Drug Information Journal, Vol. 29, pp. 51-60.

1995 0092-8615/95
Printed in the USA. All rights reserved. Copyright 0 1995 Drug Information Association Inc.

PATIENT PACKAGE INSERTS FOR

PRESCRIPTION DRUGS IN AN
INTERNATIONAL PHARMACEUTICAL
COMPANY
WILLEMK. AMERY,MD, PHD, FFPM
Vice President
VAN W INKEL,PHARMD
MARIANNE
Co-ordinator, Patient Package Inserts
International Pharmacovigilance, Janssen Research Foundation, Beerse, Belgium

Development of a patient package insert (PPI) necessitates multidisciplinary input.

Patients require information which is scientificallyfounded yet highly readable, com-
prehensiveyet concise and relevant. Health professionals demand that the PPI is con-
cordant with the summary of product characteristics (SPC) in order to achieve con-
sistency in the provision of patient information. These objectives are met by selecting
patient-relevant datafrom the SPC, and involving a medical communications consul-
tant to ensure optimal clarity. Pictographs improve readability, but text length must
be carefully considered. Patients, pressure groups.. and legislative bodies demand
comprehensive information. Some studies, however, suggest that extensive informa-
tion may interfere with the effectiveness of communication with regard to compre-
hension and retention. Other aspects to be considered include product liability and
the environmental consequencesof PPIproduction, in addition to the organizational
and financial impact on the pharmaceutical industry. At present, the need for PPIs
in Third World countries is less urgent because of the scope of medical practice, and
because of difficultiesrelated to drug distribution and language problems.

Key Words: Patient package inserts; Patient information

INTRODUCTION ucts not to the consumer (the patient), but

to appointed agents (health care profes-
THE set- sionals). Although health care profession-
tor, the pharmaceutical industry is unique
als are well supplied with product infor-
in that, in most cases, it markets its prod-
mation from a variety of sources, patients
are often given insufficient information to
meet their needs as consumers. Increas-
Based upon presentations at the Patient Package In- ingly, patients want to know how they are
sert Symposium, April 28, 1993, Ghent, Belgium and being treated and why; in many countries,
the DIA 29th Annual Meeting, July 8-12, 1993, Chi- they now have legislative support in this
cago, IL.
Reprint address: Dr. Willem K. Amery, Vice respect.
President, International Pharmacovigilance, Jans- Patient package inserts have, for the
sen Research Foundation, 2340 Beerse, Belgium. past decade, formed the basis of the com-
51
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52 Willem K . Amery and Marianne Van Winkel

munication bridge between the pharma- mended contents of a PPI are shown in
ceutical industry and the patient. Their Table 1. Visual appeal is enhanced by
role is by no means absolute: they are in- placing the text in columns, itemizing in-
tended to supplement, not replace, the in- formation, and using headings, and by
formation and advice given by the health way of pictographs. Bullets, italics, and
professional consulted. They also func- bold print are useful embellishment tech-
tion as a valuable aide-mkmoire, to con- niques.
tinue to reinforce that message long after
the original consultation and as a fall-back
NATIONAL CONSIDERATIONS
document to help the patient, should any
questions about the medicine arise. Not surprisingly, there is a disparity be-
The provision of information in this tween nations on the subject of PPIs.
way helps to create a more interactive role Manufacturer-generated PPIs were first
for the patient (1). In theory, increased mentioned in European Community (EC)
knowledge means improved understand- legislation in 1975 (Directive 75/319/
ing and therefore better compliance. A re- EEC, Articles 6 and 7) (3). Interestingly,
cent study, however, has revealed that pa- some Scandinavian countries have adopt-
tients who read a PPI are more likely to ed a different approach to the provision of
report health problems that could be side patient drug information (4). In 1985, the
effects, and hence to stop taking the drug Swedish National Corporation of Phar-
because of a presumed side effect (2). macies opted to introduce leaflets on simi-
Given the financial concerns caused by the lar groups of products supplied to the
recent PPI legislation in Europe and else- patient by the pharmacist at the time of
where, the important considerations for dispensing. This system has also been
the manufacturers now are how to use the adopted by Norway. Within the EC, Bel-
available resources to maximize the im- gium was probably the first country to for-
pact and value of PPIs. This article aims malize their use ( 5 ) . In most EC countries,
to provide an overview of the complexity PPIs are now widely used for both over-
of PPI activities in an international phar- the-counter (OTC) and prescription drugs
maceutical company, including particular dispensed in their original packs. This is
difficulties encountered in developing related to the 1992 EC legislation (Direc-
countries. tive 92/27/EEC, Articles 6, 7, 8, and 9),

