Medication package inserts do not present adequate information on potential risks for older adults in Brazil

Bulas de medicamentos não apresentam informações adequadas sobre potenciais riscos para idosos no Brasil

Vinícius Augusto Andrade Freitas

Universidade Federal de Juiz de Fora, Brasil

Sharlene Lopes Pereira sharlene.pereira@ufjf.br

Universidade Federal de Juiz de Fora, Brasil

The older population in Brazil has surpassed 30 million inhabitants in 2017, encompassing around 14% of the country’s citizens according to the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística [IBGE]).1 Considering the current and accelerated demographic transition process, relevant clinical characteristics of the geriatric age group are commonly neglected, leading to higher risks for these individuals. In this scenario, it should be noted that 85% of older adults present a chronic disease and 10% of them present five or more comorbidities.2 Therefore, considering the fast-paced growth of this population and their higher illness rates, around two-thirds of the country’s medications are prescribed to older adults.3

Various physiological alterations that happen in older adults and influence pharmacokinetics and pharmacody-namics4, 5 led to the need to propose restrictions on prescriptions for this population, with the creation of groups of potentially inappropriate medications (PIMs) for older adults. PIMs correspond to pharmacological groups that present a high risk of adverse reactions due to inappropriate posology, interactions, or indications, when there is evidence of an alternative with similar or higher effectiveness at a lower risk.6 The classification of a drug as a PIM, in any circumstance or considering specific interactions and posology, is defined by standards such as the Beers criteria, whose most recent version was published in 2019 by the American Geriatrics Society (AGS).7 These criteria have contributed to the quality and safety of prescriptions for older adults.8 They are recognized in Brazil and worldwide, providing access to knowledge on the use of medications in the population over 60 years old in a practical way in order to contribute to the medical education process and promote better health care to the geriatric population. Recommendations made by these criteria synthesize scientific evidence for decision-making, suggesting rational considerations on cost-benefit and monitoring, also serving as a tool to help in the detection of undesirable effects.9

In spite of tools such as the Beers criteria and the association between the use of PIMs and increased hospitalizations and mortality among older adults, inappropriate prescribing is still very frequent. Understanding the potential risks of the use of PIMs by the geriatric population, this study compared the guidance and warnings on the use of these drugs by older adults described by the 2019 Beers criteria and the information presented at medication package inserts made available by the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária [ANVISA]) in Brazil.

This documental study analyzed electronic prescription information on PIMs made available by ANVISA through the website: https://consultas.anvisa.gov.br/#/bulario/. This information was compared with the respective data presented at the 2019 Beers criteria.7

The following groups of PIMs present in the criteria were selected for the study: NSAIDs, benzodiazepines, antidepressants, Z-drugs, antipsychotics, antiulcer drugs, antidiabetic drugs, and muscle relaxants. In this study, we did not analyze the prescribing information on cardiovascular PIMs, as the package inserts of these drugs have been contemplated by a recent analysis.8

Among the mentioned PIM groups, 33 brand-name drugs with broad clinical use in Brazil and with active registration at ANVISA were selected for evaluation. We analyzed the information contained in the electronic prescribing information. When available at the ANVISA record, package inserts were accessed via the “ProDoctor Medicamentos” app.

After selecting medications, the presence or absence of a specific section dedicated to older adults was identified in each package insert. This specific section could have the title “Use in older adults,” or “Use in the geriatric population,” for example.

Information on the use of these PIMs by older adults contained in the package inserts was compared with the respective data contemplated by the 2019 Beers criteria.7 Data were then categorized as: complete, incomplete, absent, or discrepant. Data were considered incomplete when any of the reasons for the medication to be considered a PIM (according to the mentioned criteria) was not found in the respective package insert. When none of the reasons was found in the medication package insert, the information was considered absent. When the package insert presented data that were contrary to those contained in the Beers criteria for the same PIM, they were considered discrepant.

A Google Sheets spreadsheet was built for organizing all the collected data and for the comparative analysis and inclusion of suggestions for complementing the prescribing information on the evaluated PIMs. The methodology used in this study has been briefly described in Figure 1.

FIGURE 1
Methodology used for evaluating package inserts of potentially inappropriate medications for older adults.
*PIMs: potentially inappropriate medications; NSAIDS: nonsteroidal anti-inflammatory drugs.

