Impact to practice

  • Medication regulatory bodies need to consider better guidelines for regulating medication patient information leaflets (PILs) taking patient safety and older peoples’ needs into account.

  • Pharmaceutical industry should design more appropriate PILs for use by older people.

  • Clinical pharmacists need to be aware of the limitations of PILs for older patients to manage their medicines, and to provide appropriate supports.

Introduction

The proportion of people aged 65 and over is increasing worldwide [1]. The older population is more prone to chronic diseases and co-morbidities compared to their younger counterparts, making them the major user of medicines. Older patients often receive information about their medication treatments from healthcare professionals such as physicians and pharmacists; however, the verbal information they receive are frequently limited or inadequate [2]. They also tend to forget the content of oral consultations due to memory decline. Written information about their medications is therefore an important source for older people to manage their medicines and for many patients this is primarily obtained from the statutory PIL accompanying the medicine [3].

Since 1999, all medicines supplied in the European Union (EU) must be accompanied, by law, by a comprehensive PIL [4]. The PIL should be drawn up in accordance with the Summary of Product Characteristics (SmPC) which provides factual information about the medicine, based on data collected during clinical development [5]. However, such data are generally obtained from young and relatively fit adults who are the typical participants of clinical trials. Older patients are often excluded from these trials either by arbitrary age limits or criteria such as co-morbidity [6, 7]. Clinical outcomes generated in young adults cannot be reliably extrapolated to older patients who commonly have altered pharmacokinetics, multi-morbidity and concurrent medicines. The risk–benefit balance for a medicine in older people remains uncertain without appropriate clinical evidence.

The International Conference on Harmonization (ICH) published a guideline on geriatrics (ICH E7) in 1993 which set out the standards for clinical studies in older population [8]. This was adopted by the European Medicines Agency (EMA) who published a Questions and Answers document in 2010 to update the recommendations [9]. Despite the guidelines, older people are still under-represented in current clinical trials. A recent study analysed the availability of relevant information regarding older patients in the SmPCs for medicines receiving European marketing authorization between 2008 and 2010 [10]. Forty-one percent of SmPCs did not provide information that should have been included in accordance to the ICH E7 guideline.

It is equally important that older individuals can understand the content of the PILs supported by the appropriate use of language and layout. However, studies show that patients are often unable to read or correctly understand the information provided on the PILs [11, 12]. In 1998, the European Union issued a guideline on the readability of the labelling and package leaflets of medicines which was superseded in 2009 [13]. In the UK, all PILs are approved by the Medicines and Healthcare products Regulatory Agency (MHRA) before being supplied with the medicine. In 2003, MHRA set up a Working Group on Patient Information to address the concerns and drive improvements in the design of PILs. The Working Group published a comprehensive document to guide the production of usable PILs [14].

Aim of the study

The aim of this study was to investigate the availability of information relevant to older patients contained in PILs for cardiovascular disease and type 2 diabetes medicines available in the UK, and analyse the readability and layout of these leaflets for appropriate use in older adults.

Ethical approval

Currently in the United Kingdom, no ethical approval is required for conducting this type of study.

Methods

Selection of patient information leaflets (PILs)

The PILs available in the UK were selected for medicines for the treatment of cardiovascular disease and type 2 diabetes. The top 12 most frequently prescribed cardiovascular medicines were selected based on the published analysis by the Health and Social Care Information Centre in England [15]. For medicines used in the treatment of type 2 diabetes, all generic names listed in the British National Formulary were selected [16]. Medicine combinations were excluded and only tablet forms for oral use were included. The PILs of the selected medicines were obtained from the Electronic Medicines Compendium (eMC) [17] and analysed in August 2013.

Development of evaluation criteria

The evaluations were conducted on two separate occasions by the same reviewer to minimise any error.

Content

The content assessment was to determine the availability of information specifically relevant to the safety and efficacy of the medication in older adults. Total of ten criteria (Table 1) were developed based on the ICH E7 guideline and the subsequent Questions and Answers issued by the EMA [8, 9]. Five questions were directly related to the elderly and the other five questions (indirectly related to the elderly) were considered to be relevant for older patients to manage their medicines. The content questions were tabulated for each PIL on a “yes” answer indicating the provision of the information and “no” meaning that no such information was provided.

Table 1 PILs content and layout evaluation
Full size table

Layout

The criteria on the layout of the PILs were derived from the EU guideline and the MHRA guidance on readability and layout of PILs [13, 14]. Six questions were designed and were considered to be useful factors affecting easy information access for older people (Table 1). The compliance to the guidance for each PIL rendered a “yes” answer, otherwise a “no” is recorded.

