New Proposed

Ticlopidine hydrochloride; DE/H/0203/001; 01.02.1318.10.11-corr. Formatiert: Schriftart: 18 Pt., Nicht unterstrichen, Englisch new proposed SPC (Großbritannien) Formatiert: Zeilenabstand: einfach Page 1/16 Formatiert: Links: 2,5 cm, Rechts: 2,5 cm, Oben: 2 cm, Unten: 2 cm, Kopfzeilenabstand vom Rand: 1,3 cm, SUMMARY OF PRODUCT CHARACTERISTICS Fußzeilenabstand vom Rand: 1,3 cm

Formatiert: Schriftart: Nicht Fett 1. NAME OF THE MEDICINAL PRODUCT Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm /…/

2. QUALITATIVE AND QUANTITATIVE COMPOSITION Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Each film-coated tablet contains 250 mg ticlopidine hydrochloride. Formatiert: Schriftart: Nicht Fett, Nicht Kursiv For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Film-coated tablets

White to off-white, slightly convex.

4. CLINICAL PARTICULARS Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm 4.1 Therapeutic indications Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm For the prophylaxis of cerebral thrombotic infarct in patients after transient ischaemic attacks (TIA), reversible ischaemic neurological deficit (RIND) or for prophylaxis in patients who have suffered a cerebral thrombotic infarct (secondary prophylaxis). These indications apply only to patients for whom treatment with acetylsalicylic acid is not tolerated. Formatiert: Schriftart: Nicht Fett For inhibition of platelet aggregation in haemodialysis patients with shunt complications in cases of intolerance to preparations containing acetylsalicylic acid.

4.2 Posology and method of administration Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Posology

Adults Formatiert: Vom nächsten Absatz trennen

The usual dosage for adults for the given indications is 1 film-coated tablet /…/ twice daily (equivalent to 250 mg ticlopidine hydrochloride twice daily).

A daily dose of 500 mg of ticlopidine hydrochloride should not be exceeded.

In order to avoid or decrease possible gastrointestinal adverse reactions such as nausea and diarrhoea, the daily dose should at any rate be taken divided into only two doses, with two main meals, (after half the meal has been taken).

Duration of treatment is determined by the clinical picture. Long-term treatment is generally indicated. Formatiert: Schriftart: Fett

The use in children and adolescents is not recommended. Special populations Formatiert: Schriftart: 12 Pt., Nicht unterstrichen Use in patients with impaired liver function Formatiert: PSUR Paragraph 1

Formatiert: Nicht unterstrichen In case of impaired liver function, ticlopidine should be used with special caution. Formatiert: Vom nächsten Absatz trennen Paediatric population Formatiert: Keine Absatzkontrolle The use in children and adolescents is not recommended due to lack of experience in clinical trials. Formatiert: Unterstrichen

Method of administration

4.3 Contraindications Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Ticlopidine must not be taken by patients with known hypersensitivityHypersensitivity to Formatiert ticlopidinethe active substance or to any of the excipients. Formatiert

 Ticlopidine must not be used listed in patients with haemorrhagicsection 6.1 Formatiert  Haemorrhagic diathesis, disorders involving prolongation of bleeding time as well as organ Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Aufgezählt lesions with risk of haemorrhage, such as acute peptic/intestinal ulcers or haemorrhagic + Ebene: 1 + Ausgerichtet an: 0,63 cm + Tabstopp nach: apoplectic stroke. 1,27 cm + Einzug bei: 1,27 cm, Leerraum zwischen asiatischem und westlichem Text nicht anpassen, Leerraum zwischen asiatischem Text und Zahlen nicht anpassen,  In addition, ticlopidine must not be used in patients with pre-existing or a historyOrganic lesions Tabstopps: Nicht an 1,27 cm which are liable to bleed i.e. active gastroduodenal ulcer or haemorrhagic cerebrovascular Formatiert accident in the acute phase Formatiert  Blood disease involving prolonged bleeding time  History of blood count abnormalities, such as neutropenia, agranulocytosis orleucopenia, Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Aufgezählt thrombocytopenia. or agranulocytosis + Ebene: 1 + Ausgerichtet an: 0,63 cm + Tabstopp nach: 1,27 cm + Einzug bei: 1,27 cm, Leerraum zwischen asiatischem und westlichem Text nicht anpassen, Leerraum 4.4 Special warnings and precautions for use zwischen asiatischem Text und Zahlen nicht anpassen, Tabstopps: Nicht an 1,27 cm It is essential to comply strictly with the indications, contraindications and warnings and precautions Formatiert for use. Formatiert

Formatiert Severe, sometimes fatal forms of undesirable haematological or Haematological and haemorrhagic Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm adverse effects are most likely to can occur in cases in which. Agranulocytosis, pancytopenia and rare cases of leukaemia have been reported in postmarketing experience. Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm  monitoring is not appropriately conducted, diagnosis is made too late and unsuitable measures are taken to treat the undesirable effects, Formatiert other medicinal products which increase the risk of haemorrhage, e.g. Formatiert Serious, sometimes fatal haematological and haemorrhagic adverse effects (see section 4.8) may Formatiert occur, especially associated with: Formatiert  Inadequate monitoring, late diagnosis and inappropriate therapeutic measures for adverse effects  Concomitant administration of anticoagulants or antiplatelet agents such as acetylsalicylic acid or non-aspirin and nonsteroidal anti-inflammatory drugs medicinal products (NSAIDs) (see section 4.5), are used concomitantly). However, in case of STENT implantation, ticlopidine should be combined with aspirin (100 to 325 mg per day) for about one month following implantation.

