SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Tiaprid PMCS 100 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 111.1 mg of tiapride hydrochloride, corresponding to 100 mg of tiapride Excipient with known effect: Each tablet contains 4 mg sodium starch glycolate (type A), corresponding to 0.1848 mg of sodium. For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet Almost white, round tablets, with a dividing cross on one side and a diameter of 9.5 mm. The tablet can be divided into four equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Behaviour disorders in patients with dementia Behaviour disorders during alcohol withdrawal: - acute delirious syndrome - withdrawal syndrome Serious chorea by Huntington´s disease

4.2 Posology and method of administration

Posology

Behaviour disorders in patients with dementia: 200 – 400 mg/day. Treatment should commence with a dose of 50 mg (i.e. ½ tablet) twice daily, gradually increasing over 2-3 days to 100 mg (i.e. 1 tablet) 3 times daily. The average dose is 300 mg/day (i.e. 3 tablets daily), the maximum recommended dose is 400 mg/day (i.e. 4 tablets daily).

Behaviour disorders during alcohol withdrawal: 300 – 400 mg/day (i.e. 3-4 tablets daily) for a period of 1 – 2 months.

Huntington´s chorea: 300 – 1200 mg/day. Starting dose: to 1200 mg/day (i.e. 12 tablets), divided in at least three doses by a gradual reduction to a maintenance dose according to individual response.

Children from the age of 6: the normal dose is 100 – 150 mg/day to a maximum 300 mg/day.

Renal insufficiency: in patients with a creatinine clearance between 30–60 ml/min the dose should be reduced to 75% of the normal dose, in patients with a creatinine clearance between 10–30 ml/min to 50% of the normal dose and in patients with a creatinine clearance of less than 10 ml/min to 25% of the normal dose.

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Liver insufficiency: the product is poorly metabolised and therefore the dose does not need to be reduced.

Method of administration The tablets for oral use.

4.3 Contraindications

- hypersensitivity to the active substance or to any of the excipients listed in section 6.1 - current prolactin-dependent cancer (e.g. pituitary prolactinoma or breast cancer) - pheochromocytoma - in combination with levodopa or other dopaminergic medicines (see section 4.5)

4.4 Special warnings and precautions for use

- Prolongation of QT interval Tiapride may cause prolongation of QT interval. This effect increases the risk of serious ventricular arrhythmias such as torsades de pointes (see section 4.8). Before administration and if the patient’s conditions permits, it is recommended to monitor factors which could help bring on the incidence of these arrhythmias, such as: - bradycardia below 55 beats per minute - electrolyte imbalance, above all hypokalaemia - congenital QT interval prolongation, positive family history of QT interval prolongation - concomitant treatment with drugs that may cause the referred bradycardia (< 55 beats per min.), electrolyte imbalance, altered intracardiac conduction or QT interval prolongation (see section 4.5). The prescription of tiapride needs to be considered in patients with risk factors, which could predispose to QT interval prolongation.

- Stroke In randomised clinical trial performed with a placebo in elderly patients with dementia and treated with certain atypical antipsychotics a threefold increase was observed in the risk of strokes. The mechanism of this increased risk is unknown. An increased risk of strokes associated with other antipsychotics or a different population of patients cannot be excluded. The use of tiapride should be with caution in patients with a risk of a stroke.

- Elderly patients with dementia Elderly patients with dementia-related psychoses treated with antipsychotics are at an increased risk of death. Analyzes of 17 placebo-controlled studies (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed a 1.6 to 1.7 times higher risk of death in patients treated with the medicinal product than in placebo-treated patients. Over the course of a typical 10 week controlled study, the rate of death in patients treated with antipsychotics was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Observational studies suggest that like atypical antipsychotics, treatment with conventional antipsychotics may increase mortality. The extent to which the finding of increased mortality in observational studies can be attributed to antipsychotics, and not to patient characteristics, is not clear.

- Risk of venous thromboembolism Cases of venous thromboembolism (VTE) have been associated with the use of antipsychotics. In view of the fact that in patients treated with antipsychotics there is often the presence of acquired risk factors for VTE, these risk factors should be recognised before and during treatment with Tiaprid PMCS 100 mg and preventive measures should be subsequently implemented. Caution is required for use of Tiaprid PMCS 100 mg by patients with thromboembolism risk factors (see section 4.8).

2/9 - Breast cancer Tiapride may increase prolactin levels. Caution is thus necessary and patients with a history or family history of breast cancer must be thoroughly monitored during treatment with tiapride.

- Likewise, just as in other neuroleptics, neuroleptic malignant syndrome (with possible fatal outcome) may occur which is characterised by hyperthermia, muscle rigidity and autonomic dysfunction (see section 4.8). Cases with atypical symptoms such as missing muscle rigidity or hypertonia and lower fever were observed. Treatment using tiapride should be stopped in case of hyperthermia of an unknown origin.

