Sintrom - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Acenocoumarol

SINTROM 1 mg tablets
SINTROM 4 mg tablets

Indications Why is Sintrom used? What is it for?

Sintrom is a drug belonging to the pharmacotherapeutic group of Antithrombotics - Vitamin K antagonists.

Sintrom is indicated for the treatment and prevention of thromboembolic diseases.

Contraindications When Sintrom should not be used

  • Hypersensitivity to the active substance, to related coumarin derivatives or to any of the excipients;
  • Pregnancy
  • In women of childbearing potential not using contraceptive measures (see section 4.6 "Fertility, pregnancy and lactation").
  • Uncooperative and unsupervised patients with an associated high risk of non-adherence to treatment

Sintrom is also contraindicated in all disease states in which the risk of bleeding is greater than the possible clinical benefit, for example:

  • hemorrhagic diathesis and / or blood dyscrasia;
  • immediately before or after central nervous system surgery, as well as ophthalmic operations and traumatizing surgery with extensive tissue exposure;
  • peptic ulcer or in the presence of haemorrhage in the gastrointestinal tract, urogenital tract or respiratory system, as well as in case of cerebrovascular haemorrhages, acute pericarditis and pericardial effusions, and bacterial endocarditis;
  • severe hypertension;
  • severe hepatic insufficiency (see "Dose, method and time of administration");
  • severe renal insufficiency (see "Dose, method and time of administration");
  • increased fibrinolytic activity such as after operations on the lungs, prostate, uterus, etc. and in acute pancreatitis;
  • severe circulatory failure with liver from stasis.

Hypericum perforatum preparations should not be taken concomitantly with medicines containing acenocoumarol, due to the risk of decreased plasma levels and decreased therapeutic efficacy of acenocoumarol (see "Interactions").

Precautions for use What you need to know before taking Sintrom

Administration of Sintrom during lactation requires caution (see "Fertility, pregnancy and lactation").

Hepatic insufficiency

In patients with mild to moderate hepatic insufficiency caution should be exercised as the synthesis of coagulation factors may also be impaired or there may be underlying platelet dysfunction (see also "Dose, method and time of administration"). Use in patients with severe hepatic insufficiency is contraindicated (see "Contraindications").

Kidney failure

Due to the possibility of accumulation of metabolites in the presence of impaired renal function, caution should be exercised in patients with mild to moderate renal insufficiency (see also "Dose, method and time of administration"). Use in patients with severe renal insufficiency is contraindicated (see "Contraindications").

Heart failure

In the case of severe heart failure, a reduced dosage schedule and frequent laboratory checks should be adopted, since the activation or gamma-carboxylation of coagulation factors may be reduced in the case of hepatic congestion (see also "Dose, method and time of At the reward stage, however, it may be necessary to increase the dosage.

Diseases of the blood

Particular caution should be exercised in patients with known or suspected protein C or protein S deficiency as acenocoumarol administration has been associated with tissue necrosis (see "Undesirable effects").

Pediatric population

No adequate and well controlled studies have been conducted in the pediatric population and the optimal dose, safety and efficacy in this population are not known.

Use in the elderly

In elderly patients (≥ 65 years), special attention and more frequent monitoring of prothrombin time and INR is recommended (see also "Dose, method and time of administration").

Close medical surveillance is required in cases where conditions or diseases may reduce the protein binding of Sintrom; for example, thyrotoxicosis, tumors, kidney disease, infections and inflammation.

Disorders of gastrointestinal absorption can alter the anticoagulant effect of Sintrom.

During treatment with anticoagulants, intramuscular injections can cause hematomas and are therefore contraindicated. Intravenous and subcutaneous injections, on the other hand, do not lead to such complications.

Ongoing treatment of diagnostic, dental and surgical operations

Certain dental or surgical diagnostic procedures (angiography, lumbar puncture) may require "interruption or dose modification of therapy with SINTROM. The risks and benefits of discontinuing therapy with SINTROM, even for short periods, should be considered. L" INR must be determined immediately prior to each procedure. In patients undergoing minimally invasive procedures who need to be anticoagulated before, during or immediately after such procedures, an adjustment of the dose of SINTROM in order to keep the INR at the lowest level of the therapeutic range can safely allow maintenance of the dose. "anticoagulation.

During treatment with Sintrom it is recommended that patients carry a card which, in the event of an accident, warns of the anticoagulant therapy in progress.

Pharmacogenetics

Genetic variability in particular in relation to genes encoding CYP2C9 and VKORC1 proteins can significantly influence the dose of acenocoumarol needed to obtain the desired clinical effect. If an association with these polymorphisms is known, extreme caution should be exercised (see also paragraph 5.2).

Interactions Which drugs or foods can change the effect of Sintrom

Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.

There are many possible interactions between coumarins and other drugs. The mechanisms involved in these interactions include: disturbances in absorption, inhibition or induction of the enzymatic metabolism system, and reduced availability of the vitamin K required for gamma-carboxylation of prothrombin complex factors. It is important to note that some drugs may interact with more than a mechanism. Each therapy may carry the risk of interactions although not all interactions are significant. Hence the need for close surveillance and frequent coagulation tests (usually twice a week) when using any drug for the first time in combination with Sintrom or if a concomitant drug is discontinued.

Interactions for which concomitant use is not recommended

Effects of other drugs on acenocoumarol

The following drugs potentiate the anticoagulant effect of acenocoumarol and / or alter haemostasis and thus increase the risk of bleeding:

  • Anticoagulants (regarding the use of heparin in situations requiring rapid anticoagulation, see "Dose, method and time of administration"
  • Antiplatelet agents
  • Thrombolytics
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Serotonin reuptake inhibitors

The use of Sintrom associated with these substances is therefore not recommended. In case of use in combination with these drugs, coagulation tests must be performed more frequently.

Interactions to consider

The following drugs may potentiate the anticoagulant effect of acenocoumarol:

Allopurinol, anabolic steroids, androgens, antiarrhythmic agents (such as amiodarone, quinidine, propafenone), antibacterials (such as clindamycin, penicillins, second and third generation cephalosporins, chloramphenicol, macrolides, fluoroquinolones, neomycin, tetracyclinic acid, etimacramidline), cynacycline , fibrates, glucagon, imidazole derivatives (e.g. metronidazole and, even when administered locally, miconazole), paracetamol, statins, sulfonamides, including cotrimoxazole (= sulfamethoxazole + trimethoprim), sulfonylureas (such as tolbutamide and chlorpropamide), hormones , tamoxifen, tramadol, proton pump inhibitors, prokinetic agents (cisapride, antacids (magnesium hydroxide) and viloxazine, 5-fluorouracil and analogues, vitamin E, corticosteroids (such as dexamethasone, methylprednisolone, prednisone).