Out of the analyzed package inserts, seven (21.21%) did not present a specific section dedicated to the use of these drugs by older adults, that is, data were scattered throughout the document and not highlighted in a section titled “Use in older adults” or “Use in the geriatric population.” These package inserts were for the following drugs: alprazolam, piroxicam, ibuprofen, chlorpromazine, levomepromazine, zaleplon, and glimepiride.

The package inserts of drugs acting on the central nervous system such as benzodiazepines, Z-drugs, and muscle relaxants were incomplete or did not present information on risks for older adults (Table 1). The analyzed package inserts of antidepressants and antipsychotics were also incomplete or without any warning regarding older adults as mentioned in the Beers criteria (Table 2). The prescribing information on PIMs of great clinical importance such as antiulcer drugs, antidiabetic drugs, and NSAIDs also presented incomplete or absent data, and one of them (glimepiride) presented discrepant or contradicting data in comparison with the mentioned criteria (Table 3).

TABLE 1
Comparison of information on the use of benzodiazepines, Z-drugs, and muscle relaxants by older adults present in professional package inserts and the 2019 Beers criteria.

PIM: potentially inappropriate medication; anticholinergic effects: constipation, dry mouth, urinary retention, blurred vision.

TABLE 2
Comparison of information on the use of antidepressants and antipsychotics by older adults present in professional package inserts and the 2019 Beers criteria.

PIM: potentially inappropriate medication; anticholinergic effects: constipation, dry mouth, urinary retention, blurred vision; ECG: electrocardiogram.

TABLE 3
Comparison of information on the use of antiulcer drugs, antidiabetic drugs, and NSAIDs by older adults present in professional package inserts and the 2019 Beers criteria.

PIM: potentially inappropriate medication; NSAIDs: nonsteroidal anti-inflammatory drugs; H. pylori: Helicobacter pylori.

The analysis of the package inserts of the selected PIMs showed that 63.64% (n = 21) were incomplete, 11 (33.33%) lacked data, and one (3.03%) had discrepant information. None of the package inserts presented complete information.

This study, performed with the package inserts of Brazilian medications, identified that none of the analyzed documents presented complete data on the effects of PIMs in older adults, even though the relevance of educating health professionals on the physiological changes in older adults for adequately prescribing drugs to the geriatric population is well established.10 This reinforces the importance of widely promoting the Beers criteria7 among geriatricians and other prescribers.

Studies have shown that package inserts do not provide adequate information to patients and prescribers. In 2002, directive SVS No. 110/1997 of the Secretariat of Health Surveillance of the Ministry of Health (Secretaria de Vigilância Sanitária do Ministério da Saúde [SVS/MS]), which regulates the creation of package inserts in Brazil, was used as reference by Gonçalves et al.11 for evaluating 168 package inserts. In this study, 91.40% of the documents were considered unsatisfactory when considering “patient information,” 97.00% were considered unsatisfactory regarding “technical information,” and 86.00% did not present data on use in older patients. More recently, Marques et al.8 analyzed precautions for the use of cardiovascular drugs in older adults present in package inserts, using the 2016 Brazilian Consensus on Potentially Inappropriate Medications for Older Adults12 as a parameter, and noticed that 40.00% of the analyzed documents did not contain guidance or warnings dedicated to the older population or presented discrepant information when compared to the Brazilian Consensus. Studies performed in other countries also noticed a lack of important information in medication package inserts. A study in Iran13 evaluated the quality of 100 package inserts of the most commercialized medications in the country according to criterium by the Iran Food and Drug Administration (IFDA), which follows guidance by the American Food and Drug Administration (FDA). None of the evaluated package inserts presented all the criteria requested by IFDA and only 12.70% presented remarks on the geriatric population. Al-Aqeel14 analyzed 60 package inserts of a list of best-selling drugs in Saudi Arabia produced by different laboratories. Only 18 documents (30.00%) presented information on use in older adults. Govindadas et al.15 evaluated 263 package inserts in south India, according to their regulatory standards, and concluded that none of them were complete when considering the analyzed criteria. The study evaluated descriptions about medication use in vulnerable populations such as pregnant and lactating women, but it did not evaluate content on the older population. Qatmosh et al.16 analyzed and compared 35 package inserts of antihypertensives produced locally in Palestine and their imported analogs. None of them fulfilled the 31 analyzed criteria nor presented remarks on the geriatric population. Overall, international analyses corroborate our study, indicating a low quality of package inserts both considering general issues and restrictions directed to special groups such as the older population.

