This document provides basic drug information about Sintrom, which contains the active ingredient acenocoumarol. It is used to treat and prevent thromboembolic diseases. The tablets come in a 4 mg dose. It works by inhibiting the production of vitamin K-dependent clotting factors in the liver. Its effects can be seen within 36-72 hours and it has a narrow therapeutic index, so regular coagulation monitoring and dose adjustments are required for safe use. Common side effects include bleeding, while an overdose can cause serious or fatal hemorrhage.

1. Sintrom
Basic Drug Information
Date of issue: 17 December 1996
1. Trade name of the medicinal product
Sintrom 4 mg
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. Pharmaceutical form
Tablets.
4. Clinical particulars
4.1. Therapeutic indications
Treatment and prevention of thromboembolic diseases.

2. 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 coagulation tests 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 under “Warnings and
precautions” and “Interactions”.
Initial dosage
If the thromboplastin time before the start of treatment is within the normal range, the
following dosage schedule is recommended:
First day: 4-12 mg.
Second day: 4-8 mg.
If the initial thromboplastin time is abnormal, treatment should be instituted with caution.
Maintenance therapy and coagulation tests
The maintenance dose varies from patient to patient and must be determined on the basis of
regular laboratory measurements of the patient’s blood coagulation time. Accurate adjustment
of the individual maintenance dose can only be achieved by carefully monitoring the Quick
values or International Normalised Ratio (INR) values, (see below) at regular intervals, e.g.
once a month, so that the dosage remains within the therapeutic range. Depending on the
Quick value (or INR value), as well as on the individual patient and the nature of his or her
disease, the maintenance dose generally lies between 1 and 8 mg daily.
Before the start of treatment and up to the time when the coagulation status is stabilised
within the optimal range, measurement of the thromboplastin time should be carried out daily
in hospital. The interval between tests can later be extended. It is recommended that the blood
samples for laboratory tests always be taken at the same time of day.
The “International Normalised Ratio” (INR) was introduced for the purpose of
standardisation, and with the help of calibrated thromboplastins this makes international
comparability possible. The INR is the ratio of the patient's anticoagulated plasma
prothrombin time to the normal plasma prothrombin time using the same thromboplastin in
the same test system raised to the power of a value defined by the International Sensitivity
Index which is determined for a reference thromboplastin using the WHO procedure. The
lower the Quick value, the higher the patient's thromboplastin time and the INR.
Depending on the clinical picture or indication, the optimal intensity of anticoagulation or
therapeutic range to be aimed at generally lies between INR values of 2.0 and 4.5. Within this
range the majority of the patients treated develop neither a recurrence of thrombosis nor any
severe haemorrhagic complications.
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3. After the withdrawal of Sintrom there is generally no danger of reactive hypercoagulability
and hence no need to taper off the medication when discontinuing treatment. It has been
found, however, that in extremely rare cases and in certain high-risk patients (e.g. after
myocardial infarction) “rebound hypercoagulability” may occur. In such patients, withdrawal
of anticoagulant therapy should be gradual.
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 on anticoagulant therapy should be monitored with special care (see
'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 aftersurgical 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 special precautions for use
Warnings and precautions
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.
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4. 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 γ-carboxylation of the coagulation factors may be reduced in the presence of
hepatic congestion. 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 'Undesirable effects').
In elderly patients anticoagulant medication should be monitored with special care.
Since Acenocoumarol is extensively metabolized 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, on the other hand, lead to no
such complications.
Meticulous care should be taken where it is necessary to shorten the thromboplastin time for
diagnostic or therapeutic interventions (e.g. angiography, lumbar puncture, minor surgery,
tooth extractions, etc.).
4.5. Interaction with other medicaments 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, and reduced availability of the vitamin K necessary for the γ-
carboxylation of prothrombin-complex factors. 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.
The following drugs may potentiate the anticoagulant effect of Sintrom:
Allopurinol, anabolic steroids, androgens, antiarrhythmic agents (e.g. amiodarone, quinidine),
antibiotics (e.g. erythromycin, tetracyclines, neomycin, chloramphenicol and amoxycillin),
clofibric acid as well as derivatives and structural analogues of clofibric acid, disulfiram,
ethacrynic acid, glucagon, cimetidine, imidazole derivatives (e.g. metronidazole and, even
when administered locally, miconazole), sulfonamides including co-trimoxazole
(=sulfamethoxazole + trimethoprim), sulphonylureas such as tolbutamide and
chlorpropamide, thyroid hormones (incl. dextrothyroxine), sulfinpyrazone, simvastatin, and
tamoxifen.
