British Journal of Clinical Pharmacology

DOI:10.1111/j.1365-2125.2006.02809.x

Comparative assessment of four drug interaction

compendia
Agnes I. Vitry
Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, University of South Australia, GPO Box 2471, Adelaide SA
5001, Australia

Correspondence
Dr A. I. Vitry, Pharm. D., Ph. D.,
Quality Use of Medicines and
Pharmacy Research Centre, Sansom
Institute, University of South Australia,
GPO Box 2471, Adelaide SA 5010,
Australia.
Tel.: + 61 8 8302 2392
Fax: + 61 8 8302 1087
E-mail: [email protected]
.............................................................................................................................

Keywords
drug information, drug interaction
.............................................................................................................................

Received
12 October 2005
Accepted
19 September 2006
Published OnlineEarly
7 December 2006

Aims
To assess the consistency of inclusion and grading of major drug interactions for 50
drugs in four leading international drug interaction compendia.
Methods
Four international drug interaction compendia were compared: the drug interactions
appendix of the British National Formulary, the interaction supplement in the French
drug compendium Vidal, and two US drug interaction compendia, Drug Interaction
Facts and the Micromedex (Drug-Reax) program. Major interactions were defined as
potentially hazardous in BNF or with the warning contraindication or avoid in Vidal
or with the significance grading 1 or 2 in DIF. Major interactions for a list of 50 drugs
were searched in all four compendia.
Results
A total of 1264 interactions meeting the inclusion criteria were identified for these 50
drugs. After deletion of 169 duplicates, 1095 interactions were included in the
analysis. Of the drug interactions classified as major in any one compendium between
14% and 44% were not listed in the other compendia. The grading systems used for
the severity and the quality of the supporting evidence in Micromedex and DIF were
inconsistent.
Conclusions
There is a lack of consistency in the inclusion and grading of drug interactions of major
significance for 50 drugs across the four drug compendia examined. This may reflect
the lack of standardization of the terminology used to classify drug interactions and the
lack of good epidemiological evidence on which to base the assessment of the clinical
relevance of drug interactions.

Introduction

Medication incidents are a significant problem for all

health systems in the world [13]. Drug interactions are
one cause of medication incidents. In a Danish study of
26 337 elderly patients, 4.4% received drug combinations carrying a risk of severe interactions [4]. In a recent
prospective study in the United Kingdom, drug interactions accounted for 16.6% of adverse drug reactions
causing hospitalization [5]. Wide implementation of
2006 AstraZeneca Pharmaceuticals LP

computerized prescribing and dispensing with clinical

decision support systems is recognized as a priority to
reduce medication incidents [3, 6]. However, several
studies have shown that there is a considerable and
potentially clinically important variability in the performance of dispensing and prescribing computer programs in detecting drug interactions [79]. Drug
interaction compendia can be used to populate clinical
decision support systems. There has not been any
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A. I. Vitry

comprehensive assessment of the validity of the severity

classification used in the international drug interaction
compendia. This study aimed to assess the consistency
of four leading international drug interaction compendia
for the inclusion and the severity grading of major drug
interactions.
Methods