- As with other neuroleptic agents, tiapride should be administered with great caution to geriatric patients due to the potential risk of lowering the level of consciousness and coma.

- In patients with Parkinson’s disease tiapride should only be used in exceptional cases.

- Neuroleptic agents may reduce the threshold for epileptic seizures (see section 4.8). Therefore, patients with a history of epilepsy should be closely monitored during treatment with tiapride.

- In case of renal insufficiency, the dose should be reduced given the possible risk of coma due to overdose (see sections 4.2 and 4.9).

- Use of tiapride in children has not been monitored thoroughly. Care must be taken when prescribing the medicinal product to children (see section 4.2).

- Leukopenia, neutropenia and agranulocytosis have been reported in connection with antipsychotics, including tiapride. Unexplained infections or fever may be a symptom of blood dyscrasia (see section 4.8) and require immediate haematological examinations.

Tiaprid PMCS 100 mg contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations which are contraindicated Dopaminergic agonists, excluding patients with Parkinson´s disease (cabergoline, quinagolide), due to reciprocal antagonism between dopaminergic agonists and neuroleptics.

Combinations which are not recommended Alcohol: Alcohol may enhance the sedative effect of neuroleptics. The alteration of the vigilance can make dangerous the driving of vehicles and the use of machines. Avoid drinking alcohol and taking medicines containing alcohol.

Medications which can induce torsades de pointes or QT interval prolongation: Class Ia antiarrhythmic agents (quinidine, hydroquinidine, disopyramide) and class III antiarrhythmic agents (amiodarone, sotalol, dofetilide, ibutilide), certain neuroleptics (sultopride, pipothiazine, sertindole, veralipride, chlorpromazine, levomepromazine, trifluoperazine, thioridazine, cyamemazine, sulpiride, pimozide, haloperidol, droperidol, fluphenazine, pipamperone, flupentixol, zuclopentixol), some antiparasitic drugs (halofantrine, lumefantrine, pentamidine), other medications: i.v. erythromycin, i.v. spiramycin, moxifloxacin, sparfloxacine, imipramine antidepressants, lithium, bepridil, cisapride, diphemanil, mizolastine, i.v. vincamine. Increased risk of ventricular arrhytmias, especially torsades de pointes. If possible, discontinue the medication that can induce torsades de pointes, except for antiinfective agents. If combination therapy cannot be avoided, check the QT interval before starting treatment and monitor ECG.

Levodopa:

3/9 Reciprocal antagonism of the effects of levodopa and neuroleptics. Use minimal effective doses of each of both drugs in patients with Parkinson’s disease.

Dopaminergic agonists except levodopa (amantadine, apomorphine, bromocriptine, entecapone, lisuride, pergolide, piribedil, pramipexole, ropinirole, selegiline) in patients with Parkinson´s disease: Reciprocal antagonism of the effects of the dopaminergic agonist and neuroleptics. The dopaminergic agonist can induce or accentuate psychotic disorders. When neuroleptic therapy cannot be avoided in patients with Parkinson´s disease treated with dopaminergic agonists, these agents must be tapered off and discontinued (sudden withdrawal of dopaminergic agonists can induce neuroleptic malignant syndrome).

Methadone: Enhanced risk of ventricular arrhythmia, in particular torsades de pointes.

Combinations which require precautions for use Bradycardia-inducing agents (in particular class Ia antiarrhythmic agents, beta-blockers, some class II antiarrhythmic agents, some calcium antagonists, e.g. diltiazem and verapamil, clonidine, guanfacine; cardiac glycosides, pilocarpine, cholinesterase-inhibitors): Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and electrocardiographic monitoring.

Beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol): Enhanced risk of ventricular arrhythmia, in particular torsades de pointes. Clinical monitoring and ECG monitoring are necessary.

Medications which can induce electrolyte imbalance in particular potassium-lowering agents (potassium-lowering diuretics, stimulant laxatives, i.v. amphotericin B, glucocorticoids, tetracosactides, cosyntropin): Increased risk of ventricular arrhythmias, especially torsades de pointes. Correct any hypokalaemia before starting treatment with tiapride and ensure clinical, electrolyte and electrocardiographic monitoring.

Other combinations which have to be taken into account Antihypertensives (all): Antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

Other central nervous system depressants: Narcotics (analgesics, antitussives and opioid replacement therapy), sedative H1 antihistamines, barbiturates, benzodiazepines, other non-benzodiazepine anxiolytics, hypnotics, neuroleptics, sedative antidepressants (amitriptyline, doxepine, mianserin, mirtazapine, trimipramine), centrally acting antihypertensives; other drugs: baclofen, thalidomide, pizotifene, clonidine and derived substances. Increase of central depression. Impaired alertness may make the driving of vehicles and the use of machines dangerous.

