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SINTROM®
(acenocoumarol)
4 mg tablets
Prescribing Information
1
Name of the medicinal product
SINTROM®
2
Qualitative and quantitative composition
Active ingredient: 3-[α-(4-nitrophenyl)-β-acetylethyl]-4-hydroxycoumarin
(= acenocoumarol) as a racemic mixture. Acenocoumarol is a 4-hydroxycoumarin
derivative.
Tablets of 4 mg.
3
For a full list of excipients, see section 6.1 List of
excipients.Pharmaceutical form
Tablets for oral administration.
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White, round, flat, with bevelled edges. One side bears the imprint "CG", the other is
scored in the shape of a cross with the imprint "A" in each quadrant.
4
Clinical particulars
4.1
Therapeutic indications
Anticuagulant derived from coumarin.
4.2
Posology and method of administration
General guidelines
Sensitivity to anticoagulants varies from patient to patient and may also fluctuate in the
course of treatment. Therefore it is essential to perform regular testing of prothrombine
time (PT)/ International Normalized Ratio (INR) and to adjust the patient's dosage
accordingly. If this is not possible, Sintrom should not be used.
The daily dosage should always be prescribed as a single dose and always taken at the
same time of day.
For adaptation of the dosage to various clinical conditions, see also section 4.4 Special
warnings and precautions for use and section 4.5 Interaction with other medicinal products
and other forms of interaction.
Initial dosage
The dosing of Sintrom must be individualized. The usual starting dose of Sintrom in a
normal weight person is between 2 mg/day to 4 mg/day without administration of a
loading dose, if the PT/INR value before the start of treatment is within the normal range.
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 PT/INR value 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).
Before the start of treatment and up to the time when the coagulation status is stabilised
within the therapeutic range, measurement of the PT/INR should be carried out on a daily
basis. The interval between tests can later be extended, depending on the stability of
PT/INR results. It is recommended that the blood samples for laboratory tests always be
taken at the same time of day.
Maintenance therapy and coagulation tests
The maintenance dose varies from patient to patient and its appropriateness 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 PT, which reflects the reduction of Vitamin K dependent clotting factors VII, X and
II, is dependent on the responsiveness of the thromboplastin used for PT-testing. The
responsiveness of the respective local thromboplastin compared to World Health
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Organization international reference preparations is reflected by its International
Sensitivity Index (ISI).
The “International Normalised Ratio” (INR) was introduced for the purpose of
standardization 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.
The maintenance dose generally lies between 1 and 8 mg daily depending on the
individual patient, the underlying disease, clinical indication and the 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 and3.5(see table
1). Higher INR values up to 4.5 may be required in individual cases.
Table 1
Indication
Prophylaxis and treatment of venous thromboembolism
(including pulmonary embolism)
Atrial fibrillation
Post-myocardial infarction (with increased risk for
thromboembolic complications)
Bioprosthetic heart valves
Mechanical heart valves
Recommended INR
2.0 – 3.0
2.0 – 3.0
2.0 – 3.0
2.0 – 3.0
2.0 – 3.5
Treatment with Sintrom can generally be discontinued without the need to taper off
medication It has been found, however, that in extremely rare cases and in certain highrisk patients (e.g. after myocardial infarction) “rebound hypercoagulability” may occur . In
such patients, withdrawal of anticoagulant therapy should be gradual.
Missed Dose
The anticoagulant effect of Sintrom persists beyond 24 hours. If the patient forgets to take
the prescribed dose of Sintrom at the scheduled time, the dose should be taken as soon as
possible on the same day. The patient should not take the missed dose by doubling the
daily dose to make up for missed doses, but should refer back to his or her physician .
Conversion from heparin therapy
In clinical situations which require rapid anticoagulation, initial treatment with heparin is
preferred since the anticoagulant effect of Sintrom is delayed. Conversion to Sintrom may
begin concomitantly with heparin therapy or may be delayed depending on the clinical
situation. To ensure continuous anticoagulation, it is advisable to continue full dose
heparin therapy until Sintrom has produced the desired, stable therapeutic response as
determined by PT/INR. During the transition phase close monitoring of anticoagulation is
necessary.
