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Drug Safety
Published in: Drug Safety 4/2010

01-04-2010 | Original Research Article

Antimicrobials and the Risk of Torsades de Pointes

The Contribution from Data Mining of the US FDA Adverse Event Reporting System

Authors: Elisabetta Poluzzi, Emanuel Raschi, Domenico Motola, Ugo Moretti, Fabrizio De Ponti, MD, PhD

Published in: Drug Safety | Issue 4/2010

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Abstract

Background: Drug-induced torsades de pointes (TdP) is a complex regulatory and clinical problem due to the rarity of this sometimes fatal adverse event. In this context, the US FDA Adverse Event Reporting System (AERS) is an important source of information, which can be applied to the analysis of TdP liability of marketed drugs.
Objective: To critically evaluate the risk of antimicrobial-induced TdP by detecting alert signals in the AERS, on the basis of both quantitative and qualitative analyses.
Methods: Reports of TdP from January 2004 through December 2008 were retrieved from the public version of the AERS. The absolute number of cases and reporting odds ratio as a measure of disproportionality were evaluated for each antimicrobial drug (quantitative approach). A list of drugs with suspected TdP liability (provided by the Arizona Centre of Education and Research on Therapeutics [CERT]) was used as a reference to define signals. In a further analysis, to refine signal detection, we identified TdP cases without co-medications listed by Arizona CERT (qualitative approach).
Results: Over the 5-year period, 374 reports of TdP were retrieved: 28 anti-bacterials, 8 antifungals, 1 antileprosy and 26 antivirals were involved. Antimicrobials more frequently reported were levofloxacin (55) and moxi-floxacin (37) among the antibacterials, fluconazole (47) and voriconazole (17) among the antifungals, and lamivudine (8) and nelfinavir (6) among the antivirals. A significant disproportionality was observed for 17 compounds, including several macrolides, fluoroquinolones, linezolid, triazole antifungals, caspofungin, indinavir and nelfinavir. With the qualitative approach, we identified the following additional drugs or fixed dose combinations, characterized by at least two TdP cases without co-medications listed by Arizona CERT: ceftriaxone, piperacillin/tazobactam, cotrimoxazole, metronidazole, ribavirin, lamivudine and lopinavir/ritonavir.
Discussion: Disproportionality for macrolides, fluoroquinolones and most of the azole antifungals should be viewed as ‘expected’ according to Arizona CERT list. By contrast, signals were generated by linezolid, caspofungin, posaconazole, indinavir and nelfinavir. Drugs detected only by the qualitative approach should be further investigated by increasing the sensitivity of the method, e.g. by searching also for the TdP surrogate marker, prolongation of the QT interval.
Conclusions: The freely available version of the FDA AERS database represents an important source to detect signals of TdP. In particular, our analysis generated five signals among antimicrobials for which further investigations and active surveillance are warranted. These signals should be considered in evaluating the benefit-risk profile of these drugs.
Literature
1.
2.
3.
Owens Jr RC. QT prolongation with antimicrobial agents: understanding the significance. Drugs 2004; 64: 1091–124PubMedCrossRef
4.
Zambon A, Polo FH, Contiero P, et al. Effect of macrolide and fluoroquinolone antibacterials on the risk of ventricular arrhythmia and cardiac arrest: an observational study in Italy using case-control, case-crossover and case-time-control designs. Drug Saf 2009; 32: 159–67PubMedCrossRef
5.
De Ponti F, Poluzzi E, Cavalli A, et al. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf 2002; 25: 263–86PubMedCrossRef
6.
Recanatini M, Poluzzi E, Masetti M, et al. QT prolongation through hERG K1+ channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev 2005; 25: 133–66PubMedCrossRef
7.
De Ponti F. Pharmacological and regulatory aspects of QT prolongation. In: Vaz RJ, editor. Antitargets: prediction and prevention of drug side effects. 1st ed. Weinheim: Wiley-VCH, 2008: 109–26
8.
Darpo B, Nebout T, Sager PT. Clinical evaluation of QT/QTc prolongation and proarrhythmic potential for nonantiarrhythmic drugs: the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 guideline. J Clin Pharmacol 2006; 46: 498–507PubMedCrossRef
9.
Raschi E, Vasina V, Poluzzi E, et al. The hERG K(+) channel: target and antitarget strategies in drug development. Pharmacol Res 2008; 57: 181–95PubMedCrossRef
10.
Raschi E, Ceccarini L, De Ponti F, et al. hERG-related drug toxicity and models for predicting hERG liability and QT prolongation. Expert Opin Drug Metab Toxicol 2009; 5: 1005–21PubMedCrossRef
11.
Darpo B. Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. Eur Heart J Suppl 2001; 3: K70–80
12.
13.
Hauben M, Bate A. Decision support methods for the detection of adverse events in post-marketing data. Drug Discov Today 2009; 14: 343–57PubMedCrossRef
14.
Hochberg AM, Pearson RK, O’Hara DJ, et al. Drug-versus-drug adverse event rate comparisons: a pilot study based on data from the US FDA Adverse Event Reporting System. Drug Saf 2009; 32: 137–46PubMedCrossRef
