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There has been recent interest in the development of different formulations of atypical antipsychotics, including both short-acting and long-acting injections, solutions (that is, liquid concentrates), granules, and orally disintegrating tablets, to address some of the determinants of medication nonadherence in certain clinical situations (1–3). Medication status is an important predictor of outcome in schizophrenia, and nonadherence accounts for more than 50% of relapses (4–6). Risperidone is an atypical, or novel, antipsychotic that is available in Canada as an oral tablet, a long-acting injection, a solution, and most recently, as an orally disintegrating (orodispersible) tablet (7). This new formulation has been shown to be bioequivalent to the traditional tablet in both healthy volunteers and in patients with schizophrenia (8). It disintegrates rapidly in the mouth, releasing the polacrilex (methacrylic polymer) resin onto which risperidone is bound. The risperidone (still bound to the resin) is swallowed with the saliva and released from the resin in the digestive system. The resin does not disintegrate or dissolve and is excreted unchanged. This orally disintegrating formulation can be taken without water. Its main constituents are gelatin A, a coloring agent, and a sweetener (aspartame). It is available in 0.5-mg, 1-mg, and 2-mg mint-flavoured tablets. We report on a pilot trial investigating the disintegration profile, acceptability, and tolerability of orally disintegrating risperidone tablets in patients with schizophrenia or schizoaffective disorder. MethodsThis single-centre, open-label pilot study was approved by the University of Alberta Review Ethics Board and the Canadian regulatory authority. For inclusion, participants had to meet the following criteria: 1) outpatient, aged 18 to 65 years; 2) DSM-IV diagnosis of schizophrenia or schizoaffective disorder; 3) stable for at least 10 days on monotherapy with once-daily risperidone 2 mg to 4 mg; 4) signed informed consent; 5) ability to comply with visit schedule; 6) physically healthy; and 7) if female, not pregnant and using appropriate measures of birth control while in the study (9). Exclusion criteria were as follows: 1) serious or unstable medical illness, 2) antipsychotic use other than risperidone, 3) use of carbamazepine, 4) intolerance to aspartame, or 5) a history of neuroleptic malignant syndrome. Patients underwent a physical exam including weight, height, blood pressure and heart rate, medical and psychiatric history, and laboratory tests (biochemistry, hematology, and urine pregnancy test for women having child-bearing potential). Eligible patients were switched to the same dosage (in 1-mg and 2-mg tablets) of orally disintegrating risperidone (supplied by Janssen Ortho Inc) for 7 days. After the screening visit, visits were approximately 2 days apart, for a total of 5 visits. At each visit, 1 minute after the patient swallowed a 30-ml drink of water, the same rater placed a risperidone tablet(s) on the patient’s tongue with clean, dry (nongloved) hands. Water is not required for tablet disintegration; however, given that these patients attended a regular psychiatric clinic, it was felt important to control for recent nicotine or coffee use by ensuring the same degree of oral hydration and comparability to other studies with orally disintegrating tablets. Patients opened their mouths every 5 seconds until the start of disintegration and then at 10-second intervals. If the tablet appeared close to disintegration, patients kept their mouths open to time the exact end point of total disintegration. The same rater visually assessed disintegration by using a stopwatch to record disintegration start and end times. Adverse events (AEs) were collected at each visit. At baseline and last visit, the same investigator also assessed each patient with the Clinical Global Impression of Severity Scale (CGI-S), a 7-point scale on which 7 equals being very severely ill. At the last visit, patients were asked to rate the overall acceptability of the orally disintegrating risperidone tablet(s) on a visual analog scale (specifically, a 10-cm line with anchors of 0 = “not acceptable” and 10 = “very acceptable”). ResultsTen patients (8 men and 2 women) were enrolled, and all completed the study. Their mean age was 38.8 years, SD 11.1; 9 were white and 1 was black. Of the patients, 8 had a DSM-IV diagnosis of schizophrenia, and 2 had a DSM-IV diagnosis of schizoaffective disorder; the mean duration of illness was 7.3 years. Three patients were receiving risperidone dosages of 2 mg daily, 3 were receiving dosages of 3 mg daily, and 4 were receiving dosages of 4 mg daily. The mean duration of risperidone treatment was 3.7 years, SD 3.5. The CGI-S was rated as very mild in 3 patients and as mild in 7 patients (mean 2.7, SD 0.5) at baseline and at the last visit (day 7). All patients maintained their response over the study period. Table 1 shows the mean time to start of disintegration and to complete disintegration of the tablet at every visit.
