- Email: [email protected]
P.3.121 A comparison between rapidly disintegrating and conventional formulation risperidone tablets
P3 Psychotic disorders and antipsychotics
$508
Methodology: Twenty four months of retrospective data was collected for 68 patients with a previous diagnosis of schizophrenia/schizoaffective disorder that had received RLAI. This includes 12 months of data prior to receipt of RLAI and 12 months of data post commencement of RLAI. Data associated with psychiatric secondary care resource use was collected from 3 sites in the UK. Results: 68 patients with a mean age of 40.6 yrs were included in the study (38 male, 30 female). Results showed an average time between onset of schizophrenic symptoms and beginning RLAI of 151 months. The most common reasons for commencing RLAI were poor compliance (35%) and side-effects (32%). 60% of patients had been treated immediately prior to RLAI with an oral antipsychotic (6 patients with a typical and 35 patients with an atypical) and 40% had previously received a depot treatment. Comparison of number of bed days prior to RLAI vs. post RLAI showed a 16.8% decrease in the number o f bed days post commencement o f RLAI (table 1). Table 1: SecondaW care outcomes
12 month pre RLAI 12 month post RLAI
Hospital Consultant CPN visits bed days outpatient visits
Other secondary care visits
3045 2533
38 39
210 221
1307 1277
Conclusion: This retrospective study demonstrates that RLAI can lead to a substantial reduction in hospital bed usage. An acute inpatient bed costs £172 per day in the UK (Netten & Curtis, 2004), and hence using the data from this study each patient on RLAI is saving £1295 in hospital bed costs. This figure does not take account of medication costs, but table 1 indicates that the reduced bed usage is not accompanied by excessive community contacts. The most common (but linked) reasons for switching to RLAI are previous poor compliance or adherence with medication, and the experience of intolerable side-effects. The duration o f illness prior to RLAI shows that the study population is chronically unwell, and this combined with the reasons for switch suggest that RLAI is being selected at this time for some of the most difficult-to-treat or treatment refractory individuals. Demonstrating improvements in this group is a challenge but it is precisely this population that have a low quality of life and high service costs (Lang et al, 1997).
References [1] Netten, A. Curtis, L., 2004. Unit costs of health and social care. Personal social services research unit, University of Kent. [2] Lang, EH. Forbes, J.F. Murray, G.D. Johnstone, E.C., 1997. Service provision for people with schizophrenia. The British Journal of Psychiatry 171, 15%164.
~ A
comparison between rapidly disintegrating and conventional formulation risperidone tablets
E. Mannaert 1 *, B. Remmerie 1, B. Eriksson 2, S.F. Kushner3.
IJanssen Pharmaceutica, Pharmaceutical Research & Development, Beerse, Belgium," 2Janssen-Cilag, Clinical Research
& Development, Sweden; 3Johnson & Johnson, Pharmaceutical Research & Development, USA Background: A rapidly dissolving formulation of the atypical antipsychotic, risperidone, has been developed to aid intake and compliance in patients. We present data from several studies assessing different aspects of this rapidly dissolving tablet. Methods: A total o f 264 subjects (healthy volunteers or patients with schizophrenia) were enrolled into 9 single-dose, and 1 repeated-dose, studies, which assessed at least 2 of the following parameters: taste, speed o f dissolution, bioavailability, bioequivalence, and tolerability of risperidone rapidly disintegrating tablets (0.5 4 rag). The formulations included were manufactured from either a low-concentration (2 rag/g) or a high-concentration (4 rag/g) suspension. Apart from 2 studies, which did not have a comparator, all studies had an open-label, randomized, 2-way cross-over design, using conventional risperidone tablets as a reference. Taste was assessed using a questionnaire at various intervals post-dosing. Time to initial and complete disintegration (in seconds) was measured. Serial blood samples were taken for proper estimation o f the pharmacoldnetic parameters o f risperidone and its active moiety (risperidone plus its active metabolite 9-hydroxyrisperidone), including tmax, Cm~, AUClast, and AUCoo. The relative bioavailability was calculated as treatment ratios (rapidly disintegrating/conventional risperidone) of log-transformed Cm~ and AUC. The treatments were