GENERAL CONSIDERATIONS TABLE 1

Preferred Contents of
Patient package inserts have two basic Patlent Package Inserts
functions:
Indications
Contraindications
To help the patient to use the medicine Warnings and precautions:
appropriately and safely, and Preanancv and lactation
To bring together all relevant drug- Effects onpyschomotor function
related messages that patients are enti- Interactions
tled to receive from their doctor and/or ~~~~~~~~ administration

pharmacist. Overdosage
Storage conditions
Achieving these objectives while adher- Composition (active ingredient(s) and excip
ing to carefully researched guidelines re- ients)
garding text length, style, and content Other information (date of revision, manu-
facturer details)
requires considerable skill. The recom-

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Patient Package Inserts 53

which mentions January 1, 1994 as the tar- How does this relate to the composition
get date for the implementation of PPIs in and design of PPIs? In brief, patients re-
all Member States. quire drug information which is:
In the United States, interest in PPIs
has waned during the past decade after Scientifically-based,
some enthusiasm during the 1970s. Vari- Relevant, and
ous problems have thus far prevented their Simply written.
large scale implementation. The idea is
still alive (6), however, and according to To meet these demands, PPIs should be
rumors, there is a possibility that it will be based on the summary of product char-
revived during the Clinton administration. acteristics, but should not contain any
pharmacological or other technical infor-
mation. Preferably, a medical communi-
PATIENT CONSIDERATIONS cations consultant should be involved at
this stage. Design and formatting tech-
Satisfying the information needs of the niques are valuable in increasing patient
patient is a major concern of the pharma- acceptability, for example, the use of ap-
ceutical and health care industries. In the propriate pictographs and a sufficient font
1960s Epstein and Lasagna (7) demon- size can significantly improve readability.
strated that the right information pre-
sented in the right way (ie, an itemized
HEALTH CARE CONSIDERATIONS
summary of the most salient points) could
significantly improve comprehension and Concordance between the SPC and the
compliance (see Text Length). Converse- PPI is essential and should, therefore, be
ly, a full, detailed textual description of verified. This ensures that the message re-
both beneficial and adverse drug proper- ceived by patients about their medication,
ties greatly reduced motivation to take the both from their health care providers and
drug. from the PPI, is consistent. Consistency is
Increasingly, patients want to know necessary to avoid confusion, maintain
what they are taking and what possible ef- faith in health professionals’ advice, and
fects it could have, however remote. At encourage compliance. Patients receiving
the same time, fear of litigation has placed conflicting information from different
greater pressure on doctors, pharmacists, sources are more likely to be noncompli-
and other health care workers, as well as ant, with possible adverse consequences.
drug manufacturers, to supply such infor-
mation - even though it may be of no ben-
LANGUAGE
efit to the patient. This apparent conflict
of interests has led to recommendations Obviously, readability is one of the most
that patient information regarding ad- important aspects in ensuring the success
verse drug experience should be limited to of a PPI. The readability of a particular
events which are relatively frequent. As composition, which may be assessed by
noted by Arnold ( 8 ) , it makes little sense numerous research methods (9,10), is a
to frighten patients with comprehensive function of:
details of rare but serious adverse effects.
This applies all the more if the patient is Mean sentence length,
receiving treatment for a potentially fatal Vocabulary- both difficulty and diver-
disease. Therefore, the detail which one sity,
should provide to the patient is related to Number of concrete words, and
the therapeutic imperative. Personalization of the text.

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54 Willem K . Amery and Marianne Van Winkel

