Acenocoumarol

MEDICATION SAFETY ISSUES — Interferes with hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X)

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

PHARMACOLOGIC CATEGORY
Anticoagulant, Coumarin Derivative

DOSING: ADULTS — Note: Dosage must be individualized. The following information is based on the manufacturer's labeling in Canada.

Oral: Initial: 8-12 mg on day 1, followed by 4-8 mg on day 2. Subsequent dosage should be based on PT/INR measurements. Usual range of maintenance doses: 1-10 mg/day. Tapering of dosage is recommended prior to discontinuation.

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name

Tablet:
Sintrom® [CAN]: 1 mg, 4 mg [not available in the U.S.]

DOSAGE FORMS: CONCISE — [CAN] = Canadian brand name

Tablet:
Sintrom® [CAN]: 1 mg, 4 mg [not available in the U.S.]

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer at the same time each day.

USE — Prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders; atrial fibrillation with risk of embolism; adjunct in the prophylaxis of coronary occlusion and transient ischemic attacks

ADVERSE REACTIONS SIGNIFICANT — As with all anticoagulants, bleeding is the major adverse effect of acenocoumarol. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility.

Frequency not defined.
Cardiovascular: Hemorrhagic shock
Central nervous system: Fever, headache, stroke (hemorrhagic)
Dermatologic: Rash, urticaria, skin necrosis
Skin necrosis/gangrene, due to paradoxical local thrombosis, is a known but rare risk of oral anticoagulant therapy. Its onset is usually within the first few days of therapy and is frequently localized to the limbs, breast, or penis. The risk of this effect is increased in patients with protein C or S deficiency.

Additional adverse reactions associated with warfarin, but likely to also occur with indanediones, include priapism and skin necrosis ("purple toe" syndrome or cutaneous gangrene).
Gastrointestinal: Gastrointestinal bleeding, melena
Genitourinary: Hematuria
Hematologic: Hemorrhage, retroperitoneal hematoma, unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation. Other hematologic reactions reported with coumarin derivatives include agranulocytosis, red cell aplasia, anemia, thrombocytopenia, eosinophilia.
Hepatic: Hepatitis, hepatotoxicity, hematobilia
Ocular: Ocular hemorrhage
Respiratory: Epistaxis, hemoptysis, pulmonary hemorrhage
Miscellaneous: Hypersensitivity/allergic reactions

CONTRAINDICATIONS — Hypersensitivity to acenocoumarol or any component of the formulation; hemorrhagic tendencies; hemophilia; thrombocytopenia purpura; leukemia; recent or potential surgery of the eye or CNS; major regional lumbar block anesthesia or surgery resulting in large, open surfaces; bleeding from the GI, respiratory, or GU tract; threatened abortion; aneurysm; prolonged dietary insufficiencies (vitamin K deficiency); ascorbic acid deficiency; history of bleeding diathesis; prostatectomy; continuous tube drainage of the small intestine; polyarthritis; diverticulitis; emaciation; malnutrition; cerebrovascular hemorrhage; eclampsia/pre-eclampsia; blood dyscrasias; severe uncontrolled or malignant hypertension; severe hepatic disease; pericarditis or pericardial effusion; subacute bacterial endocarditis; visceral carcinoma; following spinal puncture and other diagnostic or therapeutic procedures with potential for significant bleeding; history of warfarin-induced necrosis; an unreliable, noncompliant patient; alcoholism; patient who has a history of falls or is a significant fall risk; pregnancy

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Anaphylaxis/hypersensitivity: May cause hypersensitivity reactions, including anaphylaxis; use with caution in patients with anaphylactic disorders. Bleeding: May cause major or fatal bleeding. Risk factors for bleeding include high intensity anticoagulation (INR >4), age (>65 years), variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, severe diabetes, malignancy, trauma, renal insufficiency, polycythemia vera, vasculitis, open wound, history of PUD, indwelling catheters, menstruating and postpartum women, drug-drug interactions and long duration of therapy. Patient must be instructed to report bleeding, accidents, or falls as well as any new or discontinued medications, herbal or alternative products used, significant changes in smoking or dietary habits. Skin necrosis/gangrene: Necrosis or gangrene of the skin and other tissues can occur (rarely) due to early hypercoagulability; risk is increased in patients with protein C deficiency. "Purple toe" syndrome, due to cholesterol microembolization, has been described with coumarin-type anticoagulants.