Treatment during dentistry and surgery
Patients on Sintrom, 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 hemostasis,
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dental and minor surgical procedures may be performed during continued anticoagulation,
without undue risk of hemorrhage. The decision to discontinue Sintrom, 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.
Use in children
Experience with oral anticoagulants including acenocoumarol in children remains limited.
Caution and more frequent monitoring of prothrombin time and INR is recommended.
Use in elderly
Elderly patients may require lower initial and maintenance doses .Elderly patients on
anticoagulant therapy should be monitored with special care (see section 4.4 Special
warnings and precautions for use and section 5.2 Pharmacokinetic properties).
4.3
•
•
•
Contraindications
Known hypersensitivity to acenocoumarol and related coumarin derivatives or to
excipients.
Pregnancy
In patients unable to cooperate and who are unsupervised (e.g. unsupervised senile
patients, alcoholics and patients with psychiatric disorders).
Sintrom is also contraindicated in conditions where the risk of haemorrhage is greater than
the possible clinical benefit, e.g.:
• Haemorrhagic diathesis or haemorrhagic blood dyscrasia.
• Shortly before or after surgical intervention on the central nervous system, as well as
eye operations and traumatising surgery involving extensive exposure of tissues.
• Peptic ulcers or haemorrhage in the gastrointestinal tract, urogenital tract, or
respiratory system, as well as cerebrovascular haemorrhages, acute pericarditis and
pericardial effusion, and infective endocarditis.
• Severe hypertension, severe hepatic or renal disease.
• Increased fibrinolytic activity as encountered after operations on the lung, prostate,
uterus, etc.
4.4
Special warnings and precautions for use
Strict medical supervision should be given in cases where the conditions or diseases may
reduce the protein binding of Sintrom, for example, thyrotoxicosis, tumours, renal
diseases, infections, and inflammation.
Particular care should be taken in patients with hepatic dysfunction, since synthesis of
coagulation factors may also be impaired or there may be an underlying platelet
dysfunction (see also section 4.2 Posology and method of administration).
Disorders affecting gastrointestinal absorption may alter the anticoagulant effect of
Sintrom.
In cases of severe heart failure, a very cautious dosage schedule must be adopted, because
activation or gamma -carboxylation of the coagulation factors may be reduced in the
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presence of hepatic congestion(see also section 4.2 Posology and method of
administration). However with the reversal of hepatic congestion, it may be necessary to
raise the dosage.
Caution should be excercised in patients with known or suspected (e.g. abnormal bleeding
after injury) protein C or protein S deficiency (see section 4.8 Undesirable effects).
In elderly patients anticoagulant medication should be monitored with special care (see
also section 4.2 Posology and method of administration).
During treatment with anticoagulants, intramuscular injections may cause haematomas
and should be avoided. Subcutaneous and intravenous injections, on the other hand, lead
to no such complications.
Meticulous care should be taken where it is necessary to shorten the PT/INR for
diagnostic or therapeutic interventions (e.g. angiography, lumbar puncture, minor surgery,
tooth extractions, etc.).
Sintrom tablets contain lactose and are not recommended in patients with rare hereditary
problems of galactose intolerance, of lactase deficiency or of glucose-galactose
malabsorption.
4.5
Interaction with other medicinal products and other forms of
interaction
There are many possible interactions between coumarins and other drugs. 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 the vitamin K necessary for the
gamma -carboxylation of prothrombin-complex factors. It is important to note that some
drugs may interact by more than one mechanism. Any form of therapy may involve the
risk of an interaction although not all interactions will be significant. Thus careful
surveillance is important and frequent (e.g. twice weekly) coagulation tests should be
carried out when initially prescribing any drug in combination with Sintrom or
withdrawing a concomitantly administered drug.