considered bioequivalent if the 90% confidence intervals (CI) o f these ratios were contained within the equivalence range o f 80 125%. Results: Taste: Subjects were generally positive about the taste of the rapidly disintegrating tablets, the majority rating the taste as neutral, pleasant, or very pleasant. Taste ratings were better for the rapidly disintegrating tablets compared with the conventional tablets (n 60). There was no significant difference in taste preference between the high- and low-strength formulations. Disintegration: In one study the mean (±SD) time until initial disintegration was 5.1±0.8 s (n 10), and until complete disintegration was 29.4±18.4s (n 10). In another study, the median time to complete disintegration was 38 s (95%CI: 33 51 s, n 60). Bioequivalence and bioavailability: When bioequivalence of the final formulations was assayed across the tablet range (0.5, 2, and 4mg), the rapidly disintegrating tablets were found to be bioequivalent to the conventional tablets in all parameters for the clinically relevant active moiety. For the parent drug, risperidone, bioequivalence was achieved for the 0.5 and 2 mg tablet strengths, while for the 4 mg formulation, the lower limit of the 90%CI of the Cm~ treatment ratio of risperidone (79% ! fell just outside the range in one of the studies (n 39). This finding is considered of minor clinical relevance, as the efficacy and safety is rather governed by the concentration of the total active moiety. Tolerability: The most common adverse events reported were dizziness, somnolence, dry mouth, and headache. Most adverse events were mild in severity and similar between formulations. Conclusions: The taste of risperidone rapidly disintegrating tablets was generally well received. Tablets dissolved rapidly, and were well tolerated. For clinical purposes, the rapidly disintegrating formulation can be considered bioequivalent to the conventional risperidone tablets.
References [1] Reyes M, Buitelaar J, Augustyns I, Eerdekens M. Relapse prevention of disruptive behavior disorders in children and adolescents: a sixmonth trial of risperidone versus placebo. Poster presented at the 16th International Association for Child and Adolescent Psychiatry and
P3 Psychotic disorders and antipsychotics Allied Professions (IACAPAP) congress, 22 26 August, 2004, Berlin, Germany.
•
Comparison of intramuscular aripiprazole and haloperidol with placebo in acutely agitated schizophrenia patients
A. Dillenschneider 1 *, D. Oren 2, R. Marcus 2, D. Kostic 3, R. McQuade 4, T. Iwamoto 5, G. Manos 2. ]Bristol-Myers Squibb,
BP 325, Reuil-Malmaison, France; 2Bristol-Myers Squibb, Wallingford, CT, USA; 3Bristol Myers Squibb, Lawrenceville, NJ, USA; 40tsuka America Pharmaceutical Inc, Princeton, NJ, USA; 50tsuka Pharmaceutical Co. Ltd., Tokyo, Japan Purpose: To compare the efficacy and safety of intramuscular (IM) aripiprazole with placebo and establish its non-inferiority to haloperidol IM for the treatment of acutely agitated patients with schizophrenia and schizoaffective disorders. Methods: In this 24-hour, multicenter, double-blind study, 448 patients presenting with acute agitation were randomized to aripiprazole IM (10mg; n 175), haloperidol IM (6.5mg; n 185) or placebo (n 88). A second dose of study treatment was permitted ~> 2 hours post-initial dose, and a third dose ~> 2 hours later. PANSS-Excited Components (PEC) and Clinical Global Impression-Improvement (CGI-I) were evaluated at baseline and at regular intervals until 24 hours after dosing. Results: A rapid reduction of PEC was observed with aripiprazole (10mg IM) and haloperidol (6.5 mg IM) compared with placebo, and was maintained for the duration of the study. Mean change from baseline PEC at 120 min: aripiprazole IM 7.27, haloperidol IM 7.75, placebo 4.78 (aripiprazole vs placebo and haloperidol vs placebo; p<0.001). Aripiprazole IM and haloperidol IM produced significant improvement in CGI-I scores compared with placebo. Mean change from baseline at 120 min: aripiprazole IM 2.42, haloperidol IM 2.37, placebo 3.10 (aripiprazole vs placebo and haloperidol vs placebo; p < 0.001). Incidence of EPS-related adverse events: aripiprazole 3 (1.7%), haloperidol 23 (12.6%), placebo 2 (2.3%). Conclusion: Aripiprazole 10 mg IM and haloperidol 6.5 mg IM rapidly reduced acute agitation in patients with schizophrenia and schizoaffective disorders. The incidence of EPS-related adverse events with aripiprazole treatment was similar to placebo and substantially lower than for haloperidol IM.
