Flupirtine is a safe alternative drug in patients with hypersensitivity to NSAIDs

Treudler, Regina; Pohle, Katja; Simon, Jan C.

doi:10.1007/s00228-011-1022-7

Cited by 14 publications

(15 citation statements)

References 8 publications

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“…In the absence of high quality, controlled studies on the abuse liability associated with FLP that is suggested from single cases and its GABAergic mechanism of action, we sought to provide first naturalistic data from a large German pharmacovigilance database. Considering that FLP is widely used in clinical practice for the treatment of various pain syndromes and still subject of ongoing research, there is a particular need for an adequate post‐authorization safety surveillance.…”

Section: Discussionsupporting

confidence: 82%

Abuse liability of flupirtine revisited: Implications of spontaneous reports of adverse drug reactions

Gahr¹,

Freudenmann²,

Connemann³

et al. 2013

The Journal of Clinical Pharmacology

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Early studies suggested that the centrally acting non-opioid and non-steroidal analgesic flupirtine (FLP) has no potential for abuse. However, FLP's agonistic effects at the GABAA receptor might prime addictive behaviors, and literature provides some anecdotal reports on FLP abuse/dependence. To shed more light on this topic we acquired and evaluated data obtained from a national German pharmacovigilance database. We analyzed all reports of FLP abuse/dependence that were recorded in the database of the German Federal Institute for Drugs and Medical Devices (BfArM). A total of n = 48 reports of FLP abuse/dependence could be identified (mean age 45 years, 62.5% female). First reports were submitted to BfArM in 1991 with increasing numbers of annual reports from the year 2006 on. Mean daily FLP dosage was 805 mg (range 200-3,000 mg). Current or previous substance abuse/dependence was reported in 21% and 17%, respectively. Mean duration of FLP abuse/dependence until report to BfArM was 23 months (range 1-84 months). Withdrawal syndromes after discontinuation of FLP were reported in n = 9 (19%). Our findings strengthen the hypothesis that FLP features a potential to cause addictive behaviors. Female sex, age >40 years, and long-term FLP-treatment may be possible risk factors for the development of FLP abuse/dependence.

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Section: Discussionsupporting

confidence: 82%

Abuse liability of flupirtine revisited: Implications of spontaneous reports of adverse drug reactions

Gahr¹,

Freudenmann²,

Connemann³

et al. 2013

The Journal of Clinical Pharmacology

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Section: Discussionmentioning

confidence: 99%

“…Flupirtine has been used as a prescription analgesic in Germany and some other countries for about 30 years, where it has generally been considered to be a safe drug with a low potential for liver enzyme elevations [3, 6, 7], as also reflected in the German prescribing information [8]. Flupirtine was even recommended as a safe alternative for patients experiencing AEs during treatment with nonsteroidal anti‐inflammatory drugs [6]. In limited studies with tinnitus patients (24 patients treated with 2 × 100 mg/day for 3 weeks [4]) or Creutzfeldt‐Jakob disease patients (13 patients treated with 3–4 × 100 mg/day for up to 10 months [10]), elevated liver enzymes were not reported.…”

Section: Discussionmentioning

confidence: 99%

“…It is undergoing clinical evaluation in fibromyalgia, tinnitus [4] and Creutzfeldt‐Jakob disease [5]. Flupirtine is generally considered safe in its licensed indication [3, 6], even upon chronic use [7], with liver enzyme elevations occurring in <0.01% of patients according to the German prescribing information [8]. Based upon promising efficacy data in animal models [9], we have performed a phase II double‐blind, randomized proof‐of‐concept trial with flupirtine in overactive bladder syndrome (OAB) patients.…”

Section: Introductionmentioning

confidence: 99%

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

Michel

Radziszewski

Falconer

et al. 2012

Brit J Clinical Pharma

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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.

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“…constipation). 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].…”

Section: Introductionmentioning

confidence: 99%

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

Siegmund

Modeß

Scheuch

et al. 2015

Brit J Clinical Pharma

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AIMSThe rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases (NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases (UGT) and glutathione S-transferases (GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine. METHODSMetabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release (IR) tablet (100 mg) and after repeated administration of modified release (MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain). RESULTSFlupirtine IR was rapidly but incompletely absorbed (∼72%). Repeated administration of flupirtine MR showed lower bioavailability (∼60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2.

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Flupirtine is a safe alternative drug in patients with hypersensitivity to NSAIDs

Abstract: International audienc

Cited by 14 publications

References 8 publications

Abuse liability of flupirtine revisited: Implications of spontaneous reports of adverse drug reactions

Abuse liability of flupirtine revisited: Implications of spontaneous reports of adverse drug reactions

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

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

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