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

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

Zur Wirkung von Divicin in menschlichen Erythrocyten

Peer Reviewe

Pharmacokinetic interaction between retigabine and lamotrigine in healthy-subjects

Purpose. The antiepileptic drugs (AEDs) retigabine (RGB) and lamotrigine (LTG) undergo predominantly N-glucuronidation and renal excretion. This study was performed to evaluate potential pharmacokinetic interactions between both AEDs. Methods. Twenty-nine healthy male subjects participated in the study. Group A (n=14) received single oral 200-mg RGB doses on day 1 and day 7, and 25 mg o.i.d. LTG on days 3-8. Group B (n=15) received single oral 200-mg LTG doses on day 1 and day 17, and was up-titrated to 300 mg RGB b.i.d. on days 6-20. Blood samples were collected to compare the pharmacokinetics of both AEDs and the N-acetyl metabolite of RGB (AWD21-360) after single and concomitant treatments. Results. RGB was rapidly absorbed and eliminated with a mean half-life (t1/2) of 6.3-1.1 h and an apparent clearance (CL/F) of 0.69-1.4 l/h/kg. Under co-administration of LTG, mean RGB t1/2 and area under the plasma concentration-time curve (AUC) were increased by 7.5% (P=0.045) and 15% (P=0.006), respectively, while CL/F was decreased by 13% (P=0.06). Consistent results were obtained for AWD21-360. LTG was moderately rapidly absorbed, eliminated with a mean t1/2 of 37-10.4 h and a CL/F of 0.028-0.007 l/h/kg. Under co-administration of RGB, mean LTG t1/2 and AUC decreased by 15% and 18%, respectively, while CL/F increased by 22% (all parameters, P=0.001). Conclusions. RGB and LTG exhibit a modest pharmacokinetic interaction on each other. The slight decline in RGB clearance due to LTG is believed to result from competition for renal elimination rather than competition for glucuronidation. The induction of LTG clearance due to retigabine was unexpected since RGB did not show enzyme induction in various other drug-drug interaction studies. Further studies in patients are needed to assess the clinical relevance of these findings for concomitant treatment with both drugs in the upper recommended dose range

Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers

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