~ A
comparative study of quetiapine and risperidone in patients with first-episode psychosis
R. Gafoor 1 *, R Power2, T. Craig 3, R. Kerwin 3, R McGuire 3.
]Institute of Psychiatty, Section of Neuroimaging, London, United Kingdom; 2Lambeth Hospital, LEO Ward, United Kingdom; 3Institute of PsychiaOy, Psychological Medicine, United Kingdom Purpose: The benefits of early intervention with optimal treatment of first-episode psychosis are well established. While atypical antipsychotics are an effective therapy for the treatment of firstepisode psychosis, there is little information available regarding the relative efficacy and safety of the different atypicals in this population. Here we compare the efficacy and tolerability of quetiapine and risperidone in patients with first-episode psychosis (Study number BU-5077 0011).
$509
Methods: We present 8-week interim data from an ongoing 52-week, randomised, rater-blinded, parallel-group study of quetiapine and risperidone in patients experiencing a first episode of schizophreniform psychosis (ICD-10 criteria). Efficacy measures included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity of Illness (CGI-S), Global Assessment of Functioning (GAF), Calgary Depression Scale for Schizophrenia (CDSS) and the Calgary Anxiety Scale for Schizophrenia (CASS). Tolerability was measured using the Antipsychotic Non-Neurological Side Effect Rating Scale (ANNSERS). Patients were assessed at baseline and at 4 and 8 weeks and analysed on a last observation carried forward basis. Patient recruitment is ongoing. Results: A total of 69 patients were randomised to treatment. Of these, 33 patients (67% male, mean age 23.7 years) received quetiapine, 34 (80% male, mean age 24.2 years) received risperidone, and 2 refused treatment. The mean rate of patient discontinuation was similar in each group (approximately 8 weeks). The mean (SD) doses at 8 weeks were 420 (174) mg and 3.3 (1.8) mg for quetiapine and risperidone, respectively. There was no difference between treatments for any of the efficacy assessments. In the overall study population, mean (SD) baseline scores on PANSS positive subscale, CGI and GAF were 17.66 (5.20), 4.94 (0.95) and 33.50 (16.20), respectively. After 8 weeks of treatment, symptoms improved by 5.96, 1.22 and +20.50 on PANSS, CGI-S and GAF, respectively (all p < 0.001). Furthermore, the overall population showed a non-significant trend towards improvement in depressive symptoms with a change in mean (SD) CDSS score from 5.08 (6.61) at baseline, to 3.31 (4.93) after 8 weeks of treatment (p 0.054). There was no significant improvement in PANSS negative subscale scores or CASS scores. Change from baseline in sexual dysfunction was not significant in the quetiapine cohort. The intensity of sexual dysfunction was greater in the risperidone treated patients compared with those receiving quetiapine (p 0.033). In the overall population, ANNSERS scores showed that the intensity of problems with sexual arousal were mild; however, the longitudinal increase was significant after 8 weeks of treatment (p 0.001). The most common side effects were hyposexuality and difficulty waking in the morning (risperidone and quetiapine groups, respectively). Very low incidences of Parkinsonian extrapyramidal symptoms, akathisia and abnormal movements were reported. All side effects were of mild-tomoderate intensity. Conclusions: Quetiapine and risperidone show comparable efficacy in a broad range of symptoms of first-episode schizophreniform psychosis. Risperidone was associated with higher levels of sexual dysfunction compared with quetiapine. These effects were evident at relatively low doses, consistent with evidence that firstepisode patients are more sensitive to the therapeutic and adverse effects of these drugs.
References [l] Gafoor R, Matthiasson P, Craig T, Power P, Kerwin R, McGuire P, Efficacy, side effects and endocrine disturbance in patients with a fit'st episode of psychosis treated with atypical antipsychotics. Abstracts of the XII th Biennial Winter Workshop on Schizophrenia. Schizophrenia Research. 2004: Vol 67 Nol Supplement. [2] Gafoor R, Power P, McGuire P, Management of a first episode of manic psychosis. Progress in Neurology and Psychiatry (supplement) 2004; 10 12.
