Age-appropriate Formulations Research Articles

Patient focused design and development of an age-appropriate paediatric formulation

Patient focused design and development of an age-appropriate paediatric formulation

Solid Oral Flexible Formulations for Pediatric and Geriatric patients: Age-appropriate Formulation Platforms

The oral route of drug administration is mostly preferred by paediatric and geriatric patients. Patient non-compliance due to poor taste and swallowing problems are major issues in paediatric and geriatric drug therapy. Lack of age-appropriate formulations, inadequate labelling instructions, non-compatible and non-palatable medicines are the main reasons for medication errors in paediatric patients. This review mainly highlights major issues of paediatric and geriatric drug therapy and provides the design of oral flexible formulations as an alternative formulation design for age appropriate formulation development. Development of solid oral flexible formulations as an alternative to existing marketed formulations such as conventional tablets, orally disintegrating tablets, chewable and dispersible tablets for paediatric and geriatrics patients is described. Details about drug properties, excipient selection and taste masking approaches were described. The need for bioavailability and bioequivalence studies for flexible formulations also described. Development of flexible formulations as an alternative to marketed different formulations of the same drug would reduce the cost of the formulation for patients particularly developing countries where accessibility to various types of formulations is less. Flexible tablet formulations can be conveniently used by the patients as orally swallowable, orally disintegrating, chewable and as dispersible tablets. Sprinkle formulations such as pellets, granules packed in capsules or sachets can be conveniently used by paediatric and geriatric patients. Properly designed and developed flexible formulations for new chemical entities and off-patent drugs are need of the hour to provide better treatment to varying age groups of paediatrics and geriatrics.

Innovation in Formulation Development for Older People

In many cases geriatric patients constitute the main users of a medicinal product and not a special population. Even though the heterogeneity of the geriatric patient population is vast with physiological changes occurring with advanced age being diverse, the presence of multi-morbidity, disability and frailty are rather common indicating a special need for age-appropriate formulations. Dosing flexibility, swallowability and overall manageability of drug products are among the issues that have been identified as most important for this age group and thus they should drive the design of therapeutic options for the geriatric population. Pharmaceutical industry is slowly starting to respond to these challenges with an increasing number of innovative geriatric-friendly formulations that have either reached the market or are currently under development. The aim of this article is to discuss the adequacy of the available geriatric-friendly formulations to meet the special needs of this age group, placing particular emphasis on a couple of marketed medicinal products with innovative geriatric-friendly formulation technologies.

State of paediatric medicines in the European Union

At the end of October, the European Commission presented a report to the European Parliament and the Council on the progress made in children’s medicines since the entry into force...

Oral medicine modification for older adults: a qualitative study of nurses

ObjectiveOral medicines are frequently modified (eg, tablets crushed) for older adults. However, these modifications can have clinical, legal and/or ethical implications. Nurses bear responsibility for medicine administration and hence, perform...

Patient acceptability, safety and access: A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations

The selection and design of age-appropriate formulations intended for use in paediatric and geriatric patients are dependent on multiple factors affecting patient acceptability, safety and access. The development of an economic and effective product relies on a balanced consideration of the risks and benefits of these factors. This review provides a comprehensive and up-to-date analysis of oral dosage forms considering key aspects of formulation design including dosage considerations, ease of use, tolerability and safety, manufacturing complexity, stability, supply and cost. Patient acceptability has been examined utilising an evidence-based approach to evaluate regulatory guidance and literature. Safety considerations including excipients and potential risk of administration errors of the different dosage forms are also discussed, together with possible manufacturing and supply challenges. Age appropriate drug product design should consider and compare i) acceptability ii) safety and iii) access, although it is important to recognise that these factors must be balanced against each other, and in some situations a compromise may need to be reached when selecting an age-appropriate formulation.

Development of Extended-Release Oral Flexible Tablet (ER-OFT) Formulation for Pediatric and Geriatric Compliance: an Age-Appropriate Formulation.

