Suitability of Oral Formulations Available to Children at the Time of Pediatric Labeling

Abstract

BACKGROUND

The pediatric drug development landscape has experienced major shifts, largely in response to legislative and regulatory initiatives. However, associated laws and guidance documents fail to mandate the manufacture of pediatric formulations for commercial marketing post-regulatory approval. This study explores the nature of commercial products available at the time of pediatric labeling.

METHODS

All orally administered drugs for which labeling changes were made from 1998-2024 were evaluated. Characteristics of each drug’s commercially marketed formulation(s) at the time of labeling were identified using product labeling (Drugs@FDA), Drugs.com, and DailyMed.

RESULTS

During the timeframe reviewed, there were 611 unique labeling changes representing 425 unique drugs available as 567 commercially marketed formulations. Of these drugs, 188 were marketed with pediatric-friendly (PF) formulations. The remainder were available only as solid oral dosage forms. For 329 pediatric labeling changes (53.8%), the only commercially marketed formulation was a solid oral dosage form, in many cases at sizes exceeding reasonable thresholds for the age group. For the remaining 282 labeling changes, a PF formulation was available alone or as a companion to the adult formulation. Among the PF formulations, 62% were suited to direct administration (liquid, orodispersible tablet, chewable/paste, transmucosal) while the remainder required manipulation (i.e. powder/granule, sprinkle/pellet, dispersible tablet). Three-fourths of the PF formulations incorporated flavorings and aromas though 13% failed to report the use of sweeteners.

CONCLUSIONS

Less than complete access to PF formulations requires attention if we are to maximize the provision of suitable pharmacotherapy for pediatric patients.

Introduction

The last several decades have seen the global emergence of legislation promoting pediatric drug development.^1,2 In the U.S. both incentives and requirements have been advanced to encourage pharmaceutical manufacturers to seek labeling for drugs in children; however, nowhere in this legislation is the explicit requirement that a suitable pediatric formulation accompany regulatory approval.^3–5 Regulatory authorities outside of the U.S. follow suit with Japan’s Pharmaceuticals and Medical Devices Agency taking the position that pediatric formulation development is a corporate decision, and the European Medicines Agency (EMA), Health Canada, the Australia’s Therapeutic Goods Administration, and others who follow their lead permitting exceptions to pediatric formulation development.^6–8

Complicating implementation of these regulatory recommendations is 1) the lack of a clear definition on what constitutes an age-appropriate pediatric formulation and 2) the absence of standardized methods for evaluating age-appropriateness. Some thought leaders center their definition on the capabilities of the child (a formulation for which a child of a specified age/age group would have the natural ability to use, without the product having to be altered from its original or intended presentation prior to administration).⁹ Others emphasize the product label as the focus (an authorised medicine used within the terms of its marketing authorisation which can be taken/used by the child without any issues on administration).¹⁰ Recognizing that no formulation is ideal for all children of a given age group, U.S. Food and Drug Administration (FDA) and EMA guidance relies largely on high-level definitions (a medicine, whose pharmaceutical design makes it suitable for use in the target age group(s)), with suggested formulation types by age group.¹¹

Without pediatric formulations, there is limited assurance that medicines can be safely and accurately administered to children. Given the lack of an enforceable mandate to market pediatric formulations, this research was undertaken to examine the nature of commercial products available at the time of pediatric labeling by the FDA. Since retrospective analyses are inapt for making determinations about the suitability and acceptability of formulations for a given age group (i.e. age-appropriateness), this paper restricts the characterization of products to those that may require extemporaneous manipulation prior to administration to children (termed “adult formulations”) and those that, in theory, should be simpler to administer to children with greater ease and/or accuracy (termed “pediatric-friendly”).¹²

Methods

Orally administered drugs granted labeling changes under the Best Pharmaceuticals for Children Act (BPCA), Pediatric Research Equity Act (PREA) and the Pediatric Rule were evaluated. Publicly accessible data available at the time of extraction (from 1998 through 06 March 2024) were updated to include labeling changes through 03 February 2025.¹³ Each drug’s commercially-marketed formulation at the time of labeling was determined from review of the product labeling available on Drugs@FDA and FDALabel.^14,15 The characteristics of each formulation were obtained from Drugs.com, DailyMed, and the product labeling.^14–17 Characteristics examined for the adult formulations included dosage form, strength, size, and shape. Characteristics of the PF formulations included the presence of flavorings and sweeteners. For the purposes of this analysis, tablets and capsules were designated adult formulations. The remaining products were designated pediatric-friendly (PF) formulations irrespective of whether they required no manipulation prior to administration (e.g. solutions, suspensions, syrups, chewables, orodispersible tablets, pastes, films, lozenges/troches, sublingual tablets) or were designed and labeled for distribution, dissolution, and/or admixture with food stuffs (e.g. powders, sprinkles, granules, pellets, dispersible tablets, oral concentrates).

