Tiklid - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Ticlopidine

TIKLID 250 mg coated tablets

Why is Tiklid used? What is it for?

TIKLID contains the active substance ticlopidine, which belongs to the class of antiplatelet agents, medicines that improve blood circulation by preventing the formation of clots (thrombi).

TIKLID is used

  • in the prevention of blockage of blood flow to the brain and heart (ischemia) in people who have a high risk of blood clot formation (peripheral arterial disease, previous myocardial infarction and recurrent or non-recurrent ischemia, ischemic stroke, unstable angina );
  • in the prevention of the closure of by-passes to the heart (aorto-coronary);
  • during surgical interventions that require artificial circulation (extracorporeal circulation);
  • during hemodialysis sessions;
  • if you suffer from thrombosis of the central retinal vein;
  • in people who have had a heart attack or ischemic attacks, only if they are intolerant to acetylsalicylic acid (ASA), or if acetylsalicylic acid therapy has been found to be ineffective.

Given the side effects, this medicine should only be used when it is irreplaceable and it is not possible to follow a treatment with another medicine, other than TIKLID.

Contraindications When Tiklid should not be used

Do not take TIKLID

  • if you are allergic to the active substance or any of the other ingredients of this medicine
  • if you have or have ever had changes in blood cell levels (leukopenia, thrombocytopenia and agranulocytosis);
  • if you suffer from bleeding disorders, such as bleeding (haemorrhagic diathesis) even prolonged;
  • if you have lesions in the esophagus or stomach with a tendency to bleed (ulcers of the gastrointestinal tract, esophageal varices, etc.);
  • if you suffer from brain circulation disorders (acute hemorrhagic cerebral vascular accidents);
  • if you have severe liver problems (severe liver disease);
  • if you are taking other medicines that can interfere with the function of the bone marrow (myelotoxic medicines);
  • if you are pregnant and breast-feeding;

Do not use this medicine for primary prevention if you do not have any of the conditions listed in section 1.

Precautions for use What you need to know before taking Tiklid

Talk to your doctor or pharmacist before taking TIKLID.

Adverse events, sometimes serious, of a haematological and haemorrhagic nature can be observed. Changes in the levels of blood components such as decreased white blood cells (agranulocytosis), decreased all blood cells (pancytopenia) and rare cases of leukemia have been reported post-marketing, sometimes even with fatal outcome.

Such serious events can be associated with:

  • inadequate control, late diagnosis and inadequate treatment of side effects
  • co-administration of anticoagulants or antiplatelet drugs such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). However, in the case of stent implantation, ticlopidine must be combined with aspirin (100-325 mg per day) for about one month after the plant.

It is essential to strictly follow the indications, precautions and contraindications of ticlopidine

The treatment must be carried out under strict medical supervision, especially in the first three months, for the onset of any side effects.

If you notice any of the following conditions, stop treatment immediately and tell your doctor:

  • sore throat, fever, mouth lesions (symptoms of neutropenia);
  • bleeding, even prolonged or bruising (hematoma), skin irritation associated with bleeding (purpura), dark stools (symptoms of thrombocytopenia and / or coagulation disorders);
  • skin irritation associated with bleeding and decreased platelets (symptoms of thrombotic thrombocytopenic purpura);
  • yellowing of the skin (jaundice), dark urine, light colored stools (symptoms of hepatitis).

If you suspect thrombotic thrombocytopenic purpura, see a specialist as there is a high risk of death. The onset can be sudden and in most cases has been reported within the first 8 weeks after initiation of therapy. symptoms are decreased platelets (thrombocytopenia) and red blood cells (haemolytic anemia), neurological symptoms similar to those of a transient ischemic attack (TIA) or stroke, kidney problems and fever.

Resuming treatment with this medicine depends on your clinical condition and the results of blood tests (haematological checks), which need to be done urgently.

Your doctor will order blood tests at the start of treatment and then every 2 weeks for the first 3 months of therapy and within 15 days of any discontinuation of TIKLID, if such discontinuation occurs within the first 3 months of therapy.

Your doctor will instruct you to stop treatment with this medicine if your white blood cells (neutropenia) and platelets (thrombocytopenia) decrease.

If you are going to have minor surgery, such as a "tooth extraction, please tell your doctor about your treatment with this medicine."

