Pediatric drug formulations: A review of challenges and progress

Pediatrics

Volumn 134, Issue 2, 2014, Pages 361-372

  Ivanovska, Verica ^a,b   Rademaker, Carin M A ^c   Van Dijk, Liset ^d   Mantel Teeuwisse, Aukje K ^a  

^a UTRECHT UNIVERSITY   (Netherlands)

^b GOCE DELCEV UNIVERSITY   (Macedonia)

^c UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^d NETHERLANDS INSTITUTE FOR HEALTH SERVICES RESEARCH   (Netherlands)

Author keywords

Administration; Age groups; Oral medications; Pediatric; Therapeutics

Indexed keywords

ABACAVIR; ALBENDAZOLE; ANTIARRHYTHMIC AGENT; ANTIASTHMATIC AGENT; ANTIDEPRESSANT AGENT; ANTIHYPERTENSIVE AGENT; ARTEMETHER PLUS BENFLUMETOL; ATORVASTATIN; AZITHROMYCIN; BENZNIDAZOLE; CARVEDILOL; CLARITHROMYCIN; CLAROSIP; DIHYDROCODEINE; DIPHENHYDRAMINE; EFAVIRENZ; EXCIPIENT; HISTAMINE H2 RECEPTOR ANTAGONIST; HYDROCHLOROTHIAZIDE; LAMIVUDINE; LAMOTRIGINE; LOPINAVIR PLUS RITONAVIR; METOPROLOL TARTRATE; MYKUNDEX; NYSTATIN; ONDANSETRON; PROTON PUMP INHIBITOR; RABEPRAZOLE; RALTEGRAVIR; SULFANILAMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZIDOVUDINE;

BODY SIZE; CHILD; CHILD HEALTH CARE; CHILDHOOD CANCER; CHILDHOOD DISEASE; DEVELOPING COUNTRY; DRUG ADMINISTRATION ROUTE; DRUG FORMULATION; DRUG SAFETY; EVIDENCE BASED PRACTICE; HUMAN; MEDICATION COMPLIANCE; MEDICATION ERROR; OFF LABEL DRUG USE; PATIENT SAFETY; PRIORITY JOURNAL; REVIEW; RISK MANAGEMENT; TASTE;

ADMINISTRATION; AGE GROUPS; ORAL MEDICATIONS; PEDIATRIC; THERAPEUTICS;

CHILD; DEVELOPING COUNTRIES; DOSAGE FORMS; DRUG ADMINISTRATION ROUTES; DRUG THERAPY; FEMALE; FLAVORING AGENTS; HUMANS; MALE; MEDICATION ADHERENCE; OFF-LABEL USE; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS; TASTE; TECHNOLOGY, PHARMACEUTICAL;

EID: 84905274839     PISSN: 00314005     EISSN: 10984275     Source Type: Journal    
DOI: 10.1542/peds.2013-3225     Document Type: Review

References (132)

