Paediatric oral dosage forms: Why do caregivers need drug modifications and how?

Abstract

Background and Aims: A major obstacle to developing appropriate medications is the lack of understanding of what is acceptable for paediatric patients and the types of alterations that can be made to the dosage form. This study aimed to identify problems encountered when administering oral dosage forms to paediatric patients and solutions identified by patients’ caregivers. Methods: A questionnaire was developed by the research team based on relevant literature and their experiences. The first part involves questions to determine the demographic characteristics of the paediatric patient and their caregivers. The second section includes 11 statements about the problems experienced by caregivers regarding the child’s medication use. The last part consists of 4 closed-ended questions and one open-ended question to evaluate the solutions offered by the patient’s caregivers. Results: A total of 419 caregivers participated in the study. In particular, it has been revealed that children experience problems regarding the taste, smell, and size of medicines. When the caregivers’ solutions are evaluated, it was observed that the most common method is convincing or forcing the child to take, followed by dosage form alterations such as breaking, crushing, and dividing the form. Conclusion: This is the first study to evaluate problems encountered when administering oral dosage forms to paediatric patients in Türkiye. The results show that the absence of age-appropriate medicines forces caregivers to alter their dosage forms. This study also highlights the necessity of considering user preferences in the dosage form design, which is an essential parameter of the target product quality profile that ensures patient compliance.

Keywords

• Acceptability
• Age-appropriate
• Alteration
• Paediatrics
• Dosage forms

Supporting Institution

None

Ethical Statement

Ethics Committee Approval: The study was conducted with the permission decisions of the Van Governorship Provincial Health Directorate numbered 73040253-044-E.438 and the Van-Bitlis-Hakkari Chamber of Pharmacists with number 2019/1626 and the World Medical Association (WMA) Declaration of Helsinki Ethical Principles in Medical Research on Human Volunteers.

Thanks

The researchers would like to thank all respondents, who answered the questionnaire voluntarily.

References

1. Adams, L. V., Craig, S. R., Mmbaga, E. J., Naburi, H., Lahey, T., Nutt, C. T., . . . Spielberg, S. P. (2013). Children’s medicines in Tanzania: a national survey of administration practices and preferences. PLoS One, 8(3), e58303. http://dx.doi.org/10.1371/ journal.pone.0058303 google scholar
2. Akram, G., & Mullen, A. B. (2012). Paediatric nurses’ knowledge and practice of mixing medication into foodstuff. International Journal of Pharmacy Practice, 20(3), 191-198. google scholar
3. Alessandrini, E., Brako, F., Scarpa, M., Lupo, M., Bonifazi, D., Pignataro, V., . . . Tuleu, C. (2021). Children’s Preferences for Oral Dosage Forms and Their Involvement in Formulation Re-search via EPTRI (European Paediatric Translational Research Infrastructure). Pharmaceutics, 13(5). http://dx.doi.org/10.3390/ pharmaceutics13050730 google scholar
4. Bergene, E. H., Nordeng, H., R0, T. B., & Steinsbekk, A. (2019). Register-based study showed that the age when children were prescribed antibiotic tablets and capsules instead of liquids in-creased from 2004 to 2016. Acta Paediatrica, 108(4), 699-706. http://dx.doi.org/10.1111/apa.14550 google scholar
5. Breitkreutz, J., & Boos, J. (2007). Paediatric and geriatric drug de-livery. Expert Opinion on Drug Delivery, 4(1), 37-45. https: //doi.org/10.1517/17425247.4.1.37 google scholar
6. Coupland, J. N., & Hayes, J. E. (2014). Physical approaches to mask-ing bitter taste: lessons from food and pharmaceuticals. Pharma-ceutical Research, 31(11), 2921-2939. http://dx.doi.org/10.1007/ s11095-014-1480-6 google scholar
7. D’Errico, S., Zanon, M., Radaelli, D., Padovano, M., Santurro, A., Scopetti, M., . . . Fineschi, V. (2021). Medication Errors in Pe-diatrics: Proposals to Improve the Quality and Safety of Care Through Clinical Risk Management. Frontiers in Medicine, 8, 814100. http://dx.doi.org/10.3389/fmed.2021.814100 google scholar
8. Doherty, C., & Mc Donnell, C. (2012). Tenfold Medication Errors: 5 Years’ Experience at a University-Affiliated Pediatric Hospi-tal. Pediatrics, 129(5), 916-924. http://dx.doi.org/10.1542/peds. 2011-2526 google scholar