Broad-spectrum antibiotics can enhance the effects of acenocoumarol by reducing the intestinal flora that produces vitamin K.

The following drugs may decrease the anticoagulant effect of acenocoumarol:

Aminoglutethimide, antineoplastic drugs (azathioprine, 6-mercaptopurine), barbiturates, carbamazepine, cholestyramine (see section 4.9), HIV protease inhibitors, griseofulvin, oral contraceptives, rifampicin and thiazide diuretics, bosentan. interactions may be anticipated, patients taking Sintrom, especially those suffering from liver dysfunction, should limit alcohol consumption.

Effects of acenocoumarol on other drugs

During concomitant treatment with hydantoin derivatives (such as phenytoin), the serum concentration of hydantoin may increase. During concomitant treatment with sulfonylurea derivatives the hypoglycemic effect of these drugs may increase.

Interactions with CYP450

Some CYP450 isoenzymes are involved in the metabolism of acenocoumarol. Therefore:

  • CYP2C9 inhibitors have the potential to enhance the effect (increased INR) of acenocoumarol by increasing acenocoumarol exposure.
  • Inducers of CYP2C9, 2C19, and / or 3A4 have the potential to decrease the effect (decreased INR) of acenocoumarol by decreasing acenocoumarol exposure.

Dietary components rich in vitamin K.

Dietary components rich in vitamin K can antagonize the effects of acenocoumarol. Some herbal preparations can cause bleeding when taken alone (for example, garlic and Ginkgo biloba) and can have anticoagulant, antiplatelet and / or fibrinolytic. These effects are expected to be additive to the anticoagulant effects of SINTROM. Conversely, some herbal products may decrease the effect of SINTROM (eg coenzyme Q10, St. John's wort, ginseng). Some herbal preparations and foods can interact with SINTROM through interactions with CYP450 (eg, echinacea, grapefruit juice, ginko, hydraste, St. John's wort).

The patient's response should be monitored with further INR determinations if any herbal preparation is started or stopped.

Some herbal preparations that can affect clotting are listed below for reference, although this list should not be considered exhaustive. Many herbal preparations have several common names and scientific names. The most widely known common names of herbal preparations are given below.


Herbal preparations that contain coumarins with a potential anticoagulant effect Agrimoniaa Celery Passionflower Angelica chinese (Angelica sinensis) Chamomile (German and Roman) Thorny ash (northern) Anise Dandelion cod Quassia Arnica Fenugreek Red clover Asafoetida (Ferula assa-foetida) Horse chestnut Sweet clover Water clover (Menyanthes trifoliata) b Horseradish Woodruff (Asperula odorata) Boldo Licoriced Dipteryx odorata Buchu (Agathosma Betulina) Meadowsweet (Filipendula ulmaria)b Capsicoc Nettle Cassiad
Various herbal preparations with anticoagulant properties Fucus vesiculosus Pau d "Arco
Herbal preparations that contain salicylates and / or have properties antiplatelet Agrimoniaa Cranberry Meadowsweet (Filipendula ulmaria) b Aspen tree Dandelion cod Policosanol Black Cohosh rubifolia Feverfew (Tanacetum parthenium) Tamarind Water clover (Menyanthes trifoliata) b Garlic and Willow Cassiad Ginger Canada tea Clove Ginko biloba a thousand leaves Ginseng (Panax spp) and Licoriced Herbal preparations with fibrinolytic properties Bromelain Garlic and Capsicoc Ginseng (Panax spp) and Salvia miltiorrhiza Herbal preparations with coagulating properties Alpha-alpha (Medicago sativa) Green vegetables (broccoli, kale, spinach, turnip greens and Brussels sprouts) St. John's wort (Hypericum perforatum) Agrimoniaa

a Contains coumarins, has antiplatelet properties, and may have coagulating properties due to the possible content of vitamin K.

b Contains coumarins and salicylates.

c Contains coumarins and has fibrinolytic properties.

d Contains coumarins and has antiplatelet properties.

e It has antiplatelet and fibrinolytic properties.

St. John's wort (Hypericum perforatum)

The therapeutic efficacy of acenocoumarol could be reduced by the simultaneous administration of preparations based on St. John's wort (Hypericum perforatum). This is due to the induction of the enzymes responsible for the metabolism of drugs by these preparations which therefore must not be administered. concomitantly with acenocoumarol. The induction effect may persist for at least 2 weeks after stopping treatment with Hypericum perforatum products. If a patient is taking Hypericum perforatum products concomitantly with acenocoumarol, the INR values ​​should be monitored and therapy with the latter should be discontinued. Monitor INR values ​​closely, as they may increase after stopping Hypericum perforatum. The acenocoumarol dosage may need to be adjusted.

Warnings It is important to know that:

Fertility, pregnancy and lactation

Ask your doctor or pharmacist for advice before taking any medicine.

Pregnancy

Sintrom, like other coumarin derivatives, can be associated with congenital malformations of the embryo. Sintrom is therefore contraindicated in pregnant women (see "Contraindications") or in those who may become pregnant. Women of childbearing age should adopt effective contraceptive measures. during treatment with Sintrom.

Feeding time

Sintrom passes into breast milk, the quantities are small and limited. The decision to breastfeed should be considered with caution and may include coagulation tests and assessment of vitamin K status in infants before advising the woman to breastfeed. Breastfeeding women who are treated with Sintrom should be monitored closely to ensure that the recommended PT / INR values ​​are not exceeded. When breastfeeding, the newborn should be given 1 mg of vitamin K1 per week for prophylaxis.

Fertility

There are no data available on the use of Sintrom and its effects on human fertility.

Effects on ability to drive and use machines

Sintrom has no known influence on the ability to drive and use machines. Patients are recommended, however, to carry a certificate of current anticoagulant therapy with them to inform rescuers in the event of an injury accident.

Important information about some of the ingredients

Sintrom contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dosage and method of use How to use Sintrom: Dosage

Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see "Precautions for use").

Dosage

General population Sensitivity to anticoagulants varies from patient to patient and may also fluctuate over the course of treatment.

Therefore, it is essential to perform regular prothrombin time (PT) / International Normalized Ratio (INR) analyzes and adjust the dosage based on the results provided by these analyzes. If this is not possible, Sintrom should not be used.

The daily dosage should always be prescribed as a single dose. Also compare "Precautions for use" and "Interactions" to adapt the dosage to the various clinical conditions.