Stop treatment at least 10 days before surgery to avoid the risk of bleeding.

In case of emergency surgery, tell your doctor about the current treatment that he will have to take the appropriate precautions to avoid the risk of bleeding.

Use this medicine with caution if you are at risk of bleeding (haemorrhage) and if you have liver problems (liver dysfunction).Your doctor will advise you to carry out liver function tests periodically, especially in the first three months of treatment.

If you suffer from kidney problems (kidney failure), please contact your doctor who may reduce the dose or stop treatment if bleeding problems or blood problems (haematopoietic disorders) arise.

Take care with the use of TIKLID if you are allergic to other medicines similar to ticlopidine (medicines belonging to the thienopyridine group), such as clopidrogrel and prasugrel, as episodes of cross-reactions may occur (See section 4). medicines can cause moderate to severe allergic reactions such as skin irritation (rash), swelling of the face, especially around the eyes and mouth (angioedema or Quincke's edema), changes in the levels of platelets and white blood cells (thrombocytopenia and neutropenia ).

Patients who have experienced allergy to one thienopyridine may have an increased risk of experiencing the same or an "other reaction to" another thienopyridine. It is recommended that cross-reactivity and signs of hypersensitivity be monitored in patients with a known allergy to thienopyridines.

Children and adolescents

The use of this medicine in children and adolescents is not recommended

Interactions Which drugs or foods may change the effect of Tiklid

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Avoid using this medicine together with other medicines that can cause changes in blood cells (myelotoxic medicines).

Tell your doctor if you take the following medicines in addition to TIKLID, as they may increase the risk of bleeding (haemorrhage):

  • non-steroidal anti-inflammatory drugs (NSAIDs);
  • antiplatelet agents, medicines used to increase blood fluidity;
  • acetylsalicylic acid (except in cases of stent implantation where the association is allowed) and derivatives;
  • oral and parenteral anticoagulants (heparin), medicines that improve circulation;

Tell your doctor and take special care if you are taking any of the following medicines, as specific precautions may need to be taken:

  • theophylline, a medicine used to treat asthma, because the dosage may need to be adjusted;
  • digoxin, a medicine used to treat heart rhythm disorders;
  • phenobarbital and phenytoin, medicines used to treat epilepsy;
  • cimetidine and other medicines used to treat stomach upset (antacids);
  • ciclosporin, an immunosuppressive medicine used in transplantation.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Do not use this medicine if you are pregnant or breast-feeding, unless absolutely necessary.

Driving and using machines

The use of this medicine causes dizziness and other side effects, which may affect the ability to drive or use machines.

Dosage and method of use How to use Tiklid: Dosage

Always take this medicine exactly as your doctor or pharmacist has told you.

If in doubt, consult your doctor or pharmacist.

For prolonged treatments, the recommended dose is 1 or 2 tablets a day, to be taken with meals.

Overdose What to do if you have taken too much Tiklid

If you accidentally take an overdose, contact your doctor immediately or go to the nearest hospital. Overdose of this medicine may increase the risk of bleeding; if prolonged, it is necessary to intervene through a transfusion of platelets. For severe stomach and intestinal problems, treatment includes induction of vomiting, gastric lavage, and other supportive measures.

If you forget to take TIKLID

Do not take a double dose to make up for a forgotten tablet.

If you stop taking TIKLID

If you stop taking this medicine within the first three months, your doctor will instruct you to have a full blood test two weeks after stopping therapy. You should check your blood parameters until they return to normal.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist

Side Effects What are the side effects of Tiklid

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

Using this medicine may cause the following side effects:

Common (may affect up to 1 in 10 people)

  • decrease in white blood cells, even severe (neutropenia, agranulocytosis);
  • headache, dizziness;
  • abnormal liver function (increase in liver enzymes, increase in alkaline phosphatase and transaminases);
  • diarrhea and nausea;
  • skin irritations (maculopapular or urticarial rush), often accompanied by itching;
  • increased cholesterol and triglycerides.