All patients should be carefully monitored for clinical signs and symptoms of adverse reactions, Formatiert: Leerraum zwischen asiatischem und westlichem especially in the first 3 months of treatment.Haematological monitoring Text nicht anpassen, Leerraum zwischen asiatischem Text und Zahlen nicht anpassen Blood count alterations Formatiert: Schriftart: Kursiv, Unterstrichen, Schriftfarbe: Schwarz Regular controls of cell counts (BCCs) with differential blood counts and platelet counts at 14 days Formatiert: Schriftart: Nicht Kursiv, Nicht unterstrichen intervals are necessary prior to initiation of therapy with ticlopidine and during the first 3 months of treatment, should be performed at the start of treatment and then every two weeks for the first three months of therapy to ensure that any blood count alterations are detected at the earliest point of time.

If the neutrophil count falls below 1,500/mm3, a second blood analysis should immediately be performed. If laboratory analysis confirms the presence of neutropenia (<1,500 neutrophilic granulocytes/mm3) or thrombopenia (<100,000 platelets/mm3), treatment with ticlopidine should be discontinued.

If therapy with ticlopidine is discontinued , and within the first 3 months for any other reason, Formatiert: Schriftfarbe: Schwarz differential blood counts should be monitored 1415 days after termination of the course of therapy. Formatiert: Schriftfarbe: Schwarz

Usually blood counts will normalise with discontinuation of the treatment (it is advisable to monitor Formatiert: Tabstopps: 0 cm, Links differential blood counts until the numbers of neutrophils and platelets have returned to normal Formatiert: Schriftfarbe: Schwarz levels)ticlopidine, should the treatment be stopped within the first three months of therapy. Formatiert: Schriftfarbe: Schwarz These bloodBlood count alterations generally occur during the first 3 months after the beginning of treatment and are not always accompanied by signs of an infection or other clinical symptoms. Formatiert: Tabstopps: 0 cm, Links 3 Haemorrhagic complications and surgeryWhen the neutrophil numbers have fallen below 1,500/mm , Formatiert: Vom nächsten Absatz trennen the values should be confirmed. If the presence of neutropenia (neutrophils <1,500/mm3) or 3 thrombocytopenia (platelets <100,000/mm ), are confirmed, the drug should be discontinued. Formatiert: Schriftart: Nicht Kursiv, Nicht unterstrichen

Patients with an increased risk of haemorrhage, e.g. after trauma, surgery or due to other pathological conditions should be closely monitoredBecause of the long plasma half-life of ticlopidine hydrochloride, it is recommended that any patient who discontinues ticlopidine for any reason within the first 90 days have an additional CBC with white cell differential count obtained two weeks after discontinuation of therapy. Formatiert

Ticlopidine should not be combined with heparin, oral anticoagulants or platelet aggregation inhibitors. However, in exceptional cases of concomitant treatment, close clinical and laboratory monitoring is required (see section 4.5)Usually blood counts will normalise with discontinuation of the treatment. Blood count parameters, including the differential leukocyte count and the platelet count, should be monitored until they return to normal values.

The prolonged bleeding time should be taken into account in cases of impending surgery, including small scale surgery, (e.g. tooth extractions).

In cases of planned surgical procedures (elective surgery), if the platelet-inhibiting effects of ticlopidine are not desired, then therapy should be discontinued 10 days prior to the surgery.

In the case of a non-planned surgery the use of corticosteroids with vasoconstrictive properties (methylprednisolone, use according to the instructions of the manufacturer) or DDAVP (desmopressin, use according to the instructions of the manufacturer) or of platelet concentrate (alone or in combination) as appropriate to the relevant tissue can be considered in order to compensate for a prolonged bleeding time and to keep the risk of haemorrhage as low as possible.

As ticlopidine is mainly metabolised in the liver, it should be used with special caution in patients with impaired liver function.

In cases of suspected impairment of hepatic function, hepatic parameters should be monitored, particularly during the first 4 months of treatment. If clinical signs of hepatitis or jaundice occur, therapy with ticlopidine should be discontinued and liver function tests carried out.

Clinical monitoring It is necessary for the patient to be informed about signs and symptoms that are possibly connected to neutropenia (fever, sore throat, ulcers in the oral cavity), thrombocytopenia, and/or haemostasis problems (prolonged or unexpected haemorrhage, ecchymosis, purpura, dark faeces) or a TTP (see below).