Development of age-appropriate formulation suitable for pediatric and geriatric patients involves various challenges. The objective of this research was to develop extended-release oral flexible tablet (ER-OFT) formulation using carbamazepine (CBZ) as model drug for pediatric and geriatric compliance. ER-microparticles of carbamazepine, a BCS class 2, and narrow therapeutic index (NTI) drug, were prepared using ethyl cellulose as matrixing polymer and hypromellose as hydrophilic pore former. Microparticles were prepared using high-shear granulator fitted with an atomizing spray system. Granulation of carbamazepine and ethyl cellulose (EC-FP) with ethanolic binder solution resulted in ER-microparticles with extended-release >16h. Release kinetics of ER microparticles showed Higuchi model by drug diffusion and erosion. Korsemeyer-peppas release exponent "n" value 0.42 suggested Fickian diffusion. ER-OFT was prepared by blending of ER-microparticles with water-insoluble compressible aid and disintegrating agent. ER-OFT was characterized for performance characteristics and elemental impurities. As the polymer content in formulation was <10%, the size of ER-OFT was smaller compared to marketed ER-formulations. ER-OFT showed in vitro disintegration time of <30s as per USP and dispersion time of ∼60 to 180s in 5 to 10mL of water. Drug release profiles of ER-microparticles and ER-OFT were comparable as f2 values were >50. In vitro dissolution of ER-OFT was comparable to the marketed ER formulation in the pH range of GIT. ER-OFT can be orally swallowed, orally disintegrating, and used as dispersible tablets. Compared to non-disintegrating type ER-formulations, ER-OFT would provide uniform drug release in GIT with low within-subject variability an essential criterion for NTI drug.

Are age-appropriate antibiotic formulations missing from the WHO list of essential medicines for children? A comparison study

ObjectiveThere is a global call for formulations, which are better suited for children of different age categories and in a variety of settings. One key public health area of interest...

Development of Oral Flexible Tablet (OFT) Formulation for Pediatric and Geriatric Patients: a Novel Age-Appropriate Formulation Platform.

Development of palatable formulations for pediatric and geriatric patients involves various challenges. However, an innovative development with beneficial characteristics of marketed formulations in a single formulation platform was attempted. The goal of this research was to develop solid oral flexible tablets (OFTs) as a platform for pediatrics and geriatrics as oral delivery is the most convenient and widely used mode of drug administration. For this purpose, a flexible tablet formulation using cetirizine hydrochloride as model stability labile class 1 and 3 drug as per the Biopharmaceutical Classification System was developed. Betadex, Eudragit E100, and polacrilex resin were evaluated as taste masking agents. Development work focused on excipient selection, formulation processing, characterization methods, stability, and palatability testing. Formulation with a cetirizine-to-polacrilex ratio of 1:2 to 1:3 showed robust physical strength with friability of 0.1% (w/w), rapid in vitro dispersion within 30s in 2-6ml of water, and 0.2% of total organic and elemental impurities. Polacrilex resin formulation shows immediate drug release within 30min in gastric media, better taste masking, and acceptable stability. Hence, it is concluded that ion exchange resins can be appropriately used to develop taste-masked, rapidly dispersible, and stable tablet formulations with tailored drug release suitable for pediatrics and geriatrics. Flexible formulations can be consumed as swallowable, orally disintegrating, chewable, and as dispersible tablets. Flexibility in dose administration would improve compliance in pediatrics and geriatrics. This drug development approach using ion exchange resins can be a platform for formulating solid oral flexible drug products with low to medium doses.

Rationale and Design of a Phase III Single-Arm Multicenter Study of Dabigatran Etexilate for the Secondary Prevention of Venous Thromboembolism in Children