Beta-blockers (except esmolol, sotalol and beta-blockers used in heart failure): Vasodilatation effect and risk of hypotension, in particular postural hypotension (additive effect).

Nitrate derivatives and related compounds: Risk of hypotension, especially postural hypotension.

4.6 Fertility, pregnancy and lactation

Pregnancy There are no or limited data on the use of tiapride in pregnant women. Tiapride passes the placenta. Animal studies have shown reproductive toxicity (see section 5.3).

4/9 The use of tiapride is not recommended during pregnancy and in women of childbearing potential not using effective contraception. If treatment is necessary to maintain proper mental balance and prevent deterioration, effective dosing must be started or continued during pregnancy. Injectable neuroleptics administered in emergency situations may cause maternal hypotension.

Neonates exposed to antipsychotics (including Tiaprid PMCS 100 mg) during the third trimester of pregnancy are at risk of adverse events including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery (see section 4.8). There have been reports of agitation, hypertonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Breastfeeding Animal studies have shown the excretion of tiapride into breast milk. It is not known whether tiapride is excreted into human breast milk. A risk to the breast-fed infant cannot be excluded. It should be decided whether either breastfeeding, or the treatment with tiapride should be discontinued, taking into account the benefit of breast-feeding to the child and the benefit of the treatment to the woman.

Fertility In animals, a decrease in fertility related to the pharmacological effect of the product (via prolactin) has been observed (see section 5.3). Similarly, tiapride may reduce fertility in humans (see section 4.8). Administration of tiapride can cause hyperprolactinaemia associated with amenorrhoea, anovulation and impaired fertility in humans due to interaction with dopaminergic receptors (see section 4.8).

4.7 Effects on ability to drive and use machines

Tiapride may worsen the ability to drive and use machines because it may cause sedation, even when used correctly (see section 4.8).

4.8 Undesirable effects

Undesirable effects are listed according to the frequency of incidence as follows: 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).

Blood and lymphatic system disorders Rare: leukopenia, neutropenia, agranulocytosis (see section 4.4).

Endocrine disorders Common: hyperprolactinaemia, which may lead to amenorrhoea, abnormal orgasm, breast enlargement and pain, galactorrhoea, gynecomastia, erectile dysfunction and is reversible upon discontinuation of treatment.

Metabolism and nutrition disorders Rare: Hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Psychiatric disorders Common: Somnolence/drowsiness/sleepiness, insomnia, agitation, lethargy. Uncommon: Confusion, hallucinations.

Nervous system disorders Common: Dizziness/vertigo, headache. Parkinsonism and related symptoms: tremor, hypertonia, hypokinesia and hypersalivation. These symptoms are usually reversible after the administration of antiparkinsonics.

5/9 Uncommon: Restlessness, dystonia (spasms, torticollis, oculogyric crisis, trismus). These symptoms are usually reversible after the administration of antiparkinsonics. Cramp, syncope. Rare: Acute dyskinesia. This symptom is usually reversible after the administration of antiparkinsonics. As with all neuroleptic agents, tardive dyskinesia (characterised by rhythmic, unintended movements, especially of the tongue and/or face) has been reported after more than three months of use of the neuroleptic. Antiparkinson agents are ineffective or may cause the symptoms to worsen. As with other neuroleptic agents, neuroleptic malignant syndrome has been reported, which may be a complication with fatal consequences. Loss of consciousness.

Cardiac disorders Rare: QT prolongation, ventricular arrhythmia such as torsades de pointes, ventricular tachycardia, which may lead to ventricular fibrillation or heart failure and sudden death.

Vascular disorders Uncommon: Hypotension, usually ortthostatic, deep vein thrombosis. Rare: Pulmonary embolism, sometimes fatal

Respiratory, thoracic and mediastinal disorders Rare: Aspiration pneumonia, respiratory depression associated with the use of other CNS depressants.

Gastrointestinal disorders Uncommon: Constipation. Rare: Intestinal obstruction, ileus.

Hepatobiliary disorders Rare: Elevated liver enzymes.

Skin and subcutaneous tissue disorders Uncommon: Rash including erythematous rash, maculopapular rash. Rare: Urticaria.

Musculoskeletal and connective tissue disorders Rare: Elevated blood creatine phosphokinase, rhabdomyolysis.

Pregnancy, puerperium and perinatal conditions Unknown frequency: Perinatal syndrome from withdrawal (see section 4.6).

Reproductive system and breast disorders Uncommon: Amenorrhoea, abnormal orgasm. Rare: Breast enlargement and pain, galactorrhea, gynecomastia and erectile dysfunction.

