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A choice of formulations of antipsychotic medications provides valuable options for treating patients with schizophrenia. Intramuscular injectable antipsychotics offer advantages over traditional oral tablets in the emergency treatment of the acute phase of schizophrenia, and long-acting depot formulations are useful in the stable phase, particularly when adherence problems exist. However, situations occur wherein patients have difficulty swallowing traditional oral tablets, or may spit out liquid medication, or for whom an injectable formulation is contraindicated or unacceptable. Likewise, there are patients who appear to comply with tablet ingestion but instead conceal the medication between their gums and cheek and subsequently spit it out (“cheeking”). This may lead the clinician to wrongly conclude that the medication is ineffective, prompting either a premature discontinuation of an effective treatment or an inappropriate increase in dosage. To address these problems that are common in real-life clinical settings, an oral lyophilisate, or orally disintegrating tablet, was developed for olanzapine. Unlike conventional tablets that must be taken with liquid and swallowed, this formulation begins to disintegrate when placed on the tongue and may therefore enhance drug adherence in patients who are less than optimally compliant. Although liquid formulations may offer similar advantages in this patient population, the orally disintegrating tablet is more convenient and easy to store and does not require measurement to ensure proper dosage. This 7-day, open-label pilot study assessed the dissolution profile, tolerability, and acceptability of once-daily orally disintegrating olanzapine tablets in schizophrenia patients who were previously stabilized on oral olanzapine tablets (1). MethodsIn this single-site, open-label study, outpatients meeting DSM-IV criteria for schizophrenia (2) who were stable on monoantipsychotic therapy with oral olanzapine (5, 10, 15, or 20 mg daily) for a minimum of 7 days were switched to the same dosage of orally disintegrating tablet (supplied by Eli Lilly) for 7 days. Patients signed written informed consent documents after the procedures and possible side effects had been fully explained. The site’s ethical review board approved the study protocol. A physical examination and laboratory investigations were completed at screening, including complete blood count (CBC) with differential thyroid stimulating hormone (TSH), hepatitis panel, and liver function tests (LFTs). For female patients, a serum beta human chorionic gonatotrophin (ß-HCG) level was also obtained. CBC and LFTs were repeated upon completion of the study. Erect and supine blood pressure and pulse were monitored at each visit, 30 minutes postdose. At each daily visit, an orally disintegrating olanzapine tablet was placed into the patient’s mouth following a drink of water. Patients opened their mouths every 15 seconds for visual assessment of elapsed time between administration and the start of disintegration. Once disintegration began, patients opened their mouths every minute to determine when disintegration was complete. The same observer administered the tablet and monitored the tablet dissolution for every patient and dose. The times to initial and complete disintegration of the orally disintegrating olanzapine tablet were summarized, using the mean and standard deviation of the times measured. Adverse events were elicited at each visit postdose. At the last visit, the observer administered a patient-acceptance questionnaire that was specifically developed for the study. Patients were asked if this was an acceptable way of taking their medication and what they had liked about this new type of tablet. ResultsAll 11 patients (6 men, 5 women; 82% white; mean age 32.5 years) completed the study. Mean duration of illness was 9.8 years, and mean duration of olanzapine therapy was 9.3 months. The mean and mean modal dosages of the orally disintegrating olanzapine tablet were 12.7 mg daily (SD5.2) and 15.0 mg daily, respectively. In nearly all cases, the tablet began to dissolve by 15 seconds, with an overall mean time to initial disintegration of 15.78 seconds (Table 1). The amount of time for the tablet to completely disappear ranged from 15 seconds to 5 minutes, with an overall mean elapsed time of 0.97 minutes. There was a decreasing trend of mean disintegration times across days of treatment. There were no serious adverse events. Of the patients, 3 reported nonserious
clinically significant adverse events. Purpuric rash (2 patients) and headache
and depression (1 patient) were reported—but were preexisting—whereas asthenia
(1 patient) and insomnia (1 patient) were new. None of the reported adverse
events led to withdrawal from the study, dosage reduction, or institution
of concomitant therapy. No abnormalities in vital signs nor changes in
laboratory values occurred during the course of the study.