Uncommon (may affect up to 1 in 100 people)

  • decrease in platelets (thrombocytopenia), accompanied by a decrease in red blood cells (haemolytic anemia);
  • severe infection of the body (sepsis) and septic shock which can occur as fatal complications of decreased white blood cells (agranulocytosis);
  • sensory disturbances (peripheral neuropathy);
  • bleeding complications, especially bruising, blood in the urine (haematuria), or bleeding from the lower part of the eye (haemorrhage of the conjunctiva), nose bleeding (epistaxis), bleeding that occurs during an operation (peri-operative bleeding) and postoperative bleeding which can be severe and sometimes with fatal consequences;
  • formation of lesions in the stomach and intestines (gastroduodenal ulcer);
  • disturbances in liver function (increased bilirubin);
  • skin irritation associated with peeling (exfoliative dermatitis).

Rare (may affect up to 1 in 1000 people)

  • decrease in all blood cells (pancytopenia), sharp decrease in bone marrow activity (medullary aplasia), blood disorders (thrombotic thrombocytopenic purpura, leukemia and thrombocytosis);
  • perception of a sound in the ear (tinnitus);
  • brain hemorrhages (intracerebral);
  • liver disorders, such as hepatitis (cytolytic and / or cholestatic hepatitis);
  • yellowing of the skin due to liver malfunction (cholestatic jaundice).

Very rare (may affect up to 1 in 10,000 people)

  • immune system disorders, such as allergic manifestations, anaphylaxis (severe allergic reaction), swelling of the face especially around the eyes and mouth (angioedema or Quincke's edema), increased white blood cells (eosinophilia), pain in the joints (arthralgia), inflammation of the blood vessels (vasculitis), irritative skin disorders, joint pain and fever (lupoid syndrome), lung disorders (allergic lung disease), kidney disorders (hypersensitivity nephropathy which may be associated with kidney failure);
  • severe diarrhea associated with inflammation of the intestines (colitis and lymphocytic colitis). If the effect is severe, stop taking this medicine;
  • fatal hepatitis and fulminant hepatitis;
  • allergic skin reactions (erythema multiforme, Stevens-Johnsons syndrome and Lyell's syndrome)
  • fever.

Not known (frequency of which cannot be estimated from the available data)

  • cross-reaction of hypersensitivity between thienopyridines, such as clopidogrel and prasugrel (See section "Warnings and precautions").

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. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.

Expiry and Retention

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

This medicine does not require any special storage conditions

Do not use this medicine after the expiry date which is stated on the package after "EXP".

The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What TIKLID contains

  • The active ingredient is ticlopidine hydrochloride. Each tablet contains 250 mg of active ingredient.
  • The other ingredients are microcrystalline cellulose, povidone, anhydrous citric acid, maize starch, stearic acid, magnesium stearate, hypromellose, titanium dioxide, macrogol 8000.

Description of what TIKLID looks like and contents of the pack

Pack of 30 coated 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.

More information about Tiklid 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 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 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 HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 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 RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

TIKLID 250 MG COATED TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains:

Active ingredient: ticlopidine hydrochloride 250 mg.

For the full list of excipients see section 6.1.

03.0 PHARMACEUTICAL FORM

Coated tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Ticlopidine is indicated in the secondary prevention of cerebro and cardiovascular occlusive ischemic events in patients at thrombotic risk (peripheral arterial disease, previous myocardial infarction, previous recurrent transient ischemic attacks, ischemic cerebral stroke, unstable angina). In patients with a history of myocardial infarction and with a history of transient ischemic attacks, the use of ticlopidine should be reserved for those patients who cannot tolerate acetylsalicylic acid (ASA) or in whom ASA has been found to be ineffective.

Ticlopidine is also indicated: in the prevention of re-occlusion of aorto-coronary bypasses, in extra-corporeal circulation, in hemodialysis and in thrombosis of the central retinal vein.

Conditions of use: Doctors are advised to use the product only in cases relating to the pathology indicated above by carrying out the checks indicated in the "Special warnings and precautions for use" and carefully respecting the contraindications.

04.2 Posology and method of administration

The recommended dosage for long-term therapy is 1 or 2 tablets per day, to be taken with meals.

Pediatric population

Use in children and adolescents is not recommended due to lack of experience in clinical trials.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

The drug is contraindicated in subjects who present or have presented leukopenia, thrombocytopenia or agranulocytosis.

Haemorrhagic diathesis (previous or current) and haemopathies that lead to a lengthening of the bleeding time.

