Acenocoumarol

Patients being treated with acenocoumarol (especially those suffering from hepatic dysfunction) should limit their alcohol intake, since it is not possible to predict the severity of any drug interactions, nor identify any early signs of such interactions.

In severe heart failure, a very cautious dosage schedule must be adopted, since hepatic congestion may reduce the activation of gamma-carboxylation of coagulation factors. However with reversal of the hepatic congestion, it may be necessary to raise the dosage.

Particular care should be taken in administration of acenocoumarol in patients with hepatic dysfunction since the synthesis of blood coagulation factors may be impaired or there may be an underlying platelet dysfunction.

Acenocoumarol may potentiate the hypoglycemic action of sulfonylurea derivatives eg glibenclamide, glimepiride.

Drugs altering haemostasis may potentiate the anticoagulant activity of acenocoumarol and thereby increase the risk of haemorrhage. Consequently, acenocoumarol should not be prescribed with such drugs, which include:

• heparin (including low-molecular-weight heparin);
• platelet-aggregation inhibitors (e.g. dipyridamole, clopidogrel), salicyclic acid and its derivatives, acetylsalicylic acid, para-aminosalicylic acid;
• diflunisal, phenylbutazone or other pyrazolone derivatives (e.g. sulfinpyrazone), and other non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors (e.g. celecoxib), high dose IV methylprednisolone.

The risk of gastrointestinal haemorrhage is increased if acenocoumarol is prescribed in combination with NSAIDs, including selective COX-2 inhibitors. In the case of unavoidable concurrent use, coagulation tests should be performed more frequently.

Concomitant therapy of acenocoumarol with hydantoin derivatives (such as phenytoin), may increase the concentration of hydantoin in blood serum.

Corticosteroids potentiate the anticoagulant effect of acenocoumarol.

Inhibitors of CYP2C9 may potentiate the anticoagulant effect of acenocoumarol.

Strict medical supervision should be given in cases where the disease or condition may reduce the protein binding of acenocoumarol (e.g. thyrotoxicosis, tumours, renal disease, infections and inflammation).

The anticoagulant effect of acenocoumarol may be potentiated by concomitant administration of the following drugs: allopurinol, anabolic steroids, androgens, anti-arrhythmic agents (e.g. amiodarone, quinidine), antibiotics: broad spectrum antibiotics (e.g. amoxicillin, co-amoxiclav) macrolides (e.g. erythromycin, clarithromycin), cephalosporins second and third generation, metronidazole, quinolones (e.g. ciprofloxacin, norfloxacin, ofloxacin), tetracyclines, neomycin, chloramphenicol, fibrates (e.g. clofibric acid), its derivatives and structural analogues (e.g. fenofibrate, gemfibrozil), disulfiram, etacrynic acid, glucagon, H₂ antagonists (e.g. cimetidine), imidazole derivatives, including topical administration (e.g. econazole, fluconazole, ketoconazole, miconazole), paracetamol, sulfonamides (including co-trimoxazole), oral antidiabetics (e.g. glibenclamide), thyroid hormones (including dextrothyroxine), sulfinpyrazone, sulphonylureas (such as tolbutamide and chlorpropamide), statins (e.g. atorvastatin, fluvastatin, simvastatin), selective serotonin re-uptake inhibitors (e.g. fluoxetine, paroxetine), tamoxifen, 5-fluorouracil and analogues, tramadol.

The anticoagulant effect may be diminished by concomitant administration of the following drugs: aminoglutethimide, antineoplastic drugs (e.g. azathioprine, 6-mercaptopurine), barbiturates (e.g. Phenobarbital), carbamazepine, colestyramine, griseofulvin, oral contraceptives, rifampicin, thiazide diuretics, St. John’s Wort/Hypericum perforatum, Inducers of CYP2C9, CYP2C19 or CYP3A4 may diminish the anticoagulant effect of acenocoumarol.

Vitamin K₁ (phytomenadione) may antagonise the inhibitory effect of acenocoumarol within 3 to 5 hours. In cases of moderate haemorrhage, 2 to 5 mg Vitamin K₁ should be given orally; in severe haemorrhage, 5 to 10mg Vitamin K₁ should be injected very slowly (at a rate less than 1mg/min) intravenously. Additional doses (up to a maximum dose of 40mg daily) should be given at 4-hour intervals. Vitamin K₁ should not be given by intramuscular injection.

Doses of Vitamin K₁ in excess of 5mg can cause resistance to further anticoagulant therapy for several days. If an anticoagulant is required, heparin may be used temporarily, although oral anticoagulant therapy should be resumed at the same time and heparin withdrawn once the therapeutic range has been reached.

In the case of life-threatening haemorrhage, intravenous transfusions of fresh frozen plasma or whole blood, complex concentrate or recombinant factor VIIa supplemented with vitamin K₁ can abolish the effects of acenocoumarol.

Patients undergoing radiation therapy are particularly susceptible to anticoagulants. In these cases, it is generally an indication of lower doses, in both original and prophylactic treatment.

Caution should be exercised in patients with known or suspected (e.g. abnormal bleeding after injury) protein C or protein S deficiency.

Disorders affecting gastro-intestinal absorption may alter the anticoagulant activity of acenocoumarol.

Acenocoumarol, like other coumarin derivatives, may be associated with congenital malformations of the embryo, therefore acenocoumarol is contra-indicated for use in pregnancy. Women of child-bearing potential should take contraceptive measures during treatment with acenocoumarol.

Acenocoumarol passes into the breast milk of lactating mothers, but in quantities so small that no undesirable effects on the infant are to be expected. However, as a precaution, the infant should be given 1mg vitamin K1 per week as a prophylactic measure.

The decision to breast-feed should be carefully considered and may include coagulation tests and vitamin K status evaluation in infants before advising women to breast-feed. Women who are breast-feeding and treated with acenocoumarol should be carefully monitored to ensure that recommended PT/INR values are not exceeded.

Fertility

There are no data available on the use of acenocoumarol and its effect on fertility in humans.

Acenocoumarol has no influence on the ability to drive and use machines.

Undesirable effects are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports.

Haemorrhage, in various organs, is the most common side-effect associated with acenocoumarol; its occurrence is related to the dosage of the drug, the patient’s age and the nature of the underlying disease (but not the duration of treatment). Fatalities have been reported. Possible sites of haemorrhage include the gastro-intestinal tract, brain, urogenital tract, uterus, liver, gall bladder and the eye. If haemorrhage occurs in a patient with a thromboplastin time within the therapeutic range, diagnosis of their condition must be clarified.

Immune system disorders

Rare: Hypersensitivity (e.g. urticaria, rash, dermatitis and fever)

Vascular disorders

Common: Haemorrhage

Very rare: Vasculitis

Gastrointestinal disorders

Rare: Decreased appetite, nausea, vomiting

Hepatobiliary disorders

Very rare: Liver injury

Skin and subcutaneous tissue disorders

Rare: Alopecia

Very rare: Skin necrosis (haemorrhagic)*

* Usually associated with congenital deficiency of protein C or its cofactor protein S.