Readability decreases with increasing sections of the document. To achieve this

sentence length. Thus, sentences should be objective, they must be readily recogniz-
brief, succinct, and uncluttered. Sentence able; while this sounds relatively simple,
construction should be simple rather than the reality is somewhat different since
complex. Choice of words may present there are no universally accepted symbols
major problems: although using a reading to denote sections of the PPI, such as side
age of nine combines optimal readability effects, indications, overdosage, and so
with better factual retention ( 1 1 ), many forth. Consequently, in 1992, Janssen Re-
patients may find this inadequate or in- search Foundation undertook an interna-
sulting. The type token ratio (TTR), tional study to assess the suitability of var-
which is the ratio of the number of differ- ious pictographs in representing sections
ent words used to the total number of of a PPI. The different sections of the PPI
words used in a passage, is used as a mea- were marked with a boxed pictograph. In
sure of comprehensibility. As the TTR ap- addition, the warnings and precautions
proaches one (ie, all the words in the pas- that are found in most PPIs were indicated
sage are different), the assimilation of by a circled pictograph. Subjects ( n =
information from the text decreases. Simi- 180) were asked to express a preference
larly, the relative amount of concrete for one of at least three different picto-
words in a passage is inversely related to graphs denoting a given section; the pre-
its lucidity. Personalization of the text is ferred symbols are shown in Figure 1.
mainly achieved by the use of dialogue
marks and of personal pronouns.
TEXT LENGTH
The language used in a PPI is, there-
fore, crucial if the document is to fulfill its In addition to assessing the suitability of
purpose as a communication tool. The gap various symbols, the patients in the above
between the pharmaceutical industry and study were asked about the length of a
the patient is, in this context, perhaps best proposed PPI for an existing product
filled by a medical communications con- which measured27.4cm x 13.4cm (about
sultant. In overseeing the preparation of the same size as the useable area of a sheet
the document, such an expert ensures that of A4 paper). The character size was 7.5
the final product is clear and unambigu- points. The results from this questionnaire
ous, yet not condescending. are shown in Figure 2. Although the PPI
used in this study was relatively brief, no
patient found it to be too short. Indeed, al-
USE OF SYMBOLS
most 60% of the group considered it to be
Pictorial symbols (pictographs) can be di- too long. This raises an important ques-
vided into two general types: tion: can all the relevant information be
provided in an easily readable and yet con-
Those that guide the patient through the cise format? A similar concern was dis-
text, and cussed by Epstein and Lasagna (7), who
Those conveying a specific message. examined the issue of how much informa-
tion to provide about adverse drug reac-
Studies have revealed that pictographs tions. In this trial, three groups of 22 sub-
which convey a specific message are often jects received separate versions of the
misinterpreted. For that reason, European activities and hazards of a drug (aspirin),
consumer lobbies have argued against the identified only as acetyl-hydroxybenzoate:
use of such message pictographs (12). It
is, therefore, the pictographs providing Form A - itemized points only,
guidance that can be particularly useful in Form B - intermediate detail, or
the PPI by directing the patient to relevant Form C - full detail.

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Patient Package Inserts 55

When to use How to use and how much willing to take the medicine than among

IPI
the refusers. At the end of the trial the 66
subjects were informed that the drug they
had taken was aspirin, and asked whether
it would be desirable to provide product
information to patients. Interestingly, all

rn
When not to use Side effects subjects who were given Form A were in

69
favor of this, whereas only 77% and 59%
of subjects who were given Forms B and
C, respectively, felt the same way.
Based on the above studies, a number
of pertinent conclusions would seem ap-
Children Overdose plicable:

@ Providing patients with excessive infor-

mation is probably counterproductive
and limits comprehension,
Pregnancy
Patients appear to be discouraged by
How to store
too much information and this can lead

@ to noncompliance, and
Despite usually requesting full informa-
tion, patients comprehend and react
more positively to summarized/item-
Breast-feeding Composition ized information.

Other medicines
E PREFERRED SECTIONS
Patients want comprehensive information
on their drugs-but what exactly do they
want information about? One of the ob-
jectives of Janssen’s 1992 PPI study was to
address this issue. Patients were asked
whether they found information on each
FIGURE 1. Preferred pictographs in a
multicenter trial involving 180 patients.
PPI section useful or useless. On the basis
Each participant was asked to express a of the percentage usefuVuseless ratio, the
preference for one of at least three differ- sections on adverse effects, and dosage
ent pictographs. and administration, were judged to be
most useful (Figure 4). Patients were less
interested in the composition of the medi-
Both comprehension of the informa- cine than they were in how to store it. This
tion and willingness to take the drug ap- contrasts with the requirement of the EC
peared to be inversely related to the length Directive 92/27/EEC (Articles 6 , 7 , 8 and
of text provided (Figure 3). Thus, the av- 9), which requires drug composition to be
erage percentage of information recalled at the beginning of PPIs. Overall, there
correctly by subjects given Form A was was also a lack of enthusiasm for informa-
67% compared with 46% and 35% for tion on treating drug overdose, but this
Forms B and C, respectively. In addition, section is often technical and aimed at
for each form, the percentage of correct emergency health care personnel rather
recall was higher among those who were than the patient.

