Acenocoumarol

Acenocoumarol: Drug information
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(For additional information see “Acenocoumarol: Patient drug information”)

Brand Names: Canada Sintrom®
Pharmacologic Category Anticoagulant, Coumarin Derivative
Dosing: Adult Note: Dosage must be individualized. The following information is based on the manufacturer’s labeling in Canada.
Prevention/treatment of thrombosis/embolism: 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: Geriatric Refer to adult dosing. Use with caution; lower dosages may be necessary.
Dosing: Renal Impairment Use with caution; the manufacturer labeling does not provide specific dosing recommendations.
Dosing: Hepatic Impairment Use with caution; the manufacturer labeling does not provide specific dosing recommendations.
Dosage Forms: Canada Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:

Sintrom®: 1 mg, 4 mg

Product Availability Not available in U.S.
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
Medication Safety Issues
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.

Other safety concerns:
Interferes with hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X)

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:

Dermatologic: Skin necrosis (including hemorrhagic forms) (rare)

Genitourinary: Priapism

Hematologic: Hemorrhage may occur at virtually any site; sites that may be predisposed to bleeding include CNS (brain), eye, GI tract (melena), liver and gall bladder (hematobilia), urogenital tract (hematuria), uterus (metrorrhagia, menorrhagia)

Hepatic: Hepatotoxicity

Reactions observed with similar coumarin derivatives: Alopecia (reversible, rare), appetite decreased, diarrhea, gangrene (rare), hypersensitivity/allergic reactions (dermatitis, fever, urticaria), nausea, purple toe syndrome (rare), vomiting

Contraindications Hypersensitivity to acenocoumarol, related coumarin derivatives, or any component of the formulation; hemorrhagic tendencies and/or blood dyscrasias (eg, hemophilia, thrombocytopenic 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; aneurysm (cerebral or dissecting aortic); cerebrovascular hemorrhage; recent surgical procedures resulting in increased fibrinolytic activity (eg, surgery of the lung, prostate, uterus); polyarthritis; diverticulitis; emaciation; malnutrition; severe hypertension; severe parenchymal lesions of the liver and kidneys; pericarditis or pericardial effusion; subacute bacterial endocarditis; ascorbic acid deficiency; uncooperative patient (eg, alcoholic, unsupervised senile, or psychotic) intramuscular injections; inadequate laboratory facilities; threatened abortion; eclampsia/pre-eclampsia; pregnancy
Warnings/Precautions
Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity: May cause hypersensitivity reactions, including anaphylaxis; use with caution in patients with anaphylactic disorders. Cross-reactivity among coumarin anticoagulants has been described.

• 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 or known genetic deficiency in CYP2C9 activity. 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. Unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation. Treatment should be withdrawn at the earliest signs of bleeding.

• 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 or S deficiency. Onset is usually within the first few days of therapy and is frequently localized to the limbs, breast, or penis.

• “Purple toe” syndrome: “Purple toe” syndrome, due to cholesterol microembolization, has been described with coumarin-type anticoagulants.

Disease-related concerns:

• Dietary insufficiency: Use with caution in patients with prolonged dietary insufficiencies (vitamin K deficiency).

• Infection: Use with caution in patients with acute infection or active TB; antibiotics and fever may alter response to acenocoumarol.

• Hepatic impairment: Use with caution in patients with hepatic impairment (undergoes hepatic metabolism).

• 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.

• Patients with genomic variants in CYP2C9 and/or VKORC1: Presence of the CYP2C9*3 allele and/or polymorphism of the vitamin K oxidoreductase (VKORC1) gene may increase the risk of bleeding. Lower doses may be required in these patients.

Other warnings/precautions:

• Patient selection: Use care in the selection of patients appropriate for this treatment; ensure patient cooperation.

Metabolism/Transport Effects Substrate of CYP1A2 (major), 2C9 (major), 2C19 (minor)
Drug Interactions
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

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 (Systemic); 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 antagonists 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; Cefditoren; Cefepime; Cefixime; Cefotaxime; Cefpodoxime; Cefprozil; Ceftaroline Fosamil; CefTAZidime; Ceftibuten; Cefuroxime; Cephalexin. Risk C: Monitor therapy

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

Chloramphenicol: May enhance the anticoagulant effect of Vitamin K Antagonists. Chloramphenicol may increase the serum concentration of Vitamin K Antagonists. 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

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

Contraceptives (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

Contraceptives (Progestins): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive. Risk D: Consider therapy modification

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

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

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Desvenlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Dexmethylphenidate: May increase the serum concentration of Vitamin K Antagonists. 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. Management: Weigh potential benefits of drotrecogin against increased bleeding risk in patients who have received oral anticoagulants within 1 week or have INR 3 or greater. Monitor for bleeding and immediately stop infusion if clinically important bleeding occurs. Risk D: Consider therapy modification

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

Erythromycin (Ophthalmic): 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

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

Ethotoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Ethotoin. Management: Anticoagulant dose adjustment will likely be necessary when ethotoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D: Consider therapy modification

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

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

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

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

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

Fluorouracil (Topical): May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Fosphenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D: Consider therapy modification

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

Ginkgo Biloba: May enhance the adverse/toxic effect of Vitamin K Antagonists. Management: Consider avoiding the use of this combination of agents. Monitor for signs and symptoms of bleeding if vitamin K antagonists and Ginkgo biloba are used concomitantly. 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 decrease the serum concentration 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

Ketoconazole (Systemic): 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: Fidaxomicin (Systemic); Spiramycin. Risk C: Monitor therapy

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

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

MetroNIDAZOLE: May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. Monitor for increased INR/bleeding risk if metronidazole is initiated/dose increased, or decreased effects if metronidazole is discontinued/dose decreased. Risk D: Consider therapy modification

