doi: 10.1111/j.1472-8206.2011.00991.x ORIGINAL Adverse drug reactions associated with the ARTICLE use of NSAIDs: a case/noncase analysis of gy spontaneous reports from the French lo pharmacovigilance database 2002–2006 o Maryse Lapeyre-Mestrea,b,c*, Sabrina Grolleaua,b, c Jean-Louis Montastruc a,b,c, Association Franc¸aise des Centres Re´gionaux a de Pharmacovigilance (CRPV)a a m Service de Pharmacologie Clinique, Centre Midi-Pyre´ne´es de Pharmacovigilance, de Pharmacoe´pide´miologie et d’Information sur le Me´dicament, Hoˆpitaux de Toulouse, Toulouse, France r bFaculte´ de Me´decine, Universite´ Paul Sabatier, Universite´ de Toulouse, Toulouse, France a cUnite´ mixte INSERM 1027, Equipe de Pharmacoe´pide´miologie, Toulouse, Toulouse, France h P Keywords ABSTRACT adverse drug reactions, gastrointestinal system, To evaluate the safety profile of eight oral nonsteroidal anti-inflammatory drugs liver, (NSAIDs) available in France, using data reported through the French pharmaco- NSAID(s), vigilance system. Data (from 2002 to 2006) were analysed for aceclofenac, seriousness, diclofenac, ketoprofen, meloxicam, naproxen, nimesulide, piroxicam and tenoxicam, Clinical skin focusing on the reported rates of serious adverse drug reactions (ADRs) in the following system organ classes: gastrointestinal, hepatic, cutaneous, renal and Received 8 October 2010; cardiovascular. A total of 42 389 serious ADR reports were identified, and 38 506 revised 27 June 2011; were included in a case/noncase analysis. Ketoprofen was associated with the highest ntal & accepted 11 August 2011 cumulative reported rate of serious ADRs (0.78 cases per million defined daily doses), e followed by diclofenac (0.58), nimesulide (0.52), naproxen (0.50), piroxicam (0.47), tenoxicam (0.42), meloxicam (0.41) and aceclofenac (0.30). The most frequently *Correspondence and reprints: maryse.lapeyre-mestre@ reported serious ADRs were cutaneous, followed by gastrointestinal, hepatic, renal univ-tlse3.fr and rarely, cardiovascular events. In the case/noncase analysis, ketoprofen, piroxicam and naproxen were associated with the highest risk of serious gastroin- testinal ADRs (odds ratios [ORs] of 6.87, 6.54 and 5.07, respectively). Nimesulide Fundam and aceclofenac were associated with the highest risk of liver ADRs (adjusted ORs of 4.53 and 3.67, respectively), as was meloxicam for cutaneous ADRs (adjusted OR of 3.15) and tenoxicam for renal ADRs (adjusted OR of 3.17). The most frequent serious ADRs reported with the selected oral NSAIDs are cutaneous, followed by gastro- intestinal, hepatic and renal events. The highest risks for serious gastrointestinal, hepatic, cutaneous and renal adverse events were linked, respectively, with ketoprofen, nimesulide, meloxicam and tenoxicam compared with the other NSAIDs. possess different chemical and clinical profiles but INTRODUCTION essentially exert the same therapeutic properties and Nonsteroidal anti-inflammatory drugs (NSAIDs) are are associated with similar adverse effects. Gastrointes- widely used to treat a large number of common acute tinal injuries, which range from dyspepsia to fatal upper and chronic inflammatory conditions. These drugs gastrointestinal tract bleeding and perforation, are ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Socie´ te´ Franc¸aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology 27 (2013) 223–230 223 224 M. Lapeyre-Mestre et al. among the most common adverse drug reactions (ADRs) corticosteroids, aspirin or anticoagulants, serious com- associated with the use of NSAID [1–3]. Other important orbidity or a history of upper gastrointestinal events ADRs include skin reactions, renal complications, aller- [10]. gic reactions, alteration in hepatic enzyme levels and, The aim of this pharmacoepidemiological study was to rarely, hepatopathies [4–7]. Hepatic ADRs associated compare the safety profile of eight-first-generation NSA- with NSAIDs are quite uncommon when compared with IDs available in France, by assessing the reporting of other pharmacological classes such as antibiotics [6,8]. serious ADRs in several system organ classes [SOCs] from Epidemiological studies have reported the incidence of data in the French pharmacovigilance system from 2002 acute liver injury to be 1–9 cases per 100 000 NSAID to 2006. users [6,7]. As recommended by the European Medicine Agency METHODS (EMA) [9], NSAIDs should be prescribed at the lowest effective dose and for the shortest time necessary to This study analysed serious ADRs spontaneously re- control symptoms. Moreover, other factors such as the ported to the French pharmacovigilance system between overall safety profile of each compound (e.g. potential 1st January 2002 and 31st December 2006 for NSAIDs gastrointestinal