1. European Medicines Agency. Guideline on pharmaceutical development of medicines for paediatric use. EMA/CHMP/QWP/805880/2012 Rev. 2
2. World Health Organization. Development of Paediatric Medicines: Points to Consider in Formulation. Geneva, Switzerland: World Health Organization; 2012. WHO Technical Report Series, No. 970, Annex 5
3. Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv. 2007;4(1):37-45 (Pubitemid 46117485)
4. Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol. 2007;59(8):1043-1055 (Pubitemid 47265351)
5. European Medicines Agency. Committee for Medicinal products for Human use (CHMP) 2005: Reflection Paper: Formulations of Choice for the Paediatric Population. EMEA/CHMP/PEG/194810/2005
6. Geiling EMK, Cannon PR. Pathological effects of elixir of sulfanilamide poisoning. JAMA. 1938;111(10):919-926
7. Hiller JL, Benda GI, Rahatzad M, et al. Benzyl alcohol toxicity: impact on mortality and intraventricular hemorrhage among very low birth weight infants. Pediatrics. 1986;77(4):500-506 (Pubitemid 16104462)
8. Brown WJ, Buist NR, Gipson HT, Huston RK, Kennaway NG. Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet. 1982;1(8283):1250 (Pubitemid 12107396)
9. World Health Organization. Promoting Safety of Medicines for Children. Geneva, Switzerland World Health Organization; 2007
10. Nahata MC. Lack of pediatric drug formulations. Pediatrics. 1999;104(3 pt 2, suppl 3):607-609 (Pubitemid 29426630)
11. Ceci A, Felisi M, Baiardi P, et al. Medicines for children licensed by the European Medicines Agency (EMEA): the balance after 10 years. Eur J Clin Pharmacol. 2006;62(11):947-952 (Pubitemid 44657629)
12. Shirkey H. Therapeutic orphans. J Pediatr. 1968;72(1):119-120
13. European Medicines Agency. Report on the Survey of all Paediatric Uses of Medicinal Products in Europe. EMA/794083/2009
14. Bazzano AT, Mangione-Smith R, Schonlau M, Suttorp MJ, Brook RH. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009;9(2):81-88
15. Mason J, Pirmohamed M, Nunn T. Off-label and unlicensed medicine use and adverse drug reactions in children: a narrative review of the literature. Eur J Clin Pharmacol. 2012;68(1):21-28
16. Best Pharmaceuticals for Children Act. In: Proceedings of 107th Congress of the United States of America. Washington, DC; January 3, 2002
17. Pediatric Research Equity Act of 2003. In: proceedings of 108th Congress of the United States of America. Washington, DC; January 7, 2003
18. US Food and Drug Administration Amendments Act of 2007. In: Proceedings of 110th Congress of the United States of America. Washington, DC; January 4, 2007
19. The European Parliament and the Council of the European Union. Regulation EC No. 1901/2006 Medicinal Products for Paediatric Use. Official Journal of the European Union L. 378/2. 27.12.2006. Available at: http://ec.europa.eu/health/ files/eudralex/vol-1/reg-2006-1901/reg-2006-1901-en.pdf. Accessed August 15, 2013
20. World Health Organization. Make medicines child size. Available at: www.who.int/childmedicines/en/. Accessed August 15, 2013
21. BPCA Collaborative Efforts. Inter-agency initiatives. Pediatric formulations platform. Inter-Agency Agreement between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the US Food and Drug Administration (FDA). Available at: http://bpca.nichd.nih.gov/ collaborativeefforts/initiatives/index.cfm. Accessed August 15. 2013
22. European Medicines Agency. Draft 5-year report to the European Commission: general report on the experience acquired as a result of the application of the Paediatric Regulation. July 8, 2012; EMA/428172/2012
23. van Riet-Nales DA, de Jager KE, Schobben AF, Egberts TC, Rademaker CM. The availability and age-appropriateness of medicines authorized for children in The Netherlands. Br J Clin Pharmacol. 2011;72(3):465-473
24. Balakrishnan K, Grieve J, Tordoff J, Norris P, Reith D. Pediatric licensing status and the availability of suitable formulations for new medical entities approved in the United States between 1998 and 2002. J Clin Pharmacol. 2006;46(9):1038-1043 (Pubitemid 44215069)