It is necessary to advise the patients to suspend medication and to immediately consult their physician in the event that one of the above signs or symptoms appears. The decision to resume the treatment can only be taken after taking into consideration clinical and laboratory records.

The patient should also be informed about symptoms of hepatitis (e.g. jaundice, pale stools, dark urine) and should be encouraged to report these symptoms to the doctor. Formatiert: Schriftfarbe: Schwarz Thrombotic-thrombocytopenic purpura (TTP, Moschcowitz-Syndrome) Formatiert: Leerraum zwischen asiatischem und westlichem Text nicht anpassen, Leerraum zwischen asiatischem Text und Clinical signs The clinical diagnosis of a rarely occurring and , potentially lethal TTP are fatal Zahlen nicht anpassen thrombotic thrombocytopenic purpura (TTP, Moschcowitz´s-Syndrome) is characterised by the Formatiert: Schriftfarbe: Schwarz presence of thrombocytopenia, signs of haemolysis, feverhaemolytic anaemia, neurological symptoms Formatiert: Schriftfarbe: Schwarz similar to those of a TIA or an apoplectic attacka stroke or symptoms of renal impairment. Theserenal Formatiert: Schriftfarbe: Schwarz dysfunction and fever. Formatiert: Schriftfarbe: Schwarz The onset may be sudden and symptoms may appear suddenly and in different levels of severity and Formatiert: Schriftfarbe: Schwarz combinations. TTP can occur peracutely, most cases being documented within the have been reported in the first 8 weeks after initiation ofof initiating therapy.

Due to the risk of fatal outcome, in casethe event of a suspected TTPthrombotic thrombocytopenic Formatiert: Leerraum zwischen asiatischem und westlichem purpura, a haematologist should be consultedspecialist team should be contacted or the patient should Text nicht anpassen, Leerraum zwischen asiatischem Text und be hospitalised in an appropriate clinic. Zahlen nicht anpassen Formatiert: Schriftfarbe: Schwarz TherapyTreatment with plasmapheresis can significantly has been reported to improve the prognosis. AsSince the applicationadministration of thrombocytes canplatelets may lead to an increased Formatiert: Schriftfarbe: Schwarz thrombosationthrombosis, it should therefore be avoided if possible. Formatiert: Schriftfarbe: Schwarz

Paediatric population

The use in children and adolescents is not recommended.

Education requirement

It is necessary for the patient to be informed about the signs and symptoms characteristic for neutropenia (fever, sore throat, mouth ulcers), thrombocytopenia and/or impaired haemostasis (prolonged or unusual haemorrhaging, haematoma, purpura, tarry stool) or signs of a TTP. It is necessary to advise the patient to suspend medication and to immediately consult his physician in the event that one of the above signs or symptoms appears. The blood counts should be checked

Ticlopidine hydrochloride; DE/H/0203/001; 01.02.1318.10.11-corr. Formatiert: Zeilenabstand: einfach new proposed SPC Formatiert: Schriftart: 18 Pt., Nicht unterstrichen, Englisch (Großbritannien) Page 5/16 immediately. The decision to resume the treatment with /…/ can only be taken after taking into consideration clinical and laboratory records.

Patients should be taught the symptoms of hepatitis (e.g. jaundice, light-coloured stools, dark urine) and instructed to report such symptoms to their physician.

 Haemostasis:

Ticlopidine must be used with caution in patients who are at increased risk of bleeding, e.g. after trauma, surgery or due to other pathological conditions. The patients should be closely monitored.

The medicinal product should not be given in combination with heparins, oral anticoagulants and antiplatelet medicinal products (see sections 4.4 and 4.5); however, in exceptional cases of concomitant treatment, close clinical and laboratory monitoring is required (see section 4.5).

In the event of even minor surgical procedures (e.g. dental extraction) prolonged bleeding time has to be expected. If the patient is to undergo elective surgery, treatment should wherever possible be stopped at least ten days before surgery (except in cases in which anti-thrombotic activity is explicitly required) in consideration of the haemorrhagic risk induced by the medicinal product.

In the event of emergency surgery, 3 means may be used alone or in combination to limit the risk of haemorrhage and prolonged bleeding time: administration of 0.5 to 1 mg/kg of methylprednisolone i.v., to be renewed; desmopressin at a dosage of 0.2 to 0.4 μg/kg; platelet transfusions.

 As ticlopidine is extensively metabolised by the liver:

The medicinal product should be used with caution in patients with impaired liver function. In case of suspected liver dysfunction, liver function tests should be carried out, especially during the first months of treatment, and treatment should be discontinued and liver function test should be performed if hepatitis or jaundice develops.

In controlled clinical trials no unexpected problems have been encountered in patients having mild renal impairment, and there is no experience with dosage adjustment in patients with greater degrees of renal impairment. Nevertheless, in renally impaired patients, it may be necessary to reduce the dosage of ticlopidine or discontinue it altogether if haemorrhagic or hematopoietic problems are encountered.

