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

Clinard, François; Sgro, C; Bardou, Marc; Hillon, Patrick; Dumas, Monique; Kreft-Jaïs, Carmen; Escousse, A; Bonithon‐Kopp, Claire

doi:10.1007/s00228-004-0761-0

Cited by 21 publications

(17 citation statements)

References 9 publications

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“…This is in line with an analysis of 54,583 reports of suspected adverse drug reactions from the French Pharmacovigilance database that suggested a six- to sevenfold higher risk for severe ADRs (hepatic injury and acute renal failure) when two NSAIDs or more were administered at the same time [27]. In light of the well known and broad spectrum of adverse drug reactions related to NSAIDs the high number of cases with NSAID as co-medications is not surprising.…”

Section: Discussionsupporting

confidence: 79%

Correlation versus Causation? Pharmacovigilance of the Analgesic Flupirtine Exemplifies the Need for Refined Spontaneous ADR Reporting

Anderson

Borlak

2011

PLoS ONE

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Annually, adverse drug reactions result in more than 2,000,000 hospitalizations and rank among the top 10 causes of death in the United States. Consequently, there is a need to continuously monitor and to improve the safety assessment of marketed drugs. Nonetheless, pharmacovigilance practice frequently lacks causality assessment. Here, we report the case of flupirtine, a centrally acting non-opioid analgesic. We re-evaluated the plausibility and causality of 226 unselected, spontaneously reported hepatobiliary adverse drug reactions according to the adapted Bradford-Hill criteria, CIOMS score and WHO-UMC scales. Thorough re-evaluation showed that only about 20% of the reported cases were probable or likely for flupirtine treatment, suggesting an incidence of flupirtine-related liver injury of 1∶ 100,000 when estimated prescription data are considered, or 0.8 in 10,000 on the basis of all 226 reported adverse drug reactions. Neither daily or cumulative dose nor duration of treatment correlated with markers of liver injury. In the majority of cases (151/226), an average of 3 co-medications with drugs known for their liver liability was observed that may well be causative for adverse drug reactions, but were reported under a suspected flupirtine ADR. Our study highlights the need to improve the quality and standards of ADR reporting. This should be done with utmost care taking into account contributing factors such as concomitant medications including over-the-counter drugs, the medical history and current health conditions, in order to avoid unjustified flagging and drug warnings that may erroneously cause uncertainty among healthcare professionals and patients, and may eventually lead to unjustified safety signals of useful drugs with a reasonable risk to benefit ratio.

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Section: Discussionsupporting

confidence: 79%

Correlation versus Causation? Pharmacovigilance of the Analgesic Flupirtine Exemplifies the Need for Refined Spontaneous ADR Reporting

Anderson

Borlak

2011

PLoS ONE

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“…Clinard et al found a dose–effect relationship between the number of NSAIDs used and some severe hepatic injuries (hepatitis, liver failure or cirrhosis). The adjusted odds ratio was 1.1 (0.9–1.4) when one NSAID was mentioned but increased to 2.2 (1.2–3.8) when more that two NSAIDs were associated [40].…”

Section: Discussionmentioning

confidence: 99%

Non‐steroidal anti‐inflammatory drug‐related hepatic damage in France and Spain: analysis from national spontaneous reporting systems

