Sinthrome^® Tablets 1mg.

Acenocoumarol BP 1mg.

White, round, flat tablets with slightly bevelled edges, with one side bearing the imprint “CG”, and the other the imprint “AA”.

Treatment and prevention of thromboembolic diseases.

Sensitivity to anticoagulants varies from patient to patient and may also fluctuate during the course of treatment. Therefore, it is essential to perform regular testing of prothrombin time (PT)/International Normalised Ratio (INT) and to adjust the patient's dosage accordingly. If this is not possible, Sinthrome should not be used.

Sinthrome should be given in a single oral dose at the same time every day.

Adults

Initial dosage: If the thromboplastin time is within the normal range before starting treatment, the following dosage schedule is recommended:

First day: Starting dose of 4 mg/day (lower doses may be required if patients are receiving heparin).

The administration of a loading dose may not be necessary if the PT/INR value before treatment is within the therapeutic range.

Second day: 4 to 8mg.

If the initial thromboplastin time is abnormal, treatment should be instituted with caution.

Elderly patients, patients with liver disease or severe heart failure with hepatic congestion or malnourished patients may require lower doses during treatment initiation and maintenance (see section 4.4 Special warnings and precautions for use).

Maintenance therapy: the maintenance dose of Sinthrome varies from patient to patient and must be determined on the basis of regular laboratory estimations of the patient's blood coagulation time.

Adjustment of the maintenance dose can only be made by monitoring the Quick value of international normalised ratio (INR) at regular intervals, ensuring that the dosage remains within the therapeutic range. Depending on the individual, the maintenance dose generally lies between 1 to 8mg daily.

Before the start of treatment, up to the time when the coagulation valency is stabilised within the optimum range, routine measurement of the thromboplastin time should be carried out daily in hospital. Blood samples for laboratory tests should always be taken at the same time of day.

The INR is the ratio of the patient's plasma thromboplastin time and the normal thromboplastin time raised to a power determined for a reference thromboplastin. As the Quick value decreases, the patient's thromboplastin time increases and the INR is greater. The therapeutic range generally lies between INR values of 2 to 4.5. Within this range, the majority of patients show no risk of severe haemorrhagic complications nor a recurrence of thrombosis.

Generally, after withdrawal of Sinthrome, there is usually no danger of reactive hypercoagulability and therefore it is not necessary to give gradually diminishing doses. However, in extremely rare cases, in some high risk patients (e.g. after myocardial infarction), withdrawal should be gradual.

Children: Not recommended.

Elderly: A dose lower than the recommended adult dose may be sufficient in elderly patients (see Section 4.4, “ Special warnings and precautions for use”).

Pregnancy. Known hypersensitivity to acenocoumarol and related coumarin derivatives or to the excipients of Sinthrome, and in patients unable to co-operate (e.g. unsupervised and senile patients, alcoholics and patients with psychiatric disorders).

All conditions where the risk of haemorrhage exceeds possible clinical benefit e.g. haemorrhagic diathesis and/or blood dyscrasia; immediately prior to, or after surgery on the central nervous system or eyes and traumatising surgery involving extensive exposure of the tissues; peptic ulceration or haemorrhage in the gastro-intestinal tract, urogenital tract or respiratory system; cerebrovascular haemorrhages; acute pericarditis; pericardial effusion; infective endocarditis; severe hypertension (due to occult risks); severe hepatic or renal disease; and in cases of increased fibrinolytic activity following operations on the lung, prostate or uterus.

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).

Particular care should be taken in patients with hepatic dysfunction since the synthesis of blood coagulation factors may be impaired or there may be an underlying platelet dysfunction (see also Section 4.2 Posology and method of administration). Disorders affecting gastro-intestinal absorption may alter the anticoagulant activity of Sinthrome. 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.

In elderly patients, anticoagulant medication should be monitored with special care (see Sections 4.2 “Posology and method of administration” and 5.2 “Pharmacokinetic properties”).

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 Undesirable effects).

Since acenocoumarol is extensively metabolised by the liver, impaired renal function will not greatly affect the elimination of the drug, although care should be taken due to the possibility of underlying platelet dysfunction.

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 malabsorption 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.

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:

o broad spectrum antibiotics (e.g. amoxicillin, co-amoxiclav) macrolides (e.g. erythromycin, clarithromycin);

o cephalosporins second and third generation;

o metronidazole;

o quinolones (e.g. ciprofloxacin, norfloxacin, ofloxacin);

o tetracyclines;

o neomycin;

o 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.

Corticosteroids (e.g. methylprednisolone, prednisone) have also been reported to potentiate the anticoagulant effect of coumarin derivatives.

Inhibitors of CYP2C9 may potentiate the anticoagulant effect of acenocoumarol.

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);

• 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 Sinthrome 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.

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 (see Section 4.9 “Overdose”);

• 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.

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. Women of child-bearing potential should take contraceptive measures during treatment with Sinthrome.

Lactation

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 Sinthrome should be carefully monitored to ensure that recommended PT/INR values are not exceeded.

