16 March, 2015

Every registered medication has an information insert in its package. This patient information leaflet (PIL) provides data on the product, which includes clinical pharmacology, recommended dose, mode of administration, how supplied, and a large section contains warnings and contraindications, adverse reactions, and precautions. With easy access of patients to information on drugs they use, mainly through the electronic media, it is very important that the text and contents of these patient leaflets are simple to understand and readable. Discussing the PIL with German patient focus groups resulted in agreements that (a) PILs contained too much risk information which was conveyed in a way that led to reduced patient compliance; (b) the current description of potential side-effects and drug interactions caused negative emotions which led to undesirable patient reactions; (c) PILs provoked certain behaviors in patients including accessing information from alternative sources or seeking support from professional and lay persons [1]. Also, most people thought that reliable information on efficacy and adverse effects of drugs should come from the treating physician, pharmacists being the second-line source. The forum suggested that, because current PILs convey risk information in a way that provoked feelings of fear and anxiety in the reader, regulators and producers of such written information should consider greater involvement of target patient groups at all stages of the production process.

Comment

How many of you read the patient information leaflets (PILs), the package inserts of the medications you prescribe? How many of you face the situation when your patient challenges you with questions based on the PIL or other external sources of information? Is it time to see how patients address the PIL and even criticize its format and contents? A study from the UK, while examining 48 PILs related to cardiovascular and diabetes medications found that only a few of the documents were fit specifically for the older population, either by failing to mention side-effects that could occur in the older generation, or by using small fonts and problematic phrasing [2].

The readability of 63% of the PILs had a score above 12, which was considered difficult for older people to understand. The investigators thought that currently available medication PILs are inappropriate for use by older adults to manage their medications effectively, which could adversely affect patient safety and adherence to drug therapy. One of the main items that was discussed in several studies is patients' understanding and reaction to the five traditional categories of side-effects, namely rated as 'very common', 'common', 'uncommon', 'rare', and 'very rare'. Not surprising was the finding among groups of physicians, pharmacists and lawyers that their definitions for those categories were very different from the standard ones used by all health authorities [3]. Needless to say that phrasing plays a vital role in patients' reaction to reading any medical materials. Words or sentences with negative connotation are frequently used in PILs (for example, unhealthy, not healthy, never, etc.). A study on PILs of hay fever medications in the Netherlands (written in Dutch) found that 21% of clauses in their PILs contained at least one negation [4]. Negations were associated with lower actual comprehension of the instruction information and were grasped as more complex and less readable texts. Also, participants reading a PIL with negations indicated lower adherence intentions for the PIL’s advice. The participants recommended making the language more comprehensible and formulating the text more positively, and suggested highlighting the important elements with bold or italic letters.

Although there are many publications on various aspects of PILs, as outlined above, only a few articles were focused on postmenopausal hormone therapy. A provocative title – 'Doctor, are you trying to kill me?': ambivalence about the patient package insert for estrogen – headed a 2002 paper discussing the history of estrogen labeling [5]. The Working Group on Women's Health and Well-Being in Menopause (all members were current or past members of the NAMS Board of Trustees) initiated a plea to the US regulatory authorities to modify the labeling of low-dose vaginal estrogen [6]. The group's main argument was that some warnings and the black box which is part of the labeling and therefore appears in the PIL are based on extrapolations of data from clinical trials of systemic hormone therapy such as the Women's Health Initiative, which involved substantially higher levels of exposure. The PIL of Vagifem, for example, brings a list of several 'serious but less common side-effects' which include breast and uterine cancer, heart attack, stroke and dementia [7]. The claim of the Working Group is that the relevance of previous data on standard systemic estrogen therapy to low-dose vaginal estrogen remains unknown, given minimal increase in serum estrogen levels with low-dose vaginal products. The group believes that the highly visible boxed warning on low-dose vaginal estrogen is unsubstantiated and not evidence-based and is harming women by discouraging the use of effective treatments that would provide substantial benefits to postmenopausal women with symptomatic vulvovaginal atrophy.

The authoritative position of the physician has been eroded, and sometimes trust lost because of easy access to new information through the electronic media, raising worries, questions and uncertainties. It is the duty of the care-giver not only to decide on the best therapy for the individual patient, but also to provide detailed information which covers both the efficacy and the safety of the medication prescribed. Furthermore, it is the physician's responsibility to ensure that fear and anxiety because of misunderstanding of reading materials, either PILs or any other sources of pharmacological or clinical information, will be tackled appropriately, to increase patient's confidence, compliance and adherence to therapy.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Herber OR, Gies V, Schwappach D, Thürmann P, Wilm S. Patient information leaflets: informing or frightening? A focus group study exploring patients' emotional reactions and subsequent behavior towards package leaflets of commonly prescribed medications in family practices. BMC Fam Pract 2014;15:163 http://www.ncbi.nlm.nih.gov/pubmed/25277783 

2. Liu F, Abdul-Hussain S, Mahboob S, Rai V, Kostrzewski A. How useful are medication patient information leaflets to older adults? A content, readability and layout analysis. Int J Clin Pharm 2014;36:827-34 http://www.ncbi.nlm.nih.gov/pubmed/24986267 

3. Ziegler A, Hadlak A, Mehlbeer S, König IR. Comprehension of the description of side effects in drug information leaflets: a survey of doctors, pharmacists and lawyers. Dtsch Arztebl Int 2013;110:669-73 http://www.ncbi.nlm.nih.gov/pubmed/24167524

4. Burgers C, Beukeboom CJ, Sparks L, Diepeveen V. How (not) to inform patients about drug use: use and effects of negations in Dutch patient information leaflets. Pharmacoepidemiol Drug Saf 2014 Jul 15. Epub ahead of print http://www.ncbi.nlm.nih.gov/pubmed/25044310 

5. Watkins ES. "Doctor, are you trying to kill me?": ambivalence about the patient package insert for estrogen. Bull Hist Med 2002;76:84-104 http://www.ncbi.nlm.nih.gov/pubmed/11875245 6. Manson JE, Goldstein SR, Kagan R, et al. Why the product labeling for low-dose vaginal estrogen should be changed. Menopause 2014;21:911-16 http://www.ncbi.nlm.nih.gov/pubmed/25140698 

7. http://www.novonordisk-us.com/Images/PDF/Vagifem_Nov_25_2009.pdf