The Brazilian Consensus on Potentially Inappropriate Medications for Older Adults, published in 2016, validated the content of the 2012 Beers and 2006 Stopp criteria in the Brazilian population. This consensus validated 43 criteria for medications that should be avoided in older adults regardless of the clinical condition and 75 criteria that depended on their clinical condition.12 As the 2016 Brazilian Consensus was based in outdated criteria when compared to the 2019 Beers criteria, this study adopted the latter as a parameter for evaluating the content of package inserts. The Brazilian Consensus should be updated according to the 2019 Beers criteria.

In this study, most of the package inserts (two-thirds) were classified as incomplete regarding the description of PIM effects in older adults. Prescribing information on zolpidem, for example, is incomplete as to the information characterizing it as a PIM for older adults, such as a higher risk of falls, fractures, and traffic accidents, as indicated by the Beers criteria.7 The same thing happened with the package insert of benzodiazepines, and these are pharmacological groups frequently and often inappropriately used by the geriatric age group. Package inserts for this group should be revised, especially those without information on the geriatric population such as clonazepam, lorazepam, and alprazolam. Regulatory authorities and the pharmaceutical industry must include information on the increased risk of overdose in case of concomitant use with drugs acting on the central nervous system, in addition to a warning about the risk of cognitive impairment, delirium, falls, fractures, and traffic accidents, especially with long-term use. A study performed in long-term care facilities in the city of Natal (RN) showed that 54.60% of older adults used PIMs, of which benzodiazepines were one of the main groups; this was associated with increased hospitalizations, deaths, and health costs.17 Moreover, a more recent study performed at Hospital Universitário da Universidade Federal de Juiz de Fora (HU-UFJF), in Juiz de Fora (MG), evaluated 187 medical records of hospitalized older patients and revealed a high prevalence of the use of PIMs, among which benzodiazepines and omeprazole were the most prevalent.18

Self-medication is a frequent practice and constitutes an important factor for the use of PIMs, especially NSAIDs, muscle relaxants, and painkillers.19 Considering that self-medication is frequent in older adults, especially considering NSAIDs, muscle relaxants, and painkillers,19 it is crucial that package inserts for these drugs contain information on the risks of their use in this population. Conversely, in this study, all the evaluated NSAID package inserts presented incomplete or absent data on their use in older adults. For example, some of the package inserts did not even mention the possibility of increased arterial pressure and/or kidney injury.7

Patient and professional package inserts should contribute to rational use of the pharmaceutical product by reinforcing the instructions received at the moment of prescription and increasing treatment adherence. The content and format of package inserts are important for patient comprehension, which influences a reduction in self-medication and adverse events.20 In recent years, studies on the comprehension of package inserts20 and analyses of better practices for optimizing the prescription given to patients21 have suggested the importance of retrieving these data for increasing adherence to pharmacological treatment and reducing self-medication, for example. Medina-Córdoba et al.20 studied factors that contributed to or hindered the comprehension of package inserts by patients, indicating that a language suitable to the patient profile as well as ordered and highlighted structure and organization were examples of characteristics of package inserts that contributed for their comprehension, whereas the presence of scientific language, medical terms, and lack of adequate structure hindered this process. The study reinforced the importance of the quality of package inserts treatment comprehension and adherence, also reducing risk behaviors such as self-medication.

According to the Beers criteria, antiulcer drugs and proton pump inhibitors increase the chances of infection by Clostridium difficile, bone loss, and fractures when used for more than eight weeks; these may be used by older adults only in case of a high risk of gastrointestinal lesions.7 Despite this risk, this information was not found in the package inserts of omeprazole and pantoprazole. The inclusion of these data is important to the rational use of these drugs, especially when long-term use is required.