Sintrom is available in 1 and 4 mg tablet form. For the intake of low doses it is recommended to use the 1 mg tablets that allow greater accuracy of dosage.

Initial dosage

Sintrom dosage must be individualized.

The usual starting dose of Sintrom is between 2 mg / day and 4 mg / day without a loading dose if the PT / INR values ​​prior to initiation of treatment are within normal range. Treatment may also be initiated. with a loading dose, usually 6 mg on the first day followed by 4 mg on the second day.

If PT / INR values ​​are initially outside the normal range, treatment should be initiated with caution.

Elderly patients (≥ 65 years), patients with liver disease or severe heart failure with hepatic congestion, or malnourished patients may require lower doses at the start of treatment and during the maintenance period (see "Precautions for use").

Starting with the second or third dose of Sintrom and until the coagulation state has stabilized within the target range, the PT / INR measurement should be performed daily. The interval between tests may subsequently be extended, based on the stability of the PT / INR results. It is recommended to always take samples for laboratory tests at the same time of the day.

Maintenance therapy and coagulation analysis

The maintenance dose varies from patient to patient and its appropriateness should be checked individually on the basis of PT / INR values. The PT / INR values ​​must be taken at regular intervals, ie at least once a month.

The maintenance dose is normally positioned between 1 and 8 mg / day based on the individual patient, the underlying disease, the clinical indication and the desired anticoagulation intensity.

Based on the clinical indication, the optimal anticoagulation intensity or target range is usually found at INR values ​​between 2.0 and 3.5 (see Table 1). In individual cases higher INR values, up to 4.5, may be required.

Table 1 - INR * recommended for oral anticoagulant therapy


Indication INR recommended 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 of thromboembolic complications) 2,0 - 3,0 Bioprosthetic heart valves 2,0 - 3,0 Secondary prophylaxis in patients with antiphospholipid syndrome 2,0 - 3,0 Patients with antiphospholipid syndrome with venous thromboembolism receiving vitamin K antagonist therapy 2,0 - 3,5 Mechanical heart valves 2,0 - 3,5

* The prothombin time (PT), which reflects the reduction of Vitamin K dependent clotting factors VII, X and II, depends on the responsiveness of the thromboplastin used for the PT test. The response capacity of the respective local thromboplastin compared with the international reference preparations of the World Health Organization is expressed as the International Sensitivity Index (ISI).

The International Normalized Ratio (INR) was introduced in order to standardize the PT. The INR is the ratio between the PT of the patient's anticoagulated plasma and the PT of a normal plasma, using the same thromboplastin in the same test system raised to power by the value defined by the International Sensitivity Index.

Discontinuation of treatment

Treatment with Sintrom can usually be stopped without the need for a tapering of the drug. However, it has been observed that in extremely rare cases and in some high-risk patients (eg after myocardial infarction) "rebound hypercoagulability" may occur. In such patients, the discontinuation of anticoagulant therapy should be gradual.

Missed dose

The anticoagulant effect of Sintrom persists for more than 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 within the same day. The patient should not take the dose. missed dose by doubling the daily dose to make up for missed doses, but you should contact your doctor.

Conversion from heparin therapy

In clinical situations requiring rapid anticoagulation, initial treatment with heparin is preferable, as the anticoagulant effect of Sintrom is not immediate. Conversion to Sintrom may commence concurrently with heparin therapy or may be deferred depending on the clinical situation. In order to ensure continued anticoagulation, it is advisable to continue with full dose heparin therapy for at least 4 days after starting Sintrom and to continue heparin therapy until the INR is within the target range for at least two consecutive days. Close monitoring of anticoagulation is required during the transition phase.

Treatment during dental treatment and surgery

Patients being treated with Sintrom, undergoing surgical or invasive procedures, require close surveillance of their coagulation status. Under certain conditions, for example when the operation site is limited and accessible to allow effective use of local haemostatic procedures, minor dental and surgical procedures can be performed during continued anticoagulation without risk of bleeding. The decision to discontinue Sintrom, even for a short period of time, must carefully consider the individual risks and benefits. The introduction of anticoagulant bridging therapy - for example with heparin - must be based on careful consideration of the expected risks of thromboembolism and bleeding.

Special populations

Kidney failure

Due to the increased risk of bleeding, the use of Sintrom is contraindicated in patients with severe renal insufficiency. In patients with mild to moderate renal impairment, caution should be exercised (see also "Contraindications" and "Precautions for" use ")

Hepatic insufficiency

Due to the increased risk of bleeding, the use of Sintrom is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, caution should be exercised (see also "Contraindications" and "Precautions for" use ")

Pediatric population

There is insufficient information from controlled clinical trials on use in children. The safety and efficacy of SINTROM in children and adolescents below 18 years of age have not been established.

Elderly (≥ 65 years old)

Use in elderly patients may require lower initial and maintenance doses. Special attention and more frequent monitoring of prothrombin time and INR is recommended (see also "Precautions for use").

Method of administration

The daily dose should always be taken at the same time of the day. The tablet should be swallowed whole with a glass of water.

Overdose What to do if you have taken too much Sintrom

While single doses, even very high ones, are generally not dangerous, the clinical manifestations of overdose can occur during prolonged use of higher daily doses than are necessary for treatment.

Signs and symptoms

The sensitivity of the individual patient to oral anticoagulants, the extent of the overdose and the duration of treatment affect the manifestation and severity of the effects.

Hemorrhages in various organs are the most important manifestation of the clinical picture. They can take the form of skin bleeding (80%), hematuria (52%), epistaxis, haematemesis, gastrointestinal bleeding, vaginal bleeding, joint bleeding, hematoma, gingival bleeding.

Additional symptoms include tachycardia, hypotension, circulatory disturbances due to blood loss, nausea, vomiting, diarrhea and abdominal pain.

Laboratory tests reveal an extremely high PT / INR value, a pronounced prolongation of recalcification or prothrombin time, and changes in the gamma-carboxylation of factors II, VII, IX and X.

Treatment

The necessity or desirability of treatment with ipecac syrup, gastric lavage in addition to activated charcoal and administration of cholestyramine is controversial. The benefits of these treatments relative to the risk of bleeding must be weighed in each patient.

Emergency and support measures

In case of severe bleeding, at any level of INR, coagulation factors can be restored to normal by administration of fresh whole blood or frozen plasma concentrates, prothrombin complex concentrate or recombinant factor VIIa supplemented with vitamin K1.

Antidote

Vitamin K1 (phytomenadione) can antagonize the inhibitory effect of Sintrom on hepatic gamma-carboxylation of vitamin K-dependent coagulation factors within 3-5 hours.

