Investigating Variations in Medicine Approvals for Attention-Deficit/Hyperactivity Disorder: A Cross-Country Document Analysis Comparing Drug Labeling

Objective: This study aimed to compare the approval of medicines for attention deficit/hyperactivity disorder (ADHD) for pediatric patients across five countries. Method: A document analysis was completed, using the drug labeling for ADHD medicines from five countries; United Kingdom, Australia, New Zealand, Canada and United States (US). Comparisons of available formulations and approval information for ADHD medicine use in pediatric patients were made. Results: The US had the highest number of approved medicines and medicine forms across the studied countries (29 medicine forms for 10 approved medicines). Approved age and dosage variations across countries and missing dosage information were identified in several drug labeling. Conclusions: The discrepancies in approval information in ADHD medicine drug labeling and differing availability of medicine formulations across countries suggest variations in the management of ADHD across countries. The update of drug labeling and further research into reasons for variability and impact on practice are needed.


Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder with an estimated pooled prevalence of 7.1% (Thomas et al., 2015).ADHD is characterized by impaired attention, motor hyperactivity and impulsivity, and symptoms often persist into adulthood which may impair social, academic and occupational functioning (Sibley et al., 2017;Thapar & Cooper, 2016).Diagnosis and subsequent prescribing and use of medicines to manage this condition in pediatric patients are increasing (Raman et al., 2018).However, the prevalence of ADHD medication use varies across countries and regions, appearing higher in North America (pooled prevalence of 4.48%) than in Northern Europe (1.95% pooled prevalence), Asia (0.95% pooled prevalence), Australia (0.95% pooled prevalence), and Western Europe (0.7% pooled prevalence) (Raman et al., 2018).
Where pharmacological treatment is indicated for ADHD, the medicine prescribed by a clinician may depend on where a person lives, local treatment guideline recommendations, and the availability and approval of medicines (Raman et al., 2018).Evidence suggests that there are variations in availability and ADHD medication use across different countries and regions, indicating differences in clinical approaches when managing ADHD (Okumura et al., 2019;Raman et al., 2018).For example, methylphenidate tends to be predominantly used in Australia, Canada, Asia, and European countries, whereas in the United States (US), the prescribing of amfetamines is more common or nearly as common as methylphenidate (Bachmann et al., 2017;Okumura et al., 2019;Raman et al., 2018;Song, 2016).In addition, nonstimulant medicines such as atomoxetine have been increasing in Korea and European countries but decreasing in the US (Bachmann et al., 2017;Song, 2016).
In most instances, the first-line pharmacological treatments recommended for ADHD are psychostimulant medicines, including methylphenidate, dexamfetamine, or amfetamines while nonstimulant medicines, such as atomoxetine, are recommended as second-line treatments (Bolea-Alamañac et al., 2014;Canadian ADHD Resource Alliance, 2020;National Institute for Health and Care Excellence, 2018;Pliszka, 2007;Taylor et al., 2018;Wolraich et al., 2019;Wolraich & Hagan, 2019).Third-line treatments include clonidine, imipramine, atypical antipsychotic, and other medicines (Canadian ADHD Resource Alliance, 2020).In the US, clonidine is recommended as a second-line pharmacological treatment, and it is also approved and marketed for ADHD (Wolraich & Hagan, 2019).In contrast, in Canada, Australia, and the United Kingdom (UK), it is not regulatory approved for use in pediatric ADHD, despite common use in practice (Ben Amor et al., 2014;Betts et al., 2014;Efron et al., 2013Efron et al., , 2017)).
It is also important to note that the availability of different medication formulations is important for individualized treatment.However, the numerous formulations of psychostimulants available have led to confusion and errors during the prescribing and dispensing of these medicines (Chavez et al., 2009).This may also be of concern where patients may seek medicines when overseas or where prescribers may move practice across countries.
The labeling of a medicine (drug labeling) is authorized by regulatory authorities such as the Food and Drug Administration (FDA) in the US or the Therapeutics Goods Administration (TGA) in Australia.Health professionals may refer to the drug labeling during practice as they are a source of important clinical trial information and safety and dosage information.However, the drug labeling may differ across countries according to the requirements of different regulatory authorities.As the drug labeling and regulatoryapproval of a medicine are supported by evidence of the safety and efficacy, it would be expected that the drug labeling would be standardized and consistent across countries.However, this does not always seem to be the case.For example, concerns have been raised about the differences in the publicly-available medication information for clonidine, where variations in regulatory-approved information could undermine patient adherence (Beckmann, 2013).
