An International Comparison of the Information in the Regulatory-Approved Drug Labeling and Prescribing Guidelines for Pediatric Depression

Introduction

Major depression in pediatric patients (“pediatric depression”) is a serious psychiatric illness, which is often underdiagnosed and undertreated (Charles and Fazeli 2017). Psychotropic medicine use in the pediatric population is widespread, with estimates of pooled global prevalence of antidepressant medicine use reported as 6.4% and antipsychotic medicine use as 5.5% (Piovani et al. 2019). Despite limited regulatory approvals, psychotropic medicines are often used in the treatment of pediatric depression, resulting in off-label use (Dorks et al. 2013; Schroder et al. 2017). Off-label use is commonly referred to as the use of a medicine outside the product license with reference to age, indication, dosage, or route of administration (Pandolfini and Bonati 2005).

The labeling of a medicine is authorized by regulatory authorities, and acts as a main source of information for health professionals. There are few clinical trials focused on psychotropic medicine use in pediatric depression (Murthy et al. 2013) and it is acknowledged that insufficient clinical data often result in a lack of pediatric dosing information in the drug labeling (Permala et al. 2010). Off-label use may be associated with an increase in medication errors (Rinke et al. 2010) and potential increased risk of adverse drug reactions (Horen et al. 2002; Jonville-Béra et al. 2005; McLaren et al. 2018). In practice, dosages for pediatric patients are often scaled from adult dosages despite insufficient methods for scaling (Johnson 2008). Further to this, the growth and developmental changes associated with youth may result in responses to psychotropic medicine treatment, which do not mirror the responses from a fully developed adult brain (McLaren et al. 2018).

Prescribing for off-label use is, however, accepted and may be the standard of care in many cases (Meadows and Hollowell 2007). Thus, prescribers are free to prescribe outside the product licensing, although they assume greater professional responsibility and liability (Sugarman et al. 2013). The General Medical Council's Good Practice guidelines for doctors recommend that prescribers should be aware of the requirements involved, including satisfaction with the current evidence, which exists or sufficient experience with the medicine and belief that it will be safe and effective in the intended patients (Sugarman et al. 2013; General Medical Council 2019).

Prescribers may refer to the drug labeling during practice as they are a source of important clinical trial information, as well as safety and dosage information. The drug labeling may, however, differ across countries, according to the requirements of different regulatory authorities. Additionally, the recommendations of prescribing guidelines are expected to differ from information in the drug labeling, as off-label medicine use in pediatric depression is widespread (Dorks et al. 2013; Palmaro et al. 2015; Deng et al. 2018). These differences could thus result in variations in treatment and prescribing in practice.

Little is known about the differences in information between prescribing guideline recommendations and the drug labeling for the treatment of pediatric depression, or the cross-country differences in approval of psychotropic medicines. Thus, the aims of this study were to determine the differences in information between prescribing guidelines and the drug labeling, as well as to compare the approval of psychotropic medicines for pediatric depression across countries.

Methods

The psychotropic medicines included within this study were defined by the Anatomical Therapeutic Chemical (ATC) classification system (WHO Collaborating Center for Drug Statistics Methodology 2019) and comprised either: Psycholeptics (N05) or Psychoanaleptics (N06).

The approval of medicines in a country is outlined by regulatory-approved drug-labeling documents, which are referred to as the “Summary of Product Characteristics” in the United Kingdom, “Product Information” in Australia, “Data Sheet” in New Zealand, “Product Monograph” in Canada, and “Prescribing Information” in the United States. These documents were sourced from online databases (DataPharm Ltd. 2019; Health Canada 2019; Medsafe 2019; Therapeutic Goods Administration 2019; U.S. National Library of Medicine 2019). There are several online databases containing drug labeling. The online databases used for this analysis are often used by health care professionals as they are easily accessible and provide efficient search methods for a large number of medicines and their drug labeling.