In case of clinically insignificant bleeding (INR <4.5), such as short epistaxis or small isolated hematomas, a temporary reduction in dosage or omission of a dose of Sintrom is often sufficient.

In case of high INR (INR 4.5-9) with insignificant bleeding, omit one or two doses of Sintrom and administer 1-2.5 mg of vitamin K1 orally, especially in patients with an increased risk of bleeding.

In case of high INR (INR> 9) with non-significant bleeding, discontinue Sintrom therapy and administer 2.5-5 mg of vitamin K1 orally. In the event of moderate to severe bleeding, Sintrom can be re-administered when the INR is in the target range.

In case of accidental ingestion / intake of an excessive dose of Sintrom, notify your doctor immediately or go to the nearest hospital.

If you have any questions about the use of Sintrom, ask your doctor or pharmacist

Side Effects What are the side effects of Sintrom

Like all medicines, Sintrom can cause side effects, although not everybody gets them.

Adverse reactions (Table 2) are listed by system-organ classes in MedDRA. Within each system-organ class, adverse reactions are ranked according to frequency, most frequent reactions first. Within each frequency group, adverse reactions are presented in order of decreasing severity. In addition, for each adverse reaction, the corresponding frequency category is also provided using the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100 - <1/10), uncommon (≥ 1 / 1,000 - <1/100); rare (≥ 1 / 10,000 - <1 / 1,000); very rare (<1 / 10,000), not known (cannot be estimated from the available data).

Hemorrhages

Bleeding in different parts of the body are the most frequently reported complications with Sintrom and have been related to the dosage, age of the patient and the nature of the underlying disease (but not the duration of treatment).

Table 2


Disorders of the immune system Rare: hypersensitivity (hives, rash, dermatitis) Vascular pathologies Common: hemorrhage Very rare: vasculitis Gastrointestinal disorders Rare: decreased appetite, nausea, vomiting Hepatobiliary disorders Very rare: liver damage Skin and subcutaneous tissue disorders Rare: alopecia Very rare: skin necrosis (haemorrhagic) *

* normally associated with congenital deficiency of Protein C or its protein S cofactor

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Expiry: see the expiry date printed on the package.

The expiry date refers to the product in intact packaging, correctly stored.

Warning: do not use the medicine after the expiry date shown on the package.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Keep this medicine out of the sight and reach of children.

Composition and pharmaceutical form

Sintrom 1 mg tablets

Each tablet contains: Active ingredient: acenocoumarol 1 mg. Excipients: anhydrous colloidal silica; hypromellose; lactose monohydrate; magnesium stearate; cornstarch; talc.

Sintrom 4 mg tablets

Each tablet contains: Active ingredient: 4 mg acenocoumarol. Excipients: anhydrous colloidal silica; lactose monohydrate; magnesium stearate; cornstarch; pregelatinised maize starch.

Pharmaceutical form and content

Sintrom 1 mg tablets: 20 and 100 tablets. Sintrom 4 mg tablets: 20 quadrisecable tablets.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Sintrom can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interaction with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.6 Pregnancy .7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER ON THE MARKET 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, FURTHER DETAILED INSTRUCTIONS AND PRE-DETAILED QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

SINTROM TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient: 3- [α- (4-nitrophenyl) -β-acetyl-ethyl] -4-hydroxycoumarin (= acenocoumarol) as a racemic mixture. Acenocoumarol is a derivative of 4-hydroxycoumarin.

Excipients with known effects: lactose monohydrate

For the list of excipients see section 6.1

03.0 PHARMACEUTICAL FORM

1 mg tablets

White, round, flat, with slightly beveled edges, CG letters embossed on one side, AA letters embossed on the other side.

4 mg tablets

White, round, flat, with slightly beveled edges, CG letters embossed on one side, cross engraving on the other side with the letter A embossed on each dial.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment and prevention of thromboembolic diseases.

04.2 Posology and method of administration

Dosage

General population

Sensitivity to anticoagulants varies from patient to patient and may also fluctuate over the course of treatment.

Therefore, it is essential to perform regular prothrombin time (PT) / International Normalized Ratio (INR) analyzes and adjust the dosage based on the results provided by these analyzes. If this is not possible, Sintrom should not be used.

The daily dosage should always be prescribed as a single dose.

For dosage adjustment to various clinical conditions, see sections 4.4 and 4.5.

Sintrom is available in 1 and 4 mg tablet form. For the intake of low doses it is recommended to use the 1 mg tablets that allow greater accuracy of dosage.

Initial dosage

Sintrom dosage must be individualized.

The usual starting dose of Sintrom is between 2 mg / day and 4 mg / day without a loading dose if the PT / INR values ​​prior to initiation of treatment are within normal range. Treatment may also be initiated. with a loading dose, usually 6 mg on the first day followed by 4 mg on the second day.

If the initial PT / INR values ​​are outside the normal range, treatment should be initiated with caution.

Elderly patients (≥ 65 years), patients with hepatic disease or severe heart failure with hepatic congestion, or malnourished patients may require lower doses at the start of treatment and during the maintenance period (see section 4.4).

Starting with the second or third dose of Sintrom and until the coagulation state has stabilized within the target range, the PT / INR measurement should be performed daily. The interval between tests may subsequently be extended, based on the stability of the PT / INR results. It is recommended to always take samples for laboratory tests at the same time of the day.

Maintenance therapy and coagulation analysis

The maintenance dose varies from patient to patient and its appropriateness should be checked individually on the basis of PT / INR values. The PT / INR values ​​must be taken at regular intervals, ie at least once a month.

The maintenance dose is normally positioned between 1 and 8 mg / day based on the individual patient, the underlying disease, the clinical indication and the desired anticoagulation intensity.

Based on the clinical indication, the optimal anticoagulation intensity or target range is generally found at INR values ​​between 2.0 and 3.5 (see Table 1). In individual cases higher INR values, up to 4.5, may be required.

Table 1 - INR * recommended for oral anticoagulant therapy


Indication INR recommended 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 of thromboembolic complications) 2,0 - 3,0 Bioprosthetic heart valves 2,0 - 3,0 Secondary prophylaxis in patients with antiphospholipid syndrome 2,0 - 3,0 Patients with antiphospholipid syndrome with venous thromboembolism receiving vitamin K antagonist therapy 2,0 - 3,5 Mechanical heart valves 2,0 - 3,5

* The prothombin time (PT), which reflects the reduction of Vitamin K dependent clotting factors VII, X and II, depends on the responsiveness of the thromboplastin used for the PT test. The response capacity of the respective local thromboplastin compared with the international reference preparations of the World Health Organization is expressed as the International Sensitivity Index (ISI).