Lapeyre‐Mestre

Castro

Bareille

et al. 2006

Fundamemntal Clinical Pharma

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Several non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with liver damage. The aim of this study was to compare proportions of hepatic adverse drug reaction reports associated with NSAIDs in France and Spain. Information from the Spanish and French pharmacovigilance databases were used from 1982 to 2001. To assess the risk of liver injury, the case/non-case methodology was applied, 'cases' being reports of liver damage and 'non-cases' or controls, all other reports. Exposure was considered as the presence of at least one NSAID. Liver injury risk was estimated for each drug in the two databases by calculation of reporting odds ratio in cases and non-cases, with its 95% confidence interval. Out of 62 456 reports from the Spanish database, 2114 (3.38%) were identified as liver injuries, whereas there were 27 372 liver injuries out of 200 046 (13.68%) in the French database. In Spain, there was a significant association between liver injuries and droxicam, sulindac, and nimesulide. The risk was also slightly above 1 for aceclofenac. In France, the risk was very high with clometacin, followed by sulindac, and was slightly above 1 for naproxen, diclofenac, piroxicam, and tenoxicam. This study shows that some NSAIDs are associated with reports of hepatic injuries when compared with other drugs, and most of those have been withdrawn from the market for this reason. However, the frequency of drug-related hepatic injuries reported differed in the French and Spanish databases, and some drugs did not show the same risk level in the two countries. These discrepancies could be explained in part not only by reporting rates, but also by difference in drug use patterns and/or by genetic or environmental factors.

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“…Observational studies indicate that antiplatelet and anticoagulant combinations, with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin re-uptake inhibitors (SSRIs) or antibacterial drugs increase bleeding risk [11,[13][14][15][16][17]. Up to 80% of anticoagulant users are described as using potentially hazardous combinations of medicines [18,19].…”

Section: Introductionmentioning

confidence: 99%

Warfarin‐associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system

Narum

Solhaug

Myhr

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Bleeding is the main adverse drug reaction of warfarin use. • Several medicines, herbal products and dietary supplements may interact with warfarin. • A high percentage of patients on warfarin receive potentially interacting substances. WHAT THIS STUDY ADDS • Potentially interacting medicines were used in more than 50% of the warfarin‐associated bleeding events reported to the Norwegian spontaneous reporting system. • Only a minority of the concomitant medicines were reported as suspected or interacting in the reporters' assessments. • There was a higher degree of under‐reporting of pharmacokinetically than of pharmacodynamically interacting medicines. AIMS To study warfarin associated bleeding events reported to the Norwegian spontaneous reporting system and evaluate the differences in assessment of potentially interacting medicines between reporters and evaluators. METHODS Data on bleeding events on warfarin were retrieved from the Norwegian spontaneous reporting system database. Key measurements were time to bleeding, use of concomitant medications and the evaluation done by reporters. RESULTS In 289 case reports a total of 1261 medicines (median 4.0 per patient, range 1–17) was used. The evaluators (authors of this article) identified 546 medicines including warfarin (median 2.0 per patient, range 1–7) that could possibly cause bleeding alone or in combination. Reporters assessed 349 medicines (median 1.0 per patient, range 1–4) as suspect. Evaluators identified 156 pharmacokinetic and 101 pharmacodynamic interactions, compared with 19 pharmacokinetic and 56 pharmacodynamic interactions reported as suspected by the reporters. Time to bleeding was stated in 224 reports. Among the early bleeding events, the reports on warfarin without interacting medicines showed the highest INR (international normalized ratio). Heparin was used in 17/21 reported bleeding events during the first week on warfarin. Among the late bleeding events, reports with pharmacokinetic interacting medicines had the highest INR. CONCLUSIONS Concomitant use of potentially interacting medicines was involved in the majority of the warfarin‐associated bleeding events reported to the Norwegian spontaneous reporting system. Reporters assessed mostly warfarin as the only contributor to bleeding. In particular, pharmacokinetically interacting medicines were not suspected as contributing to bleeding.

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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

Cited by 21 publications

References 9 publications

Correlation versus Causation? Pharmacovigilance of the Analgesic Flupirtine Exemplifies the Need for Refined Spontaneous ADR Reporting

Correlation versus Causation? Pharmacovigilance of the Analgesic Flupirtine Exemplifies the Need for Refined Spontaneous ADR Reporting

Non‐steroidal anti‐inflammatory drug‐related hepatic damage in France and Spain: analysis from national spontaneous reporting systems

Warfarin‐associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system

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