Drug labeling was retrieved for each country in July 2019 (Table 1) and saved locally for data extraction and analysis. The Canadian Product Monograph for imipramine oral tablets could not be retrieved despite a “marketed” status on the website (Health Canada 2019).

The Maudsley Prescribing Guidelines in Psychiatry (MPGP) (Taylor et al. 2018) were consulted for guidance on the use of psychotropic medicines for pediatric depression. MPGP recommends the following psychotropic medicines for pediatric depression: fluoxetine (first line), sertraline or citalopram (second line), escitalopram (third line) and recommends consideration of augmentation of antidepressant medicines with a second-generation antipsychotic medicine or lithium, or to consider mirtazapine (where sedation is required) (fourth line). No immediate second-generation antipsychotic medicines were listed.

The pediatric age group was defined by those <18 years of age. Many synonyms for the indication “depression” were used across the drug labeling for medicines approved for pediatric depression (Box 1).

To address the aims of this study, two sets of medicine comparisons were made:

We performed a cross-comparison document analysis of MPGP medicine recommendations for pediatric depression and their respective drug labeling from five conveniently selected high-income countries (the United Kingdom, Australia, New Zealand, Canada, and the United States) (Fig. 1). Medicines recommended by MPGP were searched in each online database and the drug labeling was retrieved for comparisons. MPGP medicine recommendations, which aligned with the drug labeling, were characterized as “on-label,” whereas those which did not were characterized as “off-label” due to age, indication, dosage, or route of administration. Similar to the article by Palmaro et al. (2015), dosage was compared with a 20% tolerance margin.

OPEN IN VIEWER

FIG. 1.

Process of comparing the recommendations of The Maudsley Prescribing Guidelines in Psychiatry against the drug labeling. ¹DataPharm Ltd. (2019); ²Therapeutic Goods Administration (2019); ³Medsafe (2019); ⁴Health Canada (2019); ⁵U.S. National Library of Medicine (2019).

OPEN IN VIEWER

FIG. 2.

Process of identifying psychotropic medicines and drug labeling for cross-country comparisons of approved information. ¹DataPharm Ltd. (2019); ²Therapeutic Goods Administration (2019); ³Medsafe (2019); ⁴Health Canada (2019); ⁵U.S. National Library of Medicine (2019).

Where a medicine was marketed or approved in a country under more than one trade name, or more than one formulation, resulting in multiple drug labeling, all documents were cross-checked for consistency. We found consistency across the drug labeling of different brands for the same medicine, except for imipramine and fluoxetine, due to multiple marketed formulations. To be comprehensive, approved medicines with different formulations and routes of administrations, which resulted in different dosage guidelines, were treated as different medicines (i.e., imipramine oral formulation and imipramine intramuscular injection, and fluoxetine conventional oral formulation and fluoxetine delayed-release oral formulation). Thus, only one drug labeling was assigned per medicine per country during data analysis, the nongeneric brand or a generic brand with the most recent update (where a nongeneric brand was not available) (Table 1).

Data extraction and analysis were performed by one author (L.T.), with 10% of the data independently checked by another (A.L.). Where discrepancies existed, a discussion was held until consensus was reached, and adjudicated by a third reviewer (T.F.C.).

Results

Discussion

This study is the first to compare information from the drug labeling of psychotropic medicines for use in pediatric depression against a recognized psychotropic prescribing guideline. Health care professionals looking for guidance on the use of psychotropic medicines for pediatric depression will encounter discrepancies when key resources are searched. A total of 13 psychotropic medicines were approved in one or more of the studied countries, however, only 3 of these medicines were recommended by MPGP (fluoxetine, escitalopram, and lithium). Specifically, the eight tricyclic antidepressant medicines (TCAs), which hold approval for pediatric depression in one or more of the studied countries, are not recommended for use in pediatric depression in MPGP. This recommendation is supported by a Cochrane review, which found that TCAs are not useful in treating major depression in children, and there is marginal evidence to support their use in the treatment of major depression in adolescents (Hazell and Mirzaie 2013).

