PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Franc¸ ois Clinard Æ Catherine Sgro Æ Marc Bardou
Patrick Hillon Æ Monique Dumas Æ Carmen Kreft-Jais
Andre
´
Escousse Æ Claire Bonithon-Kopp
Association between concomitant use of several systemic NSAIDs
and an excess risk of adverse drug reaction. A case/non-case study
from the French Pharmacovigilance system database
Received: 22 September 2003 / Accepted: 4 March 2004 / Published online: 22 April 2004
Ó Springer-Verlag 2004
Abstract Aims: To examine whether the risk of some
selected adverse effects increases with the number of
systemic non-steroidal anti-inflammatory (NSAID)
drugs.
Methods: The French Pharmacovigilance database was
examined for an association between drug reaction re-
ports and the exposure to one and two or more NSAIDs
using a case/non-case study design. In the analysis,
54,583 spontaneous reports of adverse drug reactions
were included, consisting of 2270 reports of hepatic
injury, 994 reports of acute renal failure, 194 reports of
gastrointestinal bleeding and 525 reports of angioedema,
among others.
Results: Use of NSAIDs significantly increased the risk
of hepatic injury, gastrointestinal bleeding, acute renal
failure and angioedema. The odds ratios tended to
increase with the number of NSAIDs for hepatic injury,
gastrointestinal bleeding and acute renal failure but not
for angioedema. In comparison with reports that did not
mention any use of NSAIDs, the odds ratios associated
with the use of a single NSAID and two or more
NSAIDs were respectively 1.2 (95%CI: 0.9–1.5) and 2.2
(95%CI: 1.3–3.8) for hepatic injury, 7.3 (95%CI: 4.9–
10.9) and 10.7 (95%CI: 2.9–40.2) for gastrointestinal
bleeding, 3.2 (95%CI: 2.5–4.1) and 4.8 (95%CI: 2.6–8.8)
for acute renal failure. For angioedema, the odds ratios
were roughly similar when a single NSAID (OR=2.7;
95% CI: 2.2–3.4) or two or more NSAIDs (OR=2.0;
95%CI: 0.7–6.0) were used. The risk of severe ADRs
(hepatic injury and acute renal failure) was six- to sev-
enfold higher in reports mentioning concomitant use of
two NSAIDs or more than in those that did not.
Conclusion: This study shows that concomitant use of
two or more NSAIDs was associated with an excess risk of
adverse effects such as hepatic injury, acute renal failure
and gastrointestinal bleeding. Although simultaneous
use of several systemic NSAIDs has no pharmacologi-
cal justification, this may raise a serious public health
problem with the increasing use of over-the-counter
non-steroidal anti-inflammatory agents.
Keywords NSAIDs Æ Adverse drug reaction Æ
Pharmacovigilance
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are
among the most frequently prescribed drugs world-wide
despite the potential severity of their adverse effects [1].
A number of studies have been performed to identify
patterns and risk factors for the occurrence of adverse
drug reaction (ADR), especially of gastrointestinal
haemorrhages. Older age, digestive history, association
with corticosteroids or anticoagulant drugs are
well-known risk factors for bleeding complications [2].
Despite the lack of any clear epidemiological evidence,
simultaneous use of several NSAIDs is also suspected to
induce ADRs more frequently than use of a single
NSAID [1, 3]. A small proportion of NSAID prescrip-
tions contains two or more systemic NSAIDs. In France,
it is estimated that around 2% of NSAID prescriptions
contain more than one systemic NSAID [4]. However, this
may have an important impact on health because of the
F. Clinard (&) Æ P. Hillon Æ C. Bonithon-Kopp
GEREPT—Centre d’Epide
´
miologie de Population de Bourgogne,
Faculte
´
sdeMe
´
decine et Pharmacie, 7 bd Jeanne d’Arc,
BP 87900, 21079 Dijon Cedex, France
E-mail: fclinard@u-bourgogne.fr
Tel.: +33-380-393340
Fax: +33-380-668251
F. Clinard Æ C. Sgro Æ M. Bardou Æ M. Dumas
De
´
partement de Pharmacologie, CHU de Dijon, France
C. Sgro
Centre Re
´
gional de Pharmacovigilance, CHU de Dijon, France
C. Kreft-Jais
Unite
´
de Pharmacovigilance, Agence Franc¸ aise de Se
´
curite
´
Sanitaire des Produits de Sante
´
, Paris, France
A. Escousse
Laboratoire de Biochimie Toxicologique,
Faculte
´
de Me
´
decine, Dijon, France
Eur J Clin Pharmacol (2004) 60: 279–283
DOI 10.1007/s00228-004-0761-0