Little is known about the differences in approval of other ADHD medicines across countries, including more commonly used psychostimulants such as methylphenidate, dexamfetamine and lisdexamfetamine.An understanding of the use and availability of medicines in different countries may help contribute to the optimization of the management of ADHD in pediatric patients.
In light of the increasing prevalence of ADHD medication use and a lack of international comparisons of medicine approvals and formulations, this study aimed to compare the approval of ADHD medicines for pediatric patients across five countries; the UK, Australia, New Zealand (NZ), Canada, and the US.
The regulatory-approved drug labeling documents outline the approval of medicines in a country.These are referred to as the "Summary of Product Characteristics" in the UK, "Product Information" in Australia, "Data Sheet" in NZ, "Product Monograph" in Canada and "Prescribing Information" in the US.These documents were sourced from online databases (DataPharm Ltd., n.d.; Health Canada, n.d.; MEDSAFE New Zealand Medicines and Medical Devices Safety Authority, n.d.; Therapeutic Goods Administration, n.d.; U.S. National Library of Medicine, n.d.).It is recognized that several online databases contain drug labeling.The online databases used for this analysis are often used by healthcare professionals as they are easily accessible and provide efficient search methods for many medicines and their drug labeling.
Drug labeling were retrieved for each country in March 2023 and saved locally for data extraction and analysis; A summary of the references for the approved ADHD medicines and their drug labeling is available in Supplemental Table S1.The pediatric age group was defined as children and adolescents aged <18 years.Any differences in the spelling of medicine names across countries were over come by standardization according to ATC code.Specifically, "amfetamine" is known as "amphetamine" and "dexamfetamine" is known as "dextroamphetamine" in the US and Canada, and metamfetamine is known as "methamphetamine" in the US.
The countries in our study were conveniently selected because they share similarities in Western culture, are highincome, are English-speaking, and have readily accessible regulatory documents online, in English.Except for the US, the other countries in our study (Australia, NZ, Canada, and the UK) also have largely public, national healthcare systems.In addition, given the strong evidence-based culture across these countries, one would expect there to be consistency in medicine guidelines and dosing.There is also significant immigration between these countries; hence, harmonizing regulatory documents and providing consistent health information is important.To address the aim of this study, a cross-comparison document analysis of drug labeling from five conveniently selected high-income countries was performed (Figure 1).All ADHD medicines comprising ATC groups N06 and C02 were searched in each online database and drug labeling were retrieved for the medicines approved for ADHD in pediatrics.
Comparisons of all the approval information for pediatric ADHD were made across countries.Where a medicine was marketed or approved in a country under more than one formulation or more than one trade name, resulting in multiple drug labeling, all documents were checked for consistency.Multiple preparations with variable immediate-release (IR), extended-release (XR) or delayed-release (DR) ratios were observed, particularly for methylphenidate and amfetamine.Formulation types included the following: capsule, chewable tablet, extendedrelease capsule (XR-C), extended-release chewable tablet, extended-release orally-disintegrating tablet (XR-ODT), extended-release suspension (XR-S), extended-release tablet (XR-T), solution, tablet and transdermal patch.Medicines and their formulations were separated into different medicine forms for analysis.During data analysis, only one drug labeling was assigned per medicine form per country; the non-generic brand or a generic brand with the most recent update (where a non-generic brand was unavailable).
Medicines with varying extended-release formulations were separated into different medicine forms based on IR to XR component ratios or XR technology as detailed in the drug labeling and/or the literature.Initially, the drug labeling was checked.Then, information was extracted from the literature where the drug labeling did not provide enough detail.Specifically, information from the literature was required to determine the IR/XR component ratios for Adderall XR ® (Greenhill et al., 2003;Swanson, 2005) and Mydayis ® (Takeda Pharmaceuticals U.S.A, 2023).Dyanavel ® XR (suspension and tablets) contain amfetamine IR and XR components, however, the ratios have not been described (Childress et al., 2019).
