The EMA quality guideline on the pharmaceutical development of medicines for paediatric use

Riet‐Nales, Diana A. van; Wang, Siri; Saint‐Raymond, Agnès; Robert, Jean-Louis

doi:10.1016/j.ijpharm.2012.05.053

Cited by 21 publications

(23 citation statements)

References 4 publications

(4 reference statements)

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“…Administration of a medication mixed with food is a drug manipulation and could affect the absorption of the active ingredient; for example, because of exposure to different pH [18]. The medicines regulatory agencies in the United States and Europe, the FDA and European Medicines Agency, respectively, recommend that any such manipulation of drug administration should be studied and verified “with respect to its potential impact on efficacy and safety,” which may include bioavailability studies to confirm if medications sprinkled onto food have the same bioavailability as direct administration [18, 19]. In accordance with this advice, several studies have assessed the bioequivalence of sprinkles vs the intact form of the medication in children and adults [20–25].…”

Section: Discussionmentioning

confidence: 99%

Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue

Daniel

Digweed

Quirke

et al. 2019

Journal of the Endocrine Society

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Background Immediate-release hydrocortisone granules in capsules for opening in pediatric-appropriate doses have recently been licensed for children with adrenal insufficiency. This study evaluated the bioavailability of hydrocortisone granules administered as sprinkles onto soft food and yogurt compared with direct administration to the back of the tongue. Methods Randomized, 3-period crossover study in 18 dexamethasone-suppressed healthy men. In each period, the fasted participants received 5 mg hydrocortisone granules either directly to the back of the tongue or sprinkled onto soft food (applesauce), or yogurt, followed by 240 mL of water. Serum cortisol was measured by liquid chromatography tandem mass spectometry. Results The cortisol geometric mean maximum concentration (Cmax) and area under the curve (AUC) for direct administration, sprinkles onto yogurt, and sprinkles onto soft food were: Cmax 428, 426, 427 nmol/L and AUC0-inf 859, 886, 844 h × nmol/L, and AUC0-t 853, 882, 838 h × nmol/L respectively. The 90% CI for the ratios of Cmax, AUC0-inf and AUC0-t for administration with soft food or yogurt to direct administration were well within the bioequivalent range, 80% to 125%. Median time to Cmax (Tmax) was similar between methods of administration: 0.63 hours administered directly, 0.75 hours on soft food and 0.75 hours on yogurt. No adverse events occurred during the study. Conclusions Hydrocortisone granules administered as sprinkles onto soft food or yogurt but not mixed with these foods are bioequivalent to those administered directly to the back of the tongue. Carers, parents, or patients may choose to administer hydrocortisone granules either directly or sprinkled onto soft food or yogurt.

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Section: Discussionmentioning

confidence: 99%

Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue

Daniel

Digweed

Quirke

et al. 2019

Journal of the Endocrine Society

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“…It is now increasingly accepted that small tablets may be applicable in young children [21]–[26]. However, the use of medium sized tablets is still discouraged, whereas the use of large sized tablets is generally considered unacceptable because of swallowing difficulties and the risk of choking [21], [27].…”

Section: Discussionmentioning

confidence: 99%

Oral Medicines for Children in the European Paediatric Investigation Plans

et al. 2014

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IntroductionPharmaceutical industry is no longer allowed to develop new medicines for use in adults only, as the 2007 Paediatric Regulation requires children to be considered also. The plans for such paediatric development called Paediatric Investigation Plans (PIPs) are subject to agreement by the European Medicines Agency (EMA) and its Paediatric Committee (PDCO). The aim of this study was to evaluate the key characteristics of oral paediatric medicines in the PIPs and the changes implemented as a result of the EMA/PDCO review.MethodsAll PIPs agreed by 31 December 2011 were identified through a proprietary EMA-database. PIPs were included if they contained an agreed proposal to develop an oral medicine for children 0 to 11 years. Information on the therapeutic area (EMA classification system); target age range (as defined by industry) and pharmaceutical characteristics (active substance, dosage form(s) as listed in the PIP, strength of each dosage form, excipients in each strength of each dosage form) was extracted from the EMA website or the EMA/PDCO assessment reports.ResultsA hundred and fifty PIPs were included corresponding to 16 therapeutic areas and 220 oral dosage forms in 431 strengths/compositions. Eighty-two PIPs (37%) included tablets, 44 (20%) liquids and 35 (16%) dosage forms with a specific composition/strength that were stored as a solid but swallowed as a liquid e.g. dispersible tablets. The EMA/PDCO review resulted in an increase of 13 (207 to 220) oral paediatric dosage forms and 44 (387 to 431) dosage forms with a specific composition/strength. For many PIPs, the target age range was widened and the excipient composition and usability aspects modified.ConclusionThe EMA/PDCO review realized an increase in the number of requirements for the development of oral dosage forms and a larger increase in the number of dosage forms with a specific composition/strength, both targeting younger children. Changes to their pharmaceutical design were less profound.

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“…Studies conducted in Norway showed that more than 50% of children prefer liquids/suspensions even for 12 years old. Younger children, especially at disease stage, strongly prefer liquids/suspensions (25, 26). Age appropriate specialty formulations in pediatric population should consider the following factors: (1) Safety: excipients, drug degradation products, potential interactions between excipients and drug substance are proven safe and acceptable to the targeted population group; (2) Easy administration and dosing accuracy: this is particularly important for medications that will be given based on body weight or surface areas.…”

Section: Discussionmentioning

confidence: 99%

Current Status of Pediatric Labeling in China and the near Future Efforts Needed for the Country

Wang

et al. 2014

Front. Pediatr.

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Background: Children are recognized as “therapeutic orphan” in many parts of the world, one expression of this is the lack of adequate pediatric labeling information. Some research studies have been done to investigate the pediatric labeling condition in the U.S. and other countries, but no national studies had been carried out in China. This survey was conducted aiming to inquire the current situation of pediatric labeling in China.Methods: We investigated 6020 child-applied medicines from 15 representative Chinese hospitals, and analyzed the information according to the dosage forms, therapeutic category, and label information integrity.Results: Among all these medicines, only 238 (3.95%) are pediatric products, the rest are adult formulations with an extended use in children. The major pediatric formulations were injection (45.95%), tablet (23.69%), and capsule (4.93%), respectively. Alimentary tract/metabolism medicine (24.70%) and infections medicines (20.60%) had the most species. In prescription drugs, only 210 of 5187 (4%) medicines had adequate pediatric labeling information. The main cause of this deficiency was lack of evidence derived from pediatric clinical trials.Conclusion: The dilemma of “therapeutic orphan” requires significant attention. Inadequate labeling information and lack of pediatric clinical trials were two prominent issues in China. It calls for more efforts from pharmaceutical industries, regulatory agencies, and legislature in China to collaborate and find solution to improve the situation.

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The EMA quality guideline on the pharmaceutical development of medicines for paediatric use

Cited by 21 publications

References 4 publications

Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue

Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue

Oral Medicines for Children in the European Paediatric Investigation Plans

Current Status of Pediatric Labeling in China and the near Future Efforts Needed for the Country

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