The International Normalized Ratio (INR) was introduced in order to standardize the PT. The INR is the ratio between the PT of the patient's anticoagulated plasma and the PT of a normal plasma, using the same thromboplastin in the same test system raised to power by the value defined by the International Sensitivity Index.

Discontinuation of treatment

Treatment with Sintrom can usually be stopped without the need for a tapering of the drug.

However, it has been observed that in extremely rare cases and in some high-risk patients (eg after myocardial infarction) "rebound hypercoagulability" may occur. In such patients, the discontinuation of anticoagulant therapy should be gradual.

Missed dose

The anticoagulant effect of Sintrom persists for more than 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 within the same day.The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should contact their doctor.

Conversion from heparin therapy

In clinical situations requiring rapid anticoagulation, initial treatment with heparin is preferable, as the anticoagulant effect of Sintrom is not immediate. Conversion to Sintrom may commence concurrently with heparin therapy or may be deferred depending on the clinical situation. In order to ensure continued anticoagulation, it is advisable to continue with full dose heparin therapy for at least 4 days after starting Sintrom and to continue heparin therapy until the INR is within the target range for at least two consecutive days. Close monitoring of anticoagulation is required during the transition phase.

Treatment during dental treatment and surgery

Patients being treated with Sintrom, undergoing surgical or invasive procedures, require close surveillance of their coagulation status. Under certain conditions, for example when the operation site is limited and accessible to allow effective use of local haemostatic procedures, minor dental and surgical procedures can be performed during continued anticoagulation without risk of bleeding. The decision to discontinue Sintrom, even for a short period of time, must carefully consider the individual risks and benefits. The introduction of a therapy

bridging - for example with heparin - must be based on careful consideration of the expected risks of thromboembolism and bleeding.

Special populations

Kidney failure

Due to the increased risk of bleeding, the use of Sintrom is contraindicated in patients with severe renal insufficiency. In patients with mild to moderate renal impairment, caution should be exercised (see sections 4.3, 4.4 and 5.1).

Hepatic insufficiency

Due to the increased risk of bleeding, the use of Sintrom is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, caution should be exercised (see sections 4.3, 4.4 and 5.1).

Pediatric population

There is insufficient information from controlled clinical trials on use in children.

The safety and efficacy of SINTROM in children and adolescents below 18 years of age have not been established.

Elderly (≥ 65 years old)

Use in elderly patients may require lower initial and maintenance doses. Special attention and more frequent monitoring of prothrombin time and INR is recommended (see section 4.4).

Method of administration

The daily dose should always be taken at the same time of the day. The tablet should be swallowed whole with a glass of water.

04.3 Contraindications

• Hypersensitivity to the active substance, to related coumarin derivatives or to any of the excipients, listed in section 6.1.

• Pregnancy.

• In women of childbearing potential who are not using contraceptive measures (see section 4.6 "Fertility, pregnancy and lactation").

• Patients unable to cooperate and unsupervised with an associated high risk of non-adherence to treatment

Sintrom is also contraindicated in all disease states in which the risk of bleeding is greater than the possible clinical benefit, for example:

• haemorrhagic diathesis and / or blood dyscrasia;

• immediately before or after central nervous system surgery, as well as ophthalmic operations and traumatizing surgery with extensive tissue exposure;

• peptic ulcer or in the presence of haemorrhage in the gastrointestinal tract, urogenital tract or respiratory system, as well as in case of cerebrovascular haemorrhages, acute pericarditis and pericardial effusions, and bacterial endocarditis;

• severe hypertension;

• severe hepatic insufficiency (see section 4.2 "Posology and method of administration");

• severe renal insufficiency (see section 4.2 "Posology and method of administration");

• increased fibrinolytic activity such as after operations on the lungs, prostate, uterus and in acute pancreatitis;

• severe circulatory failure with hepatic stasis.

Hypericum perforatum preparations should not be taken concomitantly with medicinal products containing acenocoumarol, due to the risk of decreased plasma levels and decreased therapeutic efficacy of acenocoumarol (see section 4.5).

04.4 Special warnings and appropriate precautions for use

Administration of Sintrom during lactation requires caution (see section 4.6).

Hepatic insufficiency

In patients with mild to moderate hepatic impairment, caution should be exercised as the synthesis of coagulation factors may also be impaired or there may be underlying platelet dysfunction (see also sections 4.2 and 5.1). Use in patients with severe hepatic impairment is contraindicated (see section 4.3).

Kidney failure

Due to the possibility of accumulation of metabolites in the presence of impaired renal function, caution should be exercised in patients with mild to moderate renal impairment (see sections 4.2 and 5.1). Use in patients with severe renal insufficiency is contraindicated (see section 4.3).

Heart failure

In the case of severe heart failure, a reduced dosage schedule and frequent laboratory monitoring should be used, since the activation or gamma-carboxylation of coagulation factors may be reduced in the event of hepatic congestion (see section 4.2). reward, however, it may be necessary to elevate the dosage.

Hematological diseases

Particular caution should be exercised in patients with known or suspected protein C or protein S deficiency as acenocoumarol administration has been associated with tissue necrosis (see section 4.8).

Pediatric population

No adequate and well controlled studies have been conducted in the pediatric population and the optimal dose, safety and efficacy in this population are not known.

Use in the elderly

In elderly patients (≥ 65 years), special attention and more frequent monitoring of prothrombin time and INR is recommended (see section 4.2).

Close medical surveillance is required in cases where conditions or diseases may reduce the protein binding of Sintrom, for example, thyrotoxicosis, cancer, kidney disease, infection and inflammation.

Disorders of gastrointestinal absorption can alter the anticoagulant effect of Sintrom.

During treatment with anticoagulants, intramuscular injections can cause hematomas and are therefore contraindicated. Intravenous and subcutaneous injections do not lead to such complications.

Ongoing treatment of diagnostic, dental and surgical operations

Certain dental or surgical diagnostic procedures (angiography, lumbar puncture) may require "interruption or dose modification of therapy with SINTROM. The risks and benefits of discontinuing therapy with SINTROM, even for short periods, should be considered. L" INR must be determined immediately prior to each procedure. In patients undergoing minimally invasive procedures who need to be anticoagulated before, during or immediately after such procedures, an adjustment of the dose of SINTROM in order to keep the INR at the lowest level of the therapeutic range can safely allow maintenance of the dose. "anticoagulation.

During treatment with Sintrom it is recommended that patients carry a card which, in the event of an accident, warns of the anticoagulant therapy in progress.