$508
Methodology: Twenty four months of retrospective data was collected for 68 patients with a previous diagnosis of schizophrenia/schizoaffective disorder that had received RLAI. This includes 12 months of data prior to receipt of RLAI and 12 months of data post commencement of RLAI. Data associated with psychiatric secondary care resource use was collected from 3 sites in the UK. Results: 68 patients with a mean age of 40.6 yrs were included in the study (38 male, 30 female). Results showed an average time between onset of schizophrenic symptoms and beginning RLAI of 151 months. The most common reasons for commencing RLAI were poor compliance (35%) and side-effects (32%). 60% of patients had been treated immediately prior to RLAI with an oral antipsychotic (6 patients with a typical and 35 patients with an atypical) and 40% had previously received a depot treatment. Comparison of number of bed days prior to RLAI vs. post RLAI showed a 16.8% decrease in the number o f bed days post commencement o f RLAI (table 1). Table 1: SecondaW care outcomes
12 month pre RLAI 12 month post RLAI
Hospital Consultant CPN visits bed days outpatient visits
Other secondary care visits
3045 2533
38 39
210 221
1307 1277
Conclusion: This retrospective study demonstrates that RLAI can lead to a substantial reduction in hospital bed usage. An acute inpatient bed costs £172 per day in the UK (Netten & Curtis, 2004), and hence using the data from this study each patient on RLAI is saving £1295 in hospital bed costs. This figure does not take account of medication costs, but table 1 indicates that the reduced bed usage is not accompanied by excessive community contacts. The most common (but linked) reasons for switching to RLAI are previous poor compliance or adherence with medication, and the experience of intolerable side-effects. The duration o f illness prior to RLAI shows that the study population is chronically unwell, and this combined with the reasons for switch suggest that RLAI is being selected at this time for some of the most difficult-to-treat or treatment refractory individuals. Demonstrating improvements in this group is a challenge but it is precisely this population that have a low quality of life and high service costs (Lang et al, 1997).
References [1] Netten, A. Curtis, L., 2004. Unit costs of health and social care. Personal social services research unit, University of Kent. [2] Lang, EH. Forbes, J.F. Murray, G.D. Johnstone, E.C., 1997. Service provision for people with schizophrenia. The British Journal of Psychiatry 171, 15%164.
~ A
comparison between rapidly disintegrating and conventional formulation risperidone tablets
E. Mannaert 1 *, B. Remmerie 1, B. Eriksson 2, S.F. Kushner3.
IJanssen Pharmaceutica, Pharmaceutical Research & Development, Beerse, Belgium," 2Janssen-Cilag, Clinical Research
& Development, Sweden; 3Johnson & Johnson, Pharmaceutical Research & Development, USA Background: A rapidly dissolving formulation of the atypical antipsychotic, risperidone, has been developed to aid intake and compliance in patients. We present data from several studies assessing different aspects of this rapidly dissolving tablet. Methods: A total o f 264 subjects (healthy volunteers or patients with schizophrenia) were enrolled into 9 single-dose, and 1 repeated-dose, studies, which assessed at least 2 of the following parameters: taste, speed o f dissolution, bioavailability, bioequivalence, and tolerability of risperidone rapidly disintegrating tablets (0.5 4 rag). The formulations included were manufactured from either a low-concentration (2 rag/g) or a high-concentration (4 rag/g) suspension. Apart from 2 studies, which did not have a comparator, all studies had an open-label, randomized, 2-way cross-over design, using conventional risperidone tablets as a reference. Taste was assessed using a questionnaire at various intervals post-dosing. Time to initial and complete disintegration (in seconds) was measured. Serial blood samples were taken for proper estimation o f the pharmacoldnetic parameters o f risperidone and its active moiety (risperidone plus its active metabolite 9-hydroxyrisperidone), including tmax, Cm~, AUClast, and AUCoo. The relative bioavailability was calculated as treatment ratios (rapidly disintegrating/conventional risperidone) of log-transformed Cm~ and AUC. The treatments were considered bioequivalent if the 90% confidence intervals (CI) o f these ratios were