9. Drumond, N., van Riet-Nales, D. A., Karapinar-Çarkit, F., & Stegemann, S. (2017). Patients’ appropriateness, acceptabil-ity, usability and preferences for pharmaceutical prepara-tions: Results from a literature review on clinical evidence. International Journal of Pharmaceutics, 521(1-2), 294-305. http://dx.doi.org/10.1016/j.ijpharm.2017.02.029 google scholar
10. European Medicines Agency. (2013). European Medicines Agency Guideline on Pharmaceutical Development of Medicines for Paediatric Use. Retrieved from https://www.ema.europa.eu/en/documents/scientific-guideline/ guideline-pharmaceutical-development-medicinespaediatric-use_ en.pdf, Retrieved 17.10.2023 google scholar
11. European Medicine Agency (EMA) Guideline. Addendum to E11: Clinical Investigation of Medicinal Products in the Paediatric Population E11(R1). Retrieved from https://database.ich.org/sites/ default/files/E11_R1_Addendum.pdf Retrieved 17.10.2023 google scholar
12. The International Council for Harmonisation of Technical Require-ments for Pharmaceuticals for Human Use ICH Harmonised. Retrived from https://database.ich.org/sites/default/files/Q8_R2_ Guideline.pdf, Retrieved 17.10.2023. google scholar
13. Juârez-Hernândez, J. E., & Carleton, B. C. (2022). Paediatric oral formulations: Why don’t our kids have the medicines they need? British Journal of Clinical Pharmacology, 88(10), 4337-4348. http://dx.doi.org/10.1111/bcp.15456 google scholar
14. Kim, J., & De Jesus, O. (2023). Medication Routes of Administra-tion. In StatPearls. Treasure Island (FL): StatPearls Publishing Klingmann, V. (2017). Acceptability of Mini-Tablets in Young Children: Results from Three Prospective Cross-over Studies. AAPS PharmSciTech, 18(2), 263-266. http://dx.doi.org/10.1208/ s12249-016-0639-3 google scholar
15. Kozarewicz, P. (2014). Regulatory perspectives on acceptability test-ing of dosage forms in children. International Journal of Phar-maceutics, 469(2), 245-248. http://dx.doi.org/10.1016/j.ijpharm. 2014.03.057 google scholar
16. Lajoinie, A., Henin, E., Kassai, B., & Terry, D. (2014). Solid oral forms availability in children: a cost saving investigation. British Journal of Clinical Pharmacology, 78(5), 1080-1089. http://dx. doi.org/10.1111/bcp.12442 google scholar
17. Liu, F., Ghaffur, A., Bains, J., & Hamdy, S. (2016). Acceptability of oral solid medicines in older adults with and without dysphagia: A nested pilot validation questionnaire based observational study. google scholar International Journal of Pharmaceutics, 512(2), 374-381. http: //dx.doi.org/10.1016/j.ijpharm.2016.03.007 google scholar
18. Marconati, M., Raut, S., Burbidge, A., Engmann, J., & Ramaioli, M. (2018). An in vitro experiment to simulate how easy tablets are to swallow. International Journal of Pharmaceutics, 535(1-2), 27-37. http://dx.doi.org/10.1016/j.ijpharm.2017.10.028 google scholar
19. Nahata, M. C., & Taketomo, C. (2017). Pediatrics. In J. T. DiPiro, R. L. Talbert, G. C. Yee, G. R. Matzke, B. G. Wells, & L. M. Posey (Eds.), Pharmacotherapy: A Pathophysiologic Approach, 10e. New York, NY: McGraw-Hill Education. google scholar
20. Nunn, T., & Williams, J. (2005). Formulation of medicines for chil-dren. British Journal of Clinical Pharmacology, 59(6), 674-676. http://dx.doi.org/10.1111/j.1365-2125.2005.02410.x google scholar