Data from the drug labeling were extracted using a purpose-designed form.They included the following information: medicine name, ATC code, approved/marketed formulations, approved age and approved dosage information (initial dose, dose titration and maximum dose).In addition, information relating to the use of clonidine in pediatric ADHD was also extracted, along with the corresponding section/subsection of the drug labeling.Data extraction and analysis were performed by one author (L.T.), and 10% of the data set was independently checked for accuracy by another author (A.L.).Where discrepancies existed, a discussion was held until a consensus was reached and adjudicated by a third reviewer (T.C.).

Results
Ten medicines from ATC groups N06 and C02 were approved for pediatric ADHD in one or more of the studied countries (amfetamine, atomoxetine, clonidine, dexamfetamine, dexmethylphenidate, dexmethylphenidate and serdexmethylphenidate, guanfacine, lisdexamfetamine, metamfetamine, and methylphenidate) (Table 1).From these medicines, 29 different medicine forms were identified and included in the analysis (including immediate-release and extended-release formulations, capsules, chewable tablets, orally-disintegrating tablets, solutions, suspensions, and transdermal patches), comprising a total of 62 drug labeling across the studied countries.All 29 medicine forms were approved in the US, with 11 approvals in Canada, 8 in the UK, 7 in Australia, and 7 in NZ (Table 2).
Five of the 62 drug labeling had the approval for the ADHD indication for children as young as 3 years.These included amfetamine IR (Evekeo ® ) and dexamfetamine IR (Procentra ® and Zenzedi ® ) in the US, dexamfetamine IR (Aspen dexamfetamine) in Australia and dexamfetamine IR in NZ (Aspen Dexamfetamine, 2021;Dexamfetamine Tablets, 2017;Evekeo, 2022;Procentra, 2022;Zenzedi, 2022).Amfetamine mixed salts XR (Mydayis ® ) in the US was approved for adolescents 13 years and older (Mydayis, 2022).Methylphenidate XR (CD) (Teva Pharmaceuticals US brand) was approved for children 6 to 15 years old (Methylphenidate Hydrochloride (CD), 2022).All other medicines were approved for children and adolescents 6 years and older (across 55 drug labeling).Dexamfetamine was approved for use in all five countries but there were inconsistencies in the approved ages in the drug labeling; 3 years and older in Australia (Aspen Dexamfetamine, 2021), NZ (Dexamfetamine Tablets, 2017) and the US (Focalin, 2022), and 6 years and older in the UK (Dexamfetamine Sulfate 1 mg/ mL Oral Solution, 2022) and Canada (Dexedrine/Dexedrine Spansule, 2020).All other medicines approved in two or more countries were consistent in the approved ages.The dosage information was missing or incomplete in eight drug labeling, most of which were from the US (Adderall XR ® , Desoxyn ® , Zenzedi ® and Procentra ® ), dexamfetamine in NZ, Ritalin ® in Australia and Strattera ® and Strattera ® oral solution in the UK (Table 3).The Canada drug labeling for Concerta ® provided the dose titration as "Adjust at weekly intervals."While the specific doses were not mentioned, Concerta ® is available in 18 mg, 27 mg, 36 mg, 54 mg and 72 mg strengths, which we would expect to guide those dosage adjustments.Similarly, while the US drug labeling for Daytrana ® did not specify a maximum dosage, the 30 mg/9 hour patches are the highest strength available, which we would expect to indicate the maximum dose.
Five of 29 medicine forms were approved in all five countries; atomoxetine IR, dexamfetamine IR, lisdexamfetamine IR, Methylphenidate IR, and Methylphenidate XR (Concerta ® /Concerta ® XL).Inconsistencies in the approved dosage information in the drug labeling exist across the studied countries (Table 4).A full description of the approved ages, initial dose, dose titration and maximum doses extracted from the drug labeling for all the approved ADHD medicines is available in Supplemental Table S2.