25. Moore P. Children are not small adults. Lancet. 1998;352(9128):630
26. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology - drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-1167 (Pubitemid 37122329)
27. Fernandez E, Perez R, Hernandez A, Tejada P, Arteta M, Ramos JT. Factors and mechanisms for pharmacokinetic differences between pediatric population and adults. Pharmaceutics. 2011;3(1):53-72
28. European Medicines Agency (EMEA) 2000: ICH Topic E 11. Clinical Investigations of Medicinal Products in the Paediatric Population. EMEA/CHMP/ICH/2711/99
29. Allegaert K. Neonates need tailored drug formulations. World J Clin Pediatr. 2013;2(1):1-5
30. Noel GJ, Van Den Anker JN, Lombardi D, Ward R. Improving drug formulations for neonates: making a big difference in our smallest patients. J Pediatr. 2012;161(5):947-949
31. Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006;45(11):1077-1097 (Pubitemid 44631388)
32. Strolin Benedetti M, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005;1(3):447-471
33. Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol. 2003;17(3):281-299 (Pubitemid 36774164)
34. Meissner HC, Smith AL. The current status of chloramphenicol. Pediatrics. 1979;64(3):348-356 (Pubitemid 9231685)
35. Albani M, Wernicke I. Oral phenytoin in infancy: dose requirement, absorption, and elimination. Pediatr Pharmacol (New York). 1983;3(3-4):229-236 (Pubitemid 14102406)
36. Food and Drug Administration. Specific requirements on content and format of labeling for human prescription drugs: revision of "Pediatric Use" subsection in the labeling; final rule. 21 CFR Part 201 (Docket No 92N-0165). Federal Register: December 13, 1994. Available at: http://www.fda.gov/ohrms/ dockets/ac/01/briefing/3778b1-Tab6-7-21CFR%20Part%20201.pdf Accessed August 15, 2013
37. Matsui D. Assessing the palatability of medications in children. Paediatr Perinat Drug Ther. 2007;8(2):55-60 (Pubitemid 47621484)
38. Cram A, Breitkreutz J, Desset-Brèthes S, Nunn T, Tuleu C; European Paediatric Formulation Initiative (EuPFI). Challenges of developing palatable oral paediatric formulations. Int J Pharm. 2009;365(1-2):1-3
39. Mennella JA, Beauchamp GK. Optimizing oral medications for children. Clin Ther. 2008;30(11):2120-2132
40. Davies EH, Tuleu C. Medicines for children: a matter of taste. J Pediatr. 2008;153(5):599-604, e1-e2
41. Tuleu C, Breitkreutz J. Educational paper: formulation-related issues in pediatric clinical pharmacology. Eur J Pediatr. 2013;172(6):717-720
42. Clapham D, Kirsanov D, Legin A, Rudnitskaya A, Saunders K. Assessing taste without using humans: rat brief access aversion model and electronic tongue. Int J Pharm. 2012;435(2):137-139
43. Breitkreutz J, Wessel T, Boos J. 13. Dosage forms for oral drug administration. In: Choonara I, Nunn T, Kearns G, eds. Introduction to Paediatric and Perinatal Drug Therapy. Nottingham, UK: Nottingham University Press;2003:189-205
44. Sam T, Ernest TB, Walsh J, Williams JL; European Paediatric Formulation Initiative. (EuPFI). A benefit/risk approach towards selecting appropriate pharmaceutical dosage forms - an application for paediatric dosage form selection. Int J Pharm. 2012;435(2):115-123
45. Shea KM; American Academy of Pediatrics Committee on Environmental Health. Pediatric exposure and potential toxicity of phthalate plasticizers. Pediatrics. 2003;111(6 pt 1):1467-1474
46. Haishima Y, Matsuda R, Hayashi Y, Hasegawa C, Yagami T, Tsuchiya T. Risk assessment of di(2-ethylhexyl)phthalate released from PVC blood circuits during hemodialysis and pump-oxygenation therapy. Int J Pharm. 2004;274(1-2):119-129 (Pubitemid 38457011)
47. Allegaert K, Anderson BJ, Vrancken M, et al. Impact of a paediatric vial on the magnitude of systematic medication errors in neonates. Paediatr Perinat Drug Ther. 2006;7(2):59-63 (Pubitemid 44299033)
48. Mulberg A, Silber S, van den Anker J, eds. Pediatric Drug Development. Concepts and Applications. Hoboken, NJ: J. Wiley & Sons; 2009