15.
Poluzzi E, Raschi E, Moretti U, et al. Drug-induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2009; 18: 512–8PubMedCrossRef
16.
Kessler DA. Introducing MEDWatch: a new approach to reporting medication and device adverse effects and product problems. JAMA 1993; 269: 2765–8PubMedCrossRef
17.
18.
19.
20.
Moore N, Kreft-Jais C, Haramburu F, et al. Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database. Br J Clin Pharmacol 1997; 44: 513–8PubMedCrossRef
21.
van Puijenbroek EP, Bate A, Leufkens HG, et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf 2002; 11: 3–10PubMedCrossRef
22.
Almenoff J, Tonning JM, Gould AL, et al. Perspectives on the use of data mining in pharmacovigilance. Drug Saf 2005; 28: 981–1007PubMedCrossRef
23.
Hauben M, Madigan D, Gerrits CM, et al. The role of data mining in pharmacovigilance. Expert Opin Drug Saf 2005; 4: 929–48PubMedCrossRef
24.
Almenoff JS, Pattishall EN, Gibbs TG, et al. Novel statistical tools for monitoring the safety of marketed drugs. Clin Pharmacol Ther 2007; 82: 157–66PubMedCrossRef
25.
Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 2009; 18: 427–36PubMedCrossRef
26.
27.
Owens Jr RC, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006; 43: 1603–11PubMedCrossRef
28.
Shantsila E, Watson T, Lip GY. Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial arrhythmias. Europace 2007; 9 Suppl. 4: iv37–44PubMedCrossRef
29.
30.
Hochberg AM, Hauben M. Time-to-signal comparison for drug safety data-mining algorithms vs. traditional signal criteria. Clin Pharmacol Ther 2009; 85: 600–6PubMedCrossRef
31.
32.
Hauben M, Aronson JK. Gold standards in pharmacovigilance: the use of definitive anecdotal reports of adverse drug reactions as pure gold and high-grade ore. Drug Saf 2007; 30: 645–55PubMedCrossRef
33.
van Puijenbroek E, Diemont W, van Grootheest K. Application of quantitative signal detection in the Dutch spontaneous reporting system for adverse drug reactions. Drug Saf 2003; 26: 293–301PubMedCrossRef
34.
Hauben M. Early postmarketing drug safety surveillance: data mining points to consider. Ann Pharmacother 2004; 38: 1625–30PubMedCrossRef
35.
36.
Owens Jr RC, Ambrose PG. Torsades de pointes associated with fluoroquinolones. Pharmacotherapy 2002; 22: 663–8PubMedCrossRef
37.
Shaffer D, Singer S, Korvick J, et al. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System. Clin Infect Dis 2002; 35: 197–200PubMedCrossRef
38.
Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy 2001; 21: 1468–72PubMedCrossRef
39.
Justo D, Zeltser D. Torsade de pointes induced by systemic antifungal agents: lessons from a retrospective analysis of published case reports. Mycoses 2006; 49: 463–70PubMedCrossRef
40.
Pfizer. A study to assess the effect of linezolid on QTc interval [ClinicalTrials.gov identifier NCT00795145]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://​clinicaltrials.​gov [Accessed 2009 Oct 26]
41.
42.
Zyvox® (linezolid): US prescribing information. New York: Pharmacia and Upjohn, 2008
43.
44.
Cancidas® (caspofungin acetate): US prescribing information. New York: Merck, 2009
45.
46.
Noxafil® (posaconazole): US prescribing information. New York: Schering, 2009
47.
Chinello P, Lisena FP, Angeletti C, et al. Role of anti-retroviral treatment in prolonging QTc interval in HIV-positive patients. J Infect 2007; 54: 597–602PubMedCrossRef
48.
Anson BD, Weaver JG, Ackerman MJ, et al. Blockade of HERG channels by HIV protease inhibitors. Lancet 2005; 365: 682–6PubMed
49.
Viracept® (nelfinavir mesylate): US prescribing information. San Diego (CA): Agouron, 2008
50.
Damle B, Fosser C, Ito K, et al. Effects of standard and supratherapeutic doses of nelfinavir on cardiac repolarization: a thorough QT study. J Clin Pharmacol 2009; 49: 291–300PubMedCrossRef
51.
Stephenson WP, Hauben M. Data mining for signals in spontaneous reporting databases: proceed with caution. Pharmacoepidemiol Drug Saf 2007; 16: 359–65PubMedCrossRef
52.
Hauben M, Patadia V, Gerrits C, et al. Data mining in pharmacovigilance: the need for a balanced perspective. Drug Saf 2005; 28: 835–42PubMedCrossRef
53.
Hauben M, Reich L, DeMicco J, et al. ‘Extreme duplication’ in the US FDA Adverse Events Reporting System data-base. Drug Saf 2007; 30: 551–4PubMedCrossRef
54.
Hartnell NR, Wilson JP. Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration. Pharmacotherapy 2004; 24: 743–9PubMedCrossRef
55.
Pariente A, Gregoire F, Fourrier-Reglat A, et al. Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: the notoriety bias. Drug Saf 2007; 30: 891–8PubMedCrossRef
56.
57.
Hopstadius J, Noren GN, Bate A, et al. Impact of stratification on adverse drug reaction surveillance. Drug Saf 2008; 31: 1035–48PubMedCrossRef
58.
59.
Metadata
Title
Antimicrobials and the Risk of Torsades de Pointes
The Contribution from Data Mining of the US FDA Adverse Event Reporting System
Authors
Elisabetta Poluzzi
Emanuel Raschi
Domenico Motola
Ugo Moretti
Fabrizio De Ponti, MD, PhD
Publication date
01-04-2010
Publisher
Springer International Publishing
Published in
Drug Safety / Issue 4/2010
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI
https://doi.org/10.2165/11531850-000000000-00000

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