Pharmacogenetics

Genetic variability in particular in relation to genes encoding CYP2C9 and VKORC1 proteins can significantly influence the dose of acenocoumarol needed to obtain the desired clinical effect. If an association with these polymorphisms is known, extreme caution should be exercised (see also paragraph 5.2).

Important information about some of the ingredients

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

04.5 Interactions with other medicinal products and other forms of interaction

There are many possible interactions between coumarins and other drugs. The mechanisms involved in such interactions include: disturbances in the absorption, inhibition or induction of the enzymatic metabolism system (mainly CYP2C9, see also section 5) and reduced availability of the vitamin K required for gamma-carboxylation of the prothrombin complex factors. It is important note that some drugs may interact with more than one mechanism. Each therapy may carry the risk of interactions although not all interactions are significant. Hence the need for careful surveillance and frequent coagulation tests (usually twice a week) when any drug is prescribed for the first time in combination with Sintrom or if a concomitant drug is discontinued.

Interactions for which concomitant use is not recommended

Effects of other drugs on acenocoumarol

The following drugs potentiate the anticoagulant effect of acenocoumarol and / or alter haemostasis and thus increase the risk of bleeding:

• Anticoagulants (regarding the use of heparin in situations requiring rapid anticoagulation, see section 4.2)

• Antiplatelet agents

• Thrombolytics

• Non-steroidal anti-inflammatory drugs (NSAIDs)

• Serotonin reuptake inhibitors

The use of Sintrom associated with these substances is therefore not recommended. In case of use in combination with these drugs, coagulation tests must be performed more frequently.

Interactions to consider

The following drugs may potentiate the anticoagulant effect of acenocoumarol:

Allopurinol, anabolic steroids, androgens, antiarrhythmic agents (such as amiodarone, quinidine, propafenone), antibacterials (such as clindamycin, penicillins, second and third generation cephalosporins, chloramphenicol, macrolides, fluoroquinolones, neomycin, tetracycline, ethacyramides), cimycin fibrates, glucagon, imidazole derivatives (e.g. metronidazole and, also when administered locally, miconazole), paracetamol, statins, sulfonamides, including co-trimoxazole (= sulfamethoxazole + trimethoprim), sulfonylureas (such as tolbutamide and chlorpropamide), hormones ), tamoxifen, tramadol, proton pump inhibitors, prokinetic agents (cisapride, antacids (magnesium hydroxide) and viloxazine, 5-fluorouracil and analogues, vitamin E, corticosteroids (such as dexamethasone, methylprednisolone, prednisone).

Broad-spectrum antibiotics can enhance the effects of acenocoumarol by reducing the intestinal flora that produces vitamin K.

The following drugs may decrease the anticoagulant effect of acenocoumarol: Aminoglutethymide, antineoplastic drugs (azathioprine, 6-mercaptopurine), barbiturates, carbamazepine, cholestyramine (see section 4.9), HIV protease inhibitors, griseofulvin, oral contraceptives, tampicine diuretics , bosentan.

Since neither the severity nor the first symptoms of interactions can be predicted, patients taking Sintrom, especially those with liver dysfunction, should limit the use of alcohol.

Effects of acenocoumarol on other drugs

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

During concomitant treatment with sulfonylurea derivatives, the hypoglycemic effect of these drugs may increase.

Interactions with CYP450

Some CYP450 isoenzymes are involved in the metabolism of acenocoumarol. Therefore:

• CYP2C9 inhibitors have the potential to enhance the effect (increased INR) of acenocoumarol by increasing acenocoumarol exposure.

• Inducers of CYP2C9, 2C19, and / or 3A4 have the potential to decrease the effect (lower INR) of acenocoumarol by decreasing acenocoumarol exposure.

Dietary components rich in vitamin K.

Dietary components rich in vitamin K can antagonize the effects of acenocoumarol.

Some herbal preparations can cause bleeding when taken alone (for example, garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet and / or fibrinolytic properties. These effects are expected to be additive to the anticoagulant effects of SINTROM. . Conversely, some herbal products may decrease the effect of SINTROM (eg coenzyme Q10, St. John's wort, ginseng). Some herbal preparations and foods may interact with SINTROM through interactions with CYP450 (for example, echinacea, grapefruit juice, ginko, hydraste, St. John's wort).

The patient's response should be monitored with further INR determinations if any herbal preparation is started or stopped.

Some herbal preparations that can affect clotting are listed below for reference, although this list should not be considered exhaustive. Many herbal preparations have several common names and scientific names. The most widely known common names of herbal preparations are given below.


Herbal preparations that contain coumarins with a potential anticoagulant effect Agrimoniaa Celery Passionflower Angelica chinese (Angelica sinensis) Chamomile (German and Roman) Thorny ash (northern) Anise Dandelion cod Quassia Arnica Fenugreek Red clover Asafoetida (Ferula assa-foetida) Horse chestnut Sweet clover Water clover (Menyanthes trifoliata) b Horseradish Woodruff (Asperula odorata) Boldo Licoriced Dipteryx odorata Buchu (Agathosma Betulina) Meadowsweet (Filipendula ulmaria)b Capsicoc Nettle Cassiad
Various herbal preparations with anticoagulant properties Fucus vesiculosus Pau d "Arco
Herbal preparations that contain salicylates and / or have properties antiplatelet Agrimoniaa Cranberry Meadowsweet (Filipendula ulmaria) b Aspen tree Dandelion cod Policosanol Black Cohosh rubifolia Feverfew (Tanacetum parthenium) Tamarind Water clover (Menyanthes trifoliata) b Garlic and Willow Cassiad Ginger Canada tea Clove Ginko biloba a thousand leaves Ginseng (Panax spp) and Licoriced Herbal preparations with fibrinolytic properties Bromelain Garlic and Capsicoc Ginseng (Panax spp) and Salvia miltiorrhiza Herbal preparations with coagulating properties Alpha-alpha (Medicago sativa) Green vegetables (broccoli, kale, spinach, turnip greens and Brussels sprouts) St. John's wort (Hypericum perforatum) Agrimoniaa

a Contains coumarins, has antiplatelet properties, and may have coagulating properties due to the possible content of vitamin K.

b Contains coumarins and salicylates.

c Contains coumarins and has fibrinolytic properties.

d Contains coumarins and has antiplatelet properties.

e It has antiplatelet and fibrinolytic properties.

St. John's wort (Hypericum perforatum)

The therapeutic efficacy of acenocoumarol could be reduced by the simultaneous administration of preparations based on St. John's wort (Hypericum perforatum). This is due to the induction of the enzymes responsible for the metabolism of drugs by these preparations which therefore must not be administered. concomitantly with acenocoumarol. The induction effect may persist for at least 2 weeks after stopping treatment with Hypericum perforatum products.