To identify the age-groups relevant to each labeling change, two age references were examined, 1) the minimum age for administration as approved by the FDA and 2) the lowest age reflected in clinical studies or clinical experience for which data were included in the product labeling. The latter age data were extracted in recognition that such information may potentially be used by providers to inform off-label drug use. These ages were then broadly categorized into <2 years, 2–5 years, 6–12 years, and >12 years. For drugs where dosing was based on weight thresholds, the age associated with that weight in U.S. children (on average) was assigned. For drugs where the age of menarche was referenced as the approval limit, the age of 12 was assigned. All age- and weight-related data were determined by review of the labeling.

Formulation characteristics overall and by age were examined using standard descriptive statistics. Chi square tests and Z-tests for two proportions were used to describe differences in categorical variables. Differences in continuous variables (e.g. age references) were examined by student t-tests or analysis of variance. Selected comparisons were made for timeframes before and after enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA, July 2012) which mandated pediatric study planning, and by extension engagement with the agency on these plans, earlier in the drug development process. All statistical analyses were performed in Microsoft Excel.

Results

There were 611 unique pediatric labeling changes for orally administered medications between February 1998 and January 2025. A new pediatric indication was added, or the pediatric age group expanded, in 442 instances. In 87 instances, pediatric safety information was added or enhanced, dosing changes comprised another 45, and in 131, a statement reflecting the fact that safety and/or effectiveness was evaluated but not established was added with or without the provision of supporting clinical trial data. More than one of these reasons was present in 103 cases. Owing to the inclusion of all relevant pediatric information, 32% of labeling changes referenced ages lower than the youngest age of approval. Thus, data describing safety, effectiveness and/or dose-exposure relationships were available to prescribers for ages below those for which the drug was approved. There was no significant difference in the proportion of labels with “mismatched” ages pre- and post-FDASIA; however, the average age difference between referenced and labeled ages was significantly larger for labels predating the legislation (8.0 ± 6.1 yr vs. 2.5 ± 4.8 yr, p<0.01).

The distribution of marketed formulations at the time of the labeling is depicted in Table 1 by lowest age of approval. Note that drugs manufactured in both tablet and capsule form were consolidated in this table under “solid only.” For the majority of pediatric labeling changes (n=329, 53.8%), the only commercially marketed formulation was an adult formulation. For the remaining labeling changes (n=282), a PF formulation was available, existing primarily as companions to the adult dosage forms (vs. a standalone product). Excluding duplicates, these labeling changes represented 425 unique drugs available as 567 commercially marketed formulations. Less than half of these drugs (n=188/425, 44%) were marketed with at least one pediatric-friendly formulation. An additional 10 provided instructions for, or reference to, an extemporaneous admixture to facilitate the preparation of an oral liquid from an adult solid dosage form.

Table 1.

Commercially available formulation type(s) associated with each of the 611 pediatric labeling changes at the time of labeling. Data are stratified by the lowest approved age group for the drug. Like formulation types are grouped together and counted once. For example, if a capsule and tablet were the only two commercially available formulations at the time of labeling, they are represented under ‘One formulation type: solid’

Formulations	Lowest Labeled Age of Approval
	>12 yr	6–12 yr	2–5 yr	<2 yr
One formulation type
Solid (capsule, tablet)	98	173*	31	27†
Liquid (solution, suspension)	2	14	8	8
Powder/granule (P/G)	1	7		5
Transmucosal (film, lollipop, sublingual)	1	3	3
Orodispersible tablet (ODT)		3
Sprinkle/pellets		2
Chewable/paste			3
Dispersible tablet (DT)			2	1
Two formulation types
Solid + Liquid	7	17	26	39
Solid + P/G	2	4	8	33
Solid + ODT	4	7	1
Solid + Sprinkles/Pellets	1	4	14	5
Solid + Chewable/paste		4	1	3
Solid + DT		2	2	6
Liquid + Chewable/paste		1
P/G + Chewable/paste				3
Three formulation types
Solid + Liquid + P/G	3		2	1
Solid + Liquid + ODT	1	4		1
Solid + Liquid + Chewable/paste			1	1
Solid + P/G + ODT		2
Solid + P/G + Chewable/paste			3	2
Solid + ODT + DT			3
Liquid + P/G + Chewable/paste				1

