Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
epidemiological data
Type of information:
other: tolerability data
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature

Data source

Reference
Reference Type:
review article or handbook
Title:
Tiapride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in geriatric agitation.
Author:
Steele JW
Year:
1993
Bibliographic source:
Drugs Aging. 1993; 3(5): 460-78.

Materials and methods

Study type:
other: tolerability data
GLP compliance:
not specified

Test material

Details on test material:
The SMILES included in the reference substance linked in Section 1 (General information) was used as model input.
Specific details on test material used for the study:
not specified

Results and discussion

Results:
Tiapride is well tolerated in the elderly and when merited, the dosage can be increased with minimal risk of sudden adverse events. In a 5-year surveillance period, no differences were reported in the frequency, type or severity of adverse events in the elderly compared with the general patient population except for a significant increase (4 vs 2.5%) in extrapyramidal reactions (usually worsening of existing Parkinsonian syndrome) and drowsiness (6.7 vs 5%). Prescribing information from the manufacturer indicates that possible undesirable effects of tiapride are neuroleptic malignant syndrome, sedation or sleepiness, “precocious” dyskinesias (spasmodic torticollis, oculomotor attacks, trismus), extrapyramidal effects, tardive dyskinesia, orthostatic hypotension, impotence, frigidity, amenorrhoea, galactorrhoea, gynaecomastia and hyperprolactinaemia. The manufacturer’s tolerability data for 1991 show that there were 17 spontaneous notifications of adverse events related to the use of tiapride in a variety of indications worldwide. These consisted of 2 instances of neuroleptic malignant syndrome, and 1 each of dystonia, coma, aggravation of acne, abdominal pain, vomiting, hypersalivation, vomiting blood, urine retention, malignant hyperthermia, agranulocytosis, anaemia, thrombocytopenia, circulatory collapse, uraemia, and one unexplained death. Ten of these events were regarded as severe, but the precise role of tiapride was uncertain in at least 8, because of unknown effects of concomitant drugs, other existing medical complications, or lack of information supplied to the manufacturer from countries other than France. The total of 5 severe adverse events which occurred in France resulted from an estimated 18.05 million treatment-days or 3.6 million treatment days per adverse event. It has also been reported that the total incidence of less severe adverse effects based on 3850 observations was 6.74%, with the most relevant to the use of tiapride in geriatric agitation being somnolence (2.64%), agitation (1.06%), dyskinesia (0.23%), digestive problems (0.70%), dizziness (0.23%), and weakness (0.18%). A significant increase in extrapyramidal effects was found in patients treated concomitantly with tiapride and levodopa, compared with tiapride alone (3.8 vs 2.5%). The low incidence of tardive dyskinesia is interesting in view of the high incidence reported for other neuroleptic drugs in the elderly. In comparative trials, tiapride has been better tolerated than meprobamate and chlorpromazine and as well tolerated as placebo. One instance of erythema multiforme, an acute but self-limiting condition, was reported in a 74- year old patient receiving tiapride 300 mg/day for 3 weeks. The lesions disappeared within 2 weeks of discontinuation of tiapride. The occurrence of neuroleptic malignant syndrome is of particular concern, especially when using high tiapride dosages in alcoholic patients. This adverse effect has not been reported during the treatment of senile agitation and related conditions at recommended dosages of tiapride.

Applicant's summary and conclusion

Executive summary:

Tiapride is well tolerated in the elderly and when merited, the dosage can be increased with minimal risk of sudden adverse events. In a 5-year surveillance period, no differences were reported in the frequency, type or severity of adverse events in the elderly compared with the general patient population except for a significant increase (4 vs 2.5%) in extrapyramidal reactions (usually worsening of existing Parkinsonian syndrome) and drowsiness (6.7 vs 5%). Prescribing information from the manufacturer indicates that possible undesirable effects of tiapride are neuroleptic malignant syndrome, sedation or sleepiness, “precocious” dyskinesias (spasmodic torticollis, oculomotor attacks, trismus), extrapyramidal effects, tardive dyskinesia, orthostatic hypotension, impotence, frigidity, amenorrhoea, galactorrhoea, gynaecomastia and hyperprolactinaemia. The manufacturer’s tolerability data for 1991 show that there were 17 spontaneous notifications of adverse events related to the use of tiapride in a variety of indications worldwide. These consisted of 2 instances of neuroleptic malignant syndrome, and 1 each of dystonia, coma, aggravation of acne, abdominal pain, vomiting, hypersalivation, vomiting blood, urine retention, malignant hyperthermia, agranulocytosis, anaemia, thrombocytopenia, circulatory collapse, uraemia, and one unexplained death. Ten of these events were regarded as severe, but the precise role of tiapride was uncertain in at least 8, because of unknown effects of concomitant drugs, other existing medical complications, or lack of information supplied to the manufacturer from countries other than France. The total of 5 severe adverse events which occurred in France resulted from an estimated 18.05 million treatment-days or 3.6 million treatment days per adverse event. It has also been reported that the total incidence of less severe adverse effects based on 3850 observations was 6.74%, with the most relevant to the use of tiapride in geriatric agitation being somnolence (2.64%), agitation (1.06%), dyskinesia (0.23%), digestive problems (0.70%), dizziness (0.23%), and weakness (0.18%). A significant increase in extrapyramidal effects was found in patients treated concomitantly with tiapride and levodopa, compared with tiapride alone (3.8 vs 2.5%). The low incidence of tardive dyskinesia is interesting in view of the high incidence reported for other neuroleptic drugs in the elderly. In comparative trials, tiapride has been better tolerated than meprobamate and chlorpromazine and as well tolerated as placebo. One instance of erythema multiforme, an acute but self-limiting condition, was reported in a 74- year old patient receiving tiapride 300 mg/day for 3 weeks. The lesions disappeared within 2 weeks of discontinuation of tiapride. The occurrence of neuroleptic malignant syndrome is of particular concern, especially when using high tiapride dosages in alcoholic patients. This adverse effect has not been reported during the treatment of senile agitation and related conditions at recommended dosages of tiapride.