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56 Willem K . Amery and Marianne Van Winkel

bngt' >f text OA of answers

TOTAL

9 13 I -
58%

-
T

Too long

IMPLICATIONS FOR THE

PHARMACEUTICAL COMPANY
c

points.
37% 40% -

-
Correct
G

FIGURE 2. Results of a questionnaire in which 180 patients were asked for their oplnlon
about a patlent package insert measuring 13.4cm x 27.4cm with a prlnt size of 7.5

tion for prescribed medicines is likely to

have a significant impact on the future of
PPIs. Product liability and increased scru-
Globally, new legislation concerned with tiny by pressure groups will inevitably
0% 0%
UK

0%
Too short
0%
I

the provision of adequate patient informa- mean greater demands on medical infor-
mation resources. The organizational se-
quelae, both internal and external, of this
increased demand are illustrated in Figure
'7
90
%willing to take drug
5 . Internal PPI development involves in-
put from the PPI and communication
consultants as well as the clinical, market-
ing, legal, and language departments. The
end result of the internal process, the in-
ternational PPI, is circulated to affiliated
companies, which adapt it to their na-
tional legislation and SPC. After feedback
from the head office the PPI is submitted
to the national health authorities.
Financial and environmental costs are
also likely to be incurred due to increased
paper, print, and packaging costs. A mini-
mum font size of eight points, as required
by the European consumer lobby, ensures
Form A c FormBc FormC
readability, but necessitates the use of a
FIGURE 3. influence of text style on fac- larger format of both the PPI and the
tual recall and wililngness to take the box - printing and packaging must be re-
drug. Subjects (n = 66) recelved one of designed to take account of this increased
three different formats: Itemized (Form bulk. A projection of the financial conse-
A), Intermediate detail (Form B), and full
detail (Form C). Itemized information pro- quences of such a change was carried out
duced better recall and willingness to take in 1988 and is shown in Table 2. In addi-
the drug. tion, the environmental impact of the use

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Patient Package Inserts 57

Seciion
7
WQen 10 use 1
When no! 10 use I
Specia! precauiions I
How lo use 8 how much 1
Undes red effects I
Overdose 1
How lo store I
Composirion
r
I 1

Ratio: % useful / % useless

FIGURE 4. The results of a questlonnalre In whlch 180 participants were asked whether
they thought a particular section of a patient package Insert was useful or useless.

of larger amounts of paper and cardboard fessionals, and social factors such as high
should be considered. standards of education. Theoretically,
provision of drug information in this way
promotes the safe, effective, and rational
SPECIAL CONSIDERATIONS FOR
use of medicines and leads to improved
THE THIRD WORLD
standards of pharmaceutical care. It is
Patient package inserts have been com- pertinent and timely to ask whether this
monplace in an increasing number of approach is also appropriate in Third
westernized countries for a number of World countries, and, if so, to identify
years, their success fueled by consumer de- specific problems with the use of PPIs in
mand, reinforcement by health care pro- the developing world.

PPI managemont Intern& circuit PPI management External circuit

SmPC Printed International PPI

c
1 PPI-expert

First draft ln&rnatlonal PPI

Affiliated companies
c
Nationel version r)
/ / 4 I\,
Input from communicatbn expert. marketing and clinical depertments.
c
Head office
c
Affiliate
c
Approval by healthauthorities
4
Ley-out expert 4
Printed PPls
4
Printed International PPI
c
Manufacturing

(*) In view of legidation and national datasheet

FIGURE 5. The organlzatlonal Impact (Internal and external) of patient package insert
production. SPC = summary of product characteristics.

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58 Willem K . Amery and Marianne Van Winkel

TABLE 2
Projected Flnanclal Impact of the Increased
Production of Large Format Patlent Package Inserts.
Costs are 1988 Estlmatea Glven In Belgian Francs.
costs
Area of impact Set-up Annual

Printing office
machinery 11,500,000
reconstruction 3,000,000
materials 2,000,000
9 loss of efficiency" 630,000
Packaging
machinery 171,500,000
reconstruction 11,250,000
loss of efficiency 6,976,830
Total cost 197,250,000 9,606,830
this represents the labor costs incurred

Life expectancy in many developing bution systems. This may be one of the
countries remains well below that in the reasons why medical interventions are
Western world, and appears to be in- rarely of a trivial nature.
versely related to the physician-patient ra- This is in contrast with the Western
tio (13) (Figure 6). For example, China world, where drug consumption is partly
has 30 times more doctors per person than for cosmetic or comfort purposes. Assess-
Ethiopia; its inhabitants may also expect ment of attitudes toward health risks has
to live almost twice as long. The lack of revealed that extensive information on
health care practitioners is, however, only side effects is most useful to patients tak-
one side of the coin. Socioeconomic, geo- ing medication for the latter reasons, but
graphical, and other factors have impeded that it is only of secondary importance in
the development of health care and distri- serious or life-threatening situations (Ta-