4.5.1 Effects of other drugs on acenocoumarolThe following drugs potentiate the
anticoagulant activity of acenocoumarol and/or alter haemostasis and thereby
increase the risk of haemorrhage:
Heparin, platelet-aggregation inhibitors such as salicylic acid and its derivatives (e.g.
acetylsalicylic acid, para-aminosalicylic acid, diflunisal), phenylbutazone or other
pyrazolone derivatives (e.g. sulfinpyrazone), and other non-steroidal anti-inflammatory
drugs including cyclo-oxygenase-2 inhibitors (e.g. celecoxib); high-dose intravenous
methylprednisolone. Use of Sintrom together with these substances is therefore not
recommended. When Sintrom is prescribed in combination with these drugs, coagulation
tests should be performed more frequently.
The following drugs may potentiate the anticoagulant effect of acenocoumarol:
Allopurinol, anabolic steroids, androgens, antiarrhythmic agents (e.g. amiodarone,
quinidine), antibiotics (e.g. amoxicillin, cephalosporins second and third generation,
chloramphenicol, erythromycin, fluoroquinolones, neomycin, tetracyclines), cimetidine,
disulfiram, ethacrynic acid, fibrates (e.g. clofibric acid), glucagon, imidazole derivatives
(e.g. metronidazole and, even when administered locally, miconazole), paracetamol,
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selective serotonin reuptake inhibitors SSRI (e.g. citalopram, fluoxetine, sertraline), statins
(e.g. fluvastatin, atorvastatin, simvastatin), sulfonamides including co-trimoxazole
(=sulfamethoxazole + trimethoprim), sulphonylureas (such as tolbutamide and
chlorpropamide), thyroid hormones (incl. dextrothyroxine), tamoxifen and tramadol.
Corticosteroids (e.g. methylprednisolone, prednisone). Corticosteroids have also been
reported to diminish the anticoagulant effect of coumarin derivatives.
Inhibitors of CYP2C9 may potentiate the anticoagulant effect of acenocoumarol.
The following drugs may diminish the anticoagulant effect of acenocoumarol:
Aminoglutethimide, antineoplastic drugs (azathioprine, 6-mercaptopurine), barbiturates
(e.g. phenobarbital), carbamazepine, cholestyramine (see section 4.9 Overdose), HIV
protease inhibitors (e.g. ritonavir, nelfinavir), griseofulvin, oral contraceptives, rifampicin
and St. John’s wort / hypericum perforatum (this interaction has been described with
warfarin and phenprocoumon and can not be ruled out for acenocoumarol).
Inducers of CYP2C9, CYP2C19 or CYP3A4 may diminish the anticoagulant effect of
acenocoumarol.
Since neither the severity nor the early signs of interactions can be predicted, patients
taking Sintrom, especially if they also suffer from hepatic dysfunction, should limit their
alcohol intake.
4.5.2 Effects of acenocoumarol on other drugs
During concomitant treatment with hydantoin derivatives(such as phenytoin), the serum
hydantoin concentration may rise.
Sintrom may potentiate the hypoglycaemic effect of sulfonylurea derivatives.
4.6
Pregnancy and lactation
Pregnancy
Sintrom, like other coumarin derivatives, may be associated with congenital
malformation of the embryo. Sintrom is therefore contraindicated during
pregnancy. Women of child-bearing potential
Women of childbearing potential should take contraceptive measures during treatment
with Sintrom.
Lactation
Sintrom passes into the breast milk of lactating mothers, but, with limited data available,
the quantities in breast milk are small and undesirable effects on the infant are usually not
to be expected.
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 Sintrom should be carefully monitored to
ensure that recommended PT/INR values are not exceeded.
When breast-feeding, the infant should be given 1 mg vitamin K1 per week as a
prophylactic.
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4.7
Effects on ability to drive and use machines
Sintrom has no known influence on the ability to drive or use machines. Out-patients
should nevertheless be advised to carry with them an 'anticoagulant card' in view of the
possibility of their sustaining injuries.
4.8
Undesirable effects
Adverse reactions 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
Haemorrhage in various organs is a common side effect associated with Sintrom, its
occurrence is related to the dosage to the drug, the patient’s age, and the nature of the
underlying disease (but not to the duration of treatment).