Four international drug interaction compendia were

compared: the drug interactions appendix of the British
National Formulary (BNF, update September 2003)
[10], the interaction supplement in the French drug compendium Vidal (update 2003) [11], and two US drug
interaction compendia, Drug Interaction Facts (DIF,
update January 2003) [12] and the Micromedex (DrugReax) program (updates 2003) [13]. These compendia
were selected because they are commonly used by health
professionals to obtain information on drug interactions
in countries where they are published. The Vidal interaction supplement was edited and reviewed by an expert
committee at the French drug agency. The BNF is a joint
publication of the British Medical Association and the
Royal Pharmaceutical Society of Great Britain. It is
the most highly regarded source of drug information
in the United Kingdom. DIF and Micromedex are
among the compendia most commonly used to identify
drug interactions in the United States. These resources
are also commonly used by drug information services
internationally.
The terminology and the grading systems used to
classify the clinical significance of drug interactions differed between the four compendia (Table 1). For the
purpose of the study, the definition of interactions of
major significance was based on the categorization provided in the compendia and included:
drug interactions with the mention contraindication
or avoid in Vidal, or
drug interactions identified as hazardous in BNF, or
drug interactions with the significance rating 1 or 2 in
DIF.
An overall significance rating was not provided for
Micromedex and so could not be used in the definition.
All drug interactions listed as major were searched in all
compendia. Data on severity of outcome and quality of
documentation listed in Micromedex and DIF were
extracted and tabulated when available.
Major interactions were identified for 50 drugs available in the three countries where the compendia are
published (France, United Kingdom and United States)
(Table 2). These drugs were selected for their known
high potential for interactions (e.g. warfarin, digoxin,
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Table 1
Categories used to classify drug interactions in the four
compendia
Vidal
There are four levels of seriousness that are based on the
clinical management which is recommended: contraindication
(absolute), avoid (relative contraindication), precaution for
use (combination possible if recommendations are followed),
and to take into account (no specific recommendation).
BNF
BNF uses a bullet to mark interactions that are potentially
hazardous and where combined administration of the drugs
involved should be avoided (or only undertaken with caution
and appropriate monitoring). BNF may also state specifically
whether a drug combination must be avoided or whether a
drug combination is contraindicated by the manufacturer.
DIF
DIF classifies the severity of drug interactions into three
categories (major, moderate and minor) and the
documentation level in five categories (established, probable,
suspected, possible and unlikely). A significance rating from 1
to 5 is assigned to each drug interaction based on the severity
and the documentation gradings: 1 (major severity and
documentation suspected or more), 2 (moderate severity and
documentation suspected or more), 3 (minor severity and
documentation suspected or more), 4 (major or moderate
severity and documentation possible), 5 (minor severity and
documentation possible or any severity and documentation
unlikely).
Micromedex
Micromedex classifies the severity of drug interactions into
three categories (major, moderate and minor) and the
documentation level in five categories (excellent, good, fair,
poor and unlikely). There is no overall significance rating.

theophylline) or because they were representative of a

major therapeutic class (e.g. atenolol). No more than one
drug of a given therapeutic class was included because
many drug interactions may be common to members of
the same class. Compendia were compared on a two by
two basis. When a drug interaction was not listed in the
compared compendium, the compendium index was
checked to ascertain whether the interacting drug was
marketed in the country. Drug interactions involving a
drug not marketed in the country of publication of the
compendium were not included in the specific analysis.
Discrepancies in the inclusion of major interactions
among the four compendia and correlation of the
grading systems used in DIF and Micromedex were
assessed using descriptive statistics and Spearman correlation tests performed on SPSS for Windows version
11.5.

Comparative assessment of four drug interaction compendia

Table 2
Drugs selected for analysis

allopurinol
amiloride
amiodarone
atenolol
azathioprine
bromocriptine
captopril
carbamazepine
cefamandole
cimetidine

ciprofloxacin
clozapine
co-trimoxazole
cyclosporine
diclofenac
digoxin
disulfiram
erythromycin
ethinyloestradiol
flecainide

fluoxetine
furosemide
gentamycin
glibenclamide
hydrochlorothiazide
imipramine
itraconazole
lamotrigine
lithium
isocarboxazid*

metformin
methadone
methotrexate
nevirapine
omeprazole
pethidine
phenobarbital
phenytoin
pravastatin
ritonavir

sibutramine
sildenafil
spironolactone
sumatriptan
theophylline
tramadol
valproate
verapamil
vincristine
warfarin

*There was no nonselective monoamine-oxidase inhibitor (MAOI) marketed in all

countries. Isocarboxazid is marketed in the UK and in the USA but not in France.
However, as all interactions are common to all nonselective MAOIs in Vidal, it was
assumed that these interactions were also relevant for isocarboxazid.

Table 3
Drug interactions classified as
contraindication or to avoid in Vidal:
how they were classified in other
compendia

Vidal

NI

Contraindication
Avoid
Total

29.5
21.7
24.7

BNF (%)
H
NH
67.0
65.7
66.2

3.5
12.6
9.1

NI

DIF (%)
S1
S2

OS

NI

44.6
43.3
43.9

35.6
14.7
23.4

7.9
11.2
9.8

27.9
23.5
25.3

11.9
30.8
22.9

Micromedex (%)
Maj Mod Min
61.5
40.9
49.4

10.6
34.9
94.9

0
0.7
0.4

NI = not included. H = hazardous. NH = nonhazardous. S = significance rating.