Organic lesions susceptible to bleeding (ulcers of the gastrointestinal tract, esophageal varices, etc.).

Acute hemorrhagic cerebral vascular accidents.

Severe liver diseases.

In some cases, the appearance of leukopenia or agranulocytosis, sometimes even with an irreversible outcome, has been reported during treatment with ticlopidine; therefore the drug must be used only in cases where it is irreplaceable. The use of ticlopidine in primary prevention in clinically healthy subjects must be categorically excluded. The association with other potentially myelotoxic drugs must be avoided.

Pregnancy and lactation (see section 4.6)

04.4 Special warnings and appropriate precautions for use

Adverse events, sometimes serious, of a haematological and haemorrhagic nature can be observed.

Agranulocytosis, pancytopenia and rare cases of leukemia have been reported in post-marketing experience.

Fatal consequences have sometimes been observed following haematological and haemorrhagic adverse events (see section 4.8).

Such serious events can be associated with:

- inadequate control, late diagnosis and inappropriate therapeutic measures for adverse events

- concomitant administration of anticoagulants or antiplatelet substances such as aspirin and non-steroidal anti-inflammatory drugs. However, in the case of stent implantation, ticlopidine must be combined with aspirin (100-325 mg per day) for about one month after the " plant.

It is essential to strictly follow the indications, precautions and contraindications of ticlopidine.

Hematological control

A complete blood count, including differential leukocyte and platelet counts, should be performed at the initiation of treatment and then every 2 weeks for the first 3 months of therapy and within 15 days of any discontinuation of ticlopidine, if such discontinuation occurs within first 3 months of therapy.

When the number of neutrophils falls below 1500 / mm3 the value must be confirmed. If the presence of neutropenia (neutrophils 3) or thrombocytopenia (platelets 3) is confirmed, treatment should be stopped.

Due to the long plasma half-life of ticlopidine hydrochloride, it is recommended that patients who stop ticlopidine for any reason within the first 90 days undergo an additional complete blood count, including differential leukocyte count, two weeks after stopping therapy. Blood counts, including differential white blood cell counts and platelet counts, should be monitored until they return to normal.

Clinical control

The patient should be educated on signs and symptoms possibly related to neutropenia (fever, sore throat, oral ulceration), thrombocytopenia and / or haemostasis disorders (prolonged or unexpected bleeding, bruising, purpura, dark stools) or thrombotic thrombocytopenic purpura (TPP).

The patient should be advised to discontinue the medication and to seek immediate medical attention if any of the above signs or symptoms appear.

The decision to resume treatment should only be made taking into account clinical and laboratory findings.

Cases of neutropenia, including severe neutropenia and agranulocytosis were mostly observed in the first three months of treatment with ticlopidine, and were not typically accompanied by signs of infection or other clinical symptoms (need for blood count control). In these cases the bone marrow typically showed a decrease in myeloid precursors (See section 4.8).

Cases of hepatitis (cytolytic and / or cholestatic) have been reported during the first months of treatment, after which the course was generally favorable (See section 4.8)

The patient should be informed about the symptoms of hepatitis (eg jaundice, dark urine, light colored stools) and encouraged to report these symptoms to the physician.

The clinical diagnosis of rare and potentially fatal thrombotic thrombocytopenic purpura (TTP) is characterized by the presence of thrombocytopenia, haemolytic anemia, neurological symptoms similar to those of a transient ischemic attack (TIA) or stroke, kidney disorders and fever.

Onset may be sudden. Most cases have been reported within the first 8 weeks after initiation of therapy.

If thrombotic thrombocytopenic purpura is suspected, as there is a high risk of fatal outcome, consult your specialist.

Treatment with plasmapheresis is suggested to improve prognosis. Since the administration of platelets can lead to an increased risk of thrombosis, it should be avoided if possible.

Cross-reactions between thienopyridines Patients should be evaluated for a clinical history of hypersensitivity to another thienopyridine (such as clopidogrel, prasugrel) as cross-reactivity between thienopyridines has been reported (see section 4.8 "Undesirable effects"). Thienopyridines may cause allergic reactions. moderate to severe such as rash, angioedema or haematological reactions such as thrombocytopenia and neutropenia. Patients who have experienced a previous allergic and / or haematological reaction to one thienopyridine may have an increased risk of developing the same or an "other reaction to" another Thienopyridine Monitoring for cross reactivity is recommended Monitoring for signs of hypersensitivity is recommended in patients with a known allergy to thienopyridines.