^* n=1 containing an extemporaneous compound recipe in the label

^† n=10 containing an extemporaneous compound recipe in the label

Across all adult dosage forms marketed at the time of pediatric labeling, sizes ranged from 4 to 26 mm. Notably, relatively few drugs exhibited appreciable size differences between their lowest and highest formulation strengths (Figure 1). Differences in size skewed to only a few millimeters despite differences in strength that spanned upwards of 80-fold. When restricting observations to only those products without a companion PF formulation, tablet/capsule sizes for the lowest available strength exceeded putative suitability thresholds in each age group (Figure 2). To explore whether pediatric approvals with larger tablet sizes (and no PF formulations) reflected earlier, potentially looser, labeling requirements, we compared average tablet size before and after FDASIA in the three youngest age groups. In all cases, the average tablet sizes were comparable or larger post-FDASIA (< 2 yr: 11.3 ± 4.2 mm vs. 12.1 ± 3.6 mm, p=NS; 2-5 yr: 10.8 ± 5.0 mm vs. 13.6 ± 3.4 mm, p=NS; 6-12 yr: 11.5 ± 4.7 mm vs. 14.5 ± 4.9 mm, p<0.01).

Figure 1.

Tablet and capsule sizes for marketed drugs with pediatric labeling: (left) absolute difference in product sizes between the minimum and maximum strengths for products with multiple strengths, (right) relative difference in tablet strength vs. relative difference in product size between the minimum and maximum strengths for products with multiple strengths.

Figure 2.

Tablet and capsule sizes at the time of labeling for the lowest strength of marketed drugs with a pediatric labeling change where no pediatric friendly alternative formulations exist. “Labeled” represents the minimum age for administration as approved by the FDA. “Referenced” reflects the lowest age group for which information (e.g. safety, effectiveness, pharmacokinetics) are described in the product labeling.

Among the labeling changes with PF formulations, 174 (62%) reflected formulations suited to direct administration (i.e. liquid, ODT, chewable/paste, transmucosal) while 108 (38%) required some form of manipulation by the caregiver (i.e. powder/granule, sprinkle/pellet, DT). Those labeled for direct administration constituted the majority formulation types for all age groups though it ranged from a low of 54% for infants and toddlers under 2 years to a high of 75% for children 6-12 years. To address acceptability, a vast array of flavorings and aromas, 50 in total, were represented in the PF formulations (Figure 3). Conventional fruit and candy flavors predominated, although flavors less traditionally associated with children were also represented (e.g. anise, black currant, grapefruit, coffee). More than one-quarter of the PF formulations (27%) did not report added flavoring and slightly fewer (13%) failed to report the use of any sweeteners.

Figure 3.

Flavoring (upper pie chart) and sweetener (lower pie chart) characteristics for marketed pediatric-friendly formulations. DT- dispersible tablet, ODT- orodispersible tablet.

Discussion

There are a number of complexities inherent to pediatric formulation development. Dosage forms need to be of sufficient flexibility to span the range of doses needed for this highly variable population, unpleasant or offensive tastes need to be masked, product stability must afford an adequate shelf life, the excipients required to accomplish this need to be deemed acceptable for use in children, and all of these challenges need to be overcome in a manner that is not cost-prohibitive.¹⁸ Irrespective of the underlying reason, the data presented herein affirm that less than half of drugs approved for use in children are marketed with a PF formulation. The overrepresentation of adult oral dosage forms for children does not appear restricted to the U.S. market. Initial and agreed pediatric investigation plan (PIP) filings to the EMA align with the numbers in this study, the distinction being that EMA data telegraph the intention of the sponsor whereas the data presented herein reflect the ultimate commercial marketing decisions that were made.^19,20

For products where PF formulations were available, this study suggests that reasonable attempts were made to ensure palatability with an array of flavorings, aromas, and sweeteners. Unavailable to us, however, was the extent to which palatability determinations were undertaken in children as part of pediatric labeling efforts. If pediatric study plan (PSP) submissions to the FDA resemble PIP submissions to the EMA, we can expect that approximately 1 in 10 applications will lack adequate palatability and acceptability evaluations.¹⁹ Expanding the definition of acceptable to include formulation preferences of children and their caregivers, the finding that adult dosage forms represented the only formulation accompanying over half of all pediatric labeling changes, suggests that far less consideration is given to acceptability in pediatric FDA submissions. Research on the preferences of children suggest that their willingness to take solid dosage forms is not assured, even among teenagers, and caregivers may view these formulations even less favorably than their children.²¹ In this context, medication adherence may be unreliable and medication failure a tangible risk.^22,23

Beyond stated formulation preferences are issues of capability when it comes to the ability of children to reliably swallow solid oral dosage forms where the likelihood of success drops with increasing tablet/capsule size. In this study, sizes of the lowest dosage strength ranged up to 19 mm for labels referencing children under 2 years of age and 23 mm for children in all other age groups. Reasonable standards suggest that these might exceed sizes appropriate for the specified age groups, but current guidance documents do not explicitly define criteria above which product sizes become unsuitable for children.²⁴ At present, FDA guidance addresses size only in reference to permissible deviations for generics in relation to their reference products.²⁵ Thus, the opportunity to set suitable standards for innovator products remains open.

