TY - JOUR
AU - Glass, Beverley
AB - Abstract Objectives Clozapine is an atypical antipsychotic used in the treatment of schizophrenia. Due to the patient profile there is a high rate of repackaging of clozapine into dose administration aids (DAAs). Because of reports from hospital pharmacists about discoloration of returned clozapine tablets that have been repackaged into DAAs, the aim of this study was to evaluate the chemical, physical and photostability of these tablets repackaged into a DAA. Method Clozapine tablets were repackaged into DAAs and evaluated for physicochemical stability over a 6-week period at a controlled room temperature (25 ± 1°C; 60 ± 1.5% relative humidity (RH)) and accelerated conditions (40 ± 1°C; 75 ± 1.5% RH). In addition, photostability studies were performed according to the International Committee on Harmonisation (ICH) guidelines. Key findings Chemical stability was confirmed for all storage conditions, including for those photostability (ICH conditions), with the clozapine content occurring within the British Pharmacopoeial (BP) range of 90–110%. Although the physical stability was confirmed for all tests at room temperature (weight uniformity, hardness, friability, disintegration and dissolution), under accelerated conditions the disintegration test did not meet BP requirements. However, the subsequent dissolution test was successful with 85% of clozapine dissolving in 45 min. Conclusions This study illustrates that clozapine, when correctly repackaged, maintains its physical and chemical stability for 6 weeks. As no discoloration of the tablets was observed, it is assumed that the reports received were as a result of improper handling by patients. Based on these findings, it is recommended that patients be advised on the correct handling and storage of their DAAs. clozapine, dose administration aid, repackaging, stability Introduction Usage of compliance aids, or dose administration aids (DAAs), has become increasingly prevalent in current pharmacy practice. Compliance aids are devices which have been developed to assist patients in managing their medicines by arranging individual doses according to their prescribed dose schedule throughout the day. The evidence for the use of these aids has been so favourable in Australia that in 2006 a community-based DAA programme was considered by the Professional Programs and Services Advisory Committee of the Australian Government's Department of Health and Ageing and the first phase of this programme implemented in October 2007.[1] The aim of the DAA programme was to reduce medication-related hospitalizations and adverse events by improving medication management and adherence for people in the community.[2] The programme was established under the Better Community Health Initiative of the Fourth Community Pharmacy Agreement with the Australian Government and was funded to the extent of AUS$72.9 million for provision of these aids through community pharmacy.[3] In May 2010 this funding was extended and increased to $132 million in the Fifth Pharmacy Guild Government Agreement.[3] The most common patient groups that are receiving this service are the elderly, who may be on several medications, and patients that have mental disabilities and have trouble understanding or remembering their dosage regimes. To be eligible for government funding, an evaluation is done not only on the patient but also the caregiver if necessary. This is done to determine the risk of medication misadventure through non-compliance, or the potential for decline in the patient's/caregiver's knowledge of their medication and specific regimen.[4] In identifying patients with a need for this service there are no strict criteria that cover all possible scenarios. It is recognised that while some patients on a single medication may benefit from the use of a DAA, others taking large numbers of medications may have no problems managing their medications.[5] However, it is clear that patients with disabilities or patients that have trouble with memory or understanding may have a marked benefit from utilising the DAA programme. Since the removal of a medicine from its primary packaging invalidates the stability guarantee of the manufacturer, it is the responsibility of the pharmacist to make an informed judgement as to the appropriateness and safety of repackaging medicines into DAAs. Drug manufacturers, on the whole, tend to discourage repackaging of medications as there are few supporting stability data available.[6] Indeed, only a small number of medicines have been investigated for stability following repackaging into DAAs; namely atenolol,[7] paracetamol,[8] frusemide,[9] prochloroperazine[10] and sodium valproate.