• Hemostasis:

Use ticlopidine with caution in patients who have an increased bleeding risk.

Do not administer the drug in combination with heparins, oral anticoagulants and antiplatelet drugs (see sections 4.4 and 4.5); however, in exceptional cases of concomitant treatments, close clinical and laboratory monitoring is necessary (see section 4.5).

In case of minor surgical interventions (e.g. tooth extraction), prolonged bleeding should be expected and therefore the doctor should be informed of the ongoing treatment.

Before an elective surgery, when possible, treatment should be suspended at least 10 days before (except in cases where antithrombotic activity is not expressly requested) in consideration of the bleeding risk induced by the drug: after the suspension of therapy it is advisable evaluate the possible persistence of the effect on haemostasis (bleeding time) before proceeding with the intervention.

In case of emergency surgery, 3 methods can be used as such or in combination to limit the bleeding risk and prolong the bleeding time: administration of 0.5 - 1 mg / kg of iv methylprednisolone, possibly repeated; desmopressin at a dose of 0.2 - 0.4 mcg / kg; platelet transfusions.

• Since ticlopidine is extensively metabolised in the liver:

- the drug should be used with caution in patients with liver function disorders,

- in case of suspected liver dysfunction, liver function tests should be performed, especially in the first months of treatment,

- and if hepatitis or jaundice develops, treatment should be stopped and liver function tests conducted.

Serum levels of HDL-C, LDL-C, VLDL-C and triglycerides may increase by 8 to 10% after 1-4 months of treatment. No further increase is observed with continued therapy. The ratios of lipoprotein subfractions (especially the HDL / LDL ratio) remain unchanged. Clinical trial data have shown that the effect is independent of age, sex, alcohol consumption or diabetes, and has no influence on cardiovascular risk (see section 4.8).

In controlled clinical trials no unexpected events were found in patients with mild renal impairment, and there is no experience of dose adjustment in patients with higher degrees of renal impairment. However, for patients with renal insufficiency, ticlopidine dosage may need to be reduced or discontinued altogether if bleeding or haematopoietic problems develop.

Cases of generally mild and transient diarrhea have been reported and is mainly observed in the first three months of treatment.

These disorders usually resolve within 1-2 weeks without stopping treatment (see section 4.8).

Skin rashes were generally observed in the first three months of treatment, with a mean time to onset of 11 days. If treatment is stopped, symptoms disappear within a few days (see section 4.8).

Carefully check all patients for the onset of any clinical signs and symptoms related to adverse drug reactions especially during the first 3 months of therapy.

04.5 Interactions with other medicinal products and other forms of interaction

Combinations with drugs that increase the risk of bleeding

NSAIDs

Increased risk of bleeding (increased antiplatelet activity associated with the effect of NSAIDs on the gastroduodenal mucosa). If such drugs are required, careful clinical monitoring should be undertaken.

Antiplatelet drugs

Increased risk of bleeding (increased antiplatelet activity). If such drugs are necessary, careful clinical monitoring should be undertaken.

Salicylic derivatives (by extrapolation from acetylsalicylic acid)

Increased risk of bleeding (increased antiplatelet activity associated with the effect of salicylates on the gastroduodenal mucosa). If such drugs are required, careful clinical monitoring should be undertaken.

In case of stent implantation see also section 4.4

Oral anticoagulants

Increased risk of bleeding (association of anticoagulant activity and antiplatelet activity). If such drugs are required, careful clinical and biological monitoring (INR) should be undertaken.

Heparin

Increased risk of bleeding (association of anticoagulant activity and antiplatelet activity). If such drugs are required, careful clinical and biological monitoring (APTT) should be undertaken.

Associations with potentially myelotoxic drugs

Combination with other potentially myelotoxic drugs should be avoided.

Associations requiring special precautions

Theophylline

Increased plasma theophylline levels with risk of overdose (decrease in total plasma clearance of theophylline). Conduct clinical monitoring and, if necessary, measure plasma theophylline levels. Adjust the theophylline dosage during and after ticlopidine treatment.

