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. 1/9 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