SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Tiaprid XXX 100 mg, tablets 2. QUALITATIVE AND QUANTIATIVE COMPOSITION Each tablet contains 100 mg tiapride (as hydrochloride). For the full list of excipients, see section PHARMACEUTICAL FORM Tablet White, round tablets with beveled edge and a cross on both sides. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications For the treatment of neuroleptic-induced tardive dyskinesia, mainly oro-bucco-lingual type. 4.2 Posology and method of administration Adults should take mg tiapride three times daily, depending on the severity of the disease and the body weight of the individual. The proposed daily dose for the claimed indication is mg tiapride. The effect of treatment may not be apparent until after a period of 4-6 weeks of treatment. Tiaprid XXX tablets should preferably be taken with a little liquid after meals. Tiapride is not intended for treatment in children. Dosage in renal impairment Creatinine clearance: ml/min = 75 % of the ml/min = 50 % normal less than 10 ml/min = 25 % daily dose 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant Prolactin-dependent tumours, e.g. pituitary gland prolactinoma and breast cancer. 1

2 Phaeochromocytoma. Association with levodopa or other dopaminergic medicines (see section 4.5). Neuroleptic malignant syndrome (see section 4.8). 4.4 Special warnings and precautions for use As with other neuroleptics, Neuroleptic Malignant Syndrome, a potentially fatal complication, which is characterised by hyperthermia, muscle rigidity and autonomic dysfunction may occur. In case of hyperthermia of undiagnosed origin, tiapride should be discontinued. Neuroleptic agents may reduce the seizure threshold in epilepsy, although this has not been evaluated with tiapride. Therefore, patients with a history of epilepsy should be closely monitored during tiapride treatment. In patients with renal impairment the dose has to be reduced, while in patients with severely impaired renal function tiapride should be discontinued on medical advice (see section 4.2). Tiapride should not be used in patients with Parkinson s disease, with the exception of special circumstances. Because tiapride can have an increased sedative effect in elderly patients, caution should be exercised. New researches indicate that increased prolactine levels may be associated with an increased risk of breast cancer. Notwithstanding, due to a lack of epidemiologic studies, a final conclusion on hyperprolactinemia as an independent risk factor of breast cancer can so far not be drawn. Prolongation of the QT interval Tiapride may induce a prolongation of the QT interval. This effect is known to potentiate the risk of serious ventricular arrhythmias such as torsades de pointes (see section 4.8). Before any administration, and if possible according to the patient s clinical status, it is recommended to monitor factors which could favour the occurrence of this rhythm disorder, such as for example: - bradycardia less than 55 bpm, - electrolyte imbalance in particular hypokalaemia, - congenital prolongation of the QT interval, - on-going treatment with a medication likely to produce pronounced bradycardia (< 55 bpm), electrolyte imbalance, decreased intracardiac conduction, or prolongation of the QT interval (see section 4.5). Tiapride should be prescribed with caution in patients presenting with risk factors which may predispose to prolongation of the QT interval. Venous thromboembolism Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with tiapride and preventive measures undertaken. Increased Mortality in Elderly people with dementia Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drugtreated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was 2

3 about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death in clinical trials with atypical antipsychotics 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, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Tiapride is not licensed for the treatment of dementia-related behavioural disturbances. Stroke In randomized clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic drugs or other populations of patients cannot be excluded. Tiapride should be used with caution in patients with stroke risk factors. Children In children, tiapride has not been thoroughly investigated. Therefore, tiapirde is not intended for treatment in children (see section 4.2). 4.5 Interactions 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 Medications which can induce torsades de pointes Class Ia (quinidine, hydroquinidine, disopyramide), and class III antiarrhythmic agents (amiodarone, sotalol, dofetilide, ibutilide), certain neuroleptics (sultopride, pipothiazine, sertindole, veralipide, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, pimozide, haloperidol, droperidol, fluphenazine, pipamperone, flupentixol, zuclopentixol), some antiparasitic drugs (halofantrine, lumefrantine, pentamidine), other medications: IV erythromycin, IV spiramycin, moxifloxacin, bepridil, cisapride, diphemanil, mizolastine, IV vincamine. Increased risk of ventricular arrhythmias, 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. 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. Levodopa 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 3

4 Amantadine, apomorphine, bromocriptine, entacapone, 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 antiarrhythmia agents, beta-blockers, some class II antiarrhythmia agents, some calcium antagonists, 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, inparticular torsades de pointes. Clinical monitoring and ECG monitoring are necessary. Potassium-lowering agents Potassium-lowering diuretics, stimulant laxatives, IV amphotericin B, glucocorticoids, cosyntropin. Increased risk of ventricular arrhythmias, especially torsades de pointes. Correct any hypokalaemia before starting treatment with amisulpride and ensure clinical, electrolyte and electrocardiographic monitoring. Its concomitant administration has 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); barbiturates; benzodiazepines; other non-benzodiazepine anxiolytics; hypnotics; neuroleptics; sedative antidepressants (amitriptyline, doxepine, mianserin, mirtazapine, trimipramine); sedative H1 antihistamines; centrally-acting antihypertensives; other drugs: baclofen, thalidomide, pizotifene. 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) Vasodilatator effect and risk of hypotension, in particular postural hypotension (additive effect). Nitrate derivatives and related compounds Anticholinergics such as biperiden can attenuate the action of tiapride. 4.6 Fertility, pregnancy and lactation 4