All patients should be carefully monitored for clinical signs and symptoms of adverse reactions especially during the first three months of therapy. Formatiert: Schriftfarbe: Schwarz 4.5 Interaction with other medicinal products and other forms of interaction Formatiert: Leerraum zwischen asiatischem und westlichem Text nicht anpassen, Leerraum zwischen asiatischem Text und Combinations with increased haemorrhagic risk Zahlen nicht anpassen Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, NSAIDs: Tabstopps: Nicht an 0,75 cm Increase of effects Formatiert: Schriftart: Nicht Kursiv, Nicht unterstrichen

Concomitant use of other medicinal products which haemorrhagic risk (increase the risk of Formatiert haemorrhage (e.g. oral anticoagulants or agents that influence platelet function such as heparin, Formatiert acetylsalicylic acid, other salicylates, non-steroidal anti-inflammatory agents) should be avoided. If it Formatiert: Leerraum zwischen asiatischem und westlichem is not possible to avoid the use of ticlopidine in combination with these agents, it is essential to closely Text nicht anpassen, Leerraum zwischen asiatischem Text und monitor clinical and laboratory parameters in order to check the haemostatic status of the patient (e.g. Zahlen nicht anpassen aPTT for heparin therapy or INN for anticoagulant therapy)antiaggregant activity and NSAIDs effect Formatiert on the gastro-duodenal mucous membrane). If such medicinal products are necessary, close clinical monitoring is required. Formatiert

Antiplatelet medicinal products: Increase of haemorrhagic risk (increase of platelet antiaggregant activity). If such medicinal products are necessary, close clinical monitoring is required.

Salicylic derivatives (by extrapolation from acetylsalicylic acid): Increase of haemorrhagic risk (increase of platelet antiaggregant activity and salicylic derivatives effect on the gastro-duodenal mucous membrane). If such medicinal products are necessary, close clinical monitoring is required. In case of STENT(s) implantation see section 4.4. Formatiert On changeover from use of preparations containing acetylsalicylic acid to /…/, it should be borne in Formatiert: Leerraum zwischen asiatischem und westlichem mind that the residual effects of acetylsalicylic acid may be potentiated by ticlopidine. Text nicht anpassen, Leerraum zwischen asiatischem Text und Zahlen nicht anpassen After chronic administration of cimetidine there is a significant elevation of plasma ticlopidine levels. Formatiert: Unterstrichen Formatiert: Leerraum zwischen asiatischem und westlichem If ticlopidine and theophylline are administered concomitantly a significant prolongation of Oral Text nicht anpassen, Leerraum zwischen asiatischem Text und anticoagulant: Zahlen nicht anpassen Increase of haemorrhagic risk (combination of anticoagulant activity and platelet antiaggregant activity). If such medicinal products are necessary, close clinical and biological monitoring (INR) is required.

Heparins: Increase of haemorrhagic risk (combination of anticoagulant activity and platelet antiaggregant activity). If such medicinal products are necessary, close clinical and biological monitoring (aPTT) is required.

Combinations requiring special precautions

Theophylline: Increase of plasma theophylline levels with risk of overdosage (the elimination half-life of Formatiert theophylline is prolonged from 8.6 to 12.2 hours and a corresponding reductiondecrease in the total Formatiert: Keine Absatzkontrolle, Leerraum zwischen plasma clearance of theophylline occur. In view of the risk of overdose, clinicalclearance occurs). asiatischem und westlichem Text nicht anpassen, Leerraum Clinical monitoring, and, if necessary, monitoring of plasma theophylline plasma levels are required. zwischen asiatischem Text und Zahlen nicht anpassen The dose of theophylline shouldTheophylline dosage must be adjusted during and also after treatment Formatiert with ticlopidine. Formatiert

Formatiert The plasma half-life of phenazone, which is metabolised by the microsomal hepatic enzyme system Formatiert (cytochrome P450 system), is prolonged by 25% in the presence of therapeutic doses Digoxin: Formatiert Co-administration of ticlopidine. An analogous effect can be expected for other substances with a Formatiert similar metabolic pathway (e.g. certain sedatives and hypnotics). Prolongation of plasma half-life may also occur in patients with hepatic damage. In these cases, particularly of substances with a small therapeutic index, the dosage should be adjusted on commencement and on completion of concomitant treatment with ticlopidine, in order to ensure that optimum therapeutic concentrations are maintained in blood.

Reduction in effects

Administration of ticlopidine after use of antacids results in a 20-30% decrease in plasma ticlopidine concentrations.

Concomitant use of ciclosporin leads to a decrease in plasma ciclosporin concentrations. Plasma levels of ciclosporin should be controlled and the dose should be adjusted if necessary.