MPGP recommends the consideration of augmentation of antidepressant medicines with a second-generation antipsychotic medicine (fourth-line pharmacotherapy), although the recommended second-generation antipsychotic medicines are not immediately listed, and no second-generation antipsychotic medicines are approved for pediatric depression in any of the studied countries. There is increasing evidence supporting the benefits of second-generation antipsychotic medicines for treatment-resistant major depression in adults, either as monotherapy or augmentation to antidepressant medicines. In particular, aripiprazole, brexpiprazole, olanzapine (in combination with fluoxetine) and quetiapine (extended-release) are approved in the United States for augmentation of antidepressant medicines in adults and some evidence also supports the benefits of other, unapproved, second-generation antipsychotic medicines (Han et al. 2013; Wang et al. 2016). A lack of studies in the pediatric population warrants the need for clinical trial data evaluating lithium or augmentation of antidepressant medicines with a second-generation antipsychotic medicine for pediatric depression (Han et al. 2013).

Our study found that differences in information between MPGP and the drug labeling was most often due to the recommendation of medicines outside of the approved age (24/26), followed by indication (2/26). Similarly, studies by Schroder et al. (2017) and Deng et al. (2018) comparing pediatric outpatient antidepressant medicine prescriptions against regulatory approvals found unapproved ages or indications to be the most common types of off-label use. It is important to note that both studies were not restricted to use of antidepressant medicines in pediatric depression alone, but rather extended to use in other psychiatric conditions in pediatric patients.

Fluoxetine has been found to be the leading prescribed antidepressant medicine for pediatric depression in the United Kingdom, whereas sertraline was the leading prescribed antidepressant medicine in the United States (Bachmann et al. 2016). Interestingly, fluoxetine is recommended as first-line treatment in pediatric depression by MPGP and is approved in both the United Kingdom and the United States for pediatric depression, whereas sertraline is also recommended by MPGP (second-line pharmacotherapy), but is not approved for use in pediatric depression in any of the studied countries. Other studies have also shown sertraline to be most commonly prescribed (in adolescents) in France, China, and Croatia (Marsanic et al. 2012; Deng et al. 2018; Revet et al. 2018) or second most commonly prescribed (in children and adolescents) in multiple Asian countries (Chee et al. 2016).

Despite a recent systematic review by Ignaszewski and Waslick (2018) supporting the safe use of antidepressant medicines in pediatric depression, concerns associated with clinical trial designs could limit their ability to reflect real-world responses. According to Dubicka and Brent (2017), most suicide-prone individuals treated with antidepressant medicines would not be included in clinical trials, so the real public health impact of antidepressant medicine treatment may be underestimated. Furthermore, when using psychotropic medicines off-label due to age, it is worth noting that the growth and developmental changes associated with youth may result in responses to treatment, which do not mirror the responses from a fully developed adult brain (McLaren et al. 2018). Off-label use of medicines could also expose patients to unknown side effects or safety concerns if their characteristics differ to those of the patients included in clinical trial studies (Wittich et al. 2012; Eguale et al. 2016; McLaren et al. 2018).

Many differences in regulatory approved information were identified in terms of indication, age specifications, and dosage instructions across the five countries. Despite the same available evidence and applications from a single pharmaceutical company, different regulatory processes across countries result in different regulatory decisions and outcomes. For example, Prozac^® (fluoxetine) is marketed by Eli Lilly and Company in the United Kingdom, Australia, New Zealand, and Canada, and is manufactured by Eli Lilly and Company in the United States (labeled by Dista Products Company) (Table 1), but is only approved for pediatric depression in the United Kingdom and United States, and some differences in the approved dosage information exist between the two drug labeling. Obtaining new regulatory approvals for medicines may be costly and time consuming for pharmaceutical companies (Wittich et al. 2012) and regulatory processes may differ across countries, which could explain why cross-country differences in approval exist. However, further research is required to explore these reasons.

