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.
DRUG INTERACTIONS Substrate of CYP1A2 (major), 2C9 (major), 2C19 (minor)
Note: As an oral coumarin derivative, acenocoumarol is likely subject to the same pharmacodynamic drug-drug interactions as warfarin.
Acetaminophen: May increase the effects of acenocoumarol.
Amiodarone: May increase the level/effects of acenocoumarol.
Anticoagulants: May increase the effects of acenocoumarol.
Antiplatelet agents: May increase the effects of acenocoumarol.
CYP1A2 inducers may decrease the levels/effects of acenocoumarol. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.
CYP1A2 inhibitors may increase the levels/effects of acenocoumarol. Example inhibitors include ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.
CYP2C9 inducers may decrease the levels/effects of acenocoumarol. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.
CYP2C9 inhibitors may increase the levels/effects of acenocoumarol. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.
Miconazole: May increase the level/effects of acenocoumarol.
NSAIDs: May increase the level/effects of acenocoumarol.
Salicylates: May increase the effects of acenocoumarol.
Sulfamethoxazole: May increase the effects of acenocoumarol.
Sulfinpyrazone: May increase the effects of acenocoumarol.
Tetracycline antibiotics: May increase the effects of acenocoumarol.
Trimethoprim: May increase the effects of acenocoumarol.
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)
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms of overdose include internal or external hemorrhage and hematuria. Avoid emesis and lavage to avoid possible trauma and incidental bleeding. When an overdose occurs, the drug should be immediately discontinued and vitamin K1 (phytonadione) may be administered, up to 40 mg I.V. for adults. When hemorrhage occurs, fresh frozen plasma transfusions can help control bleeding by replacing clotting factors. In urgent bleeding, prothrombin complex concentrates may be needed.
CANADIAN BRAND NAMES — Sintrom®
INTERNATIONAL BRAND NAMES — Acenocoumarol (PL); Acenocumarol (PL); Acenox (CL); Acitrom (IN); Coarol (CL); Isquelium (CL); Mini-Sintrom (FR); Neo-Sintrom (CL); Sinthrome (GB); Sintrom (AR, AT, BE, CA, CH, ES, FR, GR, IL, IT, MX, NL, PL, PT); 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
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