All 11 patients reported that the orally disintegrating tablet was an acceptable way of taking medication; subjective comments were all positive, ranging from ease of use to pleasant taste of the tablet. DiscussionThis study found that the orally disintegrating olanzapine tablet is acceptable to patients with schizophrenia. Rapid disintegration of the tablet occurs when it comes into contact with saliva. For this reason, the formulation may be an effective option for overcoming noncompliance due to cheeking. It may also be useful for patients who have difficulty swallowing, for whom an injectable medication is not feasible, or for covertly nonadherent patients. Medication noncompliance may account for up to 55% of relapse in schizophrenia (3), which may be a function of the drug administration route, its ease of use, and tolerability (4). In addition, many patients with schizophrenia do not adhere to prescribed medication because of a refusal to acknowledge that they are ill (lack of insight). Clearly, nonadherence with treatment has multiple determinants (5), but an oral medication wherein the clinician is assured of delivery may be part of an overall strategy to improve the care of schizophrenia patients. The tolerability of an antipsychotic agent is another factor that may contribute to nonadherence (6). One patient experienced asthenia (described as fatigue approximately 3 to 4 hours after ingestion of the orally disintegrating olanzapine tablet); this may have related to the study drug according to the clinical investigator. Although, in this case, the asthenia was temporally associated with olanzapine treatment, in other large-scale clinical studies, the incidence of asthenia did not differ from placebo or haloperidol (7). One patient experienced insomnia. It is possible that, in these 2 patients, the regular supervised ingestion of their medication represented a change in total weekly dosages of olanzapine, despite no change in the dosage strength during the study. Most adverse events were preexisting and thus do not appear to represent formulation-related adverse events. Unpublished data from previous Phase 1 clinical trials in healthy volunteers demonstrated that standard olanzapine tablets and orally disintegrating olanzapine tablets were bioequivalent, according to standard bioequivalence criteria (data on file, Eli Lilly and Company). Consequently, the onset of action of orally disintegrating olanzapine tablets is not faster than in standard oral olanzapine tablets, despite rapid disappearance from the mouth, because buccal absorption does not appear to occur to any measurable extent. Pharmacokinetic data were not collected, given that this was an early pilot study involving the first exposure of the orally disintegrating olanzapine tablet in patients with schizophrenia, with the primary objectives of examining practicality and tolerability in this patient population. Due to the small patient sample size and open-label study design, limited conclusions can be drawn from this pilot trial. Randomized and controlled larger-scale studies with therapeutic blood monitoring would be useful to determine longer-term compliance and tolerability with orally disintegrating olanzapine tablets, compared with standard tablets. Similarly, to assess the utility and acceptability of this formulation in more severely ill patients, studies that involve patients in inpatient and emergency settings are desirable. The results of the present study suggest that orally disintegrating olanzapine tablets have a dissolution profile that is practical for use in patients with schizophrenia and is well tolerated and accepted with no additional safety concerns. Funding and SupportEli Lilly and Company sponsored this study. AcknowledgementsThe authors would like to acknowledge members of the study team, including Drs P Silverstone, M Cummins, J-M Le Melledo, N Coupland, P Tibbo, and S Asghar. References1. Chue P, Jones B, Adams C. Olanzapine rapidly disintegrating tablet in schizophrenic patients. Poster presented at the 11th World Congress of Psychiatry; August 6–11, 1999; Hamburg, Germany. 2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Press; 1994. 3. Hogarty GE, Goldberg SC. The Collaborative Study Group. Drug and sociotherapy in the aftercare of schizophrenic patients: one-year relapse rates. Arch Gen Psychiatry 1973;28:54–64. 4. Fenton WS, Blyler CR, Heinssen RK. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull 1997;23:637–51. 5. Kampman O, Lehtinen K. Compliance in psychoses. Acta Psychiatr Scand 1999;100:167–75. 6. Corrigan PW, Lieberman RP, Engel JD. From compliance to collaboration in the treatment of schizophrenia. Hosp Community Psychiatry 1990;41:1203–11. 7. Tollefson GD, Beasley CM Jr, Tran PV, Street JS, Krueger JA, Tamura RN, and others. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997;154:457–65.
Manuscript received October 2001, revised and accepted July 2002. 1 Associate Professor of Psychiatry, University of Alberta Hospital, Edmonton, Alberta. 2 Clinical Research Physician, Eli Lily Canada, Scarborough, Ontario. 3 Senior Scientific Communications Associate, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana. 4 Associate Professor, Department of Psychiatry, University Of Calgary, Calgary, Alberta; Clinical Research Physician, Eli Lilly Canada, Scarborough, Ontario. Address for correspondence: Dr P Chue, 3rd Floor, 9942-108 Street, Edmonton, AB T5K 2J5 e-mail: pchue@ualberta.ca
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