Ticlopidine hydrochloride, DE/H/0203/001, 11.04.16

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

/…/

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 250 mg ticlopidine hydrochloride.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

White to off-white, slightly convex.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

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

Posology

Adults 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.

Duration of treatment is determined by the clinical picture. Long-term treatment is generally indicated.

Special populations

Use in patients with impaired liver function In case of impaired liver function, ticlopidine should be used with special caution.

Paediatric population The use in children and adolescents is not recommended due to lack of experience in clinical trials.

1 Ticlopidine hydrochloride, DE/H/0203/001, 11.04.16

Method of administration

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).

4.3 Contraindications

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1  Haemorrhagic diathesis  Organic lesions which are liable to bleed i.e. active gastroduodenal ulcer or haemorrhagic cerebrovascular accident in the acute phase  Blood disease involving prolonged bleeding time  History of blood count abnormalities, such as leucopenia, thrombocytopenia or agranulocytosis

4.4 Special warnings and precautions for use

It is essential to comply strictly with the indications, contraindications and warnings and precautions for use.

Haematological and haemorrhagic adverse effects can occur. Agranulocytosis, pancytopenia and rare cases of leukaemia have been reported in postmarketing experience.

Serious, sometimes fatal haematological and haemorrhagic adverse effects (see section 4.8) may occur, especially associated with:  Inadequate monitoring, late diagnosis and inappropriate therapeutic measures for adverse effects  Concomitant administration of anticoagulants or antiplatelet agents such as aspirin and nonsteroidal anti-inflammatory medicinal products (NSAIDs) (see section 4.5). However, in case of STENT implantation, ticlopidine should be combined with aspirin (100 to 325 mg per day) for about one month following implantation.

Haematological monitoring Blood cell counts (BCCs) with differential and platelet counts 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, and within 15 days after discontinuation of ticlopidine, should the treatment be stopped within the first three months of therapy.

Blood 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.

When the neutrophil numbers have fallen below 1,500/mm3, the values should be confirmed. If the presence of neutropenia (neutrophils <1,500/mm3) or thrombocytopenia (platelets <100,000/mm3), are confirmed, the drug should be discontinued.

Because 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.

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.

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

2 Ticlopidine hydrochloride, DE/H/0203/001, 11.04.16 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.

Thrombotic-thrombocytopenic purpura (TTP, Moschcowitz-Syndrome) The clinical diagnosis of a rare, potentially fatal thrombotic thrombocytopenic purpura (TTP, Moschcowitz´s-Syndrome) is characterised by the presence of thrombocytopenia, haemolytic anaemia, neurological symptoms similar to those of a TIA or a stroke or renal dysfunction and fever.

The onset may be sudden and symptoms may appear in different levels of severity and combinations. TTP can occur peracutely, most cases have been reported in the first 8 weeks of initiating therapy.

Due to the risk of fatal outcome, in the event of suspected thrombotic thrombocytopenic purpura, a specialist team should be contacted or the patient should be hospitalised in an appropriate clinic.

Treatment with plasmapheresis has been reported to improve the prognosis. Since the administration of platelets may lead to increased thrombosis, it should be avoided if possible.

 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.

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4.5 Interaction with other medicinal products and other forms of interaction

Combinations with increased haemorrhagic risk

Selective Serotonin Reuptake Inhibitors SSRIs: Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with ticlopidine should be undertaken with caution.

Pentoxifylline: Because of the increased risk of bleeding, the concomitant administration of pentoxifylline with ticlopidine should be undertaken with caution.

NSAIDs: Increase of haemorrhagic risk (increase of platelet antiaggregant activity and NSAIDs effect on the gastro-duodenal mucous membrane). If such medicinal products are necessary, close clinical monitoring is required.

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.

On changeover from use of preparations containing acetylsalicylic acid to /…/, it should be borne in mind that the residual effects of acetylsalicylic acid may be potentiated by ticlopidine.

Oral anticoagulant: 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 theophylline is prolonged from 8.6 to 12.2 hours and a corresponding decrease in total plasma theophylline clearance occurs). Clinical monitoring, and if necessary, plasma theophylline levels are required. Theophylline dosage must be adjusted during and after treatment with ticlopidine.

Digoxin: Co-administration of ticlopidine and digoxin leads to a slight decrease (approximately 15%) in plasma digoxin levels. This should not affect the therapeutic efficacy of digoxin.

Phenytoin: In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of phenytoin. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in 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

4 Ticlopidine hydrochloride, DE/H/0203/001, 11.04.16 with ticlopidine and it may be useful to remeasure phenytoin blood concentrations. The dosage should be adjusted if necessary.

Other concomitant therapies

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

In 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 blood level should be monitored in case of coadministration and the dose should be adjusted if necessary.

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of ticlopidine in pregnant women has not been established. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). Unless absolutely necessary, ticlopidine should not be used during pregnancy.

Breastfeeding

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

The safety of ticlopidine in nursing women has not been established. Unless absolutely necessary, ticlopidine should not be used during 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

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

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Tabulated list of adverse reactions The following CIOMS frequency rating is used, when applicable: very common ( 1/10), common ( 1/100 to  1/10), uncommon ( 1/1,000 to  1/100), rare ( 1/10,000 to  1/1,000), very rare ( 1/10,000), not known (cannot be estimated from the available data).

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 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

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System Organ Common Uncommon Rare Very rare Not known Class 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 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

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System Organ Common Uncommon Rare Very rare Not known Class 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.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued 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 listed in Appendix V.

4.9 Overdose

Based 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.

If prompt correction of prolonged bleeding time is required, platelet transfusion, the application 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) may reverse the effects of ticlopidine (see section 4.4).

It is not possible to dialyse ticlopidine.

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Platelet aggregation inhibitor excl. heparin, ATC-code: B01A C05

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

8 Ticlopidine hydrochloride, DE/H/0203/001, 11.04.16 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

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

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.

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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 PARTICULARS

6.1 List of excipients

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

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30 °C.

6.5 Nature and contents of container

Blister pack made of aluminium foil/PVC film

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

6.6 Special precautions for disposal

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No special requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY} Date of latest renewal: {DD month YYYY}

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

{MM/YYYY} {DD/MM/YYYY} {DD month YYYY}

[To be completed nationally]

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