Clonidine oral formulations include immediate-release and extended-release preparations across the studied countries and of these, only clonidine XR (Kapvay ® ) is approved for pediatric ADHD in the US (Table 2).Excerpts from the drug labeling relating to the use of clonidine for pediatric ADHD identified inconsistencies in the drug labeling between the US (clonidine XR) and other countries (clonidine IR in the UK, Australia, NZ, and Canada) (Table 5).The US drug labeling advises that the safety and efficacy of clonidine for use in pediatric ADHD have been established in pediatric patients.In contrast, the drug labeling in other countries (UK, Australia, NZ, and Canada) signify a lack of safety and efficacy in this population.It is important to note that the formulation approved in the US (XR) differs from that of other countries (IR) for pediatric ADHD.Furthermore, the US drug labeling for clonidine IR does not include information on its use in pediatric ADHD (Clonidine Hydrochloride, 2023).

Discussion
Our study provides a five-country cross-comparison of the approval of ADHD medicines for pediatric patients.Our findings indicate differences in the approval and availability of ADHD medicines and their formulations across countries and conflicting information about clonidine for use in pediatric ADHD in the drug labeling.A lack of dosage information was identified in several drug labeling.Our findings identify a need for the review and update of the relevant information in the drug labeling of ADHD medicines.
We found differences in the number of approved ADHD medicines and available formulations across the studied countries.In particular, we found the highest number of approved ADHD medicines and formulations were available in the US (29 medicine forms available for 10 medicines), where pediatric ADHD diagnoses are highest (9.4%) (Danielson et al., 2018).In the US, prescribing guidelines recommend the use of methylphenidate (preschool children) or FDA-approved psychostimulants (aged 6 years and older) as first-line pharmacological agents,     2018;Taylor et al., 2018).Concerns have been raised about a lack of availability and accessibility to appropriate formulations of psychostimulants for young children (Schirm et al., 2003).In addition, dosing inconvenience, swallowing difficulties and social stigma contribute to ADHD treatment discontinuation in pediatric patients (Gajria et al., 2014).
Although the drug labeling recommend that some capsules can be opened and dispersed into food or drinks, this carries a risk of unreliable dosing or incomplete dose delivery (Childress et al., Where alternative formulations which are not commercially available may be required, for example, oral suspensions or dispersible formulations for children with swallowing difficulties (Cortese et al., 2017;Gajria et al., 2014), special pharmaceutical compounding may be required, however, this may not be easily accessible and is often substantially more expensive for patients.
The differences in approval of ADHD medicines and formulations across countries identified in our study could also result in the need for prescribers in other countries to change a patient's therapy should they travel or move overseas.This could be confusing or distressing for the patient and their family, especially where unnecessary changes to treatment are made.As the population and prevalence of pediatric ADHD differs across countries, and the market size changes, this probably influences the number of marketed products and available formulations.Prescribers and patients/carers will need to work together to manage changes in medicines, should they patient move to a country with different medicine and formulation availabilities.The findings of this study may be helpful to improve clinicians' awareness of these issues, particularly for those who may be moving their practice overseas, or managing patients who have arrived from abroad.
Amfetamines were approved in children as young as 3 years old in our study; amfetamine IR (Evekeo ® in the US), amfetamine mixed salts IR (Adderall ® in the US) and dexamfetamine in Australia, NZ, and the US.Interestingly, methylphenidate has more extensive research supporting its safe and efficacious use in the 3 to 5-year age group (Kollins    et al., 2006).However, methylphenidate, along with the other ADHD medicines identified in our study, were approved by regulatory agencies for children 6 years and older in the studied countries (Supplemental Table S2).
While the regulatory-approved age in the drug labeling may influence a prescriber's decision, off-label prescribing may be deemed necessary in practice, and if so, it should align with current evidence and sufficient experience using the medicines (General Medical Council, 2019;Sugarman et al., 2013) In line with findings from other studies, we encountered missing or incomplete dosage information (particularly maximum dosage and dose titration guidelines) in several drug labeling (Arguello et al., 2014;Beers et al., 2013;Salgado et al., 2013;San Miguel et al., 2005;Weersink et al., 2019).Our analysis found that the maximum dosage was absent in six drug labeling and the dose titration guidelines were incomplete in another two drug labeling (Table 3).The maximum doses in drug labeling can provide a guide to healthcare professionals during the prescribing and supply of medicines.A recent meta-analysis found a range of recommended maximum doses for methylphenidate used in clinical studies but no discernible scientific justification for any recommendations (Ching et al., 2019).There are also concerns that prescribers may not adhere to regulatory or prescribing guidelines in practice (Epstein et al., 2014).Further, deficiencies in the content information in drug labeling may contribute to variability in practice and elicit uncertainty among healthcare professionals utilizing the drug labeling in practice, with concerns about the reliability of the included information.Therefore, there is a need to review and update the content information in drug labeling of ADHD medicines to ensure the completeness of the included information.