Background: In children, the incidence of venous thromboembolism (VTE) is increasing and is often associated with underlying diseases such as cancer, or risk factors such as thrombophilia. Following treatment for acute VTE, thrombosis or thromboembolic events can recur particularly if a clinical risk factor for VTE persists. The efficacy and safety of the oral anticoagulant dabigatran etexilate (DE) have been demonstrated in a number of thrombosis-related indications in adults, including for secondary VTE-prevention. There are, however, potential differences between adults and children related to developmental physiology and pharmacology and therefore trials to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of DE in children are required. To date, all pediatric phase IIa studies conducted have shown a similar PK and PK/PD relationship of DE in comparison to adult studies.Objective: To describe the design of a study to evaluate the safety and PK-PD of DE for secondary prevention of VTE in children aged 0-<18 years.Methods: This phase III, open-label, single-arm, multicenter study will be conducted at ~100 sites worldwide (NCT02197416). Eligible patients will have completed a course of initial treatment for confirmed acute VTE (for ≥ 3 months) and be considered at high risk for VTE recurrence due to the remaining presence of a clinical risk factor. Approximately 100 subjects between 0-<18 years of age will be included. Treatment with DE will extend up to 12 months, or less if the clinical risk factor resolves, with a follow-up visit 28 days after the last dose. DE will be administered twice daily as capsules, pellets or oral liquid formulation, depending on subject age and their ability to swallow capsules or pellets. A dosing nomogram will be used to scale down an adult dose based on the child’s age and weight. Initial doses calculated using the nomogram should achieve steady-state trough concentrations of DE of between 50 and < 250 ng/ml, a range which is assumed to result in safe and effective use of DE in this pediatric population; after about 3 days, trough dabigatran plasma concentration will be measured and DE may be titrated up or down to achieve the target steady-state trough plasma concentration.Results: Demographic and medical history data will be collected for all participants. The primary outcomes to be evaluated are instances at 6 and 12 months of image-proven VTE recurrence; major and minor bleeding, including clinically relevant non-major bleeding; and overall and thrombotic/thromboembolic mortality. All elements of the primary endpoints will be evaluated by an independent adjudication committee that will confirm or refute outcome events. The secondary outcomes are rates of post-thrombotic syndrome at 6 and 12 months; PK and PD (e.g., activated partial thromboplastin time and ecarin clotting time); and the number of DE dose adjustments required during the treatment period. Data on the acceptability of the age-appropriate drug formulation, the tolerability of the study medication, adverse events, treatment discontinuations due to an adverse event, and laboratory and clinical parameters will also be collected during the study. Safety and tolerability will be monitored by the independent Data Monitoring Committee.Conclusion: This phase III study has been designed to provide data on the safety and PK-PD of DE for the secondary prevention of VTE in children aged 0-<18 years. DisclosuresLuciani:Boehringer Ingelheim: Other: Member of Pediatric Expert Working Group for Boehringer Ingelheim. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Manastirski:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Wang:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Mitchell:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy. Huang:Boehringer Ingelheim: Employment. Halton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim.

Pharmacokinetics and Safety of Valganciclovir in Pediatric Heart Transplant Recipients 4 Months of Age and Younger.

Valganciclovir (VGCV) effectively prevents cytomegalovirus disease in adult and pediatric solid organ transplant recipients. A dosing algorithm for VGCV for pediatric patients, based on body surface area and renal function, provides a personalized dose using age-appropriate formulations. The suitability of this dosing algorithm has not been assessed specifically in infants and neonates 4 months of age and younger receiving a solid organ transplant. This multicenter prospective study evaluated the pharmacokinetics (PK) and safety of VGCV oral solution in 17 heart transplant recipients 4 months of age and younger who received 2 doses of VGCV on consecutive days using the pediatric dosing algorithm. Plasma concentrations of ganciclovir (GCV) were analyzed at specified times up to 24 hours post VGCV administration. GCV concentration data were available from 16 patients. The combined data from this study and historic study datasets were used to establish a 2-compartment population PK model with first-order formation to describe the PK of GCV after oral VGCV administration in patients across all pediatric age ranges, including those younger than 4 months of age. Estimated mean area under the curve during the 0-24 hours dosing interval for these patients was 68.1 μg·h/mL. The pediatric dosing algorithm for VGCV (utilizing individuals' body surface area and renal function) provides systemic GCV exposures in patients younger than 4 months that are similar to those observed in older pediatric populations. The data indicate that this dosing algorithm is appropriate across the entire pediatric age range, including this youngest age group.

Hemodynamic and metabolic effects of a new pediatric dobutamine formulation in hypoxic newborn pigs.