General disorders and administration site conditions Common: Asthenia/fatigue. Uncommon: Weight gain.

Injury, poisoning and procedural complications Unknown frequency: Falls, in particular in elderly patients.

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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

Symptoms Experience with overdose is limited. Drowsiness and sedation, coma, hypotension and extrapyramidal symptoms may be observed. Fatal consequences were reported in combination with other psychotropic agents, but also in tiapride monotherapy.

Therapy In case of an acute overdose, the possibility of simultaneous ingestion of other substances must be considered. In view of the fact that tiapride is very weak to dialyse, hemodialysis to eliminate the substance is not effective. No specific antidote to tiapride exists. Therefore, it is recommended to begin monitoring the patient carefully controlling the vital functions and constantly monitoring cardiac activity (risk of QT interval prolongation and subsequent ventricular arrhythmias) until his condition is adjusted. Anticholinergic substances should be administered in case of serious extrapyramidal symptomatology.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics, benzamides. ATC code: N05AL03

Mechanism of action Tiapride is an atypical neuroleptic, which in vitro selectively blocks D2 and D3 subtypes of dopaminergic receptors without effect on receptor subtypes of major central neurotransmitters (including serotonin, noradrenaline and histamine). In vivo neurochemical and behavioural studies confirm these properties and show antidopaminergic properties without sedation, catalepsy and cognitive impairment.

In addition:  Tiapride is especially effective on dopamine-sensitized receptors, explaining its effect on dyskinesia.  Anxiolytic activity in several animal models exposed to stress, including alcohol withdrawal, was confirmed in mice and primates.  Tiapride did not cause physical or psychological dependence.

This atypical pharmacological profile may be responsible for its clinical efficacy in many disorders with increased dopaminergic function, such as dyskinesia and psycho-behavioural disorders observed in patients with dementia or in alcoholics it causes fewer neurological adverse effects than typical neuroleptics.

5.2 Pharmacokinetic properties

Absorption The absorption of tiapride is rapid. The average mean value tmax is 1 hour per tablet.

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Following oral administration of a single 100 mg dose in healthy volunteers, the average volume of maximum plasma concentration of tiapride (C) is 560 ng/ml. Cmax is slightly increased upon intramuscular administration. Cmax is lower in tablets with prolonged release of the active substance compared to immediate release.

Absolute bioavailability following oral administration is approximately 75 – 78%.

In most patients, the plasma concentration increases proportionally with the dose.

Food intake increases Cmax by 20% for immediate-release tablets.

Distribution Tiapride practically does not bind to plasma proteins. The average distribution volume is 1.43 l/kg, identical with accumulation in tissue.

Biotransformation In humans, up to 15% of tiapride is metabolised into largely pharmacologically inactive metabolites. No conjugates were observed.

Elimination Tiapride is primarily eliminated through the urine, in practically unchanged form. Within twenty-four hours after oral administration, approximately 75% of the administered dose of tiapride is excreted in the urine, which indicates that the biotransformation of tiapride is mild. Renal clearance (average 18 l/h) showed that renal excretion occurs by glomerular filtration and tubular secretion.

The average elimination half-life in humans is around 3 – 5 hours, as the metabolites are largely pharmacologically inactive. No conjugates were observed.

The average elimination half-life is around 3 – 5 hours in healthy young volunteers following oral administration immediate-release tablets.

An increase in the plasma concentration and elimination half-life to 21.6 hours was recorded in patients with severe renal insufficiency. For this reason, the dose should be reduced in case of renal insufficiency (see section 4.2).

5.3 Preclinical safety data

Tiapride does not have any regular organ-specific, teratogenic or mutagenic risk. Effects observed in animals are directly related to pharmacological activity and particularly with hyperprolactinaemia. In regards to carcinogenicity, a prolactin-producing tumour observed in rodents is species-specific and does not indicate any special risk for human therapeutic use. Animal embryo-fetal development studies have not shown direct or indirect harmful effects with regard to teratogenicity and embryo-fetotoxicity in rodents. However, studies in rabbits have shown an embryotoxic effect at the highest doses tested (80 and 160 mg / kg / day). Animal studies are insufficient for disorders of the development of the nervous system in pups.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol Microcrystalline cellulose granulated Povidone 25 Sodium starch glycolate (type A) Silica, colloidal anhydrous

8/9 Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Store in the original package below 25 °C.

6.5 Nature and contents of container

PVC/PVDC/Al blister. Pack size: 20, 30, 50, 60, 90, 100 or 500 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

PRO.MED.CS Praha a.s. Telčská 377/1 Michle, 140 00 Prague 4 Czech Republic

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: [To be completed nationally] Date of latest renewal: [To be completed nationally]

10. DATE OF REVISION OF THE TEXT

[To be completed nationally]

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