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

Abstract

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.

Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1

“…Immune-mediated processes might also be involved in flupirtine-induced liver injury as a plasma cell rich hepatitis occurred in one patient after re-exposure [18]. The putative toxic-allergic mechanism is also in line with observations on rapid recurrence or worsening of DILI symptoms after unintended re-challenge with flupirtine [13]. Whatever downstream mechanisms may contribute to flupirtine-induced liver injury, the initial key point mechanism may likely be metabolic activation of flupirtine by peroxidases to quinone diimines.…”

“…Since 2007, flupirtine-induced liver injury has been in the focus of an ongoing debate in Germany in response to an increasing prescription rate and the number of hepatobiliary adverse events [44]. The incidence of flupirtine-related hepatobiliary adverse events was estimated to be about 8 in 100 000 patients according to a recent re-evaluation of 226 unselected, spontaneously reported cases in the BfArM database [13].…”

“…Normally, it is well tolerated and a safe alternative in patients with hypersensitivity to NSAIDs [12]. The spectrum of side effects includes a very rare, mild and transient elevation of liver enzymes, aggravation of preexisting liver disease and, in single cases, severe and fatal liver failure [13][14][15][16][17][18]. There is evidence that the liver injury may be initiated by metabolic formation of hepatotoxic metabolites [19].…”

Data Mining Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA Adverse Event Reporting System (AERS)

“…There should also be a commitment to improving the quality of the data, which is ultimately the rate limiting step. A recent study address some challenges and limitations of current pharmacovigilance processes in terms of data completeness and resorted to use the case of flupirtine to exemplify the need for refined ADR reporting [62].…”

Predicting idiosyncratic drug-induced liver injury – some recent advances

“…Therefore, its clinical diagnosis is largely based on exclusion of other conditions rendering a definitive diagnosis of DILI challenging, while an assessment of the medical history frequently involves complex comedications as well as complementary alternative medicines and over-the-counter products. Thus, establishing a causal relationship is often difficult, and the strength and weaknesses in the causality assessment methods have been dealt with in various reviews and cases studies [12][13][14]. Positive outcomes of rechallenging exposures would lead to definitive answer and would be of high value for the search and identification of biomarker candidates.…”