Across all visits, the overall mean time to initial disintegration was 5.1 seconds (SD 0.8, range 5 to 10 seconds), and the mean time to complete disintegration was 29.4 seconds (SD 18.4, range 12 to 118 seconds). The mean time to initial disintegration was the same regardless of the number of orally disintegrating risperidone tablets placed on the patient’s tongue; the mean time to complete disintegration was also similar. The total time to complete disintegration was a mean of 36.6 seconds for the 2-mg dose (one 2-mg tablet), 23.8 for the 3-mg dose (one 1-mg tablet and one 2-mg tablet), and 28.3 for the 4-mg dose (two 2-mg tablets). At the end of the study, mean patient acceptability of the tablets was 9.61 (SD 0.61, range 8.2 to 10). Five patients reported AEs, all of which were rated mild. There were no serious AEs reported and no abnormalities in vital signs during the study. The most frequently reported AE, somnolence, likely resulted from a change in dosing time from bedtime to afternoon. None of the AEs required any intervention or withdrawal from the study. DiscussionOrally disintegrating tablets may be particularly useful for patients who have difficulty swallowing or who do not like to swallow traditional tablets. They may also be another option in emergency room situations for patients who do not wish to take short-acting injectable forms of medication or for patients who “cheek” medications. Currier and others found that risperidone liquid concentrate and oral lorazepam compared very favourably with intramuscular (IM) haloperidol and IM lorazepam in the treatment of psychotic agitation (10). Risperidone orally disintegrating tablets may be useful in similar clinical situations. In addition, they may offer advantages over orally disintegrating olanzapine tablets by virtue of their larger size and more rapid disintegration, which make concealment of the tablets in the mouth more difficult (11). In this study, disintegration times for orally disintegrating risperidone tablets (both time to onset and mean time to complete disintegration) were significantly more rapid than those reported for orally disintegrating olanzapine tablets (12). To summarize, in this study, orally disintegrating risperidone tablets were well tolerated and rated as very acceptable by patients with schizophrenia or schizoaffective disorder. Further, all patients maintained their stable clinical status with no changes in CGI-S from baseline. Funding and SupportJanssen Ortho Inc sponsored this study. AcknowledgementsThe authors acknowledge the statistical support of Jenny Wang, PhD. References1. Kelleher JP, Centorrino F, Albert MJ, Baldessarini RJ. Advances in atypical antipsychotics for the treatment of schizophrenia: new formulations and new agents. CNS Drugs 2002;16:249–61. 2. Altamura AC, Sassella F, Santini A, Montresor C, Fumagalli S, Mundo E. Intramuscular preparations of antipsychotics: uses and relevance in clinical practice. Drugs 2003;63:493–512. 3. Kinon BJ, Hill AL, Liu H, Kollack-Walker S. Olanzapine orally disintegrating tablets in the treatment of acutely ill non-compliant patients with schizophrenia. Int J Neuropsychopharmacol 2003;6:97–102. 4. Davis JM. Maintenance therapy and the natural course of schizophrenia. J Clin Psychiatry 1985;46:18–21. 5. Gitlin M, Nuechterlein K, Subotnik K, Ventura J, Mintz J, Fogelson D, and others. Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia. Am J Psychiatry 2001;158:1835–42. 6. Gaebel W, Pietzcker A. Multidimensional study of the outcome of schizophrenic patients 1 year after clinic discharge. Predictors and influence of neuroleptic treatment. Eur Arch Psychiatry Neurol Sci 1985;235:45–52. 7. Summary of Product Characteristics. Risperdal Quicklet orodispersible tablets. Available: www.janssen-cilag.co.uk/product/pdf/spc00158.pdf. Accessed 2003 Jan 7. Revised 2004 May 18. 8. Van Schaick EA, Lechat P, Remmerie BM, Ko G, Lasseter KC, Mannaert E. Pharmacokinetic comparison of fast-disintegrating and conventional tablet formulations of risperidone in healthy volunteers. Clin Ther 2003;25:1687–99. 9 .American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Press; 1994. 10. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry 2001;62:153–7. 11. Freudenreich O. Treatment noncompliance with orally disintegrating olanzapine tablets [letter]. Can J Psychiatry 2003;48:353–4. 12. Chue P, Jones B, Taylor CC, Dickson, R. Disintegration profile, tolerability, and acceptability of orally disintegrating olanzapine tablet in patients with schizophrenia. Can J Psychiatry 2002; 47:771–4. Author(s)Manuscript received August 2003, revised, and accepted November 2003. 1. Associate Professor of Psychiatry, University of Alberta Hospital, Edmonton, Alberta. 2. Clinical Pharmacist, Alberta Hospital, Edmonton, Alberta. 3. Director, Clinical Affairs-CNS, Janssen Ortho Inc, Toronto, Ontario. Address for correspondence: Dr P Chue, 9942 108 Street, Edmonton, AB T5K 2J5 e-mail: pchue@ualberta.ca
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