The aim of our study was to measure drug-related changes in hemodynamics and oxygen metabolism in response to different doses of an age-appropriate dobutamine formulation in hypoxic pigs. A secondary aim was to validate superior vena cava flow (SVCF) as a marker of cardiac index (CI) for subsequent clinical trials of this formulation in humans. Newborn pigs (n = 18) were exposed to 2-h hypoxia (10-15% oxygen) followed by reoxygenation (21-30% oxygen 4 h). After 1-h reoxygenation, pigs were randomized to: control group (no treatment), dobutamine infusion at a rate of 10-15 or 15-20 µg/kg/min. Dobutamine groups received two dobutamine doses during 30 min with a 60 min washout period between doses. Cardiovascular profile and oxygen metabolism were monitored. In four animals, an ultrasonic perivascular flow probe was placed around superior vena cava to measure SVCF. Hypoxia significantly decreased CI, systemic vascular resistance and mean arterial blood pressure (MABP). Dobutamine doses significantly increased heart-rate, CI, and oxygen-delivery without changes in stroke-volume and MABP. Only 10-15 µg/kg/min increased oxygen consumption and peripheral tissue oxygenation measured by Near-infrared spectroscopy. A positive correlation was observed between SVCF and CI. The new pediatric dobutamine formulation improved hemodynamic status, with dose-specific differences in metabolic response. SVCF may be a useful surrogate for CI in subsequent clinical trials.

Access to age-appropriate essential medicines: a retrospective survey of compounding of medicines for children in hospitals in Nigeria and implications for policy development.

Policies to improve access to medicines for children in Nigeria do not include compounding as a source of medicines. Compounding is often applied as a last resort in health institutions to provide age-appropriate formulations usually for oral use in young children; but it bears some risk. Some countries have adopted policies aimed at reducing the risk based on available data. There is not much data for Nigeria. This retrospective study examined compounding records from January to December 2011 in a sample of seven hospitals to describe what medicines for oral use were commonly compounded in Nigeria. It then determined if these medicines were commercially available in forms suitable for use in children in selected countries—the United Kingdom, United States and India. The study found that out of 2845 items compounded, over 65% were medicines for cardiovascular conditions, diarrhoea or tuberculosis. The main reason (96%, n = 2399) for compounding was the unavailability of age-appropriate formulations. Medicines were almost all compounded using simple syrup, vitamin C or vitamin B syrups as suspending vehicles. Final products were all oral liquids. Comprehensive stability testing was not reported for the products. Almost all of the commonly compounded medicines were found to be commercially available in dosage forms suitable for use in children in the selected countries. These medicines were all listed in the World Health Organization Essential Medicines List for children as well as in the current edition of the Essential Medicines List of Nigeria. The fact that they were compounded highlights the need for improved access to age-appropriate dosage forms for children in Nigeria. The study recommends policy expansion through a three-pronged approach to improving access: increased supply through facilitated importation/accelerated product registration, or in-country manufacturing; rational drug use including therapeutic substitution, and establishment of a national formulary for compounding.

Novel age-appropriate formulation of mebendazole (Vermox) tablets 500 mg for who's children without worm donation programme

Novel age-appropriate formulation of mebendazole (Vermox) tablets 500 mg for who's children without worm donation programme

Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development

Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.

Dividing the Tablets for Children – Good or Bad?

Introduction: To investigate the dosing accuracy using split tablets in paediatric patients. Methods: Five brands of tablets (Alvedon ® (paracetamol), Catapresan ® (clonidine), Hydrocortone ® (hydrocortisone), Prednisolon ® (prednisolon) and Tavegyl ® (clemastine) were split into halves and quarters by hand or by using a tablet splitter. The resulting halves and quarters were weighed. Results: Three out of the five tablet brands passed the test in the Ph. Eur. (European Pharmacopoeia) for subdivision of tablets when split once and when split twice to yield quarters only one of the tablets passed the test. When also applying the limit for relative standard deviation (RSD) from the US Pharmacopoeia only one of the tablet halves passed and the other two was just outside the limit. None of the tablet quarters passed the RSD limit. Conclusion : Our results indicate that tablets larger than 8 mm might be split once. Tablets should not be split more than once, due to uncertainty in dose accuracy. There is a need for more commercially available age-appropriate formulations. Extemporaneously prepared formulations should be considered as an alternative to the use of split tablets. Key words: Dosing accuracy, Manipulation of drugs, Paediatric patients, Subdivision of tablets, Tablet splitting

Febuxostat Pharmacokinetic/Pharmacodynamic Bridging from Adults to Pediatrics for Effective Prophylaxis of Tumor Lysis Syndrome: From Florence to Floret Study