If a patient is taking Hypericum perforatum products concomitantly with acenocoumarol, the INR values ​​should be monitored and therapy with the latter should be discontinued.

Monitor INR values ​​closely, as they may increase after stopping Hypericum perforatum. The acenocoumarol dosage may need to be adjusted.

04.6 Pregnancy and lactation

Pregnancy

Sintrom, like other coumarin derivatives, may be associated with congenital malformations of the embryo. Sintrom is therefore contraindicated in pregnant women (see section 4.3) or in women who may become pregnant. Women of childbearing potential should use effective contraceptive measures during Sintrom treatment.

Pregnancy

Sintrom passes into breast milk, the quantities are limited. The decision to breastfeed should be considered with caution and may include coagulation tests and assessment of vitamin K status in infants before advising the woman to breastfeed. Breastfeeding women who are treated with Sintrom should be monitored closely to ensure that the recommended PT / INR values ​​are not exceeded.

When breastfeeding, the newborn should be given 1 mg of vitamin K1 per week for prophylaxis.

Fertility

There are no data available on the use of Sintrom and its effects on human fertility.

04.7 Effects on ability to drive and use machines

Sintrom has no known influence on the ability to drive and use machines. Patients are, however, recommended to carry a certificate of current anticoagulation with them to inform rescuers in the event of an injury accident.

04.8 Undesirable effects

Adverse reactions (Table 2) are listed by system-organ classes in MedDRA. Within each system organ class, adverse reactions are ranked according to frequency, with the most frequent reactions first.Within each frequency group, adverse reactions are presented in order of decreasing severity. In addition, for each adverse reaction, the corresponding frequency category is also provided using the following convention (CIOMS III): very common: (≥ 1 / 10); common (≥ 1/100 -

Hemorrhages

Bleeding in different parts of the body are the most frequently reported complications with Sintrom and have been related to the dose, the age of the patient and the nature of the underlying disease (but not the duration of treatment).

Table 2


Disorders of the immune system Rare: hypersensitivity (hives, rash, dermatitis) Vascular pathologies Common: hemorrhage Very rare: vasculitis Gastrointestinal disorders Rare: decreased appetite, nausea, vomiting Hepatobiliary disorders Very rare: liver damage Skin and subcutaneous tissue disorders Rare: alopecia Very rare: skin necrosis (haemorrhagic) *

* normally associated with congenital deficiency of Protein C or its protein S cofactor

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse".

04.9 Overdose

While single doses, even very high ones, are generally not dangerous, the clinical manifestations of overdose can occur during prolonged use of higher daily doses than are necessary for treatment.

Signs and symptoms

The sensitivity of the individual patient to oral anticoagulants, the extent of the overdose and the duration of treatment affect the manifestation and severity of the effects.

Hemorrhages in various organs are the most important manifestation of the clinical picture. They can take the form of skin bleeding (80%), hematuria (52%), epistaxis, haematemesis, gastrointestinal bleeding, vaginal bleeding, joint bleeding, hematoma, gingival bleeding.

Additional symptoms include tachycardia, hypotension, circulatory disturbances due to blood loss, nausea, vomiting, diarrhea and abdominal pain.

Laboratory tests reveal an extremely high PT / INR value, a pronounced prolongation of recalcification or prothrombin time, and changes in the gamma-carboxylation of factors II, VII, IX and X.

Treatment

The necessity or desirability of treatment with ipecac syrup, gastric lavage in addition to activated charcoal and administration of cholestyramine is controversial. The benefits of these treatments relative to the risk of bleeding must be weighed in each patient.

Emergency and support measures

In case of severe bleeding, at any level of INR, coagulation factors can be restored to normal by administration of fresh whole blood or frozen plasma concentrates, prothrombin complex concentrate or recombinant factor VIIa supplemented with vitamin K1.

Antidote

Vitamin K1 (phytomenadione) can antagonize the inhibitory effect of Sintrom on hepatic gamma-carboxylation of vitamin K-dependent coagulation factors within 3-5 hours.

In case of clinically insignificant bleeding (INR

In case of high INR (INR 4.5-9) with insignificant bleeding, omit one or two doses of Sintrom and administer 1-2.5 mg of vitamin K1 orally, especially in patients with an increased risk of bleeding.

In case of high INR (INR> 9) with non-significant bleeding, discontinue Sintrom therapy and administer 2.5-5 mg of vitamin K1 orally.

If there is evidence of significant bleeding (at any level of INR), discontinue Sintrom therapy and inject 5-10 mg of vitamin K1 intravenously, very slowly (at a rate not exceeding 1 mg / minute). In case of bleeding Sintrom can be re-administered when the INR is in the prefixed range.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotics. Vitamin K antagonists.

ATC code: B01AA07

Acenocoumarol, active substance of Sintrom, is a coumarin derivative and acts as an antagonist of vitamin K. The antagonists of vitamin K produce their anticoagulant effect through the inhibition of the epoxy reductase of vitamin K with a consequent reduction of the gamma-carboxylation of certain molecules of glutamic acid located at different sites near both ends of coagulation factors II (prothrombin), VII, IX and X, as well as protein C or its cofactor protein S. This gamma-carboxylation has a significant relationship with the interaction between the aforementioned coagulation factors and calcium ions Without this reaction, blood clotting cannot begin.

Based on the initial dosage, acenocoumarol causes prolongation of PT / INR within approximately 36-72 hours. Upon discontinuation of treatment, PT / INR generally returns to normal after a few days.

05.2 Pharmacokinetic properties

Absorption

Acenocoumarol, a racemic mixture of R (+) and S (-) optical enantiomers, is rapidly absorbed orally; at least 60% of the dose becomes available systemically. After a single dose of 10 mg, peak plasma concentrations are achieved of 0.3 ± 0.05 μg / mL within 1 to 3 hours Peak plasma concentrations and areas under the blood concentration curve (AUC) are dose proportional over a range of 8-16 mg.

Plasma concentrations between individual patients vary in such a way that no correlation can be established between dose, plasma acenocoumarol concentrations and measurable prothrombin level.

Distribution

Most of the administered dose is distributed into the plasma fraction of the blood, where 98.7% is bound to plasma proteins, mainly albumin. The apparent volume of distribution is 0.16-0.18 L / kg per liter. "R (+) enantiomer and 0.22-0.34 L / kg for the S (-) enantiomer.

Acenocoumarol passes into breast milk, but only in very small amounts, which cannot be detected by common analytical methods. It also crosses the placental barrier (see section 4.6).