Interestingly, we identified differences in the guidelines for dose titration in the drug labeling of Concerta ® / Concerta ® XL (Methylphenidate XR) across the five approved countries (the UK, Australia, NZ, Canada, and the US), despite marketing by the same pharmaceutical company, Janssen.Similarly, the dosage information for Strattera ® (atomoxetine) differs across the drug labeling from the approved countries, despite being marketed by Eli Lilly and Company in all the countries.Previous studies have also identified differences in the content information of drug labeling for ADHD medicines (Aagaard & Hansen, 2013;Warrer et al., 2014) and antidepressants across countries (Tanana et al., 2021).Our findings raise questions about how such discrepancies can materialize and could potentially indicate variations in the prescribing and management of ADHD across countries.Regulatory processes may vary across countries, which could explain the differences in the content information in the drug labeling.Further research may be needed to determine why differences in drug labeling exist across countries and any impacts on practice.
Clonidine (extended-release) is approved for ADHD in pediatric patients either as monotherapy or an adjunct to stimulants in the US.On the other hand, other clonidine (immediate-release) drug labeling comment on lacking evidence to support the efficacy of clonidine in ADHD (Australia, NZ, and the UK drug labeling) and provide a warning that concomitant use of clonidine with methylphenidate is associated with serious adverse events, including death, so the combination is not recommended (Australia, Canada, and NZ drug labeling) (Table 5).Comparatively, the US drug labeling for clonidine (immediate-release) does not comment on its use in ADHD (Clonidine Hydrochloride, 2023).Despite only being approved in the US for pediatric ADHD, clonidine is commonly prescribed to pediatric ADHD patients in the US, Canada, and Australia (Ben Amor et al., 2014;Betts et al., 2014;Efron et al., 2013).Guidelines recommend the use of clonidine for ADHD in certain circumstances, as a third-line medicine (Canadian ADHD Resource Alliance, 2020; Taylor et al., 2018), as a second-line agent (Wolraich & Hagan, 2019) or with advice from a tertiary ADHD service (National Institute for Health and Care Excellence, 2018).Furthermore, studies have determined the efficacy and well-tolerated use of clonidine for ADHD in pediatric patients (Catalá-López et al., 2017;Childress et al., 2020;Health Products Regulatory Authority, n.d.;Ming et al., 2011).Drug labeling are publicly available online, meaning that patients and carers from different countries can access them.Such conflicting information in the drug labeling and outdated safety information could undermine medication adherence (Beckmann, 2013).Changes to the current drug labeling to reflect updated safety information and improved consistency in the included approval information across countries may be warranted.
Regulatory agencies have implemented changes in recent years to improve the format of drug labeling and to harmonize drug labeling with international regulators (New Zealand Medicines and Medical Devices Safety Authority, 2017; Therapeutic Goods Administration, 2020).Our international comparisons identify other areas for consideration during the update of drug labeling and support the decisions of regulatory bodies wishing to improve global harmonization of regulatory documents, such as the Australian TGA (Therapeutic Goods Administration, 2020) and New Zealand Medicines and Medical Devices Safety Authority (New Zealand Medicines and Medical Devices Safety Authority, 2017).Furthermore, the international standardization of medicine names used in drug labeling could help to overcome potential confusion in practice, especially when using prescribing guidelines from different countries.For example, "dexamfetamine" is the medicine name used in Australia, NZ, and the UK, but "dextroamphetamine" is used in the US and Canada.Our study concept also aligns with the aims of The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), to improve regulatory process harmonization worldwide (The International Council for Harmonisation, n.d.).