[11] Pharmacists thus rely largely on individual drug storage recommendations, available national guidelines for repackaging (e.g. in Australia,[12] the UK[13] and the USA[14]) and their basic understanding of inherent drug stability to make recommendations as to whether repackaging is appropriate. Clozapine is a drug taken by patients with schizophrenia who are unresponsive to other antipsychotics,[15] and due to the typical patient profile encountered and the need to closely monitor for severe side effects, including agranulocytosis,[15] this medication is frequently dispensed in a DAA. There are two clozapine brands available in Australia (Clopine® and Clozaril®) and the most commonly used DAA is the Websterpak®, which is made up of a clear plastic blister outer with a heat-sealed (iron-on) foil backing. DAA services are offered by public hospitals in Australia, for example Townsville Hospital, to rehabilitation patients and those patients who are prescribed clozapine, in an effort to encourage these patients to be self-sufficient in managing their medicines in the community. The Monthly Index of Medical Specialities (MIMS) Consumer Medicine Information (CMI) for Clopine and Clozaril advises patients to keep the medication in its original packaging until it is time to take it, keeping it in a cool dry place where the temperature stays below 30°C.[16,17] The only difference between the storage conditions of the two brands outlined is that the Clopine® CMI indicates that packaging also requires protection from light.[16] Because of reports received from hospital pharmacists about discoloration of returned clozapine tablets that have been repackaged into DAAs, and the evidence in the literature that it is susceptible to oxidation,[18] the aim of this study was to evaluate the chemical, physical and light stability of these tablets when repackaged into a DAA. Methods Physicochemical studies were performed on clozapine tablets (Clopine® from Hospira, batch 32210, expiry date October 2013; and Clozaril® from Novartis, batch U1486, expiry date March 2014) removed from their original blister packaging and repackaged into separate DAAs frequently employed in practice (Websterpak®),[8,19] over a 6-week period. Physical characteristics of the tablets, namely tablet weight uniformity, physical appearance, thickness, hardness, friability, disintegration and dissolution, were determined according to British Pharmacopoeia (BP) requirements, and the chemical stability was confirmed by high-performance liquid chromatography (HPLC) (detailed below). Photostability studies (Q1B) were performed as per International Committee on Harmonisation (ICH) guidelines.[20] Storage conditions The DAAs were stored under two sets of environmental conditions, namely (1) accelerated conditions (40 ± 1°C; 75 ± 1.5% relative humidity (RH)) using a Binder Climate Chamber KBF 720 and (2) controlled room temperature conditions (25 ± 1°C; 60 ± 1.5% RH) by placing the DAA with the blister side facing up on a windowsill in the laboratory that was exposed to window-filtered sunlight and fluorescent lights. The various tests were performed at defined intervals over a 6-week period and the results were compared to control samples stored in the original packaging at the above environmental conditions. Chemical stability HPLC was used to provide accurate, precise and specific quantification of clozapine in the presence of its excipients and possible degradation products. Method validation for accuracy, precision, specificity and linearity was carried out as per ICH guidelines.[21] The Varian Prostar system consisted of a 240-solvent delivery module, 410 autosampler and a 330 photodiode array detector. The stationary phase was a Varian pursuit xRs C8 (150 × 4.6 mm) reverse-phase column. A methanol/water/triethylamine (800 : 200 : 0.75) mobile phase and detection wavelength of 257 nm was used. The flow rate was 1 ± 0.1 ml/min and the injection volume was 10 µl. A calibration curve for clozapine was constructed from 25–200 µg/ml. Triplicate samples were prepared by accurately weighing and finely crushing 20 tablets for each of the storage conditions. The powder was mixed and diluted appropriately with mobile phase to prepare a solution containing approximately 125 µg/ml clozapine which was then filtered through a 0.45 µm filter (Millipore) prior to analysis. Photostability DAAs were placed blister side up in a Heraeus Suntest CPS+ (ATLAS, Gelnhausen, Germany) and exposed to the visible wavelength range 400–800 nm at 1.2 million lux hours and the UV wavelength range 300–400 nm at 200 W h/m2 as per ICH guidelines.