Readability

The readability of the PILs was evaluated using the Gunning Fogs Index formula [18]. The formula examines the average sentence length and percentage of hard words (number of words of more than two syllables) in a written document and gives a general score range of 6–20. Typically, short sentences written in Plain English achieve a lower score than long sentences written in complicated language. Examples of reading materials of high scores include The Independent (score 19), Daily Mirror (score 12) and British Medical Journal (score 15) and a score above 12 was deemed as difficult for older people to read [18].

Data analysis

A descriptive data analysis was performed and the results were expressed in absolute numbers and percentage frequencies. Paired T test was performed to determine any significant differences (p < 0.05) in the availability of information directly and indirectly related to the elderly and independent T test was conducted to compare the two therapeutic categories. All statistical analysis was conducted using SPSS version 20.0 (IBM SPSS Inc., Chicago, IL, USA).

Results

Total of 48 PILs (25 medicines, 28 companies) were analysed. Five out of the 48 PILs available on the eMC were in a format which could not be evaluated on layout and readability and therefore 43 PILs were used (“Appendix”).

Availability of information related to the elderly

All PILs analysed contained some information on safety and/or efficacy of the medication in elderly population, whereas no single PIL fulfilled all ten content criteria (Table 1). In addition, information directly related to the elderly was significantly less available compared to indirect information (p < 0.05).

Fifteen percent of the PILs mentioned the age of the older person. Four PILs provided information for patients over 65 years old; although only one specified that this is the definition of the elderly. Two PILs gave information for patients aged 75 years and older and one gave a special warning for the over 80s. The remaining PILs, where relevant information was available for older patients, simply referred to “the elderly”. Only one out of the 48 PILs contained information on pharmacokinetic changes in the elderly where it commented that the clearance of the drug was reduced. About 30 % of the PILs provided some warning for the elderly. However, only seven PILs presented specific side effects that could affect older people. Dose instruction for the elderly was generally contained in the PILs (65 %); yet, only two PILs specified the exact dose recommendations for older patients.

Over half (57 %) of the PILs gave recommendations on whether the dosage form could be modified before administration. The majority indicated that the tablet should be swallowed whole or should not be crushed or chewed. Nearly all PILs provided information on drug–drug and drug–disease interactions (94 and 88 % respectively). This general information was applied to all patient populations and only two PILs accounted specific drug–drug interactions and one PIL stated a specific drug–disease interaction in the elderly. Information on special warning or dose adjustment for renally or hepatically impaired patients was available on most PILs (88 and 82 % respectively). Again only two PILs specified problems related to the elderly.

Layout analyses

No single PIL fulfilled all six criteria on layout. Only four PILs had main text font size above 12. The median font size for the main body of the text was nine (range 7–15) and nine (21 %) PILs had a text font size of 7. All PILs, except two, used bullet points to list side effects. Around 40 % of PILs met the requirement of maximum 5–6 bullet points in a list. The mean (±SD) number of bullet points in a list was 9.8 ± 6.2 and there was a significant difference (p < 0.05) between cardiovascular and diabetes medicines (12.1 ± 7.2 and 6.4 ± 0.8 respectively). The use of unjustified right-hand margins was the only criterion in both content and layout analyses that all PILs had a positive answer. Eleven PILs contained italic fonts and four contained underlining text, both of which were not recommended by the guidelines. About half of the PILs used capitals, however, the majority of these were used in headings and only two PILs used capitals for both headings and warning.

Readability

The median readability score of the 43 PILs using the Gunning Fogs Index formula was 12.4 (range 9.1–15.6). Twenty seven (63 %) of the PILs had a score above 12, regarded as the upper limit for ease of reading by the elderly. Five PILs (12 %) had a reading score of 14 and over.

Discussion

This study analysed the PILs of medicines available in the UK for the treatment of cardiovascular disease and type 2 diabetes. These two therapeutic classes were selected because their prevalence is disproportionately high in older adults [19]. The result from the current study suggests that medication PILs do not provide essential information required for older patients to gain reliable information on their medicines. The ICH E7 guideline on geriatrics emphasises the inclusion of older patients in clinical trials, particularly the “older-old”, patients aged 75 years and over, and patients with co-morbidities and co-medications [8, 9]. Medication treatments in these patients are more complex and the lack of clinical knowledge in this particular patient group could account for an increased number of adverse drug reactions (ADRs) [20]. The majority of the PILs analysed in this study did not specify the age of the patient if any geriatric information was provided. A recent study found that 73 % of newly approved SmPCs in the EU lacked information on the definition of the older population studied in clinical trials [10], and this could provide explanations on the findings of this study. Although ageing is a continuous process, the older population is by no means a homogenous group. To categorise geriatric information under one banner of “the elderly” does not reflect the complexity of the population and could confuse older patients who might question whether the information is applicable to them.

