androgen, Testosterone, may incrase the anticoagulant effect of the Vitamin K antagonist, Acenocoumarol. Monitor for changes in the therapeutic effect of Acenocoumarol if Testosterone is initiated, discontinued or dose changed.

Testosterone Propionate: The androgen, Testosterone, may incrase the anticoagulant effect of the Vitamin K antagonist, Acenocoumarol. Monitor for changes in the therapeutic effect of Acenocoumarol if Testosterone is initiated, discontinued or dose changed.

Tetracycline: Tetracycline may increase the anticoagulant effect of acenocoumarol.

Thiabendazole: The strong CYP1A2 inhibitor, Thiabendazole, may increase the effects and toxicity of Acenocoumarol by decreasing Acenocoumarol metabolism and clearance. Monitor for changes in the therapeutic and adverse effects of Acenocoumarol if Thiabendazole is initiated, discontinued or dose changed.

Thiopental: Thiopental may increase the metabolism of the Vitamin K antagonist, Acenocoumarol. Acenocoumarol dose adjustment may be required.

Tiaprofenic acid: Increased risk of bleeding.

Tigecycline: Tigecycline may increase the anticoagulant effect of acenocoumarol.

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Acenocoumarol. Consider alternate therapy or monitor for changes in Acenocoumarol therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Tolmetin: Increased risk of bleeding. Monitor for signs and symptoms of bleeding.

Treprostinil: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Acenocoumarol. Monitor for increased bleeding during concomitant thearpy.

Triamcinolone: The corticosteroid, triamcinolone, alters the anticoagulant effect, acenocoumarol.

Trimetrexate: The anticoagulant effect of Acenocoumarol, a Vitamin K antagonist, may be altered by antineoplastics such as Trimetrexate. Monitor for changes in the anticoagulant effects of warfarin and other coumarin derivatives during concomitant use.

Zafirlukast: Zafirlukast may inhibit the metabolism of the vitamin K antagonist Acenocoumarol and increase INR and risk of bleeding.