70j
75

65
c
C
G
=
=
Eg =
P
In
=
=
China
Guatemala
Egypt
Pakistan
India
G Is = Indonesia
Ng = Nigeria
2 = Zaire
IC = Ivory coast
Np = Nepal
Et = Ethlopia

45 -
Et
40 I I I 1 I
0 loo00 20000 30000 40000 5OOOO 6OOOO
Number of inhabitanWphysician (1980)

FIGURE 6. Relatlonshlp between llfe expectancy and the number of people per physl-
clan In Thlrd World countrles (13).

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Patient Package Inserts 59

TABLE 3
Usefulness of Patient Package Inserts in Relation to
Gravity of Illness or Disease and the Willingness of
Patients to Accept Risks inherent in Taking Medication

Purpose of
medication’ Risk attitude’ Usefulness of PPis

Comfort Risk aversion +++

Risk acceptance +++
Curative Risk acceptance +to++
Life-saving Risk-taking f to+
‘adapted from reference 8
brarely used in the Third World

ble 3). Extending this to the Third World, educational, cultural, and linguistic diffi-
there would appear to be a lesser need for culties. Therefore, emphasis should be
PPIs at present since the use of comfort placed on providing health care profes-
drugs is limited. sionals, rather than patients, with reliable
The effectiveness of PPIs is also under- and up-to-date information which sup-
mined by medicine distribution problems ports their clinical practice. This meets the
commonly encountered in Third World wishes of the World Health Organization
countries. These include: (14), namely that “Pharmacists and other
health care workers responsible for dis-
Availability of medicines on the “black pensing drugs should accept every oppor-
market,” tunity to inform consumers about the ra-
Dispensing without prescription, tional use of these products at the time
Parallel importing, they are dispensed.”
Counterfeiting of medicines, and
Other supply problems.
CONCLUSIONS
In addition, the ethnic, cultural, and In most Westernized countries, the inclu-
educational heterogeneity of many devel- sion of PPIs with dispensed and OTC
oping countries presents yet more obsta- medication is part of the pharmaceutical
cles to the use of PPIs. Many nations have industry’s response to the growing demand
many languages, and PPIs would, there- for a more consumer-oriented approach.
fore, have to take account of this fact. PPIs are undoubtedly useful in enhancing
Cultural factors may create problems in patient understanding and participation in
the interpretation of pictographs, and their treatment, but their success depends
with certain routes of administration. Per- on the input of a skilled multidisciplinary
haps the single most important factor, team at the development stage. This team
however, is that of general educational must take into account the requirements
level; illiteracy is still a major problem in of the four parties involved: the patient,
many countries, and one which signifi- the health care professional, the regula-
cantly obstructs the use of PPIs. Clearly, tory authorities, and the industry itself.
it is difficult to envisage pictographs that The patient needs concise, relevant, and
could compensate for such problems. yet comprehensive information in a form
In summary, there is a lesser demand which is easily digestible. Health care pro-
for PPIs in developing countries at pres- viders, however, require reassurance that
ent. Furthermore, the introduction of the information in a PPI is concordant
PPIs would appear impractical because of with other medical literature, particularly

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 Willem K . Amery and Marianne Van Winkel

the summary of product characteristics. sert. In: Bogaert et al., eds. Patient Package In-
Companies themselves must develop PPI serts as a Source of Drug Information. Amster-
dam: Excerpta Medica; 1989:49-52.
programs which meet the new demands 6. Kessler DA. Communicating with Patients about
and yet are economically and ecologically their Medications. NEng JMed. 1991;325:1650-
viable. 1652.
In the Third World, the use of patient 7. Epstein LC, Lasagna L. Obtaining Informed
package inserts may be less urgently Consent. Arc Int Med. 1%9;123:682-688.
8 . Arnold PC. Information about Side Effects-
needed in view of the serious nature of the How much to tell the patient. Med J Australia.
illnesses being treated, and is impractical 1992;57:335-336.
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problems. In addition, many developing package insert. In: Bogaert et al., eds. Patient
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tion. Amsterdam: Excerpta Medica; 1989:97-
pounding these difficulties. 100.
10. van der Stichele R, Bogaert MG. Patient Package
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