[20] Protected samples (wrapped in aluminium foil) were used as dark controls to evaluate the contribution of any thermally induced change. Triplicate samples were prepared and analysed by the HPLC method described above. Physical stability Tablet weight uniformity was determined using an AND HM-200 analytical balance. Tablet friability was determined using a Vankel dual drum friabilator and tablet hardness and thickness determined using a Vankel VK 200 tester. Disintegration was determined using a Vankel 35–1300 disintegration tester. A disc was added to each tube and purified water (Millipore ELIX10 electro-deionisation system) (37 ± 0.5°C) was used as the medium. Dissolution tests were performed on a BP Apparatus II (paddle apparatus) (Vankel, VK 7000) operating at 100 rpm, using an acetate buffer (pH 5.8) (BDH Merck) dissolution medium (900 ml) maintained at 37 ± 0.5°C. Samples were filtered through a 0.45 µm filter (Millipore) and the filtrate diluted 1 : 5 with dissolution medium and assayed on a Cary 100 UV/VIS spectrophotometer at 290 nm. Photographs of the tablets were taken to record any colour changes. Results Chemical stability The retention time for clozapine was approximately 4.25 min with peak purity determined through spectral library comparison and peak purity determinations (Varian Prostar Polyview 2000) of the respective samples and standard solutions. The absence of co-eluting degradants and excipients was verified with spectral similarities of more than 0.999 (photodiode array detection) for the pure and sample clozapine peaks achieved. Linearity was confirmed over the concentration range used (r2 = 0.9999). Concentrations of clozapine in the samples were determined from respective peak areas in relation to constructed standard curves and then converted to a percentage of the initial clozapine concentration. The amount of clozapine per tablet (versus the labelled amount) as a function of storage time is shown in Table 1. The chemical stability of both brands of clozapine under all experimental parameters was confirmed by the HPLC method. All samples tested were within the BP limits of not less than 90.0% and not more than 110.0% of the labelled amount of clozapine (C18H19ClN4). Table 1 Chemical stability of clozapine tablets (A, Clopine; B, Clozaril) under (1) accelerated (40 ± 1°C; 75 ± 1.5% relative humidity (RH)) conditions in a climate chamber and (2) under controlled-room-temperature (25 ± 1°C; 60 ± 1.5% RH) conditions (values expressed as mean ± SEM, n = 3) Storage conditions . Clozapine remaining (%) . Control (A) 93.29 Clopine  Week 3 (1) 91.14  Week 3 (2) 100.33  Week 6 (1) 90.40  Week 6 (2) 91.64 Control (B) 91.92 Clozaril  Week 3 (1) 98.86  Week 3 (2) 98.46  Week 6 (1) 99.00  Week 6 (2) 98.42 Storage conditions . Clozapine remaining (%) . Control (A) 93.29 Clopine  Week 3 (1) 91.14  Week 3 (2) 100.33  Week 6 (1) 90.40  Week 6 (2) 91.64 Control (B) 91.92 Clozaril  Week 3 (1) 98.86  Week 3 (2) 98.46  Week 6 (1) 99.00  Week 6 (2) 98.42 Open in new tab Table 1 Chemical stability of clozapine tablets (A, Clopine; B, Clozaril) under (1) accelerated (40 ± 1°C; 75 ± 1.5% relative humidity (RH)) conditions in a climate chamber and (2) under controlled-room-temperature (25 ± 1°C; 60 ± 1.5% RH) conditions (values expressed as mean ± SEM, n = 3) Storage conditions . Clozapine remaining (%) . Control (A) 93.29 Clopine  Week 3 (1) 91.14  Week 3 (2) 100.33  Week 6 (1) 90.40  Week 6 (2) 91.64 Control (B) 91.92 Clozaril  Week 3 (1) 98.86  Week 3 (2) 98.46  Week 6 (1) 99.00  Week 6 (2) 98.42 Storage conditions . Clozapine remaining (%) . Control (A) 93.29 Clopine  Week 3 (1) 91.14  Week 3 (2) 100.33  Week 6 (1) 90.40  Week 6 (2) 91.64 Control (B) 91.92 Clozaril  Week 3 (1) 98.86  Week 3 (2) 98.46  Week 6 (1) 99.00  Week 6 (2) 98.42 Open in new tab Photostability Irradiation under ICH conditions resulted in 98.36 and 95.58% of clozapine remaining for Clopine and Clozaril, respectively, while 99.33% was reported for the dark controls (Heraeus Suntest CPS+ was maintained at 40°C). This confirms that the minimal degradation which occurred was due to light and not to heat generated on exposure. Physical stability The average weight and friability at each sampling period for both brands, under all storage conditions, conformed to the BP standards. In terms of hardness, the most notable change was a 59.0% increase in the Clozaril formulation's hardness after 6 weeks under accelerated conditions. This coincided with a failed result in the BP disintegration test. However, the requirement of not less than 85% of active substance dissolved by the 45 min point was met by both Clopine and Clozaril at all times and under all experimental conditions, including for those tablets exposed to photostability testing. Therefore, the quality of clozapine tablets was confirmed regarding their disintegration, hardness, weight uniformity, friability and dissolution rate over the 6-week period. There were no noticeable colour changes in the tablets stored under the controlled room temperature and accelerated conditions; however, tablets that were removed from the DAA and left on the windowsill in the lab next to the controlled-room-temperature samples displayed a pronounced (orange/pink) discoloration after 6 weeks (Figure 1). Figure 1 Open in new tabDownload slide Photographic comparison of the colour of clozapine tablets from left to right: control sample, sample stored under controlled-room-temperature conditions after 6 weeks, and a sample left out of the DAA packaging on the windowsill after 6 weeks (Clopine is shown on the top row, Clozaril on the bottom row). Discussion The physical and chemical stability of clozapine