Digoxin

The concomitant administration of ticlopidine and digoxin induces a slight reduction (about 15%) in the plasma levels of digoxin: this reduction should not affect the therapeutic efficacy of digoxin.

Phenobarbital

In healthy volunteers, the inhibitory effects of ticlopidine on platelet aggregation are not affected by chronic administration of phenobarbital.

Phenytoin

From studies in vitro it was found that ticlopidine does not modify the plasma protein binding of phenytoin.

However, there are no studies in vivo on the interaction of ticlopidine and its metabolites on protein binding. On the other hand, there are rare reports of increased phenytoin levels and its toxicity when ticlopidine is prescribed in combination. Particular attention should be paid to the simultaneous administration of this drug with ticlopidine and it may be useful to re-monitor the blood concentrations of phenytoin.

Other concomitant therapies

In various clinical studies, ticlopidine was administered in combination with beta-blockers, calcium channel blockers and diuretics: no clinically significant adverse interactions were reported.

Studies in vitro show that ticlopidine binds reversibly to plasma proteins (98%) but does not interact with the protein binding of propanolol, the basic drug, which is also highly bound to proteins.

The biological half-life of antipyrine which is metabolised via the cytochrome P 450 system is increased by 25% when co-administered with ticlopidine. This is also expected for substances with similar hepatic metabolism. Especially for substances with a narrow therapeutic index, a dose adjustment is necessary at the beginning and after the discontinuation of the concomitant administration.

Concomitant administration of ticlopidine and antacids results in a 20-30% lower plasma ticlopidine level.

Chronic cimetidine therapy significantly increases plasma ticlopidine levels.

In very rare cases, a reduction in the blood levels of cyclosporine has been reported, therefore the blood concentration of cyclosporine should be monitored in case of concomitant administration.

04.6 Pregnancy and breastfeeding

Pregnancy

The safety of ticlopidine in pregnant women has not been established. Ticlopidine should not be used during pregnancy unless absolutely necessary.

Feeding time

Studies in rats have shown that ticlopidine is excreted in milk.

The safety of ticlopidine in breastfeeding women is not established.

Ticlopidine should not be used during breastfeeding unless absolutely necessary.

04.7 Effects on ability to drive and use machines

Undesirable effects of ticlopidine, such as dizziness, may impair the ability to drive or use machines.

04.8 Undesirable effects

Adverse events are classified according to frequency: very common (> 1/10), common (≥ 1/100,

System and organ classification common Uncommon Rare Very rare Not known Blood and lymphatic system disorders 1 neutropenia, including severe, agranulocytosis (see section 4.4) cases of isolated thrombocytopenia, in exceptional cases accompanied by haemolytic anemia. Sepsis and septic shock can be fatal complications of agranulocytosis Pancytopenia, bone marrow aplasia, thrombotic thrombocytopenic purpura, leukemia and thrombocytosis (see section 4.4). Disorders of the immune system immunological reactions with different manifestations, for example allergic reactions, eosinophilia, anaphylaxis, Quincke's edema, arthralgia, vasculitis, lupoid syndrome, allergic pulmonary disease, hypersensitivity nephropathy sometimes resulting in renal failure Hypersensitivity cross-reaction between thienopyridines (such as clopidogrel and prasugrel) (see section 4.4) Nervous system disorders headache, dizziness sensory disturbances (peripheral neuropathy) tinnitus Vascular pathologies haemorrhagic complications, mainly bruising or ecchymosis and epistaxis, conjunctival haematuria or haemorrhage, peri and postoperative haemorrhages which can be serious and sometimes with fatal consequences (see section 4.4). intracerebral hemorrhages Gastrointestinal disorders diarrhea and nausea (see section 4.4). gastroduodenal ulcer severe diarrhea with colitis (including lymphocytic colitis). If the effect is severe and persistent, therapy should be discontinued. Hepatobiliary disorders increase in liver enzymes, increase (isolated or not) in alkaline phosphatase and transaminases (more than two-fold increase above the upper limit of normal) (see section 4.4) increased bilirubin hepatitis (cytolytic and / or cholestatic) and jaundice with ecstatic (see section 4.4) cases of fatal hepatitis and fulminant hepatitis Skin and subcutaneous tissue disorders skin rash, mostly maculopapular or urticarial, often accompanied by itching. These skin rashes can be generalized exfoliative dermatitis erythema multiforme, Stevens-Johnsons syndrome and Lyell syndrome General disorders and administration site conditions Fever Diagnostic tests increased cholesterol and triglyceridemia. (see section 4.4).