contained within the equivalence range o f 80 125%. Results: Taste: Subjects were generally positive about the taste of the rapidly disintegrating tablets, the majority rating the taste as neutral, pleasant, or very pleasant. Taste ratings were better for the rapidly disintegrating tablets compared with the conventional tablets (n 60). There was no significant difference in taste preference between the high- and low-strength formulations. Disintegration: In one study the mean (±SD) time until initial disintegration was 5.1±0.8 s (n 10), and until complete disintegration was 29.4±18.4s (n 10). In another study, the median time to complete disintegration was 38 s (95%CI: 33 51 s, n 60). Bioequivalence and bioavailability: When bioequivalence of the final formulations was assayed across the tablet range (0.5, 2, and 4mg), the rapidly disintegrating tablets were found to be bioequivalent to the conventional tablets in all parameters for the clinically relevant active moiety. For the parent drug, risperidone, bioequivalence was achieved for the 0.5 and 2 mg tablet strengths, while for the 4 mg formulation, the lower limit of the 90%CI of the Cm~ treatment ratio of risperidone (79% ! fell just outside the range in one of the studies (n 39). This finding is considered of minor clinical relevance, as the efficacy and safety is rather governed by the concentration of the total active moiety. Tolerability: The most common adverse events reported were dizziness, somnolence, dry mouth, and headache. Most adverse events were mild in severity and similar between formulations. Conclusions: The taste of risperidone rapidly disintegrating tablets was generally well received. Tablets dissolved rapidly, and were well tolerated. For clinical purposes, the rapidly disintegrating formulation can be considered bioequivalent to the conventional risperidone tablets.
References [1] Reyes M, Buitelaar J, Augustyns I, Eerdekens M. Relapse prevention of disruptive behavior disorders in children and adolescents: a sixmonth trial of risperidone versus placebo. Poster presented at the 16th International Association for Child and Adolescent Psychiatry and
P3 Psychotic disorders and antipsychotics Allied Professions (IACAPAP) congress, 22 26 August, 2004, Berlin, Germany.
•
Comparison of intramuscular aripiprazole and haloperidol with placebo in acutely agitated schizophrenia patients
A. Dillenschneider 1 *, D. Oren 2, R. Marcus 2, D. Kostic 3, R. McQuade 4, T. Iwamoto 5, G. Manos 2. ]Bristol-Myers Squibb,
BP 325, Reuil-Malmaison, France; 2Bristol-Myers Squibb, Wallingford, CT, USA; 3Bristol Myers Squibb, Lawrenceville, NJ, USA; 40tsuka America Pharmaceutical Inc, Princeton, NJ, USA; 50tsuka Pharmaceutical Co. Ltd., Tokyo, Japan Purpose: To compare the efficacy and safety of intramuscular (IM) aripiprazole with placebo and establish its non-inferiority to haloperidol IM for the treatment of acutely agitated patients with schizophrenia and schizoaffective disorders. Methods: In this 24-hour, multicenter, double-blind study, 448 patients presenting with acute agitation were randomized to aripiprazole IM (10mg; n 175), haloperidol IM (6.5mg; n 185) or placebo (n 88). A second dose of study treatment was permitted ~> 2 hours post-initial dose, and a third dose ~> 2 hours later. PANSS-Excited Components (PEC) and Clinical Global Impression-Improvement (CGI-I) were evaluated at baseline and at regular intervals until 24 hours after dosing. Results: A rapid reduction of PEC was observed with aripiprazole (10mg IM) and haloperidol (6.5 mg IM) compared with placebo, and was maintained for the duration of the study. Mean change from baseline PEC at 120 min: aripiprazole IM 7.27, haloperidol IM 7.75, placebo 4.78 (aripiprazole vs placebo and haloperidol vs placebo; p<0.001). Aripiprazole IM and haloperidol IM produced significant improvement in CGI-I scores compared with placebo. Mean change from baseline at 120 min: aripiprazole IM 2.42, haloperidol IM 2.37, placebo 3.10 (aripiprazole vs placebo and haloperidol vs placebo; p < 0.001). Incidence of EPS-related adverse events: aripiprazole 3 (1.7%), haloperidol 23 (12.6%), placebo 2 (2.3%). Conclusion: Aripiprazole 10 mg IM and haloperidol 6.5 mg IM rapidly reduced acute agitation in patients with schizophrenia and schizoaffective disorders. The incidence of EPS-related adverse events with aripiprazole treatment was similar to placebo and substantially lower than for haloperidol IM.
