Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Norgine Pharmaceuticals Limited, Norgine House, Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, UK
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 (INR) 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.
The dosing of Sinthrome must be individualised. If the PT/INR value is within the normal range before starting treatment, the following dosage schedule is recommended:
The usual starting dose is between 2 mg/day to 4 mg/day without administration of a loading dose. Treatment may also be initiated with a loading dose regimen, usually 6 mg on the first day followed by 4 mg on the second day.
If the initial thromboplastin time is abnormal, treatment should be instituted with caution.
Elderly patients (≥65), 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).
Measurement of the thromboplastin time should be carried out daily in hospital starting from second or third dose of Sinthrome and up to the time when the coagulation status is stabilized within the target range. The interval between tests can later be extended, depending on the stability of PT/INR results. Blood samples for laboratory tests should always be taken at the same time of day.
The maintenance dose of Sinthrome varies from patient to patient and must be checked individually on the basis of PT/INR values. PT/INR should be assessed at regular intervals, i.e. at least once a month.
The maintenance dose generally lies between 1 to 8mg daily depending on the individual patient, the underlying disease, clinical indication and desired intensity of anticoagulation.
Depending on the clinical indication, the optimal intensity of anticoagulation or therapeutic range to be aimed at generally lies between INR values of 2.0 and 3.5 (see Table 1). Higher INR values up to 4.5 may be required in individual cases.
Table 1. Recommended INR* for Oral Anti-coagulant Therapy:
| Indication | Recommended INR |
|---|---|
| Prophylaxis and treatment of venous thromboembolism (including pulmonary embolism) | 2.0–3.0 |
| Atrial fibrillation | 2.0–3.0 |
| Post-myocardial infarction (with increased risk for thromboembolic complications) | 2.0–3.0 |
| Bioprosthetic heart valves | 2.0–3.0 |
| Secondary prophylaxis in patients wth antiphospholipid syndrome | 2.0–3.0 |
| Antiphospholipid syndrome patients with venous thromboembolism on therapeutic vitamin K antagonist | 2.0–3.5 |
| Mechanical heart valves | 2.0–3.5 |
* The PT, which reflects the reduction of Vitamin K dependent clotting factors VII, X and II, is dependent on the responsiveness of the thrombosplastin used for PT-testing. The responsiveness of the respective local thromboplastin compared to World Health Organisation international reference preparations is reflected by its International Sensitivity Index (ISI).
The “International Normalised Ratio” (INR) was introduced for the purpose of standardisation of the PT. The INR is the ratio of the patient’s anticoagulated plasma PT to the normal plasma PT using the same thromboplastin in the same test system raised to the power of a value defined by the International Sensitivity Index.
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.
The anticoagulant effect of Sinthrome persists beyond 24 hours. If the patient forgets to take the prescribed dose of Sinthrome at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not double the daily dose to make up for a missed dose, but should refer back to his or her doctor.
In clinical situations which require rapid anticoagulation, initial treatment with heparin is preferred since the anticoagulant effect of Sinthrome is delayed. Conversion to Sinthrome may begin concomitantly with heparin therapy or may be delayed depending on the clinical situation. To ensure continuous anticoagulation, it is advisable to continue to prescribe full dose heparin therapy for at least 4 days after initiation of Sinthrome and to continue heparin therapy until the INR has been in the target range on at least two consecutive days. During the transition phase close monitoring of anticoagulation is necessary.
Patients on Sinthrome, who undergo surgical or invasive procedures require close surveillance of their coagulation status. Under certain conditions, e.g. when the operation site is limited and accessible to permit effective use of local procedures for haemostasis, dental and minor surgical procedures may be performed during continued anticoagulation, without undue risk of haemorrhage. The decision to discontinue Sinthrome, even for a short period of time, should carefully consider individual risks and benefits. The introduction of bridging anticoagulant treatment, e.g. with heparin should be based on careful assessment of the expected risks of thromboembolism and bleeding.
Sinthrome is contraindicated in patients with severe renal impairment due to an increased risk of haemorrhage. Caution should be exercised in patients with mild to moderate renal impairment (see section 4.3 Contraindications, Section 4.4 Special warnings and precautions and Section 5.2 Pharmacokinetic properties).
Sinthrome is contraindicated in patients with severe hepatic impairment due to an increased risk of haemorrhage. Caution should be exercised in patients with mild to moderate hepatic impairment. (see -Section 4.3 Contraindications, Section 4.4 Special warnings and precautions and Section 5.2 Pharmacokinetic properties).
Experience with oral anticoagulants including acenocoumarol in children remains limited. Caution and more frequent monitoring of PT/INR is recommended (see Section 4.4 Special warnings and precautions for use).
A dose lower than the recommended adult dose may be sufficient in elderly patients. Caution and more frequent monitoring of PT/INR is recommended (see Section 4.4 Special warnings and precautions for use and Section 5.2 Pharmacokinetic properties).
The daily dosage should always be taken at the same time of day. The tablet should be swallowed whole with a glass of water.
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.
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.
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.
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.
Vitamin K1 (phytomenadione) may antagonise the inhibitory effect of Sinthrome on hepatic gamma-carboxylation of the vitamin K-dependent coagulation factors within 3 to 5 hours. In cases of clinically insignificant haemorrhages, such as a brief nose-bleed or small isolated haematomas, a temporary reduction or omission of the dose of Sinthrome is often sufficient. In cases of moderate to severe haemorrhage, Vitamin K1 can be given orally.
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.
Sinthrome should be resumed when INR is in target range in case of moderate to severe haemorrhage.
3 years.
None stated.
Blister packs of 100 tablets.
No special requirements.
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