Unexpected frequent hepatotoxicity of a prescription drug, flupirtine, marketed for about 30 years

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Flupirtine has been on the market for about 30 years in several European countries as an analgesic. This use has not resulted in regulatory action concerning hepatotoxicity. WHAT THIS STUDY ADDS• When used in a novel indication, hepatotoxicity was frequent with flupirtine, questioning the general assumption that the safety profile in one indication can be extrapolated to other indications. AIMSTo determine efficacy of the analgesic flupirtine in the treatment of overactive bladder syndrome in a proof-of-concept study. METHODSDouble-blind, double-dummy, three-armed comparison of flupirtine extended release (400 mg/day, titrated to 600 mg/day), tolterodine extended release (4 mg/day) and placebo for 12 weeks. RESULTSWhen major elevations of liver enzymes (more than three times the upper normal limit) were detected in several flupirtine-exposed patients, the study was prematurely discontinued. Based on study-end data, hepatotoxicity was detected in 31% of patients receiving flupirtine for Ն6 weeks. CONCLUSIONSUnexpected frequent and relevant toxicity can occur when testing an established drug for a new indication.

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

“…cytokines regulating inflammation and immune response) and in turn the individual risk for DILI [45][46][47]. A common feature of flupirtine-induced liver injury is the dose-independent behaviour, a latency period of several weeks to months and absence of correlations between severity and cumulative dose [16,18,48]. …”

“…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].…”

Emerging drugs for overactive bladder

“…A double-blind randomized placebocontrolled trial with 229 participants failed to show that ZD0947 25 mg was superior to placebo in treating OAB [96]. Another Phase II trial was terminated due to unexpected frequent hepatotoxicity [97]. KCOs have a limited role in treating OAB due to the cardiovascular effects, mainly hypotension.…”

Fragen eines lesenden Schmerzmediziners

“…Denn neben den erwähn-ten Fallberichten liegen hierzu auch Daten aus prospektiven Studien vor: So kam es bei 3% nach 1-wöchiger [14] bzw. bei 31% der Patienten nach 6-wöchiger Flupirtinbehandlung zu Leberwerterhöhungen, was zum Studienabbruch führte [15] …”