49. UNICEF/WHO. Priority essential medicines for child survival report, Copenhagen, Denmark. Available at: www.who.int/childmedicines/progress/Unicef- prioriry-meds-child-survival.pdf. Accessed August 15, 2013
50. Fabiano V, Mameli C, Zuccotti GV. Paediatric pharmacology: remember the excipients. Pharmacol Res. 2011;63(5):362-365
51. Nahata MC. Safety of "inert " additives or excipients in paediatric medicines. Arch Dis Child Fetal Neonatal Ed. 2009;94(6):F392-F393
52. American Academy of Pediatrics Committee on Drugs. "Inactive" ingredients in pharmaceutical products: update (subject review). Pediatrics. 1997;99(2):268-278
53. Hiller JL, Benda GI, Rahatzad M, et al. Benzyl alcohol toxicity: impact on mortality and intraventricular hemorrhage among very low birth weight infants. Pediatrics. 1986;77(4):500-506 (Pubitemid 16104462)
54. Shehab N, Lewis CL, Streetman DD, Donn SM. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr Crit Care Med. 2009;10(2):256-259
55. American Academy of Pediatrics. Ethanol in liquid preparations intended for children. Pediatrics. 1984;73(3):405-407
56. Arulanantham K, Genel M. Central nervous system toxicity associated with ingestion of propylene glycol. J Pediatr. 1978;93(3):515-516 (Pubitemid 8384118)
57. Martin G, Finberg L. Propylene glycol: a potentially toxic vehicle in liquid dosage form. J Pediatr. 1970;77(5):877-878
58. MacDonald MG, Getson PR, Glasgow AM, Miller MK, Boeckx RL, Johnson EL. Propylene glycol: increased incidence of seizures in low birth weight infants. Pediatrics. 1987;79(4):622-625 (Pubitemid 17051431)
59. Glasgow AM, Boeckx RL, Miller MK, MacDonald MG, August GP, Goodman SI. Hyperosmolality in small infants due to propylene glycol. Pediatrics. 1983;72(3):353-355 (Pubitemid 13051212)
60. Balistreri WF, Farrell MK, Bove KE. Lessons from the E-Ferol tragedy. Pediatrics. 1986;78(3):503-506 (Pubitemid 16026182)
61. US Food and Drug Administration. Drug Safety Communication: Serious Health Problems Seen in Premature Babies Given Kaletra (Lopinavir/Ritonavir) Oral Solution. Available at: www.fda.gov/Drugs/DrugSafety/ucm246002.htm. Accessed August 15, 2013
62. Whittaker A, Currie AE, Turner MA, Field DJ, Mulla H, Pandya HC. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):F236-F240
63. Lass J, Naelapää K, Shah U, et al. Hospitalised neonates in Estonia commonly receive potentially harmful excipients. BMC Pediatr. 2012;12:136
64. Salunke S, Giacoia GP, Tuleu C. The STEP (safety and toxicity of excipients for paediatrics) database. Part 1-A need assessment study. Int J Pharm. 2012;435(2):101-111
65. Salunke S, Brandys B, Giacoia GP, Tuleu C. The STEP (Safety and Toxicity of Excipients for Paediatrics) database: part 2 - the pilot version. Int J Pharm. 2013;457(1):310-322
66. Paediatric Formulation Initiative. STEP database: database of safety and toxicity of excipients for paediatrics. Available at: www.eupfi.org/gpage11. html. Accessed August 15, 2013
67. Turner MA, Storme T. European Study for Neonatal Excipient Exposure (ESNEE). Eur J Hosp Pharm. 2012;19(2):67
68. Schirm E, Tobi H, de Vries TW, Choonara I, De Jong-van den Berg LT. Lack of appropriate formulations of medicines for children in the community. Acta Paediatr. 2003;92(12):1486-1489 (Pubitemid 38114502)
69. Milne CP, Bruss JB. The economics of pediatric formulation development for off-patent drugs. Clin Ther. 2008;30(11):2133-2145
70. Institute of Medicine (US) Committee on Clinical Research Involving Children. The necessity and challenges of clinical research involving children. In: Field M, Behrman R, eds. Ethical Conduct of Clinical Research Involving Children. Washington, DC: National Academies Press; 2004
71. Institute of Medicine (US). Addressing the barriers to pediatric drug development: Workshop summary. Forum on Drug Discovery, Development, and Translation. Washington, DC: The National Academies Press; 2008
