SINTHROME Tablet Ref.[6052] Active ingredients: Acenocoumarol

Hepatic impairment

Caution should be exercised in patients with mild to moderate hepatic impairment since the synthesis of blood coagulation factors may be impaired or there may be an underlying platelet dysfunction (see Section 4.2 and Section 5.2).

Renal impairment

Due to the possibility of accumulation of metabolites in impaired renal function, caution should be exercised in patients with mild to moderate renal impairment. (see Section 4.2 and Section 5.2).

Heart failure

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.

Haematological

Caution should be exercised in patients with known or suspected (e.g. abnormal bleeding after injury) protein C or protein S deficiency (see Section 4.8).

Calciphylaxis

Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with high mortality. The condition is mainly observed in patients with end-stage renal disease on dialysis or in patients with known risk factors such as protein C or S deficiency, hyperphosphataemia, hypercalcaemia or hypoalbuminaemia. Rare cases of calciphylaxis have been reported in patients taking vitamin K antagonists including Sinthrome also in the absence of renal disease. In case calciphylaxis is diagnosed, appropriate treatment should be started and consideration should be given to stopping treatment with Sinthrome.

Hemorrhage

Sintrom can cause major (including hemorrhagic and hypovolemic shock) or fatal bleeding. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥ 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see section 4.5),. Regular monitoring of INR should be performed on all treated patients ¹³⁸. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy.

Special populations

In paediatric and elderly patients (≥65 years), caution and more frequent monitoring of PT/INR is recommended (see Sections 4.2 Posology and method of administration and 5.2 Pharmacokinetic properties).

Miscellaneous

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

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

During treatment with anticoagulants, intramuscular injections may cause haematomas and should be avoided. Subcutaneous and intravenous injections may be given without such complications.

Meticulous care should be taken where it is necessary to shorten the PT/INR (thromboplastin time) for diagnostic or therapeutic procedures (eg angiography, lumbar puncture, minor surgery, tooth extractions etc).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorbtion should not take this medicine.

There are many possible interactions between coumarins and other drugs; those of clinical relevance are given below. Many of these are isolated reports only or have been reported with warfarin rather than acenocoumarol; for completeness, all have been included. The mechanisms of these interactions include disturbances of absorption, inhibition or induction of the metabolising enzyme system (mainly CYP2C9), see Section 5.2 Pharmacokinetic properties), and reduced availability of vitamin K₁, necessary for gamma-carboxylation of prothrombin–complex factors. It is important to note that some drugs may interact by more than one mechanism. Every form of therapy may involve the risk of an interaction, although not all will be significant. Thus careful surveillance is important and frequent coagulation tests (e.g. twice weekly) should be carried out when initially prescribing any drug in combination with Sinthrome, or when withdrawing a concomitantly administered drug.

Interactions resulting in concomitant use not being recommended

The following drugs potentiate the anticoagulant activity of acenocoumarol and/or alter haemostasis and thereby increase the risk of haemorrhage:

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

• heparin (including low-molecular-weight heparin) (except in situations which require rapid anticoagulations; see Section 4.2 Posology and method of administration);
• antibiotics (e.g. clindamycin);
• platelet-aggregation inhibitors (e.g. dipyridamole, clopidogrel), salicyclic acid and its derivatives, (e.g. acetylsalicylic acid, para-aminosalicylic acid, diflunisal);
• clopidogrel, ticlopidine, 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.

Increased INR has been reported in patients taking glucosamine and oral vitamin K antagonists. Patients treated with oral vitamin K antagonists should therefore be closely monitored at the time of initiation or termination of glucosamine therapy.

The risk of gastrointestinal haemorrhage is increased if Sinthrome is prescribed in combination with these substances. In the case of unavoidable concurrent use, coagulation tests should be performed more frequently.

Interactions to be considered

The anticoagulant effect 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.
• imidazole derivatives, including topical administration (e.g. econazole, fluconazole, ketoconazole, miconazole);
• sulfonamides (including co-trimoxazole);
• fibrates (e.g. clofibric acid), its derivatives and structural analogues (e.g. fenofibrate, gemfibrozil);
• disulfiram;
• etacrynic acid;
• glucagon;
• oral antidiabetics (e.g. glibenclamide);
• sulphonylureas (such as tolbutamide and chlorpropamide);
• H₂ antagonists (e.g. cimetidine);
• paracetamol;
• thyroid hormones (including dextrothyroxine);
• sulfinpyrazone;
• statins (e.g. atorvastatin, fluvastatin, simvastatin);
• selective serotonin re-uptake inhibitors (e.g. citalopram,fluoxetine, sertraline,paroxetine);
• tamoxifen;
• 5-fluorouracil and analogues;
• tramadol;
• proton pump inhibitors (e.g. omeprazole);
• plasminogen activators (e.g. urokinase; streptokinase and alteplase);
• thrombin inhibitors (e.g. argatroben);
• prokinetic agents (e.g. cisapride);
• antacids (e.g. magnesium hydroxide);
• viloxazine.
• Inhibitors of CYP2C9 may potentiate the anticoagulant effect of acenocoumarol.

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;
• cholestyramine (see Section 4.9 “Overdose”);
• griseofulvin;
• oral contraceptives;
• rifampicin;
• HIV protease inhibitors (e.g. ritonavir, nelfinavir);
• thiazide diuretics;
• St. John’s Wort/Hypericum perforatum;
• Inducers of CYP2C9, CYP2C19 or CYP3A4 may diminish the anticoagulant effect of acenocoumarol.

Vitamin E and corticosteroids (e.g. methylprednisolone, prednisone) may diminish the anticoagulant effect of coumarin derivatives.

Unpredictable effect on anticoagulation, including both increase and decrease in anticoagulant activity have been reported with the following drugs: protease inhibitors (e.g. indinavir, nelfinavir, ritonavir, saquinavir).

Effects of acenocoumarol on other drugs:

During concomitant treatment with hydantoin derivatives (such as phenytoin), the serum hydantoin concentration may rise.

Sinthrome may potentiate the hypoglycaemic effect of sulphonylurea derivatives e.g. glibenclamide, glimepiride.

Patients being treated with Sinthrome (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.

Cranberry juice should be avoided in patients receiving Sinthrome due to a theoretical risk of enhanced anti-coagulation. Increased medical supervision and INR monitoring should be considered for any patient receiving Sinthrome and regularly drinking cranberry juice. It is not known whether other cranberry products, such as capsules or concentrates, might also interact with Sinthrome. Therefore similar caution should be observed with these products.

Pregnancy

Sinthrome, like other coumarin derivatives, may be associated with congenital malformations of the embryo, therefore Sinthrome is contra-indicated for use in pregnancy (see Section 4.3 Contraindications). Women of child-bearing potential should take contraceptive measures during treatment with Sinthrome.

Lactation

Acenocoumarol passes into the breast milk, 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 K 1 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 Sinthrome should be carefully monitored to ensure that recommended PT/INR values are not exceeded.

Fertility

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

Sinthrome has no influence on the ability to drive and use machines. However, patients should be advised to keep their anticoagulant card with them.

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 Sinthrome; its occurrence is related to the dosage of the drug, the patient’s age and the nature of the underlying disease. 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.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

None stated.