Ticlopidine hydrochloride; DE/H/0203/001; 01.02.1318.10.11-corr. Formatiert: Zeilenabstand: einfach new proposed SPC Formatiert: Schriftart: 18 Pt., Nicht unterstrichen, Englisch (Großbritannien) Page 7/16 Concomitant use of digoxin leads to a slight decrease (aboutapproximately 15%) in plasma digoxin Formatiert concentrations.levels. This doesshould not appear to result in any substantial change inaffect the Formatiert therapeutic effectefficacy of digoxin. Formatiert Other forms ofPhenytoin: Formatiert: Unterstrichen In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of phenytoin. Formatiert: Leerraum zwischen asiatischem und westlichem Text nicht anpassen, Leerraum zwischen asiatischem Text und However, the protein binding interactions of ticlopidine and its metabolites have not been studied in Zahlen nicht anpassen vivo. There have been rare reports of increased phenytoin levels and phenytoin toxicity when ticlopidine is co-prescribed. Caution should be exercised in coadministering this medicinal product Formatiert: Vom nächsten Absatz trennen, Leerraum zwischen asiatischem und westlichem Text nicht anpassen, with ticlopidine and it may be useful to remeasure phenytoin blood concentrations. The dosage should Leerraum zwischen asiatischem Text und Zahlen nicht be adjusted if necessary. anpassen Formatiert: Schriftart: Nicht Kursiv, Nicht unterstrichen Other concomitant therapies Formatiert: Schriftart: Nicht Kursiv, Nicht unterstrichen

In a study on healthy volunteers chronic administration of phenobarbital showed no effect on the inhibition of platelet aggregation by ticlopidine.

Clinically relevant interactions with beta-receptor blockers, calcium antagonists and diuretics have so far not been observed.

Interactions with substances which also have a high degree of plasma protein binding, such as propranolol or phenytoin, have not been reported in in vitro investigations. However, as the possible effect of ticlopidine and its metabolites on the plasma protein binding of phenytoin has not yet been investigated in vivo, concomitant treatment with phenytoin and ticlopidine should only be carried out with caution. There have been rare reports of increased phenytoin levels and phenytoin toxicity when ticlopidine was co-prescribed. Plasma levels of phenytoin should be measuredIn clinical studies, ticlopidine was given concomitantly with beta-blockers, calcium channel blockers and diuretics: no clinically significant adverse interactions were reported.

In-vitro studies demonstrate that ticlopidine does not interact with plasma protein binding of propranolol.

The biological half-life of Antipyrine which is metabolized via the Cytochrome P 450 system is prolonged by 25% during coadministration with ticlopidine. This is also expected for substances with similar hepatic metabolism (e.g. certain sedatives and hypnotics). Prolongation of plasma half-life may also occur in patients with hepatic damage. Especially for substances with a narrow therapeutic index, dose adjustment is necessary at the beginning and after discontinuation of coadministration, in order to ensure that optimum therapeutic concentrations are maintained in blood.

The coadministration of ticlopidine and antacids leads to a 20-30% lower ticlopidine plasma level.

Chronic therapy with cimetidine increases the ticlopidine plasma level significantly.

In very rare instances, lowering of cyclosporine blood level has been reported. Therefore, cyclosporine Formatiert: Leerraum zwischen asiatischem und westlichem Text nicht anpassen, Leerraum zwischen asiatischem Text und blood level should be monitored in case of coadministration and the dosagedose should be adjusted if Zahlen nicht anpassen necessary. Formatiert 4.6 Fertility, pregnancy and lactation Formatiert Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Pregnancy Tabstopps: Nicht an 0,75 cm Formatiert There are no adequate data from the useThe safety of ticlopidine in pregnant women has not been Formatiert: Tabstopps: 1,5 cm, Links + 1,75 cm, Links established. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). Formatiert ThereforeUnless absolutely necessary, ticlopidine should not be used during pregnancy unless clearly Formatiert necessary. Formatiert

Lactation

Breastfeeding

Studies in rats have shown that ticlopidine is excreted in the milk. As it is not known whether this substance is excreted in human milk

The safety of ticlopidine in nursing women has not been established. Unless absolutely necessary, Formatiert ticlopidine should not be used during lactation. breast feeding. If treatment becomes necessary during lactation, breast-feeding should be interrupted.

Fertility

Ticlopidine was found to have no effect on fertility in rat studies (see section 5.3).

4.7 Effects on ability to drive and use machines Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Even when used as recommended, this medicinal product can influence reactions to such an extent that the ability to take an active part in road traffic or to operate machines may be impaired. The side- effects of ticlopidine, such as dizziness, may adversely affect the ability to drive or use machines. This is particularly the case after concomitant ingestion of alcohol.

4.8 Undesirable effects Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm The adverse events are reported below according to the Tabulated list of adverse reactions The following CIOMS frequency convention:

Veryrating is used, when applicable: very common≥ ( 1/10 Common ≥), common ( 1/100 to < 1/10 Uncommon ≥), uncommon ( 1/1,000 to < 1/100 Rare ≥), rare ( 1/10,000 to < 1/1,000 Very), very rare < ( 1/10,000 Not ), not known Frequency (cannot be estimated from the available data). Formatiert: PSUR Paragraph 1, Einzug: Links: 0 cm, Erste Zeile: 0 cm Blood and lymphatic system disorders Formatiert: Schriftart: 12 Pt.