72. Balakrishnan K, Tordoff J, Norris P, Reith D. Establishing a baseline for the monitoring of medicines availability for children in the UK: 1998-2002. Br J Clin Pharmacol. 2007;63(1):85-91 (Pubitemid 44902881)
73. Chui J, Tordoff J, Kennedy J, Reith D. Trends in accessibility to medicines for children in New Zealand: 1998-2002. Br J Clin Pharmacol. 2004;57(3):322-327 (Pubitemid 38296995)
74. Chui J, Tordoff J, Reith D. Changes in availability of paediatric medicines in Australia between 1998 and 2002. Br J Clin Pharmacol. 2005;59(6):736-742 (Pubitemid 40835510)
75. Osterberg RE. 4. FDA Approach to Pediatric Testing. In: Hoberman AM, Lewis EM, eds. Pediatric Nonclinical Drug Testing: Principles, Requirements, and Practices. Hoboken, NJ: John Wiley & Sons, Inc; 2012:59-78
76. European Medicines Agency. Report on the survey of all paediatric uses of medicinal products in Europe. December 10, 2010, EMA/794083/2009
77. Tobias LD, Harkness J. IAPO Briefing Paper on Paediatric Medicines and Clinical Research (November 2006). International Alliance of Patients' Organizations (IAPO) Available at: www.patientsorganizations. org/paediatrics. Accessed May 23, 2014
78. Nahata MC, Allen LV Jr. Extemporaneous drug formulations. Clin Ther. 2008;30(11):2112-2119
79. Choonara I, Conroy S. Unlicensed and off-label drug use in children: implications for safety. Drug Saf. 2002;25(1):1-5 (Pubitemid 34208327)
80. European Medicines Agency. Evidence of Harm From Off-Label or Unlicensed Medicines in Children. EMEA/126327. EMEA; 2004
81. Shah SS, Hall M, Goodman DM, et al. Off-label drug use in hospitalized children. Arch Pediatr Adolesc Med. 2007;161(3):282-290 (Pubitemid 46364332)
82. Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf. 2006;5(5):703-718 (Pubitemid 44322888)
83. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr. 2005;164(9):552-558 (Pubitemid 41225059)
84. Lowey A, Jackson M. Handbook of Extemporaneous Formulation - A Guide to Pharmaceutical Compounding. London, UK: Pharmaceutical Press; 2010
85. Best BM, Capparelli EV, Diep H, et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. J Acquir Immune Defic Syndr. 2011;58(4):385-391
86. Kairuz TE, Gargiulo D, Bunt C, Garg S. Quality, safety and efficacy in the 'off-label' use of medicines. Curr Drug Saf. 2007;2(1):89-95 (Pubitemid 46723173)
87. PharmInfoTech. eMixt database: database of oral liquid formulations. Available at: www.pharminfotech.co.nz/manual/Formulation/mixtures/. Accessed August 15, 2013
88. Boots I, Sukhai RN, Klein RH, et al. Stimulation programs for pediatric drug research - do children really benefit? Eur J Pediatr. 2007;166(8):849-855 (Pubitemid 46988181)
89. European Medicines Agency. General report on the experience acquired as a result of the application of the Paediatric Regulation. Summary of the replies to the public consultation. SANCO/D5/FS/ci D (2013) 27105 Available at: http://ec.europa.eu/health/files/paediatrics/2013-pc-paediatrics/ 2013-paediatric-report-summary.pdf. Accessed August 15, 2013
90. Best Pharmaceuticals for Children Act (BPCA). Priority List of Needs in Pediatric Therapeutics, 2012. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Best Pharmaceuticals for Children Act. Available at: http://bpca.nichd.nih.gov/prioritization/upload/2012-Priority- List-FINAL.pdf. Accessed August 15, 2013
91. European Medicines Agency. Revised priority list for studies into off-patent paediatric medicinal products. EMA/98717/2012, August 2013. Available at: www.ema.europa.eu/docs/en-GB/document-library/Other/2009/10/WC500004017. pdf. Accessed August 15, 2013
92. World Health Organization. Report of the informal expert meeting on dosage forms of medicines for children. WHO Headquarters, Geneva, Switzerland, 2008. Available at: www.who.int/selection-medicines/committees/ expert/17/application/paediatric/Dosage-form-reportDEC2008.pdf. Accessed August 15, 2013
93. World Health Organization. WHO model list of essential medicines for children, 4th list. WHO, Geneva, April 2013. www.who.int/medicines/publications/ essentialmedicines/4th-EMLc-FINAL-web-8Jul13.pdf. Accessed August 15, 2013