Specific safety warnings for older patients and explicit side effects that could occur in the older population were rarely presented in the PILs. A study conducted by Steinmetz et al. [21] examined geriatric information on medicine package inserts (PIs) available in the US and reported that while 54 % of PIs had precautions or warnings for older people collectively, most did not provide details of any specific risks relating to this patient group [21]. It was reported that pharmacokinetic information was well presented in the SmPCs (60 %) [10]; however, this was not translated to the PILs. Age-related physiological changes consequently alter drug pharmacokinetics profiles and should be communicated in PILs [22]. More than half of the PILs provided dose instructions to the elderly, but very rarely did these PILs include precise dose recommendations. Older patients will therefore have to rely solely on the dose instruction given by their physicians. The study conducted by Steinmetz et al. [21] stated that dose information for the elderly on PIs which are intended to be used by physicians was vague and difficult to locate. This again makes it difficult for the physician to prescribe appropriate doses to older patients.

While the PILs generally lacked information directly related to the elderly, there was more information available on categories indirectly relevant to them, for example renal and hepatic impairments and drug–disease/drug–drug interactions. It is worth noting that such data are more likely to be collected in younger and fitter adults than older people. Yet, the complexity of these issues in older patients cannot be compared to that in the younger population. It was reported that drug–drug and drug–disease interactions are particularly associated with ADRs in older patients [23]. Older people experience swallowing difficulties and consequently, a common practice is altering medication dosage forms, such as crushing tablets or opening capsules [24]. Almost half of PILs did not mention whether the tablet could be crushed before administration. Inappropriate modification of medicines can result in stability issues, changes in efficacy and safety profiles of the product, and potentially patient harm [25]. Older patients need to be aware of the risks when these undesirable effects are likely to happen due to crushing tablets.

The presentation of the PILs analysed in this study are not appropriate to address older people’s needs. Firstly, the font sizes were too small for older people to read. The use of small text fonts in medication leaflets is not uncommon; a study analysed the PILs of 13 over the counter medicines in the UK and reported that none of the PILs had a type size as large as 12 [26]. In general, regardless of age, patients found it easier to extract information from PILs using larger prints rather than smaller text sizes [27]. Older patients particularly preferred larger font sizes compared to younger ones due to the tendency of decreased visual and cognitive functions [28].

Categorised information such as bullet points can facilitate understanding compared to paragraphs [14]; however, in the PILs often a long list of bullet points were used for side effects. For example, in one case, as many as 34 bullet points were listed under the section for side effects. Patients may be confused or overwhelmed by a long list of side effects. The EU guideline recommended that side effects on PILs could be set out by frequency of occurrence while considering the appearance of any serious side effects at the start of the section [13]. Adhering to this presentation style should help to break up the side effects into groups and avoid long lists. However, one study showed that only 12 % of PILs of the 50 most frequently prescribed medicines in the UK adhered to this guideline [29].

More than half of the PILs studied here were deemed to be difficult to read by older people based on the Gunning Fogs Index score. Some of the PILs reached a readability score of 14 or above which is similar to the readability level of the British Medical Journal [18]. Older people tend to have low health literacy skills and this can limit their understanding of medication information, affecting adherence and health outcomes [11]. A leaflet written in simple language is most desirable for older patients to access their medication information.

We are entering an era of partnership with patients in terms of prescribing and drug therapy [30]. Patients want more information on their medications than are generally provided to them [2]. The adequacy of information provision to patients is under the spotlight, as experts suggested that regulations governing the labelling and packaging of medicines should be rewritten to take patient safety into account [31]. A recent workshop organised by EMA on safe and effective medicines for older patients highlighted that providing information for the older population should also consider the PIL not only focusing on the SmPC [32]. A single point of access to medication information for physicians and patients was proposed to simplify the access route. It was hoped that the progress in regulation and the recognition of the importance of the issue will lead to the improvement of the PIL.

The current study has its limitations. Firstly, the study was only performed in medicines belonging to two therapeutic categories. A wider study including more disease categories commonly encountered in the older generation is required. Secondly, older people’s perceptions on the use of PILs were not sought in the study. The assumption of the analysis is that all relevant information should be presented in the leaflets. Although studies show that patients value detailed explanatory information about their medicines, the extent to which older patients appreciate this information needs to be better understood. The readability of the leaflets was assessed using the Gunning Fogs Index formula which only measures the sentence length and word length as the indicators of readability; however, many other factors could influence readability. The EU and MHRA guidelines recommended user testing or consultation for the design of effective PILs. No reading score or layout analysis could substitute for testing on the intended audience and the views of older patients, the biggest consumer group of medicines, should be emphasised during these tests.

Conclusions

There was inadequate information available to older patients in PILs accompanying commonly prescribed medicines for cardiovascular disease and type 2 diabetes in the UK. The lack of information is pronounced when it is directly related to older people. The mentioning of the age of the patient and communicating specific risks associated with the older population is lacking. The omission of such data poses potential risks to patient safety and highlights the need of including older people in clinical trials. The layout and readability of the current leaflets also need improvement for the benefit of the older generation, especially the use of larger text fonts and simple language.