OS = other significance ratings. Maj = major severity. Mod = moderate severity.
Min = minor severity.

Results

Overall, 1264 drug interactions meeting the inclusion

criteria were identified (range 387 per drug). After
deletion of 169 duplicates, 1095 interactions were
included in the analysis.
Of the interactions classified as contraindication or
avoid in Vidal, 57 (24.7%) were not included in BNF,
107 (43.9%) were not included in DIF and 64 (25.3%)
were not included in Micromedex (Table 3). Twentyfive drug interactions classified as contraindication
or to avoid in Vidal were not included in any other
compendium.
Of the interactions classified as hazardous in BNF,
282 (42.2%) were not included in Vidal, 259 (40.2%)
were not included in DIF and 182 (27.4%) were not
included in Micromedex (Table 4). Eighty drug interactions classified as hazardous in BNF were not included
in any other compendium. Eighteen drug interactions
which were specifically highlighted as avoid or con-

traindicated by the manufacturer in BNF were not

included in any other compendium.
Of the interactions classified with a significance rating
1 or 2 in DIF, 176 (38.6%) were not included in Vidal,
120 (26.5%) were not included in BNF and 70 (14.6%)
were not included in Micromedex (Table 5). Thirty-four
drug interactions with the rating 1 or 2 in DIF were not
included in any other compendium.
Eighty major interactions were included in all
compendia.
Among the interactions common to Micromedex and
DIF, 53 (33%) of the 161 interactions classified as major
in Micromedex were classified as moderate in DIF and
44 (29%) of the 150 interactions classified as major in
DIF were classified as moderate in Micromedex. There
was a weak correlation between these two compendia
for the grading of the severity and the quality of the
supporting evidence (respective Spearman correlation
coefficients 0.546 and 0.430).
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BNF

NI

Vidal (%)
CI
A

NI

DIF (%)
S1
S2

Micromedex (%)
NI
Maj Mod Min

OS

Hazardous 42.2
8.8 14.0 35.0 40.2 15.6 26.2 18.0 24.4 24.0 44.8
Avoid
39.5 31.2 17.4 11.9 41.8 32.7 16.4
9.1 20.4 61.1 16.8

Table 4
Drug interactions classified as hazardous
or avoid in the BNF: how they were
classified in other compendia

3.8
1.7

NI = not included. CI = contraindication. A = avoid. O = other categories including to

take into account and precautions. S = significance rating. OS = other significance
ratings. Maj = major severity. Mod = moderate severity. Min = minor severity.

DIF

NI

Vidal (%)
CI
A

S1
S2
Total

25.9
43.9
38.6

26.7
5.0
11.4

17.8
14.6
15.6

NI

29.6
36.5
34.4

17.7
30.0
26.5

BNF (%)
H
NH
77.7
18.3
35.3

4.6
51.7
38.2

NI
6.0
18.5
14.6

Micromedex (%)
Maj
Mod Min
66.2
12.1
29.1

24.8
64.6
53.0

0
4.8
3.3

Table 5
Drug interactions classified with
significance rating 1 and 2 in the DIF:
how they were classified in other
compendia

NI = not included. CI = contraindication. A = avoid. O = other categories including

to take into account and precautions. S = significance rating. Maj = major
severity. Mod = moderate severity. Min = minor severity.

Discussion

This study shows that there are important discrepancies

among four of the leading international drug interaction
compendia for the identification and classification of
major interactions. Between 14% and 44% of the drug
interactions classified as major in any one compendium
are not listed in other compendia. Only 80 major interactions are common to the four compendia for the 50
drugs in this analysis. The grading systems used for the
severity and the quality of the supporting evidence in
DIF and Micromedex are inconsistent.
Three previous studies have examined the concordance among American drug interaction compendia.
Fulda et al. [14] compared the inclusion of drug interactions for five drug classes in five American drug interactions compendia. Individual interactions were rarely
listed in more than one or two of the compendia. Chao &
Maibach [15] found considerable discrepancies among
four American drug compendia for the inclusion of drug
interactions on selected at-risk dermatologic drugs.
Abarca et al. [16] assessed the agreement of four American drug interaction compendia for major drug interactions. Overall, 406 major drug interactions were listed in
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one or more of the four compendia. Only nine (2.2%)