94. World Health Organization. Priority lifesaving medicines for women and children 2012 Geneva, WHO/EMP/MAR/2012. Available at: http://apps.who.int/iris/ bitstream/10665/75154/1/WHO-EMP-MAR-2012.1-eng.pdf. Accessed August 15, 2013
95. World Health Organization. WHO Model Formulary for Children. WHO, Geneva, Available at: www.who.int/selection-medicines/list/WMFc-2010.pdf. Accessed August 15, 2013
96. World Health Organization. Maternal, newborn, child and adolescent health. Documents on child health. Available at: www.who.int/maternal-child- adolescent/documents/child/en/. Accessed August 15, 2013
97. World Health Organization. WHO List of Prequalified Medicinal Products. Available at: http://apps.who.int/prequal/97. Accessed August 15, 2013
98. National Institutes of Health (NICHD) Funding Opportunities. Development of appropriate pediatric formulations and pediatric drug delivery systems (R01, R03, R21, R41/R43). Available at: http://grants.nih.gov/grants/guide. Accessed August 15, 2013
99. Zajicek A. The National Institutes of Health and the Best Pharmaceuticals for Children Act. Paediatr Drugs. 2009;11(1):45-47
100. European Commission. EU Research Projects FP7 Health. CORDIS (Community Research and Development Information Centre). Available at: http://cordis. europa.eu/projects/home-en.html. Accessed August 15, 2013
101. Pediatric Formulations Platform. BPCA, National Institutes of Health. Inter-agency agreement between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the US Food and Drug Administration (FDA). Oral formulations platform-report 1. Available at: http://bpca.nichd.nih.gov/collaborativeefforts/initiatives/upload/ Formulations-Table-for-Web-11-02-11.pdf Accessed August 15, 2013
102. Nunn T, Williams J. Formulation of medicines for children. Br J Clin Pharmacol. 2005;59(6):674-676 (Pubitemid 40835500)
103. Stoltenberg I, Winzerburg G, Breitkreutz J. Solid oral forms for children - formulations, excipients and acceptance issues. J App Ther Res. 2010;7(4):141-146
104. Abdulla S, Sagara I, Borrmann S, et al. Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, singleblind, multicentre trial. Lancet. 2008;372(9652):1819-1827
105. Kayitare E, Vervaet C, Ntawukulilyayo JD, Seminega B, Bortel V, Remon JP. Development of fixed dose combination tablets containing zidovudine and lamivudine for paediatric applications. Int J Pharm. 2009;370(1-2):41-46
106. Vanprapar N, Cressey TR, Chokephaibulkit K, et al. IMPAACT P1056 Team. A chewable pediatric fixed-dose combination tablet of stavudine, lamivudine, and nevirapine: pharmacokinetics and safety compared with the individual liquid formulations in human immunodeficiency virus-infected children in Thailand. Pediatr Infect Dis J. 2010;29(10):940-944
107. Chokephaibulkit K, Cressey TR, Capparelli E, et al; IMPAACT P1069 Team. Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children. Antivir Ther. 2011;16(8):1287-1295
108. Larka. Press release. Aptalis announces European Commission approval for new formulation of Viread. Available at: www.pharmaceutical-technology.com/ contractors/drug-delivery/eurand/pressaptalis-ec-approval-new-formulation-of- viread.html. Accessed August 15, 2013
109. Eisai Inc. Press release. FDA approves ACIPHEX Sprinkle (Rabeprazole Sodium) for use in children ages 1 to 11. Available at: http://us.eisai.com/wps/ wcm/connect/Eisai/Home/Press+Room/Press+Releases/2013/ FDAapprovesaciphexsprinkle.html. Accessed August 15, 2013
110. World Health Organization. Benznidazole: child-adapted dosage form approved. WHO Drug Information. 2012;26(1):21-22
111. Food and Drug Administration. Lamictal medication guide. Available at: www.fda.gov/downloads/Drugs/DrugSafety/UCM152835.pdf. Accessed August 15, 2013
112. Drug Information online. Press release 2012: FDA approves Zuplenz. Available at: www.drugs.com/newdrugs/fda-approves-strativa-pharmaceuticals- zuplenz-ondansetron-oral-soluble-film-2208.html. Accessed August 15, 2013