Our study had some limitations.Our findings are limited to the five countries in our analysis, so they may not be generalizable to other developed, low or middle-income countries.It is acknowledged that drug labeling change over time, necessitating an update to these findings in the future.We recognize that only one researcher extracted all of the data, so a second author randomly and independently checked 10% of the data set to provide robustness.No significant discrepancies between the two authors were noted.Additionally, we acknowledge that medicines marketed for each formulation did not necessarily indicate bioequivalence between countries.However, we utilized research in the current literature and a detailed analysis of the drug labeling to justify brand comparisons across countries.

Conclusion
Overall, our study identified missing dosage information and variability in the approval information in drug labeling for some ADHD medicines across countries.Additionally, we noted differences in the number of approved ADHD medicines and their marketed formulations across countries, which could indicate variations in the management of ADHD across countries and implications for those who may want to travel or live in another country.We also identified a need for the update of the drug labeling to reflect current evidence about safety and efficacy (i.e., for clonidine use in ADHD).Prescribers and patients require reliable and consistent information to inform them of the appropriate selection of a medicine, its formulation and appropriate dosage for the management of ADHD in pediatric patients.The similarities in Western culture between the five English-speaking countries selected in our study, as well as the similarities in their public national healthcare systems (except that of the US) may lead us to expect uniformity in the regulatory approval of medicines.However, we identified differences in approved medicines, age groups and regulatory information, which raise questions about the reasons for variability in drug labeling, prompting the need for further research.Considering the vulnerable nature of the pediatric age group, an improvement in the consistency of drug labeling across these Western countries could hopefully encourage the harmonization of regulatory information across other Western and non-Western countries.Better harmonization of regulatory information may reduce variability in the management of pediatric ADHD across different countries, thereby optimizing patient care and treatment outcomes.
Gray fill: Not marketed in the respective country.chew tab = chewable tablet; XR = extended-release; XR-C = extended-release capsule; XR-chew tab = extended-release chewable tablet; XR-ODT = extended-release orallydisintegrating tablet; XR-S = extended-release suspension; XR-T = extended-release tablet; IR = immediate-release; ODT = orally-disintegrating tablet.a Dyanavel XR ® (solution and tablets) contain both IR and XR components of amfetamine, although the ratio of IR to XR is unknown.Reference: Childress et al. (2020).b ". ..They contain three types of drug-releasing beads, an immediate release and two different types of delayed release (DR) beads.The first DR bead releases amphetamine at pH 5.5 and the other DR bead releases amphetamine at pH 7.0."Reference: Mydayis (2022

Table 1 .
Approval of Medicines for ADHD in Pediatric Patients Across Five Countries.

Table 2 .
Medicine Forms Approved for ADHD in Pediatric Patients Across Five Countries.
The initial absorption of methylphenidate into plasma is delayed such that no more than 5% of total drug is available within the first 10 hours after dosing.After the lag period, the absorption of methylphenidate occurs in a single peak with a median T 14.0 hours, followed by a gradual decline throughout the rest of the day. .." ). c ". ..JORNAY PM extended-release capsules contain beads with two functional film coatings (outer delayed-release and inner extended-release) surrounding a drug core coated with methylphenidate hydrochloride.The outer, delayed-release coating delays the initial release of methylphenidate while the inner extended-release coating controls the release throughout the day. ..", ". ..dQuillichew ER ® (30% IR, 70% XR components) differs from methylphenidate CD TEVA brand (30% IR, 70% XR beads components) due to the pharmacokinetic profile and extended-release technology, so they were treated as different drug formulations.e Medikinet ® LA has shown to be bioequivalent to Ritalin LA under fasting conditions, but NOT in the fed state.Reference: Haessler et al. (2008).

Table 3 .
Missing Dosage Information in Drug Labeling for Pediatric ADHD Medicines.
Note.Full dosage information can be accessed in Supplemental Table2.XR = extended-release; IR = immediate-release.

Table 4 .
Dosage Comparisons for ADHD Medicines Approved in All Five Countries (Australia, Canada, New Zealand, the United Kingdom, and the United States).

Table 4 . (continued)Table 5 .
Excerpts From Drug Labeling of Clonidine Relating to Use in Pediatric ADHD.Clonidine XR oral formulation is only marketed in the United States, thus drug labeling were not available for this formulation in Australia, Canada, New Zealand and the United Kingdom.Additional information relating to the approval of clonidine extended-release oral tablet for pediatric ADHD can be found in the United States drug labeling.
a b