of the major drug interactions were listed in all four
compendia.
This study confirms and expands the results of these
studies as it compares leading compendia published in
different countries. BNF is regarded as the main independent source of drug information in the United
Kingdom. The Vidal interaction supplement was prepared by a committee at the French drug agency. Both
DIF and Micromedex are among the most commonly
used resources by US health professionals.
There are several limitations to this study. Only the
major drug interactions listed for 50 drugs were examined. However, by including 1095 drug interactions,
about one fifth of the estimated 5000 known drug interactions have been assessed [17]. There is little reason
to think that this selection could bias the comparisons
as the drugs selected are well known for their interactive potential or are representative of a major therapeutic class. Furthermore, many interactions with drugs
not included in the list were included in the analysis as
they were drug interactions described for other drugs
of the list (for example there were 15 interactions with

Comparative assessment of four drug interaction compendia

quinidine and 16 interactions with rifampicin included

in the dataset). Only four compendia have been
included in this study but it seems unlikely that
increasing the number of compendia compared would
decrease the variability of the findings. Stockleys drug
interactions [18], which is a well-known British drug
interaction compendium, was not included in the study
as it did not provide an explicit ranking system in
terms of the clinical significance or severity of the drug
interaction or quality of the supporting evidence.
Subtle differences between compendia were not taken
into account, for example a drug interaction may be
classified as a drugdrug interaction in one compendium and as a drugclass interaction in another
compendium.
Reasons for discrepancies

This study does not attempt to provide explanations for

the discrepancies observed between the compendia.
However, a number of factors may explain the differences observed. First, each compendium uses different
inclusion criteria. For example, Vidal includes interactions between drugs of the same therapeutic class (e.g.
interaction between amiloride and other potassium
sparing diuretics), interactions between drugs with
antagonist pharmacological properties (e.g. pethidine
with nalbuphine) that other compendia have decided not
to include. DIF includes interactions with food and nonmedicinal drugs (e.g. cocaine). Second, discrepancies
may partly be due to different information sources, for
example, publications in a language other than English
(e.g. French), unpublished reports released by drug companies, spontaneous drug interaction reports collected
through national post-marketing surveillance systems,
and information provided in summaries of product characteristics. The latter may differ between countries and
may include undiscriminatory class labellings [19, 20].
In many cases the original and complete evidence supporting this information is not published and its clinical
relevance is unknown. Furthermore, there are only few
epidemiological studies which have focused on drug
interactions. Most of these studies have limitations as
they relied on a single drug interaction compendium to
identify potential drug interactions or did not provide
enough details to identify which drug interactions are
most problematic or analyses were not adjusted for
potential confounders [16].
Third, compendia do not always make the same
assumptions when extrapolating from a drug interaction
observed with one drug to the other drugs in the therapeutic class. Inappropriate class labelling was recently
criticized in an evaluation of the BNF [17].

Fourth, there is no consensus on the severity classification of drug interactions and the best way to assess
their clinical relevance. Hansten et al. [21] considered
that the criteria used in the classification of drug interactions by several compendia, such as the severity and
quality of the supporting evidence, were inadequate and
too limited. They proposed additional criteria such as the
biological plausibility, the likely frequency of the concurrent use of the two drugs in the general patient population and the existence of warnings in the product
information. More recently, the Partnership to Prevent
DrugDrug Interactions (PP-DDIs) tried to define a list
of serious drug interactions using a 16-item instrument
which included evidence supporting the interaction,
severity, probability of the interaction and probability of
co-administration of two drugs [22]. However, the relevance of this list for clinical practice has been questioned [23].
In conclusion, there is a lack of consistency in the
inclusion and grading of interactions of major significance for the 50 drugs across the four drug compendia
examined. This may reflect the lack of standardization of
the terminology used to classify drug interactions and
the lack of good epidemiological evidence on which to
base the assessment of the clinical relevance of drug
interactions. A concerted effort is needed to identify
better clinically relevant interactions and communicate
relevant information to health professionals.
I thank the Drug Information Association Foundation
for funding this research. I thank those who have commented on this project, Ms Simone Rossi, Assistant Professor Libby Roughead and Dr Nick Buckley.
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