113. Stoltenberg I, Breitkreutz J. Orally disintegrating mini-tablets (ODMTs) - a novel solid oral dosage form for paediatric use. Eur J Pharm Biopharm. 2011;78(3):462-469
114. Pfizer Medic and News 2009. Pfizer announces European Union approval of a new form of Lipitor (atorvastatin) for use in children. Available at: http://press.pfizer.com/press-release/pfizer-announces-european-union-approval- new-form-lipitor-atorvastatin-use-children. Accessed August 15, 2013
115. Merck News Room. FDA approves Merck's ISENTRESS (raltegravir) for use in children ages two years and older as part of HIV-1 combination therapy. Available at: www.mercknewsroom.com/press-release/prescription-medicine-news/ fda-approves-mercks-isentress-raltegravir-use-childrenages. Accessed August 15, 2013
116. Breitkreutz J. Arzneiformen für Kinder. Nach der EU-Reform. Pharmazie in unserer Zeit 2009;38(1):30-37.
117. Yeung VW, Wong IC. When do children convert from liquid antiretroviral to solid formulations? Pharm World Sci. 2005;27(5):399-402 (Pubitemid 41778819)
118. Garvie PA, Lensing S, Rai SN. Efficacy of a pill-swallowing training intervention to improve antiretroviral medication adherence in pediatric patients with HIV/AIDS. Pediatrics. 2007;119(4). Available at: www.pediatrics.org/cgi/content/full/119/4/e893
119. Thomson SA, Tuleu C, Wong IC, Keady S, Pitt KG, Sutcliffe AG. Minitablets: new modality to deliver medicines to preschool-aged children. Pediatrics. 2009;123(2): Available at www.pediatrics.org/cgi/content/full/123/2/ e235
120. Spomer N, Klingmann V, Stoltenberg I, et al. Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study. Arch Dis Child. 2012;97(3):283-286
121. Klingmann V, Spomer N, Lerch C, et al. Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children. J Pediatr. 2013;163(6):1728-1732.e1
122. Walsh J, Bickmann D, Breitkreutz J, Chariot-Goulet M; European Paediatric Formulation Initiative (EuPFI). Delivery devices for the administration of paediatric formulations: overview of current practice, challenges and recent developments. Int J Pharm. 2011;415(1-2):221-231
123. World Health Organization. Priority medicines for Europe and the World Update Report. WHO Geneva, 2013. Available at: www.who.int/medicines/areas/ priority-medicines/en/. Accessed August 15, 2013
124. Ricci BM. Bridging studies in support of oral pediatric formulation development. Int J Pharm. 2013;457(1):323-326
125. Havenaar R, Anneveld B, Hanff LM, et al. In vitro gastrointestinal model (TIM) with predictive power, even for infants and children? Int J Pharm. 2013;457(1):327-332
126. Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5). Available at: www.pediatrics.org/cgi/content/full/128/5/e1242
127. Giacoia GP, Taylor-Zapata P, Zajicek A. Eunice Kennedy Shriver National Institute of Child Health and Human Development Pediatrics Formulation Initiative: proceedings from the Second Workshop on Pediatric Formulations. Clin Ther. 2012;34(11):S1-S10
128. Menjoge AR, Kannan RM, Tomalia DA. Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications. Drug Discov Today. 2010;15(5-6):171-185
129. Timko BP, Kohane DS. Materials to clinical devices: technologies for remotely triggered drug delivery. Clin Ther. 2012;34(11):S25-S35
130. Krishnan V, Xu X, Barwe SP, et al. Dexamethasone-loaded block copolymer nanoparticles induce leukemia cell death and enhance therapeutic efficacy: a novel application in pediatric nanomedicine. Mol Pharm. 2013;10(6):2199-2210
131. van Riet-Nales DA, Schobben AF, Egberts TC, Rademaker CM. Effects of the pharmaceutical technologic aspects of oral pediatric drugs on patient-related outcomes: a systematic literature review. Clin Ther. 2010;32(5):924-938
132. United States Government Accountability Office. Pediatric medical devices. Provisions support development, but better data needed for required reporting. Report to Congressional Committees. Available at: www.gao.gov/assets/590/587164.pdf. Accessed August 15, 2013