21. Özkan, S., Kocaman, G., & Ozturk, C. (2013). Effect of strategies for preventing medication administration errors in pediatric in-patients. Turk Pediatri Arsivi, 48, 299-302. http://dx.doi.org/10. 4274/tpa.540 google scholar
22. Patel, A., Jacobsen, L., Jhaveri, R., & Bradford, K. K. (2015). Effec-tiveness of pediatric pill swallowing interventions: a systematic re-view. Pediatrics, 135(5), 883-889. http://dx.doi.org/10.1542/peds. 2014-2114 google scholar
23. Phillips, J., Beam, S., Brinker, A., Holquist, C., Honig, P., Lee, L. Y., & Pamer, C. (2001). Retrospective analysis of mortalities associ-ated with medication errors. American Journal of Health-System Pharmacy, 58(19), 1835-1841. http://dx.doi.org/10.1093/ajhp/58. 19.1835 google scholar
24. Pirhan R. , Özcelikay G. (2005). Role of the pharmacist in pediatric medicine use. Journal of Faculty of Pharmacy of Ankara Univer-sity, 34(2), 95-105. google scholar
25. Ranmal, S. R., Cram, A., & Tuleu, C. (2016). Age-appropriate and acceptable paediatric dosage forms: Insights into end-user perceptions, preferences and practices from the Chil-dren’s Acceptability of Oral Formulations (CALF) Study. International Journal of Pharmaceutics, 514(1), 296-307. http://dx.doi.org/10.1016/j.ijpharm.2016.07.054 google scholar
26. Sanghera, I.S., Franklin, B.D. & Dhillon, S. (2007). The attitudes and beliefs of healthcare professionals on the causes and re-porting of medication errors in a UK Intensive care unit. Anes-thesia, 62(1),53-61. http://dx.doi.org/10.1111/j.1365-2044.2006. 04858.x google scholar
27. Schiele, J. T., Quinzler, R., Klimm, H. D., Pruszydlo, M. G., & Haefeli, W. E. (2013). Difficulties swallowing solid oral dosage forms in a general practice population: prevalence, causes, and relationship to dosage forms. European Journal of Clinical Pharmacology, 69(4), 937-948. http://dx.doi.org/10.1007/s00228-012- 1417-0 google scholar
28. Sears, K., O’Brien-Pallas, L., Stevens, B., & Murphy, G. T. (2013). The relationship between the nursing work environment and the occurrence of reported paediatric medication administration er-rors: A Pan Canadian study. Journal of Pediatric Nursing, 28(4), 351-356. https://doi.org/10.1016/j.pedn.2012.12.003 google scholar
29. Shah, R. B., Collier, J. S., Sayeed, V. A., Bryant, A., Habib, M. J., & Khan, M. A. (2010). Tablet splitting of a narrow therapeutic index drug: a case with levothyroxine sodium. AAPS PharmSciTech, 11(3), 1359-1367. http://dx.doi.org/10.1208/s12249-010-9515-8 google scholar
30. Stegemann, S., Ternik, R. L., Onder, G., Khan, M. A., & van Riet-Nales, D. A. (2016). Defining patient centric pharmaceutical drug product design. AAPS Journal, 18(5), 1047-1055. http://dx.doi. org/10.1208/s12248-016-9938-6 google scholar
31. Stratton, K. M., Blegen, M. A., Pepper, G., & Vaughn, T. (2004). Reporting of medication errors by pediatric nurses. Journal of Pe-diatric Nursing, 19(6), 385-392. http://dx.doi.org/10.1016/j.pedn. 2004.11.007 google scholar
32. Stucky, E. R. (2003). Prevention of medication errors in the pediatric inpatient setting. Pediatrics, 112(2), 431-436. http://dx.doi.org/10. 1542/peds.112.2.431 google scholar