Consistent with other studies (San Miguel et al. 2005; Beers et al. 2013; Salgado et al. 2013; Arguello et al. 2014; Weersink et al. 2019) we also found deficiencies in many drug labeling, especially in relation to missing or ambiguous approval information. For example, the approval of clomipramine for pediatric depression in New Zealand is ambiguous and the general dosage guidelines provided are not specifically mapped to a particular age group, raising questions about whether these dosages are applicable to pediatric patients. This was also the case for other drug labeling. Additionally, pediatric depression dosage information was often not provided, raising concerns about the completeness of the included information. Such deficiencies in the approval information leave the decision making up to the health care professional and may potentially contribute to variations in dosing and prescribing habits in practice. Our findings identify an opportunity to update and improve the clarity of drug labeling, and this may be useful for pharmaceutical companies who are undergoing the revision of drug labeling, particularly for psychotropic medicines for use in pediatric depression. It is worth noting that some drug labeling provided a clear and complete summary of the approval information necessary for the analysis of this study. An example is the U.S. Prescribing Information for escitalopram.

The findings of this study relating to the international comparisons of drug labeling may facilitate the decisions of regulatory bodies, such as the U.S. Food and Drug Administration, Therapeutic Goods Administration (Australia), the U.K. Medicines and Healthcare Products Regulatory Agency, and others, to aid the global harmonization of these documents. Changes have been implemented in recent years by regulatory agencies across different countries, including Australia and New Zealand, to improve the format of drug labeling and to harmonize with international regulators (New Zealand Medicines and Medical Devices Safety Authority 2017; Therapeutic Goods Administration 2020). Our findings show further areas for consideration during the update of drug labeling. Additionally, the concept of our study is in line with the mission of The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), for greater harmonization of regulatory processes, worldwide (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 2020).

This study has some limitations. This study examined the approval of psychotropic medicines from five countries and findings may not be generalizable to other countries. Additionally, the ambiguity and deficiencies in information in the drug labeling may have impacted on the reporting of results. We acknowledge that only one researcher extracted all of the data. To provide robustness, 10% of the data set was randomly and independently checked by a second author. No significant discrepancies between the two authors were noted. Furthermore, it is recognized that only one prescribing guideline was used during this analysis, however, MPGP is internationally recognized and provides relevance and significance to this study from the perspective of all the countries included.

Future studies examining information from other prescribing guidelines and drug labeling extending to other countries could provide a wider understanding of the differences between the two resources and could positively influence progression toward global harmonization of the regulatory approval of medicines. Additionally, a further analysis into other sections of the drug labeling may also add to the findings of this study and help to strengthen the quality of these regulatory documents. It is acknowledged that the drug labeling change over time, necessitating an update to these findings in the future. Alongside the findings of this study and the limited research available regarding the off-label use of psychotropic medicines in pediatric depression, there is a need for further investigation into reasons for variability in information in the drug labeling across countries, and the implications of off-label use in practice.

Conclusions

In summary, there are significant differences in information between the recommendations of MPGP and the approved drug labeling for psychotropic medicines for use in pediatric depression, most often due to unapproved age or indication parameters. Additionally, the cross-country discrepancies in approval information, and deficiencies in information in the drug labeling identified during our study support the need for the update and global harmonization of these documents. Further research into the reasons for variability between drug labeling across countries, as well as the impact of off-label use in practice may be needed.

Clinical Significance

Drug labeling and prescribing guidelines provide guidance on the use of psychotropic medicines from regulatory and clinical practice perspectives, respectively. The off-label use of psychotropic medicines in pediatric depression is widespread, despite limited research, and research into the impact of off-label use in practice is needed. Drug labeling has been shown to lack in important medicine information, and our findings indicate that this extends to psychotropic medicines for use in pediatric depression. Cross-country discrepancies in the drug labeling and ambiguity and deficiencies in the included information necessitate the update and global harmonization of these documents.