An early iteration of an EMA guideline proposed age-specific thresholds for tablet sizes (<2 yr: 3 to 5 mm, 2–5 yr: 5 to 10 mm, 6–11 yr: 10 to 15 mm, 12–18 yr: from 15 mm),²⁶ but subsequently removed them from the document following public criticism for the lack of corroborating evidence.²⁷ In this context, there does exist a small body of literature that examines the ability of children to swallow various sized products.^28–30 However, the primary takeaway seems to be that this is highly patient specific and influenced by more than simply age. For example, children with chronic conditions (including those as young as 3 years) and those with prior experience swallowing tablets have better success rates, and success rates can be improved with training, but this is not practical in all settings.^31–34 Given that variations in tablet strength far exceed those of tablet size, and the majority of these products are constituted by inert fillers, it would appear that opportunities exist for manufacturers to explore innovative formulation strategies better suited to pediatric populations, such as microparticles or mini-tablets.^35,36 Enhanced guidance from regulatory agencies regarding appropriate product sizes for children could encourage the development of more child-friendly formulations.

This analysis justifiably focused on formulation availability by labeled age group, yet we would be remiss not to acknowledge that nearly 1 in 3 product labels contained information for children below the approval age. In select few cases it was clear that formulation availability shaped pediatric labeling (e.g. The safety and effectiveness of APTIVUS, co-administered with ritonavir have been established in pediatric patients greater than 2 years of age or weighing less than 36 kg, but not recommended due to lack of a suitable pediatric formulation), but other examples exist where safety and effectiveness data were available absent a recommendation for use. Understandably, this has the potential to influence provider utilization and by extension lead us to underestimate the impact of the absence of PF formulations. For context, the FDA’s position on the extent of information included in the labeling has changed over the timespan of labels reviewed in this study. Prior to passage of the FDA Amendments Act (FDAAA) in 2007, relatively little product experience was included in the labeling, after which point it was determined that all pediatric study information should be made available.⁵ Ultimately a more conservative approach was re-introduced with the attempt to provide all relevant information short of that which would encourage inappropriate use of the drug in children. It is not our intent to adjudicate the extent of information that should be available but to simply acknowledge that prescribers and regulators may view product labeling differently resulting in well-established rates of off-label medication use in children.^37–39

Whether used on- or off-label, the lack of commercially available PF formulations places the onus of safe and accurate medication administration on healthcare providers, patients, and primary caregivers. Extemporaneous compounding can, and does, offset some of these delivery challenges, accounting for over 3 million pediatric prescriptions each year in the U.S., but the practice is not free of risk.^40–42 Prescribers need to decide whether desired exposure-response targets are likely to be achieved with the formulation; compounding pharmacies must resolve stability, compatibility, contamination, and excipient risks; caregivers need to manage adherence and acceptability issues; and all involved need to accept the lack of quality control and associated possibility of human error.⁴² Admittedly, decisions to manufacture and market a drug are multifactorial and the reliance on publicly accessible data in this study limited the ability to determine why PF formulations were not commercialized. However, the findings reveal an opportunity for manufacturers, clinicians, and regulators to collaborate and explore solutions that may lead to improved medication options for pediatric patients.

Conclusions

The objective of this research was to examine the nature of commercially marketed products available at the time of pediatric labeling. The resulting data reinforce that suitable PF formulations accompany less than half of all pediatric approvals while the product sizes for the available adult dosage forms may exceed reasonable thresholds for administration to children at the ages approved. The absence of PF formulations requires attention if we are to maximize the provision of suitable pharmacotherapy for pediatric patients.

ABBREVIATIONS

BPCA

Best Pharmaceuticals for Children Act

DT

dispersible tablet

EMA

European Medicines Agency

FDA

U.S. Food and Drug Administration

FDAAA

FDA Amendments Act

FDASIA

Food and Drug Administration Safety and Innovation Act

ODT

orodispersible tablet

PF

pediatric-friendly

PIP, PREA

Pediatric Research Equity Act; pediatric investigation plan

PSP

pediatric study plan