An important aspect identified in this study is that one-third of the analyzed prescribing information did not present information characterizing the medication as a PIM according to the Beers criteria.7 The general population considers the package insert as a reliable source of information and often does not research other data; it is thus vital that all clinically relevant considerations be presented in medication package inserts, especially considering the relationship between admissions of older adults to hospital emergency sectors with adverse effects due to the use of PIMs.22

The standards and requirements for elaborating package inserts in different countries are considerably heterogeneous. Ramírez-Telles and Argotti-Rodríguez23 evaluated 25 Latin American and Caribbean countries and observed that only Brazil, Argentina, Chile, Peru, and Venezuela required a clear and defined structure for medication package inserts. Out of the evaluated countries, 32.00% required patient and professional package inserts (including Brazil), 8.00% only required patient package inserts, and 60.00% only required professional package inserts. The study concluded that countries in this region present little consistency in the requirements of their respective regulatory agencies about the content of package inserts, and a standardization of these documents is lacking. The study does not approach aspects referring to the content of package inserts in special populations such as older adults.

Package inserts with accurate and updated information are important to drug safety and efficacy,15 and this whole process is a responsibility of regulatory agencies. In Brazil, Collegiate Board Resolution (Resolução da Diretoria Colegiada [RDC]) No. 47, published by ANVISA in 2009, provides standards for creating and updating patient and professional package inserts. Documents dedicated to health professionals should present information on contraindications in special populations such as older adults, as well as warnings and precautions directed at these groups; these data are also required in patient package inserts. Both patient and professional package inserts should be made available at the ANVISA electronic record. This resolution also grants the agency the right to demand changes to package inserts whenever new pharmacovigilance data are available or due to technical and scientific reasons.24

In the USA, the FDA also establishes rules and guidelines for elaborating package inserts and defines as drug labeling any information provided with the prescription of a drug regulated by the agency. Their main goal is to ensure patient safety, providing health professionals with a summary of the drug’s safety and efficacy. The development of prescribing information is not directed at the patients, as a drug’s administration is always overseen by a health professional licensed to prescribe it. The package inserts, in addition to containing various topics such as indications, contraindications, precautions, adverse reactions, and interactions, is also required to provide information on the use in specific populations, such as older adults.25

In Europe, the European Medicines Agency (EMA) provides information on pharmaceutical products in official approved documents for patients and for health professionals, such as package inserts and the summary of product characteristics (SmPC), and frequently revises their content and conducts research and surveys aiming to update and improve regulatory standards. Regarding the use of medications by older adults, the EMA has the important role of ensuring that their needs are considered throughout drug development, approval, and use in the European Union. For this, the agency designs guidelines and guides (Geriatrics Medicine Strategy [GMS]) which guidance, precautions, and warnings referring to the use of medications by older adults.26

Our results are in agreement with other studies and suggest that most package inserts of medications used in Brazil are unsatisfactory and lack important data, enabling inappropriate use of medications and increasing risks of adverse events and hospitalizations, especially among older adults. This is the fastest growing population in Brazil and worldwide, also consuming more medications than any other age group.

In this study, we did not evaluate parameters such as the legibility and comprehension of package inserts, nor did we analyze the proportion of individuals who were used to reading package inserts and whether this habit could affect pharmacotherapy. Future studies are required to analyze the real impact of package insert quality in the rational use of medications and treatment adherence by patients.

In this study, none of the analyzed package inserts presented complete information on the risks of PIMs for older adults. Package inserts presented incomplete data or lacked information characterizing the drug as a PIM for older adults. Moreover, even when relevant data were present, we observed a lack of organization when presenting them in some package inserts; no specific sections described the use of the drug by the geriatric population, thus hindering data visualization by professionals and patients.

Our data indicate that some package inserts of drugs used in Brazil are not satisfactory and could lead to higher rates of inappropriate prescribing for older adults along with higher iatrogenesis. It is worth noting the importance of pharmaceutical companies complying with the required technical information and better organizing the content of package inserts, in addition to a more strict surveillance by ANVISA. Possible strategies for minimizing the use of PIMs by older adults consist in educational measures that favor deprescribing; constant revisions of package inserts of currently used medication; and wide promotion of the Beers criteria along with periodical updates of the Brazilian Consensus on Potentially Inappropriate Medications for Older Adults.