Disease-related concerns: Infection: Use with caution in patients with acute infection or active TB; antibiotics and fever may alter response to acenocoumarol. Renal impairment: Use with caution in patients with renal impairment. Thyroid disease: Use with caution in patients with thyroid disease.

Special populations: Elderly: The elderly may be more sensitive to anticoagulant therapy. Ovulating women: May be at risk of developing ovarian hemorrhage at the time of ovulation. Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions: Patient selection: Use care in the selection of patients appropriate for this treatment; ensure patient cooperation especially from the alcoholic, illicit drug user, demented, or psychotic patient.

RESTRICTIONS — Not available in U.S.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (major), 2C9 (major), 2C19 (minor)

DRUG INTERACTIONS
Acetaminophen: May enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

Allopurinol: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Aminoglutethimide: May increase the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification

Amiodarone: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Androgens: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Anticoagulants: May enhance the anticoagulant effect of other Anticoagulants. Risk C: Monitor therapy

Antineoplastic Agents: May enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Exceptions: Alitretinoin; Altretamine; Aminoglutethimide; Anastrozole; Asparaginase; AzaCITIDine; Bleomycin; Capecitabine; CARBOplatin; Carmustine; Chlorambucil; CISplatin; Cladribine; Cytarabine; Cytarabine (Liposomal); Dacarbazine; DACTINomycin; DAUNOrubicin Citrate (Liposomal); DAUNOrubicin Hydrochloride; Denileukin Diftitox; Docetaxel; DOXOrubicin (Liposomal); Epirubicin; Estramustine; Etoposide Phosphate; Exemestane; Fludarabine; Goserelin; Hydroxyurea; IDArubicin; Irinotecan; Letrozole; Leuprolide; Lomustine; Mechlorethamine; Megestrol; Mitomycin; Mitoxantrone; Nilutamide; Paclitaxel; Pegaspargase; Pentostatin; Polyestradiol; Porfimer; RiTUXimab; Streptozocin; Tamoxifen; Temozolomide; Teniposide; Thioguanine; Thiotepa; Topotecan; Toremifene; Tretinoin (Oral); Valrubicin; VinBLAStine; Vinorelbine. Risk C: Monitor therapy

Antiplatelet Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Antithyroid Agents: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

AzaTHIOprine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification

Bicalutamide: May increase the serum concentration of Vitamin K Antagonists. Specifically, free concentrations of the vitamin K antaogonists may be increased. Risk C: Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Vitamin K Antagonists. Risk C: Monitor therapy

Bosentan: May increase the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy

Capecitabine: May increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

Cephalosporins: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Cefaclor; Cefadroxil; Cefdinir; Cefepime; Cefixime; Cefonicid; Cefotaxime; Cefpodoxime; Cefprozil; Ceftazidime; Ceftibuten; Ceftizoxime; Ceftobiprole; Cefuroxime; Cephalexin; Cephradine [Off Market]. Risk C: Monitor therapy

Cimetidine: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Coenzyme Q-10: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Contraceptive (Progestins): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Risk D: Consider therapy modification

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification

CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Dicloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Disulfiram: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Dronedarone: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Drotrecogin Alfa: Vitamin K Antagonists may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification

Efavirenz: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Esomeprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Etoposide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Fenugreek: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Fibric Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Fluconazole: May increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

Fluorouracil: May increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

Gefitinib: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Ginkgo Biloba: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Glucagon: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Glutethimide: May increase the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification

Green Tea: May enhance the adverse/toxic effect of Vitamin K Antagonists. Particularly, the risk of bleeding may be increased due to possible antiplatelet effects of green tea. Green Tea may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Griseofulvin: May increase the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk D: Consider therapy modification

HMG-CoA Reductase Inhibitors: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Atorvastatin. Risk C: Monitor therapy

Ifosfamide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Itraconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Ivermectin: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Ketoconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Lansoprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Leflunomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Vitamin K Antagonists. Exceptions: Dirithromycin [Off Market]; Spiramycin. Risk C: Monitor therapy

Mercaptopurine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

MetroNIDAZOLE: May decrease the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification

Miconazole: May increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

Nafcillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

NSAID (COX-2 Inhibitor): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

NSAID (Nonselective): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Omeprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Oral Contraceptive (Estrogens): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Risk D: Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates (High risk). Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Pentoxifylline: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Phenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