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

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

Milnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

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

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

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

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. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. 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 enhance the anticoagulant effect 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 INR/PT might be unchanged in the face of increased bleeding. Risk C: Monitor therapy

QuiNINE: May enhance the anticoagulant effect of Vitamin K Antagonists. 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

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Risk X: Avoid combination

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

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

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

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

Venlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. 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 increase the serum concentration 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: Vitamin K can reverse the anticoagulation effects of acenocoumarol; large amounts of food high in vitamin K (such as beef liver, pork liver, green tea, and green leafy vegetables) may reverse acenocoumarol, decrease prothrombin time, and lead to therapeutic failure. Patients should not change dietary habits once stabilized on acenocoumarol therapy. A balanced diet with a consistent intake of vitamin K is essential.

High doses of vitamin A, E, or C may alter PT; use caution with fish oils or omega-3 fatty acids; cranberry juice or other cranberry products may increase the INR in patients receiving a similar agent (warfarin) and cause severe bleeding (flavonoids found in cranberries may inhibit cytochrome P450 isoenzyme CYP2C9 which metabolize warfarin). Similar risks might be anticipated with acenocoumarol as it also undergoes CYP2C9 metabolism.

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 Acenocoumarol crosses the placenta. Teratogenic effects have been reported with coumarin derivative anticoagulants following first trimester exposure and may include coumarin embryopathy (nasal hypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Adverse events to the fetus have also been observed following second and third trimester exposure with coumarin derivative anticoagulants and may include CNS abnormalities (including ventral midline dysplasia, dorsal midline dysplasia). 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.
Breast-Feeding Considerations Very small quantities of acenocoumarol can be detected in breast milk and undesirable effects in nursing infants are not anticipated. The manufacturer recommends prophylaxis therapy with phytonadione (1 mg administered once weekly) and monitoring of the infant for signs of bleeding.
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 an adult diet contain a consistent vitamin K content of 75-120 mcg/day. Check with healthcare provider before changing diet. Avoid using multivitamins that contain vitamin K.
Monitoring Parameters PT/INR (Note: To obtain a valid PT in patients receiving heparin, allow 4-5 hours after last I.V. dose and 12-24 hours after last SubQ dose before blood is drawn); hepatic function, CBC, urinalysis (for albuminuria/proteinuria)
International Brand Names Acenox (CN); Acitrom (IN); Neo-Sintrom (CN); Nistrom (IN); Sinthrome (GB); Sintrom (AR, AT, BE, BG, CH, FR, GR, IL, IT, MX, NL, PT, PY); Syncumar (HN, PL, RU)
Mechanism of Action Hepatic synthesis of coagulation factors II, VII, IX, and X, as well as proteins C and S, requires the presence of vitamin K. These clotting factors are biologically activated by the addition of carboxyl groups to key glutamic acid residues within the proteins’ structure. In the process, “active” vitamin K is oxidatively converted to an “inactive” form, which is then subsequently reactivated by vitamin K epoxide reductase complex 1 (VKORC1). Coumarins are thought to inhibit VKORC1, thus depleting functional vitamin K reserves and hence reduce synthesis of active clotting factors.
Pharmacodynamics/Kinetics
Onset of action: Peak anticoagulant effect: Oral: 36-48 hours

Absorption: Rapid

Distribution: Vd: 0.16-0.34 L/kg

Protein binding: 99%

Metabolism: Hepatic, via oxidation: R-enantiomer (by CYP2C9 [primary], 1A2, and 2C19; S-enantiomer primarily by CYP2C9) and via keto-reduction to inactive metabolites; also undergoes nitro-reduction via gut flora. (Thijssen, 2000)

Bioavailability: 60%

Half-life elimination: R-enantiomer: ~11 hours; S-enantiomer: <2 hours (Thijssen, 1986)

Time to peak, plasma: 1-3 hours

Excretion: Urine (60% as metabolites; minimal amount as unchanged drug); feces (29% as metabolites)

REFERENCES
Suvarna R, Pirmohamed M, and Henderson L, “Possible Interaction Between Warfarin and Cranberry Juice,” BMJ, 2003, 327(7429):1454. [PubMed 14684645]
Tàssies D, Freire C, Pijoan J, et al, “Pharmacogenetics of Acenocoumarol: Cytochrome P450 CYP 2C9 Polymorphisms Influence Dose Requirements and Stability of Anticoagulation,” Haematologica, 2002, 87(11):1185-91. [PubMed 12414349]
Teichert M, van Schaik RH, Hofman A, et al, “Genotypes Associated With Reduced Activity of VKORC1 and CYP2C9 and Their Modification of Acenocoumarol Anticoagulation During the Initial Treatment Period,” Clin Pharmacol Ther, 2009, 85(4):379-86. [PubMed 19225451]
Thijssen HH, Janssen GM, and Baars LG, “Lack of Effect of Cimetidine on Pharmacodynamics and Kinetics of Single Oral Doses of R- and S-Acenocoumarol,” Eur J Clin Pharmacol, 1986, 30(5):619-23. [PubMed 3758150]
Thijssen HH, Flinois JP, and Beaune PH, “Cytochrome P4502C9 is the Principal Catalyst of Racemic Acenocoumarol Hydroxylation Reactions in Human Liver Microsomes,” Drug Metab Dispos, 2000, 28(11):1284-90. [PubMed 11038154]
Touloupidis S, Zoumpos I, Kalaitzis C, et al, “Acenocoumarol Associated Priapism: Report of a Case,” Andrologia, 2004, 36(1):47-9. [PubMed 14871265]