Common: Alterations in blood count, such as neutropenia, including severe neutropenia, or agranulocytosis, typically accompanied by a reduction of myeloid precursor cells in the bone marrow. Uncommon: Thrombocytopenia (<80,000/mm3), isolated or in combination with haemolytic anaemia. Rare: Bone marrow aplasia, pancytopenia, potentially fatal thrombotic-thrombocytopenic purpura (TTP, Moschcowitz’s syndrome). Clinical signs of TTP are thrombocytopenia, signs of haemolysis, fever, neurological symptoms similar to those of a TIA or apoplectic attack, or symptoms of renal impairment.

Life-threatening undesirable haematological and haemorrhagic effects have been reported.

For necessary blood count controls and further instructions, see section 4.4.

Very rare: Immulological reactions with different manifestations, such as allergic skin reactions, Quincke's oedema, vasculitis, anaphylaxis, arthralgia, allergic pneumopathy, lupus erythematosus, nephritis, eosinophilia

Metabolism and nutrition disorders

Uncommon: Anorexia

Psychiatric disorders

Rare: Insomnia, nervousness, depressed mood

Nervous system disorders

Uncommon: Dizziness, headache Rare: Light-headedness, dysaesthesia, changes in the sense of taste

Ear and labyrinth disorders

Rare: Tinnitus

Cardiac disorders

Rare: Palpitations

Vascular disorders

Not known: Haemorrhagic adverse reactions such as haematoma, ecchymosis, epistaxis, haematuria, gastrointestinal haemorrhage. Peri- and postoperative and intracranial haemorrhages have been observed.

Gastrointestinal disorders

Common: Gastrointestinal disturbances (e.g. diarrhoea, nausea, vomiting etc). These adverse reactions which predominantly occur during the first 3 months and are mostly moderate, usually wear off spontaneously during the course of therapy, frequently within 1-2 weeks. Very rare: Severe diarrhoea with colitis (including lymphocytic colitis). If these symptoms are severe therapy should be discontinued. Rehydration may be necessary in patients with severe diarrhoea.

Hepatobiliary disorders

Rare: Disorders of hepatic function such as hepatitis (cytolytic and/or cholestatic) and cholestatic jaundice in the first months of treatment. Cholestatic symptoms predominate, with often marked increases in alkaline phosphatase and conjugated bilirubin, and generally moderate increases in transaminases. The highest levels were detected in the first 4 months of treatment. Very rare: Cases of fatal hepatic function disorders have been reported. Not known: Cases of fulminant hepatitis have been reported.

Very rare: Marked and sometimes generalised skin rashes, erythema multiforme, Stevens- Johnson syndrome and Lyell syndrome have been reported. Not known: Allergic skin reactions (e.g. exanthema, pruritus, urticaria), which usually occur within the first 3 months of treatment with a mean time to onset of 11 days. If treatment is discontinued, remission of symptoms is observed within a few days.

General disorders and administration site conditions

Uncommon: Asthenia, pain in diverse locations Rare: Sweating, malaise Very rare: Isolated fever

Investigations

System Organ Common Uncommon Rare Very rare Not known Class Blood and Neutropenia Isolated Pancytopenia, bone lymphatic system including severe thrombocytopenia marrow aplasia, disorders1 neutropenia (see (<80,000/mm3) or thrombotic section 4.4), exceptionally thrombocytopenic agranulocytosis, accompanied by purpura (TTP, typically haemolytic Moschcowitz’s accompanied by anaemia. syndrome), a reduction of Sepsis and septic leukaemia, myeloid shock may be thrombocytosis precursor cells in fatal (see section 4.4). the bone complications of marrow. agranulocytosis. Immune system Immunological disorders reactions with different manifestations such as allergic reactions, eosinophilia, anaphylaxis, Quincke oedema, arthralgia, vasculitis, lupus syndrome, allergic pneumopathy, hypersensitivity nephropathy sometimes resulting in renal failure Metabolism and Anorexia nutrition disorders Psychiatric Insomnia, disorders nervousness, depressed mood Nervous system Headache, Sensory Tinnitus, changes

Ticlopidine hydrochloride; DE/H/0203/001; 01.02.1318.10.11-corr. Formatiert: Zeilenabstand: einfach new proposed SPC Formatiert: Schriftart: 18 Pt., Nicht unterstrichen, Englisch (Großbritannien) Page 11/16 System Organ Common Uncommon Rare Very rare Not known Class disorders dizziness disturbances in the sense of taste (peripheral neuropathy)