Background Febuxostat, a potent and selective xanthine oxidase inhibitor, showed a significantly superior serum uric acid (sUA) control during chemotherapy (CT) in comparison to Allopurinol (Spina M. et al, ASCO 2014 and Annals of Oncology in press) when given as 120 mg oral fixed daily dosed and has been recently approved in the European Union (EU) for the prevention and treatment of hyperuricemia in adult patients undergoing CT for hematologic malignancies (HM) at intermediate- high Tumor Lysis Syndrome (TLS) risk, with recognition of the high relevance of its clinical benefit. Some pediatric HM are highly prone to develop TLS; an age-appropriate drug formulation for TLS prophylaxis is lacking in this population, resulting in an unmet medical need that Febuxostat is going to address. The similarities between adult and pediatric patients in terms of TLS pathogenesis, clinical manifestations and current management allow using pharmacokinetic (PK) information to extrapolate clinical efficacy and safety from adult to pediatric patients, as well as within the different pediatric ages (EMEA/CHMP/EWP/147013/2004).Methods A phase I/II study (Floret) has been designed to explore the PK/pharmacodynamic (PK/PD) profile of Febuxostat in the pediatric population in comparison to adults. Febuxostat daily dose will be 120 mg for adolescents and adults with a lower 80 mg dose to be administered to adolescents only, to obtain confirmatory data on the optimal exposure in terms of safety and effectiveness compared to adults. Considering the difference in body size and organ maturation, the selected daily doses of Febuxostat to be tested in children aged 6 to 11 years are 40 and 60 mg. As the only approved strengths of Febuxostat in the EU are 80 and 120 mg, an age-appropriate 20 mg tablet formulation of Febuxostat is developed to ensure the adequate dosing in children. In accordance to the European Medicines Agency Guidelines CHMP/EWP/147013/2004 and CHMP/EWP/18599/2006, the choice of population PK analysis, using non-linear mixed effect models, is considered appropriate to obtain the necessary precision of PK parameters estimates for the comparability assessment between the groups of patients. The PD/efficacy measurement, namely the sUA area under curve from baseline to the evaluation visit, corresponding to the primary efficacy measure explored during the Florence study, a Phase III comparative trial in adults vs Allopurinol (Spina M et al, ASCO 2014), together with the exposure data will abridge the efficacy results from the Florence to the Floret study and will confirm that potential PK deviation, if any, is of no clinical relevance.Conclusion: The present PK/PD approach allows reducing the number of blood samples from each patient, in particular the lowest aged pediatric patients, while replacing a conventionally designed PK study and a robust sized Phase III study in pediatrics. By bridging PK/PD data, the Floret study not only will allow Febuxostat to rapidly address an unmet medical need in a vulnerable population, but it offers a model - whenever applicable - to be adopted to accelerate new drugs availability to the pediatric population while fully complying with regulatory requirements and minimize the number of patients in clinical trials. DisclosuresSpina:Menarini Ricerche SpA: Consultancy. Off Label Use: Febuxostat in pediatric Tumor lysis syndrome. Mazzei:Menarini Ricerche SpA: Employment. Baldini:Menarini Ricerche SpA: Employment. Pedretti:Menarini Ricerche SpA: Employment. Mezzalana:Menarini Ricerche SpA: Employment. Matera:Menarini Ricerche SpA: Employment. Manunta:Menarini Ricerche SpA: Employment. Calamai:Menarini Ricerche SpA: Employment. Scordari:Menarini Ricerche SpA: Employment. Scartoni:Menarini Ricerche SpA: Employment. Capriati:Menarini Ricerche SpA: Employment. Simonelli:Menarini Ricerche SpA: Employment.

Availability of Oral Formulations Labeled for Use in Young Children in Serbia, Germany and the USA.