Phytonadione: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Posaconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Propafenone: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Propoxyphene: May decrease the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy

QuiNIDine: May enhance the anticoagulant effect of Vitamin K Antagonists. Note that the prothrombin time might be unchanged in the face of increased bleeding. Risk C: Monitor therapy

Quinolone Antibiotics: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy

Salicylates: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Salsalate. Risk D: Consider therapy modification

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

St Johns Wort: May increase the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification

Sucralfate: May diminish the anticoagulant effect of Vitamin K Antagonists. Sucralfate may decrease the serum concentration of Vitamin K Antagonists. Specifically, sucralfate may decrease the absorption of Vitamin K Antagonists. Management: Administer vitamin K antagonists at least 2 hours before or at least 6 hours after sucralfate. Risk D: Consider therapy modification

Sulfinpyrazone [Off Market]: May decrease the metabolism of Vitamin K Antagonists. Sulfinpyrazone [Off Market] may decrease the protein binding of Vitamin K Antagonists. Risk D: Consider therapy modification

Sulfonamide Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Tamoxifen: May increase the serum concentration of Vitamin K Antagonists. Risk X: Avoid combination

Tetracycline Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Thyroid Products: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Tricyclic Antidepressants: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Vitamin A: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Vitamin E: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Voriconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Vorinostat: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Zafirlukast: May decrease the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: Avoid ethanol. Acute ethanol ingestion (binge drinking) decreases the metabolism of oral anticoagulants and increases PT/INR. Chronic daily ethanol use increases the metabolism of oral anticoagulants and decreases PT/INR.

Food: The anticoagulant effects of acenocoumarol may be decreased if taken with foods rich in vitamin K. Vitamin E may increase anticoagulant effect.

Herb/Nutraceutical: St John's wort may decrease oral anticoagulant levels. Alfalfa contains large amounts of vitamin K as do many enteral products. Coenzyme Q10 may decrease response to oral anticoagulants. Avoid cat's claw, dong quai, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, and ginkgo (all have additional antiplatelet activity).

PREGNANCY IMPLICATIONS — Oral anticoagulants cross the placenta and produce fetal abnormalities. Fatal hemorrhage in the fetus has been reported even when the mother's acenocoumarol levels were in the therapeutic range. Acenocoumarol should not be used during pregnancy because of significant risks. Adjusted-dose heparin can be given safely throughout pregnancy in patients with venous thromboembolism. Women of childbearing potential are advised to use effective contraception during treatment.

LACTATION — Enters breast milk/not recommended (per manufacturer)

DIETARY CONSIDERATIONS — Foods high in vitamin K (eg, beef liver, pork liver, green tea, and leafy green vegetables) inhibit anticoagulant effect. Do not change dietary habits once stabilized on acenocoumarol therapy. A balanced diet with a consistent intake of vitamin K is essential. Avoid large amounts of alfalfa, asparagus, broccoli, Brussels sprouts, cabbage, cauliflower, green teas, kale, lettuce, spinach, turnip greens, watercress; these decrease efficacy of oral anticoagulants. It is recommended that the diet contain a CONSISTENT vitamin K content of 70-140 mcg/day. Check with healthcare provider before changing diet. Avoid using multivitamins that contain vitamin K.

MONITORING PARAMETERS — PT/INR; hepatic function, CBC, urinalysis (for albuminuria/proteinuria)

CANADIAN BRAND NAMES — Sintrom®

INTERNATIONAL BRAND NAMES — Acenocoumarol (PL); Acenocumarol (PL); Acenox (CN); Acitrom (IN); Neo-Sintrom (CN); Sinthrome (GB); Sintrom (AR, BE, BG, CH, FR, GR, IL, IT, MX, NL, PL, PT, PY); Syncumar (PL)

MECHANISM OF ACTION — Interferes with hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X)

PHARMACODYNAMICS / KINETICS
Onset of action: Peak anticoagulant effect: Oral: 36-48 hours

Absorption: Oral: 60%

Protein binding: 99%

Metabolism: Hepatic, via oxidation (possibly by CYP1A2, 2C9, and 2C19) to inactive metabolites

Half-life elimination: 8-11 hours

Time to peak, plasma: 1-3 hours

Excretion: Urine (60%) and feces (29%) as metabolites