Table 2
Immune system disorders
Rare:
Allergic reactions (e.g. urticaria, rash)
Vascular disorders
Very rare:
Vasculitis
Gastrointestinal disorders
Rare:
Loss of appetite, nausea, vomiting
Hepatobiliary disorders
Very rare:
Liver damage
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)
4.9
Overdose
Whereas single doses even if very large do not usually prove dangerous, clinical
manifestations of overdosage may set in during prolonged use of daily doses higher than
are necessary for treatment.
Signs and symptoms
The onset and severity of the symptoms are dependent on the individual's sensitivity to
oral anticoagulants, the severity of the overdosage, and the duration of treatment.
Bleeding is the major sign of poisoning with oral anticoagulant drugs. The most frequent
symptoms observed are: cutaneous bleeding (80%), haematuria (52%), haematomas,
gastrointestinal bleeding, haematemesis, uterine bleeding, epistaxis, gingival bleeding and
bleeding into the joints.
Laboratory tests reveal an extremely high PT/INR value, pronounced prolongation of the
recalcification time or thromboplastin time, and disturbed gamma-carboxylation of factors
II, VII, IX, and X.
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Treatment
The necessity, or desirability, of the treatment with syrup ipecac, 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.
If the patient has not been previously receiving anticoagulants, presents for treatment
within 1 hour of ingestion, is not obtunded, comatose, or convulsing, and has no evidence
of bleeding from any source, emesis with syrup of ipecac and gastric lavage with a largebore orogastric tube can be attempted. Gastric lavage may also provoke bleeding. After
gastric lavage, activated charcoal may be administered. In patients who are already
anticoagulated, emesis should not be induced. Vitamin-K mediated reversal of
anticoagulation may be dangerous for patients who require constant anticoagulations (e.g.
for prostetic heart valves).
Cholestyramine may markedly increase elimination of the drug by inhibiting the
enterohepatic circulation.
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 Sintrom on hepatic
gamma-carboxylation of the vitamin K-dependent coagulation factors within 3-5 hours.
In the event of clinically insignificant haemorrhages, such as brief nose-bleed or small
isolated haematomas, a temporary reduction of the dose of Sintrom is often sufficient.
In cases of moderate haemorrhage, give 2-5 mg vitamin K1 by oral route. If there is
evidence of significant anticoagulation give 5-10 mg vitamin K1 very slowly i.v. (at a rate
not exceeding 1 mg per minute).
5
Pharmacological properties
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotic, vitamin K antagonists. ATC code: B01AA07
Acenocoumarol, the active substance of Sintrom, is a coumarin derivative and functions as
vitamin K antagonist. Vitamin K antagonists produce their anticoagulant effect by
inhibition of the vitamin K-epoxide-reductase with a subsequent reduction of the gammacarboxylation of certain glutamic acid molecules which are located at several sites near the
terminal end both of coagulation factors II (prothrombin), VII, IX, and X, and of protein C
or its cofactor protein S. This gamma-carboxylation has a significant bearing on
interaction of the aforementioned coagulation factors with Ca ions. Without this reaction,
blood clotting cannot be initiated.
Depending on the size of the initial dosage, acenocoumarol causes prolongation of the
PT/INR within approx. 36 - 72 hours. Following withdrawal of the medication the PT/INR
usually reverts to normal after a few days.
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5.2
Pharmacokinetic properties
Absorption
Acenocoumarol, a racemic mixture of the optical R(+) and S(-) enantiomers, is rapidly
absorbed by the oral route, and at least 60% of the dose is systemically available. Peak
plasma concentrations of 0.3 ± 0.05 microgram/mL are attained within 1-3 hours after a
single dose of 10 mg. The peak plasma concentrations and the areas under the blood
concentration curve (AUC) are proportional to the dose over a dosage range of 8-16 mg.
The between-patient plasma concentrations vary to such an extent that no correlation can
be established between the dose, plasma concentrations of acenocoumarol and the
apparent prothrombin level.