33. van Riet-Nales, D. A., de Jager, K. E., Schobben, A. F., Egberts, T. C., & Rademaker, C. M. (2011). The availability and age-appropriateness of medicines authorized for children in The Netherlands. British Journal of Clinical Pharmacology, 72(3), 465-473. http://dx.doi.org/10.1111/j.1365-2125.2011.03982.x google scholar
34. van Riet-Nales, D. A., de Neef, B. J., Schobben, A. F., Ferreira, J. A., Egberts, T. C., & Rademaker, C. M. (2013). Acceptability of different oral formulations in infants and preschool children. Archives of Disease in Childhood, 98(9), 725-731. http://dx.doi. org/10.1136/archdischild-2012-303303 google scholar
35. van Riet-Nales, D. A., Doeve, M. E., Nicia, A. E., Teerenstra, S., Notenboom, K., Hekster, Y. A., & van den Bemt, B. J. (2014). The accuracy, precision and sustainability of different techniques for tablet subdivision: breaking by hand and the use of tablet splitters or a kitchen knife. International Journal of Pharmaceutics, 466(1-2), 44-51. http://dx.doi.org/10.1016/j.ijpharm.2014.02.031 google scholar
36. van Riet-Nales, D. A., Schobben, A. F., Egberts, T. C., & Rademaker, C. M. (2010). Effects of the pharmaceutical technologic aspects of oral pediatric drugs on patient-related outcomes: a systematic literature review. Clinical Therapeutics, 32(5), 924-938. http://dx. doi.org/10.1016/j.clinthera.2010.05.005 google scholar
37. Venables, R., Batchelor, H., Stirling, H., & Marriott, J. (2016). Barriers to administering non-oral formulations in a paediatric population: A semi-structured interview study. International Journal of Phar-maceutics, 497(1-2), 12-17. http://dx.doi.org/10.1016/j.ijpharm. 2015.11.010 google scholar
38. Walsh, J., Cram, A., Woertz, K., Breitkreutz, J., Winzenburg, G., Turner, R.,& Tuleu, C. (2014). Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients. Ad-vanced Drug Delivery Reviews, 73, 14-33. http://dx.doi.org/10. 1016/j.addr.2014.02.012 google scholar
39. Walsh, J., Ranmal, S. R., Ernest, T. B., & Liu, F. (2018). Patient acceptability, safety and access: A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric popula-tions. International Journal of Pharmaceutics, 536(2), 547-562. http://dx.doi.org/10.1016/j.ijpharm.2017.07.017 google scholar
40. Wargenau, M., Reidemeister, S., Klingmann, I., & Klingmann, V. (2022). A composite endpoint for acceptability evalua-tion of oral drug formulations in the pediatric population. Therapeutic Innovation & Regulatory Science, 56(6), 903-909. http://dx.doi.org/10.1007/s43441-022-00406-z google scholar
41. Woo, Y., Kim, H. E., Chung, S., & Park, B. J. (2015). Pediatric medication error reports in Korea adverse event reporting sys-tem database, 1989-2012: comparing with adult reports. Journal of Korean Medical Science, 30(4), 371-377. http://dx.doi.org/10. 3346/jkms.2015.30.4.371 google scholar
42. Zajicek, A., Fossler, M. J., Barrett, J. S., Worthington, J. H., Ternik, R., Charkoftaki, G., . . . MacLaren, D. D. (2013). A report from the pediatric formulations task force: perspectives on the state of child-friendly oral dosage forms. AAPS Journal, 15(4), 10721081. http://dx.doi.org/10.1208/s12248-013-9511-5 google scholar
43. Zhao, N., Zidan, A., Tawakkul, M., Sayeed, V. A., & Khan, M. (2010). Tablet splitting: Product quality assessment of metoprolol suc-cinate extended release tablets. International Journal of Phar-maceutics, 401(1-2), 25-31. http://dx.doi.org/10.1016/j.ijpharm. 2010.09.004 google scholar