5 Pregnancy If drug therapy is needed to maintain a good mental balance and to avoid decompensation, it must be instituted or continued at effective dose throughout the pregnancy. There are limited amount of data from the use of tiapride in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Injectable neuroleptics used in emergency situations can cause maternal hypotension. In neonates born to mothers receiving prolonged high-dose neuroleptic treatment, extrapyramidal syndromes (hypertonia, tremor) have been described in rare cases. Neonates exposed to antipsychotics (including tiapride) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. Breastfeeding It is not known whether tiapride is excreted in breast milk. Breast-feeding during treatment with tiapride is not recommended. Fertility A decrease in fertility was observed in animals treated with tiapride. In humans, because of the interaction with dopamine receptors, tiapride may cause hyperprolactinemia which can be associated with amenorrhea, anovulation, and impaired fertility (see section 4.8). 4.7 Effect on ability to drive and use machines Even when used as recommended, tiapride may cause sedation so that the ability to drive vehicles or operate machinery can be impaired (see section 4.8). 4.8 Undesirable effects Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Undesirable effects are indicated in accordance with the following incidences: 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). Data of clinical studies During controlled clinical studies the following adverse effects were reported. It should be noted that in some instances it can be difficult to differentiate adverse events from symptoms of the underlying disease. Endocrine disorders Common: hyperprolactinemia* * Hyperprolactinemia may in some cases induce galactorrhea, amenorrhea, gynecomastia, menstrual disorders or erectile dysfunction. Psychiatric disorders Common: drowsiness/sleepiness, insomnia, agitation, impassivity. Nervous system disorders Common: Dizziness/vertigo, headache. 5

6 Parkinsonism and symptoms related symptoms: tremor, hypertonia, hypokinesia, hypersalivation. These symptoms are generally reversible upon administration of antiparkinsonian medicines. Uncommon: Akathisia, dystonia (spasm, torticollis, oculogyric crisis, and trismus). These symptoms are generally reversible upon administration of antiparkinsonian medicines. Rare: Acute dyskinesia. This symptom is generally reversible upon administration of antiparkinsonian medicines. Reproductive system and breast disorders Uncommon: Galactorrhea, amenorrhea, breast enlargement, breast pain, impotence. General disorders and administration site conditions Common: Asthenia/fatigue Uncommon: Weight increase Post marketing data In addition to the above, cases of the following adverse reactions have been reported (spontaneous reporting only). Nervous system disorders Not known: Tardive dyskinesia (characterized by rhythmic, involuntary movements primarily of the tongue and/ or the face) have been reported, as with all neuroleptics, after a neuroleptic administration of more than 3 months. Antiparkinson treatment is ineffective, and it may even lead to aggravation of the symptoms. As in case of all antipsychotic agents, neuroleptic malignant syndrome may occur (see section 4.4), that is a complication with a potentially fatal outcome. Cardiac disorders Not known: QT interval prolongation, ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest and sudden death (see section 4.4). Vascular disorders Not known: Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs. Hypotension, usually orthostatic. Pregnancy, puerperium and perinatal conditions Not known: Drug withdrawal syndrome neonatal (see 4.6). 4.9 Overdose Signs and symptoms Experience regarding the overdose of tiapride is limited. Drowsiness, sedation, coma, hypotension and extrapyramidal symptoms may be observed. Treatment Hemodialysis should not be used in overdose to remove the active substance, because tiapride is moderately dialysed. There is no specific antidote to tiapride. Appropriate supportive measures (monitoring vital and cardiac functions) should therefore be instituted. In case of severe extrapyramidal symptoms, anticholinergic medicines should be administered. 6

7 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Benzamide-antipsychotics ATC code: NO5AL3 Tiapride is an atypical neuroleptic which exhibits selectivity in in-vitro studies for D2 and D3 dopamine subtype receptors without any affinity for subtype receptors of the principal central neurotransmitters (including serotonin, noradrenaline and histamine). These properties have been confirmed in neurochemical and behavioural studies in which antidopaminergic properties have been demonstrated in the absence of sedation, catalepsy and cognitive impairment. 5.2 Pharmacokinetic properties Tiapride is rapidly absorbed. Maximal concentration of the active substance are reached as early as within one hour. The absolute bioavailability of the tablets is 80%. Tiapride is mostly eliminated in the first 24 hour urine. Tiapride is mainly eliminated as the parent compound, although two metabolites have been identified. These are the N-oxide and the N-monodesethyl derivatives of the active substance. The elimination half-life is about 3 hours. 5.3 Preclinical safety data An increased incidence of breast tumours was observed in rats. This was probably due to hyperprolactinaemia as a consequence of the pharmacological action of the substance. This is probably a species-specific effect and does not constitute any particular risk to humans in therapeutic use. Other abnormalities seen in experimental animals were associated with the known pharmacological action. In studies on reproductive toxicity no signs of teratogenicity were observed, however, embryotoxic effects occurred. In a study on peri-postnatal toxicity toxic effects in the offspring were seen following high doses. A tiapride-induced reduced fertility was observed in rats due to a suppression of the estrous cycle in females and a reduced libido in males. These effects are related to the pharmacological effect of tiapride on prolactin secretion. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Mannitol (E421) Microcrystalline cellulose (E460) Magnesium stearate (E470b) Povidone K30 (E1201) Silica colloidal anhydrous (E551) 6.2 Incompatibilities 7

8 Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and content of containers PVC/Aluminium blister pack Pack of 10 tablets Pack of 20 tablets Pack of 50 tablets Pack of 60 tablets Pack of 100 tablets Hospital pack: 500 (10 x 50 tablets) Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 8