The paucity of marketed drug products that have been adequately studied in infants and children and subsequently, licensed (or labeled) for pediatric use has caused abundant use of off-label and unauthorized products in this patient population. In those instances where insufficient pharmacologic or therapeutic information exists for children, the potential for off-label use of medicines to result in therapeutic misadventure does as well. In the USA, a series of regulatory measures have been introduced since 1997 which have increased both the number and scope of pediatric drug trials and also, fostered the development of ageappropriate drug formulations by pharmaceutical companies. Provisions of these regulations for previously marketed drugs include the potential for a company to be granted 6 months of marketing exclusivity, thereby providing them with a financial incentive. For new drugs being developed that have potential pediatric use, the regulations mandate the inclusion of children in the drug development process. In the EU comparable measures have been very recently (Jan 2007) signed into European law to overcome the therapeutic orphan status of the infants and children of Europe. The aims of this study was to compare the availability of age-appropriate oral formulations labeled for use in children less than 12 years of age in Serbia, Germany and USA in 2007, and to investigate if certain drug groups of therapeutic importance to children had fewer medicines appropriately labeled for pediatric patients available. The primary sources of information for determining the ageappropriate oral dosage forms, and their licensing and labeling status were the official manuals on drug information and national formularies in 2007. The general availability of oral drugs was the highest in the USA (304), followed by Germany (235) and Serbia (156). From all these oral drugs the availability of labeled age-appropriate pediatric dosage formulations was only between 21.2% and 47.7%. Moreover, there were striking differences between the three countries in the availability of labeled age-appropriate formulations for certain drug groups such as cardiovascular (absent in Serbia) and antiparasitic drugs (absent in Serbia and Germany). Our data suggest that significant country-to-country differences continue to exist in both the number and type of oral drug formulations that have pediatric labeling. Potential contributing factors include country-specific differences in the drug regulatory process, capacity for pharmaceutical development and the regulatory lag time associated with the implementation of drug regulation specifically addressing pediatric product development and labeling. We hypothesize that the new European regulation concerning medicines and children will improve the current unacceptable situation.

Safety of Excipients in Pediatric Formulations-A Call for Toxicity Studies in Juvenile Animals?

The development of drug products for pediatric use often requires age-appropriate formulations which can be more complex and may involve a broader range of excipients than adult dosage forms. Excipients established for adult use are not always appropriate for use in children because they can affect children differently than adults. Therefore, a comprehensive safety assessment of the excipients in a pediatric formulation is essential before use, referring to existing safety data from adult human and animals as well as safety data from pediatric use and juvenile toxicity studies, when available. The overall risk assessment needs to consider the safety risk from the excipients and the extent to which the risk from the disease as such will be ameliorated by the drug formulation. Non-clinical safety studies in juvenile animals are used to assess for specific toxicities or sensitivities of excipients and for establishing safe exposures in pediatric age groups. As for any active ingredient, non-clinical safety studies in juvenile animals should only be performed for excipients if important for clinical risk assessment and labelling. Pharmaceutical companies should be critical of excessive demands for juvenile animal testing, particularly of excipients when critically needed for significant therapeutic benefit.

'Acceptability' of a new oral suspension formulation of mercaptopurine in children with acute lymphoblastic leukaemia.

The aim of this questionnaire-based survey was to determine the 'acceptability' of Xaluprine®, a new oral liquid formulation of mercaptopurine, when administered chronically to children during the maintenance treatment phase of acute lymphoblastic leukaemia. This was a single centre survey of children (aged 3 to 16 years) and their parents at a routine follow-up visit during the maintenance phase of acute lymphoblastic leukaemica treatment. The questionnaire probed for their views on overall acceptability such as taste, smell, incidences of vomiting, ease and willingness to take Xaluprine® on a daily basis, and utilised a 5-point facial hedonic scale (1 = bad, 5 = good) as well as open/closed questions. Twenty-two children were recruited; 17 (77%) scored taste between 3 and 5 ('okay' to 'good') and 20 (91%) scored smell between 3 and 5. Only four children (18%) reported an aftertaste. Of the five children (23%) who scored taste as 1 or 2 ('bad'), three found taking all oral medicines difficult. Six children (27%) reported vomiting, but this was not considered related to Xaluprine®. Seven children (32%) sometimes complained that they did not want to take Xaluprine®; 15 (68%) never complained. In response to the question, 'How easy is it for you to take Xaluprine®?' 18 children (82%) reported that it was 'Easy all the time.' This was more favourable than other oral liquid medicines that they were taking concurrently. The results of this survey show that Xaluprine® has good overall acceptability in the paediatric population and suggests that Xaluprine® is an important, alternative, age-appropriate formulation of mercaptopurine.