Cardiac Palpitations disorders

Vascular Haemorrhagic Intracerebral Gastrointesti disorders adverse reactions bleeding nal such as haemorrhage haematoma, bruising, ecchymosis, epistaxis, haematuria, conjunctival haemorrhage, peri-and postoperative bleedings, haemorrhage that may be severe and sometimes fatal consequences have been observed Gastrointestinal Gastrointestinal Gastroduodenal Severe diarrhoea disorders disturbances ulcer with colitis (e.g. diarrhoea, (including nausea, vomiting lymphocytic etc). colitis) If these These adverse symptoms are reactions which severe therapy predominantly should be occur during the discontinued. first 3 months Rehydration may and are mostly be necessary in moderate, patients with usually wear off severe diarrhoea spontaneously during the course of therapy, frequently within 1-2 weeks Hepatobiliary Increase in Elevation of Disorders of Cases of fatal disorders hepatic enzymes, bilirubin hepatic function hepatic function increase of such as hepatitis disorders and alkaline (cytolytic and /or hepatitis phosphatases cholestatic) and reported with and cholestatic jaundice fatal outcome, transaminases. in the first months fulminant (see section 4.4). of treatment. hepatitis Skin and Skin rashes, Exfoliative Erythema subcutaneous particularly dermatitis multiforme, tissue disorders maculopapular Stevens-Johnson or urticarial, syndrome, Lyell often syndrome

Ticlopidine hydrochloride; DE/H/0203/001; 01.02.1318.10.11-corr. Formatiert: Zeilenabstand: einfach new proposed SPC Formatiert: Schriftart: 18 Pt., Nicht unterstrichen, Englisch (Großbritannien) Page 12/16 System Organ Common Uncommon Rare Very rare Not known Class accompanied by pruritus, these skin rashes may be generalized, usually occur within the first 3 months of treatment with a mean time to onset of 11 days. If treatment is discontinued, remission of symptoms is observed within a few days. General Asthenia, pain in Sweating, malaise Fever disorders and diverse locations administration site conditions

Investigations Increased serum cholesterol and triglyceride levels2

1 Blood cell counts (BCCs) were closely monitored in two large clinical studies conducted in 2,048 TIA/stroke patients treated with ticlopidine (multicentre controlled clinical trials CATS and TASS) (see section 4.4). 2 Long-term treatment with ticlopidine leads to an elevation of serum concentrations of high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), cholesterol and triglycerides. Serum levels may be increased by 8-10% over baseline 1 to 4 months after initiation of therapy. A subsequent increase has not been registered during continuation of therapy. The relation of the lipoprotein subfractions (in particular HDL to LDL ratio) remains unchanged. Clinical trials have demonstrated that this effect is not correlated with age, sex, consumption of alcohol or diabetes. There is also no related cardiovascular risk. See also section 4.4. Formatiert Formatiert: Leerraum zwischen asiatischem und westlichem 4.9 Overdose Text nicht anpassen, Leerraum zwischen asiatischem Text und Zahlen nicht anpassen In case of overdose, account must be taken of the increased risk of bleeding associated with the Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, pharmacological properties of ticlopidine. Tabstopps: Nicht an 0,75 cm

CloseBased on its pharmacodynamic properties, a risk of bleeding can be expected. Following overdosage, close monitoring of the patient as well as induced emesis, gastric lavage and other general supportive measures are recommended.

Ticlopidine is not dialysable.

In order to compensate a If prompt correction of prolonged haemorrhagingbleeding time is required, Formatiert platelet transfusion, the application of corticosteroids with vasoconstrictive properties Formatiert (methylprednisolone, use according to the instructions of the manufacturer) or DDAVP (desmopressin, use according to the instructions of the manufacturer) or of platelet concentrate (alone or in combination) as appropriate to the relevant tissue can be consideredmay reverse the effects of ticlopidine (see section 4.4). Formatiert

It is not possible to dialyse ticlopidine.

Severe gastrointestinal disorders have been occasionally observed in animal studies after overdose.

5. PHARMACOLOGICAL PROPERTIESPHARMACOLOGICAL PROPERTIES Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm 5.1 Pharmacodynamic properties Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Pharmacotherapeutic group: Platelet aggregation inhibitor excl. heparin , ATC-code: B01A C05 Formatiert: Tabstopps: Nicht an 1,5 cm + 1,75 cm

Ticlopidine is an ADP-antagonising platelet aggregation inhibitor with a characteristic pharmacological profile. After oral administration the substance causes dose- and time-dependent inhibition of platelet aggregation and release of platelet factors and prolongs bleeding time. The substance does not exhibit significant in vitro activity. However, no active metabolite has been identified to date in man.

Ticlopidine modifies platelet membrane function by suppressing ADP-induced platelet fibrinogen binding and platelet-platelet interactions. The exact mechanism of action is not fully understood. In contrast with acetylsalicylic acid, however, ticlopidine does not influence prostacyclin–thromboxane antagonism. It would also seem that the mechanism of action of ticlopidine is not dependent on the concentrations of cyclic adenosine monophosphate (cAMP) in platelets.

At therapeutic doses platelet aggregation, induced by ADP at a concentration of 2.5 µmol/l, is inhibited by 50-70%. There is a correspondingly reduced inhibitory effect at lower doses.

An inhibition of platelet aggregation can be detected within two days of the administration of 250 mg ticlopidine hydrochloride b.i.d.. The maximum effect occurs after 5-8 days administration of 250 mg twice daily.