Distribution
The bulk of the acenocoumarol administered is to be distributed in the plasma fraction of
the blood, where 98.7% becomes bound to plasma proteins, notably to albumin. The
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.
Acenocoumarol passes into the breast milk, but only in very small quantities which cannot
be detected by the usual analytical methods. It also crosses the placental barrier.
BiotransformationAcenocoumarol is extensively metabolised. 6- and 7-hydroxylation of
both enantiomers of acenocoumarol are the major metabolites and the cytochrome P450
2C9 is the major catalyst for the formation of these four metabolites. Other enzymes
involved in the metabolism of (R)-acenocoumarol are CYP1A2 and CYP2C19.By
reduction of the keto group two different carbinol metabolites are formed. Reduction of
the nitro group results in an amino metabolite. None of these metabolites contribute to the
anticoagulant activity of the parent drug in man, but they are all active in an animal model.
CYP2C9-related genetic variability accounts for 14% of the interindividual variability in
acenocoumarol pharmacodynamic response.
Elimination
Acenocoumarol is eliminated from the plasma with a half-life of 8-11 hours. The apparent
plasma clearance amounts to 3.65 L/h after oral administration. The total plasma clearance
of the R (+) enantiomer of acenocoumarol, which possesses significantly higher
anticoagulant activity, is much lower than that of the S(-) enantiomer.
Only 0.12-0.18% of the dose is excreted unchanged in the urine. Cumulative excretion of
metabolites and acenocoumarol over 1 week amounts to 60% of the dose in urine and 29%
in the faeces.
Characteristics in patients
In one study, the plasma concentrations of acenocoumarol which produced a given
prothrombin level appeared to be higher in patients over 70 years of age than in younger
patients although the doses administered were not larger.
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5.3
Preclinical safety data
Toxicity
After a single (acute) oral and/or intravenous dose, acenocoumarol showed a low degree
of toxicity in mice, rats, and rabbits. The dog showed moderate toxicity.
In repeated-dose studies, the liver is suggested to be the main target organ in the toxicity
of coumarin derivatives including acenocoumarol. The administration of these substances
at excessive pharmacological doses can cause haemorrhages.
Reproduction toxicity, teratogenicity
No animal experiments were performed with acenocoumarol. However, placental and
transplacental interference with vitamin K dependent coagulation factors may give rise to
embryonic or fetal anomalies and neonatal haemorrhages both in animals and in humans.
Mutagenicity
From investigations on bacterial and mammalian cell systems in vitro, including a DNA
repair assay on rat hepatocytes, it can be concluded that acenocoumarol and/or its
metabolites did not exert any mutagenic effects. An in vitro study on human lymphocytes
has shown some mild mutagenic activity. However, in this experiment the effective
concentrations of acenocoumarol, ≥188 and ≥250 microgram/mL (with and without
metabolic activation, respectively), were 500 to 1000 times higher than concentrations
determined in human plasma after medication with acenocoumarol.
Carcinogenicity
No lifetime-exposure studies were carried out in animals with acenocoumarol.
Coumarin, at doses clearly exceeding the maximum tolerated dose (MTD), induced an
increase in the incidence of liver tumours in rats, without impact on survival. No such
finding was recorded for mice. The induction of hepatoma seen in rats with anticoagulants
of the coumarin class is not likely to indicate an increased carcinogenic risk in humans.
Hepatoxicity of coumarin and its derivatives in the rat is understood to be associated with
enzyme induction and the metabolic pathway of coumarin and/or its metabolites peculiar
to this rodent species.
6
Pharmaceutical particulars
6.1
List of excipients
Anhydrous colloidal silica (silica aerogel), lactose monohydrate, magnesium stearate,
maize starch and pregelatinized maize starch.
6.2
Special precautions for storage
Sintrom tablets do not require any special storage conditions.
Sintrom must be kept out of the reach and sight of children.
Manufacturer:
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Novartis Farma SPA, Torre Annunziata, Italy
For: Novartis Pharma AG, Basel, Switzerland.
Lisence holder:
PharmaExcel Ltd.
23 Hasivim St. Petach-Tikva
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