tablets repackaged into a DAA and stored for a period of 6 weeks was confirmed for all storage conditions; namely, controlled-room-temperature conditions (25 ± 1°C; 60 ± 1.5% RH), accelerated conditions (40 ± 1°C; 75 ± 1.5% RH) and ICH light conditions. No discoloration of the tablets was noted over the 6 week period for any of the above conditions. However, removal of the tablets from the DAA with subsequent exposure to light, air and moisture under ambient conditions resulted in significant coloration of the tablets after a 6 week period outside of the DAA packaging. This study was conducted according to international guidelines for ambient, accelerated and ICH light conditions. It was also completed over an appropriate 6 week storage period to account for a maximum 2 week repackaging period in the hospital and the subsequent 4 week storage period in the patient's home. Since no discoloration of the tablets was observed for the above ICH storage conditions, and to address the reports from hospital pharmacists regarding the discoloration seen in some of the repackaged clozapine tablets, tablets were removed from the DAA packaging and exposed to light, air and moisture for a period of 6 weeks to mimic a worst-case scenario in terms of possible incorrect storage and handling in patient's homes. A progressive discoloration was noticed over the 6-week period for these exposed tablets. A limitation of the study is that the exact manner or extent to which medicines repackaged in DAAs were incorrectly stored and handled in patient's homes is not known, and further research should be undertaken in this area. Stability implications of repackaging drugs in DAAs frequently employed in practice have previously been investigated.[7–22] Results from these studies have provided some specific information on drugs at risk for repackaging into DAAs. For those medicines sensitive to moisture, such as paracetamol, the importance of using an appropriate well-sealed DAA was noted. For light-sensitive drugs such as frusemide and prochlorperazine, the pharmacist's role in minimising light exposure during repackaging and counselling the patient on the storage of the DAA, in terms of protection from light, was confirmed. Since the literature has shown the susceptibility of clozapine to oxidation,[18] it is assumed that an oxidative process in part played a role in the discoloration of these tablets. This study provides further evidence to inform healthcare professionals and enable them to ensure the quality of medicines repackaged into DAAs. Clozapine tablets, when correctly repackaged into DAAs and appropriately stored protected from light and heat in the pharmacy and in the patient's home, will maintain physical and chemical stability for 6 weeks. This study highlights the important role of the pharmacist in ensuring the stability of repackaged drug products in the pharmacy by limiting the time between removal of these tablets from the original packaging and repackaging into the DAA. In addition, the pharmacist should counsel the patient on the importance of maintaining the integrity of the DAA, because of the discoloration observed when clozapine tablets were removed from the DAA and exposed to light, air and moisture. The following practical recommendations for patients include: (1) monitoring the integrity of the DAA throughout the in-use period; (2) careful removal of tablets from the DAA to prevent accidental rupture of nearby blisters, thus exposing tablets to air, moisture and light; and (3) consideration of an appropriate location to store the DAA to avoid unnecessary exposure to light, heat and humidity. This information should be given to all patients who receive their medicines in a DAA to ensure the quality of their repackaged medicines. Conclusions The physicochemical stability of the repackaged clozapine has been assured for 6 weeks when exposed to both accelerated conditions relating to temperature, humidity and light and the standard temperature, lighting and humidity conditions that may occur both in a pharmacy, and in a patient's home. This study therefore provides evidence that clozapine when appropriately repackaged by pharmacists and handled by carers/patients is stable for 6 weeks. However, the discoloration reported by health professionals in the practice has been observed to occur when the clozapine tablets are removed from the packaging and thus has the potential to occur if the DAA is damaged either during packaging in the pharmacy or use by the patient. Thus, in addition to adding to the body of evidence on stability implications of repackaging drugs into DAAs, the study again highlights that the role of the pharmacist is not only in repackaging these medications into DAAs but in counselling patients on their appropriate storage and use, particularly in the careful removal of tablets from the DAA to prevent accidental rupture of adjacent blisters, thus exposing tablets to air, light and moisture. Declarations Conflict of interest The Authors declare that they have no conflicts of interest to disclose. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Acknowledgement We acknowledge Novartis Pharmaceuticals Australia Pty Ltd for the generous donation of clozapine raw material. References 1 Australian Government Department of Health and Ageing: Pharmacy . Previous Community Pharmacy Agreements . www.health.gov.au/internet/main/publishing.nsf/Content/previous-community-pharmacy-agreements (accessed 4 August 2011). 2 Pharmacy Guild of Australia . The Roadmap . www.guild.org.au/The_Guild/tab-Pharmacy_Services_and_Programs/The_Roadmap/The+Roadmap.page (accessed 4 August 2011). 3 Australian Government . The Fifth Community Pharmacy Agreement between the Commonwealth Government and the Pharmacy Guild of Australia . www.5cpa.com.au/iwov-resources/documents/The_Guild/PDFs/Other/Fifth%20Community%20Pharmacy%20Agreement.pdf (accessed 4 August 2011). 4 Pharmaceutical Society of Australia . Professional Practice Standards. Version 4. Standard 7: Dose Administration Aids Service . Canberra : Pharmaceutical Society of Australia ; 2010 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 5 Pharmaceutical Society of Australia . Professional Practice Standards, version 4. Standard 7: Dose Administration Aids Service . www.psa.org.au/site.php?id=6166 (accessed 4 August 2011). 6 Church C , Smith J. How stable are medicines moved from original packs into compliance aids? Pharm J 2006 ; 276 : 75 – 81 . Google Scholar OpenURL Placeholder Text WorldCat 7 Chan K et al. Pilot study of the short-term physico-chemical stability of atenolol tablets stored in a multi-compartment compliance aid . EJHP Sci 2007 ; 13 : 60 – 66 . Google Scholar OpenURL Placeholder Text WorldCat 8 Haywood A et al. Stability implications of repackaging paracetamol tablets into Dose Administration Aids . J Pharm Prac Res 2006 ; 36 : 21 – 24 . Google Scholar OpenURL Placeholder Text WorldCat 9 Bowen L et al. Stability of frusemide tablets repackaged in Dose Administration Aids . J Pharm Prac Res 2007 ; 37 : 178 – 181 . Google Scholar Crossref Search ADS WorldCat 10 Glass B et al. Prochlorperazine tablets repackaged into dose administration aids: can the patient be assured of quality? J Clin Pharm Ther 2009 ; 34 : 161 – 169 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Llewelyn VK et al. Stability of sodium valproate tablets repackaged into dose administration aids . J Pharm Pharmacol 2010 ; 62 : 838 – 843 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Pharmaceutical Society of Australia . Guidelines and standards for pharmacists: dose administration aids service . July 2007. www.psa.org.au/site.php?id=2065 (accessed 19 January 2011). 13 Royal Pharmaceutical Society of Great Britain . Medicines, Ethics, and Practice: A Guide for Pharmacists , vol. 27. London : Pharmaceutical Press , 2003 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 14 US Pharmacopeial Convention. US Pharmacopeia 33 – National formulary 28 <681 > Repackaging into single-unit containers and unit-dose containers for nonsterile solid and liquid dosage forms . 2010 . 15 Australian Medicines Handbook . Australian Medicines Handbook , 10th edn. Adelaide : Australian Medicines Handbook , 2010 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 16 MIMS Australia . Clopine® CMI. MIMS Online [electronic resource] . 2011 . 17 MIMS Australia . Clozaril® CMI. MIMS Online [electronic resource] . 2011 . 18 Kohara T et al. Y-931, a novel atypical antipsychotic drug, is less sensitive to oxidative phenomena . Chem Pharm Bull (Tokyo) 2002 ; 50 : 818 – 821 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Ware GJ et al. Unit dose calendar packaging and elderly patient compliance . N Z Med J 1991 ; 104 : 495 – 497 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 20 ICH Steering Committee. ICH Harmonised Tripartite Guideline. Stability Testing: photostability testing of new drug substances and products Q1B . 1996. www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1B/Step4/Q1B_Guideline.pdf (accessed 11 May 2011). 21 ICH Steering Committee. ICH Harmonised Tripartite Guideline. Validation of Analytical Procedures: Text and Methodology Q2(R1) . 2005. www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf (accessed 11 May 2011). 22 Glass BD et al. Compliance aids and medicine stability: new evidence of quality assurance . Curr Drug Saf Jan 2009 ; 4 : 74 – 78 . Google Scholar Crossref Search ADS WorldCat © 2011 The Authors. IJPP © 2011 Royal Pharmaceutical Society This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2011 The Authors. IJPP © 2011 Royal Pharmaceutical Society
TI - Clozapine repackaged into dose administration aids: a common practice in Australian hospitals
JF - International Journal of Pharmacy Practice
DO - 10.1111/j.2042-7174.2011.00155.x
DA - 2012-01-11
UR - https://www.deepdyve.com/lp/oxford-university-press/clozapine-repackaged-into-dose-administration-aids-a-common-practice-3ee7TrEcQx
SP - 4
EP - 8
VL - 20
IS - 1
DP - DeepDyve
ER -