~ A
comparative study of quetiapine and risperidone in patients with first-episode psychosis
R. Gafoor 1 *, R Power2, T. Craig 3, R. Kerwin 3, R McGuire 3.
]Institute of Psychiatty, Section of Neuroimaging, London, United Kingdom; 2Lambeth Hospital, LEO Ward, United Kingdom; 3Institute of PsychiaOy, Psychological Medicine, United Kingdom Purpose: The benefits of early intervention with optimal treatment of first-episode psychosis are well established. While atypical antipsychotics are an effective therapy for the treatment of firstepisode psychosis, there is little information available regarding the relative efficacy and safety of the different atypicals in this population. Here we compare the efficacy and tolerability of quetiapine and risperidone in patients with first-episode psychosis (Study number BU-5077 0011).
$509
Methods: We present 8-week interim data from an ongoing 52-week, randomised, rater-blinded, parallel-group study of quetiapine and risperidone in patients experiencing a first episode of schizophreniform psychosis (ICD-10 criteria). Efficacy measures included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity of Illness (CGI-S), Global Assessment of Functioning (GAF), Calgary Depression Scale for Schizophrenia (CDSS) and the Calgary Anxiety Scale for Schizophrenia (CASS). Tolerability was measured using the Antipsychotic Non-Neurological Side Effect Rating Scale (ANNSERS). Patients were assessed at baseline and at 4 and 8 weeks and analysed on a last observation carried forward basis. Patient recruitment is ongoing. Results: A total of 69 patients were randomised to treatment. Of these, 33 patients (67% male, mean age 23.7 years) received quetiapine, 34 (80% male, mean age 24.2 years) received risperidone, and 2 refused treatment. The mean rate of patient discontinuation was similar in each group (approximately 8 weeks). The mean (SD) doses at 8 weeks were 420 (174) mg and 3.3 (1.8) mg for quetiapine and risperidone, respectively. There was no difference between treatments for any of the efficacy assessments. In the overall study population, mean (SD) baseline scores on PANSS positive subscale, CGI and GAF were 17.66 (5.20), 4.94 (0.95) and 33.50 (16.20), respectively. After 8 weeks of treatment, symptoms improved by 5.96, 1.22 and +20.50 on PANSS, CGI-S and GAF, respectively (all p < 0.001). Furthermore, the overall population showed a non-significant trend towards improvement in depressive symptoms with a change in mean (SD) CDSS score from 5.08 (6.61) at baseline, to 3.31 (4.93) after 8 weeks of treatment (p 0.054). There was no significant improvement in PANSS negative subscale scores or CASS scores. Change from baseline in sexual dysfunction was not significant in the quetiapine cohort. The intensity of sexual dysfunction was greater in the risperidone treated patients compared with those receiving quetiapine (p 0.033). In the overall population, ANNSERS scores showed that the intensity of problems with sexual arousal were mild; however, the longitudinal increase was significant after 8 weeks of treatment (p 0.001). The most common side effects were hyposexuality and difficulty waking in the morning (risperidone and quetiapine groups, respectively). Very low incidences of Parkinsonian extrapyramidal symptoms, akathisia and abnormal movements were reported. All side effects were of mild-tomoderate intensity. Conclusions: Quetiapine and risperidone show comparable efficacy in a broad range of symptoms of first-episode schizophreniform psychosis. Risperidone was associated with higher levels of sexual dysfunction compared with quetiapine. These effects were evident at relatively low doses, consistent with evidence that firstepisode patients are more sensitive to the therapeutic and adverse effects of these drugs.
References [l] Gafoor R, Matthiasson P, Craig T, Power P, Kerwin R, McGuire P, Efficacy, side effects and endocrine disturbance in patients with a fit'st episode of psychosis treated with atypical antipsychotics. Abstracts of the XII th Biennial Winter Workshop on Schizophrenia. Schizophrenia Research. 2004: Vol 67 Nol Supplement. [2] Gafoor R, Power P, McGuire P, Management of a first episode of manic psychosis. Progress in Neurology and Psychiatry (supplement) 2004; 10 12.