1): A complete blood count was carefully monitored in 2 large clinical trials involving 2,048 TIA / stroke patients treated with ticlopidine (CATS and TASS controlled multicenter clinical trials) see section 4.4)

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 www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Based on the pharmacodynamic properties, overdose may lead to a risk of haemorrhage.

Based on animal studies, overdose can lead to severe gastrointestinal intolerance. In the event of such an occurrence, induction of vomiting, gastric lavage and other general supportive measures are recommended.

If rapid correction of prolonged bleeding time is required, a platelet transfusion can reverse the effects of ticlopidine. (see section 4.4)

Ticlopidine is not removed by dialysis.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic, antiplatelet agent.

ATC code: B01AC05.

Ticlopidine is an inhibitor of platelet aggregation, inhibits platelet aggregation in a dose dependent manner, as well as the release of platelet factors and induces a prolongation of the bleeding time. The drug is not endowed with any significant activity in vitro but only in vivo, and there is no evidence for the existence of a circulating active metabolite.

Ticlopidine interferes with platelet aggregation by inhibiting the ADP-dependent binding of fibrinogen on the platelet membrane; moreover, unlike aspirin, it does not inhibit cyclooxygenase. Cyclic platelet AMP does not appear to play a role in the mechanism of "action.

The bleeding time calculated with a cuff pressure of 40 mm Hg, measured with the Ivy method, is longer than twice the baseline value. The lengthening of the bleeding time, measured without the cuff, is less pronounced.

Upon discontinuation of treatment, bleeding time and other platelet function tests return to normal within one week in most patients.

The inhibition of platelet aggregation is evident within two days of the administration of ticlopidine 250 mg twice daily. The maximum antiplatelet effect is obtained after 5-8 days at the dose of 250 mg twice daily.

At the therapeutic dose, ticlopidine inhibits ADP-induced platelet aggregation (2.5 mcmol / l) by 50-70%.

Lower doses are associated with less inhibition of platelet aggregation.

The effect of ticlopidine on the risk of vascular events has been studied in some controlled, blinded clinical studies.

05.2 Pharmacokinetic properties

After oral administration of a single standard dose of ticlopidine there is rapid absorption and peak plasma is observed approximately 2 hours after dose administration. Absorption is in fact complete. Administration of ticlopidine after meals improves its bioavailability.

Steady-state plasma levels are obtained after 7-10 days with doses of 250 mg twice daily.

The mean terminal elimination half-life of ticlopidine at steady state is approximately 30-50 hours. However, inhibition of platelet aggregation does not correlate with plasma drug levels. Ticlopidine is extensively metabolised in the liver. After an oral dose of the drug. radiolabelled product, 50-60% is found in the urine and the rest in the faeces.

05.3 Preclinical safety data

The toxicity assessment of ticlopidine was performed in the rat and mouse. The routes of administration used were oral and intravenous for the rat and oral and intraperitoneal for the mouse. The LD50 in the rat was 1400 ± 220 mg / kg orally and 60.6 ± 8.6 mg / kg by the venous route, respectively. The LD50 in mice was 630 ± 87 mg / kg orally and 123 ± 37 mg / kg intraperitoneally, respectively.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Microcrystalline cellulose, povidone, anhydrous citric acid, corn starch, stearic acid, magnesium stearate, hypromellose, titanium dioxide, macrogol 8000.

06.2 Incompatibility

There are no known incompatibilities.

06.3 Period of validity

3 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

Cardboard box containing 2 blisters of 15 tablets each.

06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

Sanofi S.p.A. - Viale L. Bodio, 37 / B - Milan

08.0 MARKETING AUTHORIZATION NUMBER

A.I.C. n. 024453021

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 15 June 1981

Renewal: 1 June 2010

10.0 DATE OF REVISION OF THE TEXT

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

none:  dental-extraction alcohol-and-spirits hypertension