and other concerns) and individual risk available in France. It has been compulsory since 1995 factors must be considered for improved patient man- for all prescribers in France to report any ADR defined as agement [10]. ‘serious’ and/or ‘unexpected’ [16]. ‘Serious’ ADRs are Differences in safety profiles between NSAIDs are a key defined as those being fatal, life-threatening, causing discriminator for choosing between one NSAID and hospitalization, resulting in persistent or significant another, and not all NSAIDs have the same level of risk disability or incapacity, requiring intervention to prevent for inducing gastrointestinal ADRs. First-generation permanent damage or causing a congenital anomaly NSAIDs are nonselective and block the activity of both [16]. This study focused on serious ADRs associated with COX-1 and COX-2. Second-generation agents, the COX-2 gastrointestinal, hepatic, cutaneous, renal and cardio- inhibitors, were developed with the aim of reducing the vascular systems. incidence of gastrointestinal adverse effects by sparing Serious ADRs of interest were identified from specific the gastrointestinal protective functions of COX-1 while codes of the World Health Organisation Adverse Reac- still inhibiting inflammation [11,12]. However, it was tions Terminology (WHO-ART) classification of selected clear reasonably soon after their commercialization that organ class disorders (Table I). the use of these COX-2 inhibitors (i.e. rofecoxib and valdecoxib) was associated with an increase in cardio- Study design vascular risk, leading to their withdrawal from the The data collected were analysed for the reporting of market [13,14]. These events led to a revision of the serious ADRs in the population treated with the selected overall safety profile of all NSAIDs, particularly in regard NSAIDs and to calculate the odd ratios (ORs) of the to their renal and cardiovascular risk profile. Moreover, association of these ADRs with the NSAIDs in this a number of studies evaluating the gastrointestinal population, using a case/noncase analysis. tolerability of COX-2 inhibitors did not demonstrate a For the estimation of ADR reporting, data were lower risk of upper or lower gastrointestinal events analysed and compared for eight oral formulations of [15,16]. NSAIDs: aceclofenac, diclofenac, ketoprofen, meloxicam, Several factors influence a patient’s risk of developing naproxen, nimesulide, piroxicam and tenoxicam. different ADRs while receiving NSAIDs; for example, Case/noncase analysis has been widely used in the elderly patients or those with cardiovascular disorders, last decade in several spontaneous reporting data- chronic renal disease, rheumatoid arthritis or chronic bases, including the French pharmacovigilance database obstructive pulmonary disease are at greater risk of [17,18]. For example, this analytical method was applied cardiovascular ADRs [15]. Gastrointestinal ADRs are to data from the French and Spanish pharmacovigilance important indicators when evaluating the overall risk national databases to compare the risk of hepatic profile of NSAIDs because of the risk of gastrointestinal damage with the administration of different NSAIDs bleeding and perforation. Risk factors for gastrointestinal [19]. In this method, ‘cases’ are the ADRs of interest and complications, according to the National Institute for the ‘noncase’ control group corresponds to all other Clinical Excellence, include age over 65 years, the use of ADRs recorded in the database. The principle is to ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Socie´ te´ Franc¸aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology 27 (2013) 223–230 Adverse drug reactions related to oral NSAIDs’ use 225 Table I World health organisation adverse reactions terminology (WHO-ART) codes for selected system organ class (SOC) disorders. WHO-ART codes SOC disorder 0700 Liver and biliary system disorders (hepatic failure or necrosis, abnormal hepatic functions, hepatitis, cholestasis, increase in liver enzymes) 0600 Gastrointestinal system disorders (ulcer, gastritis, gastrointestinal haemorrhage, intestinal perforation…) 0100 Skin and appendages disorders (dermatitis, eruption, toxic epidermic necrosis, drug-related eruption, Lyell and Stevens–Johnson syndrome…) 1300 Urinary system disorders (nephritis, renal failure, decrease in renal clearance, tubular nephropathy…) 1020 Myo-, endo-, pericardial and valve disorders (angor, myocardial infarction, coronary thrombosis, coronary arteriosclerosis) 1040 Vascular (extracardiac) disorders (cerebral infarction, embolism; arterial, peripheral embolism/ischaemia; arterial, carotid, cerebral, upper limb thrombosis…) 1810 Body as a whole – general disorders (ischaemic necrosis)