The following drugs alter haemostasis and may potentiate the anticoagulant activity of
Sintrom and thereby increasing the risk of gastrointestinal haemorrhage:
Heparin, platelet-aggregation inhibitors such as salicylic acid and its derivatives (e.g.
acetylsalicylic acid, para-aminosalicylic acid, diflunisal), phenylbutazone or other pyrazolone
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5. derivatives (sulfinpyrazone), and other non-steroidal anti-inflammatory drugs. Use of Sintrom
together with these substances is therefore highly unadvisable. When Sintrom is prescribed in
combination with these drugs, coagulation tests should be performed more frequently.
The following drugs may diminish the anticoagulant effect of Sintrom:
Aminoglutethimide, barbiturates, carbamazepine, cholestyramine (see under 'Overdose'),
griseofulvin, oral contraceptives, and rifampicin.
Other interactions
During concomitant treatment with hydantoin derivatives, the serum hydantoin concentration
may rise.
Sintrom may potentiate the hypoglycaemic effect of sulfonylurea derivatives.
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.
4.6. Pregnancy and lactation
Sintrom, like other coumarin derivatives, may be associated with congenital malformation of
the embryo. Sintrom is therefore contraindicated during pregnancy. Women of childbearing
potential should take contraceptive measures during treatmentwith Sintrom. Sintrom 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, the infant should be given 1 mg vitamin K1 per
week as a prophylactic.
4.7. Effects on ability to drive and use machines
Sintrom has no 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
Frequency estimate: very rare < 0.01%; rare ≥ 0.01% to < 0.1%; uncommon ≥ 0.1% to <
1%; common ≥ 1% to < 10%; very common ≥ 10%.
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). 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.
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6. Gastrointestinal tract and liver
Rare: loss of appetite, nausea, vomiting.
Very rare: liver damage.
Skin
Rare: allergic reactions in the form of urticaria and other rashes, as well as reversible loss of
hair (alopecia).
Very rare: haemorrhagic skin necrosis, usually associated with congenital deficiency of
protein C or its cofactor protein S, vasculitis.
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 (with renal colic) (52%),
haematomas, gastrointestinal bleeding, haematemesis, uterine bleeding, epistaxis, gingival
bleeding and bleeding into the joints.
Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to
loss of blood, nausea, vomiting, diarrhoea and abdominal pains.
Laboratory tests reveal an extremely low Quick value (or high INR value), pronounced
prolongation of the recalcification time or thromboplastin time, and disturbed γ-carboxylation
of factors II, VII, IX, and X.
Treatment
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 large-bore 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
circulatuion.
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.
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7. Antidote
Vitamin K1- (phytomenadione) may antagonise the inhibitory effect of Sintrom on hepatic γ-
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 mouth. 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). Additional doses (up to a maximum dose of 40 mg daily) should be given
at 4-hour intervals. Vitamin K1 should not be given by intramuscular injection.
Doses of Vitamin K1 in excessof 5 mg 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.
5. Pharmacological propeties
5.1. Pharmacodynamic properties
Coumarin derivatives are vitamin K antagonists. They inhibit the γ-carboxylation 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 γ-carboxylation has a significant bearing on interaction of the aforementioned
coagulation factors with Ca ions. Without this reaction, blood clotting cannot be initiated.
Precisely how coumarin derivatives prevent vitamin K from bringing about γ-carboxylation of
the glutamic acid molecules in these coagulation factors has not yet been determined.
Depending on the size of the initial dosage, acenocoumarol causes prolongation of the
thromboplastin time within approx. 36 - 72 hours. Following withdrawal of the medication the
thromboplastin time usually reverts to normal after a few days.
5.2. Pharmacokinetic properties
Absorption (and plasma concentration)
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 µg/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 size of 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 plasma concentrations of acenocoumarol and the apparent
prothrombin level.
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8. Distribution
The bulk of the acenocoumarol administered is to be found in the plasma fraction of the
blood, where 98.7% becomes bound to plasma proteins, notably 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.
Metabolism
Acenocoumarol is extensively metabolised. The oxidative pathway results in two hydroxy
metabolites and at least one additional unidentified, strongly polar metabolite. 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.
Elimination (excretion)
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
ofthe 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.
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 or fetal anomalies and neonatal haemorrhages both in animals and in humans.
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9. 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 µg/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
Silica aerogel, lactose, magnesium stearate, maize starch.
6.2. Special precautions for storage
Medicines should be kept out of the reach of children.
Manufacturer:
Novartis Farma SPA, Torre Annunziata, Italy
for: Novartis Pharma AG, Basel, Switzerland.
Lisence holder:
Promedico Ltd.
4 Baltimor St., Petach-Tikva.
P:RonaPrescribing InformationSintronSintrom physician leaflet correction Oct. 2002.doc
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