None known.

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 (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.

Rare effects noted with acenocoumarol and similar coumarin derivatives include gastro-intestinal disorders (loss of appetite, nausea, vomiting), allergic reactions (urticaria and other rashes, dermatitis and fever) and reversible alopecia. Isolated cases of haemorrhagic skin necrosis (usually associated with congenital protein C deficiency or its cofactor protein S), vasculitis and liver damage have also been reported.

Clinical manifestations of overdosage are unlikely with large single doses, but more likely following prolonged use of daily doses exceeding those required therapeutically.

Hospital referral is recommended for any amount of Sinthrome taken above the therapeutic dose.

Symptoms:

The onset and severity of the symptoms are dependent on the individual's sensitivity to oral anticoagulants, the severity of the overdose and the duration of treatment.

Haemorrhage is the prominent feature of an overdose and may occur within 1 to 5 days after ingestion. Nose-bleeds, haematemesis, haemoptysis, gastro-intestinal haemorrhage, vaginal bleeding, haematuria (with renal colic), cutaneous haemorrhages, gingival bleeding, haematomata, and bleeding into the joints or menorrhagia may be experienced.

Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains.

Laboratory tests will show an extremely low Quick value (or high PT/INR value), pronounced prolongation of the recalcification time or thromboplastin time and disturbed gamma-carboxylation of factors II, VII, IX and X.

Treatment:

The necessity, or desirability of the treatment by gastric lavage in addition to the activated charcoal and cholestyramine administration is controversial. The benefits of these treatments should be balanced against the risk of bleeding in each patient.

For patients who have not previously received anticoagulants, arriving within 1 hour of ingestion, who are not obtunded, comatose or convulsing, and show no signs of bleeding from any source, then drug absorption may be reduced by gastric lavage. (However, note that gastric lavage may provoke bleeding). This may then be followed by the administration of activated charcoal. It should also be noted that vitamin-K mediated reversal of anticoagulation may be dangerous for patients who require constant anticoagulation such as those with prosthetic heart valves. Colestyramine may markedly enhance the drug's elimination by inhibiting the enterohepatic circulation.

A temporary reduction of the dose of Sinthrome is often sufficient to control slight bleeding.

Emergency and supportive measures:

In emergency situations of severe haemorrhage, clotting factors can be returned to normal by administering fresh whole blood or fresh frozen plasma, complex concentrate or recombinant factor VIIa supplemented with vitamin K1.

Antidote:

Vitamin K₁ (phytomenadione) may antagonise the inhibitory effect of Sinthrome 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 Sinthrome.

Pharmacotherapeutic group: Antithrombotic, vitamin K antagonists. ATC code: B01AA07

To initiate blood clotting, Vitamin K causes gamma-carboxylation of certain glutamic acid molecules on the coagulation factors II, VII, IX and X, and of protein C and its cofactor protein S. Coumarin derivatives, such as Sinthrome, prevent gamma-carboxylation of these proteins by Vitamin K, although the precise nature of this antagonism has yet to be established.

Depending on the initial dosage, Sinthrome prolongs the thromboplastin time within approximately 36 to 72 hours. Following withdrawal of Sinthrome, the thromboplastin time usually reverts to normal after a few days.

Absorption

Following oral administration, Sinthrome is rapidly absorbed; at least 60% of the administered dose is systemically available. Peak plasma concentrations are achieved within 1 to 3 hours after a single dose of 10mg and AUC values are proportional to the size of the dose over a dosage range of 8 to 16mg.

No correlation between plasma concentrations of acenocoumarol and the apparent prothombin levels can be established, due to the variation of plasma drug concentrations between patients.

Plasma drug concentrations are generally higher in patients of 70 years or over when compared with younger patients, after the same dose.

Distribution

Over 98% of acenocoumarol is protein-bound, mainly to albumin. The calculated apparent volume of distribution is 0.16-0.18 L/kg for the R(+) enantiomer and 0.22-0.34 L/kg for the S(-) enantiomer.

Metabolism

Acenocoumarol is extensively metabolised, although the metabolites appear to be pharmacologically inactive in man.

Elimination

The elimination half-life of acenocoumarol from the plasma is 8 to 11 hours. 29% is excreted in the faeces and 60% in the urine, with less than 0.2% of the dose renally excreted being unchanged.

There are no other clinically relevant pre-clinical safety data in addition to those mentioned in other sections of the Summary of Product Characteristics.

Aerosil 200 (silica aerogel), hypromellose, lactose, magnesium stearate, maize starch and talc.

None stated.

3 years.

None stated.

Blister packs of 100 tablets.

None stated

Alliance Pharmaceuticals Ltd.

Avonbridge House

2 Bath Road

Chippenham

Wiltshire

SN15 2BB

PL16853/0013

25 June 1998

March 2007

POM

Alliance, Alliance Pharmaceuticals and associated devices are registered Trademarks of Alliance Pharmaceuticals Ltd.