Biotransformation / Metabolism

Acenocoumarol is extensively metabolised. The 6- and 7- hydroxylates of both acenocoumarol enantiomers are the major metabolites and cytochrome P450 2C9 is the major catalyst for the formation of these 4 metabolites. CYP1A2 and CYP2C19 are other enzymes involved in metabolism. of (R) -acenocoumarol. Through the reduction of the ketone group two different alcoholic metabolites are formed. An amino metabolite is obtained by reduction of the nitro group. All these metabolites are pharmacologically inactive in humans, while they are active in an animal model. The variability related to CYP2C9 accounts for 14% of the interindividual variability in the pharmacodynamic response to acenocoumarol.

Elimination

Acenocoumarol is eliminated from plasma with a half-life of 8-11 hours. After oral administration the apparent plasma clearance is approximately 3.65 L / h. The total plasma clearance of the R (+) enantiomer which possesses significantly greater anticoagulant activity , is 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 unchanged active substance during one week is equivalent to 60% of the dose in the urine and 29% of the dose in the stool.

Special populations

Elderly patients

In one study, higher plasma concentrations of acenocoumarol (which produced certain prothrombin levels) were seen in patients over the age of 70 following administration of the same daily dose compared to younger patients.

Kidney failure

No information is available on the clinical pharmacokinetics of acenocoumarol in renal insufficiency. Based on the urinary elimination of acenocoumarol, the possibility of accumulation of metabolites in the event of impaired renal function cannot be excluded. Therefore the use of acenocoumarol is contraindicated in patients with severe renal insufficiency and caution should be exercised in patients with mild to moderate renal insufficiency (see sections 4.2, 4.3 and 4.4).

Hepatic insufficiency

No information is available on the clinical pharmacokinetics of acenocoumarol in hepatic insufficiency. Based on the metabolism of acenocoumarol and the possible reduced enzyme activities, clearance of CYP2C9, CYP1A2 and CYP3A4 is likely to be reduced. Therefore the use of acenocoumarol is contraindicated in patients. with severe hepatic impairment and caution should be exercised in patients with mild to moderate hepatic impairment (see sections 4.2, 4.3 and 4.4).

Ethnicity

CYP2C9 enzyme systems are expressed polymorphically and their frequency differs across the population. In Caucasians, the occurrence frequencies of CYP2C9 * 2 and CYP2C9 * 3 are 12 and 8%, respectively. Patients with one or more variants of these CYP2C9 alleles have reduced S-acenocoumarol clearance. In African patients, CYP2C9 * 2 and CYP2C9 * 3 appear at allele frequencies 1-4% and 0.5-2.3% lower, respectively, than those of Caucasians The Japanese population has lower allele frequencies of 0.1% and 1-6% for CYP2C9 * 2 and CYP2C9 * 3, respectively.

The maintenance dose of acenocoumarol differs on the basis of the genotype.

Detailed mean and median maintenance dose information based on CYP2C9 genotype is provided in the table below:

Table 3 - Maintenance dose of acenocoumarol according to CYP2C9 genotype


Genotype No. Average dose (mg / week) SD Median dose (mg / week) Range CYP2C9 * 1 169 17,1 8,7 15,8 2,3-61 CYP2C9 * 2 90 14,4 6,3 13,5 3,5-37,3 CYP2C9 * 3 48 11,0 5,1 10,5 2,3-22

05.3 Preclinical safety data

Toxicity

After a single oral and / or intravenous dose, acenocoumarol demonstrated a mild degree of toxicity in mice, rats and rabbits. In dogs, it exhibited high acute oral toxicity.

In repeat-dose studies, the liver was the major target organ for toxicity of coumarin derivatives, including acenocoumarol. Pharmacologically excessive administration of these substances can cause bleeding.

Reproductive toxicity and teratogenicity

Animal studies have not been conducted with acenocoumarol. However, placental and transplacental interference with vitamin K-dependent coagulation factors may lead to embryo or fetal malformations and haemorrhages in neonates, both animals and humans (see section 4.6).

Mutagenesis

In in vitro tests performed on bacterial or mammalian cell lines, including a DNA repair test in rat hepatocytes, acenocoumarol and its metabolites did not induce any mutagenic effects. An in vitro study in human lymphocytes showed a mild mutagenic activity. However, in this experiment, the effective acenocoumarol concentrations of ≥ 188 and ≥ 250 mcg / ml (in the presence and without metabolic activation, respectively) were 500 to 1000 times higher than those determined in human plasma after administration. of the drug.

Carcinogenesis

Animal carcinogenicity studies have not been performed with acenocoumarol. Coumarin induced an increased incidence of lung tumors and benign liver tumors in mice and liver tumors and benign renal tumors in rats. Hepatic tumors in rats and tumors in mice are known to be associated with species-specific metabolic pathways. these species.

It is known that the hepatotoxicity of coumarin and its derivatives in rats is associated with enzyme induction and that the biotransformation of coumarin and / or its metabolites is characteristic of this rodent species. Kidney tumors observed in male mice are considered to be species-specific effects.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Sintrom 1 mg tablets: anhydrous colloidal silica; hypromellose; lactose monohydrate; magnesium stearate; cornstarch; talc.

Sintrom 4 mg tablets: anhydrous colloidal silica; lactose monohydrate; magnesium stearate; cornstarch; pregelatinised maize starch.

06.2 Incompatibility

No special instructions.

06.3 Period of validity

Sintrom 1 mg tablets: 3 years

Sintrom 4 mg tablets: 5 years

06.4 Special precautions for storage

This medicine does not require any special storage conditions.

06.5 Nature of the immediate packaging and contents of the package

Non-toxic opaque PVC (or PVC / PE / PVDC) blister

Sintrom 1 mg tablets: 20 and 100 tablets

Sintrom 4 mg tablets: 20 quadrisecable tablets

06.6 Instructions for use and handling

No special instructions

07.0 MARKETING AUTHORIZATION HOLDER

Novartis Farma S.p.A.

Largo Umberto Boccioni, 1 - 21040 Origgio (VA)

08.0 MARKETING AUTHORIZATION NUMBER

Sintrom 1 mg tablets - 20 tablets - A.I.C .: 011782024

Sintrom 1 mg tablets - 100 tablets - A.I.C .: 011782036

Sintrom 4 mg tablets - 20 tablets - A.I.C .: 011782012

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Sintrom 1 mg tablets Authorization: 31.10.1994 Renewal: 01.06.2010

Sintrom 4 mg tablets Authorization: 6.11.1956 Renewal: 01.06.2010

10.0 DATE OF REVISION OF THE TEXT

AIFA Determination of February 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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