The effects of ticlopidine on platelet function are irreversible. Fibrinogen binding continues to be suppressed even after washing of the platelets, as is platelet aggregation after resuspension of the platelets in a buffered medium.

Bleeding time at a cut-off pressure of 40 mmHg was doubled in comparison with baseline, when measured using the simplate/template method. The prolongation of bleeding time without application of a tourniquet is far less marked.

After discontinuation of therapy with ticlopidine, bleeding time and other platelet function tests normalise within one week in the majority of patients. At recommended therapeutic doses ticlopidine has no other significant pharmacological effects apart from the inhibition of platelet function.

5.2 Pharmacokinetic properties Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm After oral administration of a single therapeutic dose of ticlopidine hydrochloride it is rapidly and almost completely absorbed. Peak plasma concentrations occur approximately 2 hours after administration. Bioavailability is improved if ticlopidine is administered after meals. As currently no injectable form of ticlopidine is available, the absolute bioavailability is not measurable.

Steady-state plasma concentrations are achieved 7-10 days after administration of 250 mg ticlopidine hydrochloride twice daily. The mean terminal elimination half-life at steady-state is approximately 30- 50 hours. However, the plasma concentrations of the substance do not correlate with its inhibitory effects on platelet aggregation.

Ticlopidine is reversibly bound (to 98%) to plasma proteins, mainly to serum albumin and lipoproteins. There is no saturation of the capacity for binding to these two proteins over a wide concentration range. In contrast, binding to acid alpha1-glycoprotein shows saturation. Some of the metabolites exhibit covalent binding to plasma proteins.

Ticlopidine is mainly metabolised in the liver. No unchanged ticlopidine is recovered in urine. After oral administration of radioactively labelled ticlopidine, 50-60% of the radioactivity was recovered in urine and 23-30% in the faeces. An enterohepatic circulation exists.

Patients with impaired hepatic function have higher plasma concentrations of unchanged ticlopidine than healthy volunteers after single and repeated administration.

5.3 Preclinical safety data Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Acute toxicity

Acute toxicity studies of ticlopidine hydrochloride after oral administration in the mouse and rat reported LD50 values of 600-850 mg/kg and 1,500-1,938 mg/kg body weight, respectively. In baboons, the oral LD50 was reported to be above 5 g/kg body weight. Due to the significant emetic effect, an exact value could not be determined for this species. With increasing effective doses, the symptoms leading to death presented as nervous disorders.

Chronic toxicity

In studies of chronic toxicity in rats and baboons it was found that the liver was the organ which was mainly affected. The results of animal trials (in rats and baboons: increased weight of the liver, elevation of cytochrome P450 with slight inhibition of its activity, in rats in addition: hypercholesterolaemia, hypertrophy of the hepatocytes, proliferation of the endoplasmic reticulum) cannot, however, be directly applied to man.

The results of the investigation of specific haematotoxicity were similar. No suitable animal model has been found which adequately explains the blood count alterations observed in man.

Reproduction toxicity

Investigation of reproductive toxicity in the rat, mouse and the rabbit have produced no evidence of a teratogenic potential of ticlopidine.

At the maximum doses administered in the mouse (200 mg ticlopidine hydrochloride/kg bodyweight/day) and at maternotoxic doses in the rat (400 mg/kg bodyweight/day) there were signs of fetotoxic effects in both species (increased rate of fetal reabsorption, reduced fetal growth, impaired ossification). In the rabbit, there were no effects on fetuses even at maternotoxic doses of 200 mg ticlopidine hydrochloride/kg bodyweight/day.

No impairment of fertility was observed.

Mutagenic or carcinogenic potential

There is no evidence that ticlopidine has a mutagenic or carcinogenic potential.

6. PHARMACEUTICAL PARTICULARSPHARMACEUTICAL PARTICULARS Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm 6.1 List of excipients Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm

Macrogol 6000, titanium dioxide (E 171), hypromellose, povidone K25, microcrystalline cellulose, maize starch, magnesium stearate, colloidal silicon dioxide.

6.2 Incompatibilities Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Not applicable.

6.3 Shelf life Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm 3 years

6.4 Special precautions for storage Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Do not store above 30 °C.

6.5 Nature and contents of container Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm Blister pack made of aluminium foil/PVC film

Pack sizes: 10, 20, 30, 60, 90 film-coated tablets

6.6 Special precautions for disposal Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm No special requirements.

7. MARKETING AUTHORISATION HOLDERMARKETING AUTHORISATION Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, HOLDER Tabstopps: Nicht an 0,75 cm

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8. MARKETING AUTHORISATION NUMBER(SMARKETING AUTHORISATION Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, NUMBER(S) Tabstopps: Nicht an 0,75 cm Formatiert: Nicht Großbuchstaben <[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm

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10. DATE OF REVISION OF THE TEXTDATE OF REVISION OF THE TEXT Formatiert: Einzug: Links: 0 cm, Hängend: 1 cm, Tabstopps: Nicht an 0,75 cm {MM/YYYY} {DD/MM/YYYY} {DD month YYYY}

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