Yonsei Med J.  2017 May;58(3):564-569. 10.3349/ymj.2017.58.3.564.

Signal Detection of Imipenem Compared to Other Drugs from Korea Adverse Event Reporting System Database

• Park K
• Soukavong
• Kim J
• Kwon KE
• Jin XM
• Lee J
• Yang BR
• Park BJ

• KMID: 2419114
• DOI: http://doi.org/10.3349/ymj.2017.58.3.564

Abstract

PURPOSE
To detect signals of adverse drug events after imipenem treatment using the Korea Institute of Drug Safety & Risk Management-Korea adverse event reporting system database (KIDS-KD).
MATERIALS AND METHODS
We performed data mining using KIDS-KD, which was constructed using spontaneously reported adverse event (AE) reports between December 1988 and June 2014. We detected signals calculated the proportional reporting ratio, reporting odds ratio, and information component of imipenem. We defined a signal as any AE that satisfied all three indices. The signals were compared with drug labels of nine countries.
RESULTS
There were 807582 spontaneous AEs reports in the KIDS-KD. Among those, the number of antibiotics related AEs was 192510; 3382 reports were associated with imipenem. The most common imipenem-associated AE was the drug eruption; 353 times. We calculated the signal by comparing with all other antibiotics and drugs; 58 and 53 signals satisfied the three methods. We compared the drug labelling information of nine countries, including the USA, the UK, Japan, Italy, Switzerland, Germany, France, Canada, and South Korea, and discovered that the following signals were currently not included in drug labels: hypokalemia, cardiac arrest, cardiac failure, Parkinson's syndrome, myocardial infarction, and prostate enlargement. Hypokalemia was an additional signal compared with all other antibiotics, and the other signals were not different compared with all other antibiotics and all other drugs.
CONCLUSION
We detected new signals that were not listed on the drug labels of nine countries. However, further pharmacoepidemiologic research is needed to evaluate the causality of these signals.

Keyword

Imipenem; KIDS-KAERS database; signal; pharmacovigilance; pharmacoepidemiology

MeSH Terms

Adverse Drug Reaction Reporting Systems/*statistics & numerical data
Anti-Bacterial Agents/*adverse effects/therapeutic use
Data Mining
Databases, Factual/statistics & numerical data
Drug Labeling
Drug-Related Side Effects and Adverse Reactions/*epidemiology
Female
Humans
Imipenem/*adverse effects/therapeutic use
Male
Odds Ratio
Pharmacoepidemiology
Pharmacovigilance
Republic of Korea
Anti-Bacterial Agents
Imipenem

Reference

1. World Health Organizaion-Uppsala Mornitoring Centre. What is a signal? 2013. accessed on 2015 August 18. Available at: https://www.who-umc.org/research-scientific-development/signal-detection/what-is-a-signal/.

2. Trifirò G, Pariente A, Coloma PM, Kors JA, Polimeni G, Miremont-Salamé G, et al. Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor? Pharmacoepidemiol Drug Saf. 2009; 18:1176–1184.

3. 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; 26:293–301.

4. Egberts AC, Meyboom RH, van Puijenbroek EP. Use of measures of disproportionality in pharmacovigilance: three Dutch examples. Drug Saf. 2002; 25:453–458.

5. Hornik CP, Herring AH, Benjamin DK Jr, Capparelli EV, Kearns GL, van den Anker J, et al. Adverse events associated with meropenem versus imipenem/cilastatin therapy in a large retrospective cohort of hospitalized infants. Pediatr Infect Dis J. 2013; 32:748–753.

6. National Institutes of Health-U.S. National Library of Medicine. Label: imipenem and cilastatin-imipenem and cilastatin sodium injection, powder, for solution. 2012. accessed on 2015 August 18. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6ab0ca9e-9a79-4cab-9f09-470eda06952e.

7. Ministry of Food and Drug Safety. Imipenem-precautions. 2013. accessed on 2015 August 1. Available at: http://drug.mfds.go.kr/html/bxsSearchDrugProduct.jsp?item_Seq=200500891.

8. Korea Institute of Drug Safety and Risk Management. User guide: Korea Institute of Drug Safety and Risk Management-Korea adverse event reporting system database (KIDS-KD). 2014. accessed on 2015 August 1. Available at: https://www.drugsafe.or.kr/iwt/ds/ko/openinfo/DrugAdrDataProc.do.

9. Ye X, Fu Z, Wang H, Du W, Wang R, Sun Y, et al. A computerized system for signal detection in spontaneous reporting system of Shanghai China. Pharmacoepidemiol Drug Saf. 2009; 18:154–158.

10. Wilson AM, Thabane L, Holbrook A. Application of data mining techniques in pharmacovigilance. Br J Clin Pharmacol. 2004; 57:127–134.

11. Seong JM, Choi NK, Jung SY, Kim YJ, Lee JY, Park BJ. Signal detection of sildenafil in Korean spontaneous adverse event reports. J Pharmacoepidemiol Risk Manag. 2009; 2:38–44.

12. Gould AL. Practical pharmacovigilance analysis strategies. Pharmacoepidemiol Drug Saf. 2003; 12:559–574.

13. Bate A, Lindquist M, Orre R, Edwards IR, Meyboom RH. Data-mining analyses of pharmacovigilance signals in relation to relevant comparison drugs. Eur J Clin Pharmacol. 2002; 58:483–490.

14. Li C, Xia J, Deng J, Chen W, Wang S, Jiang J, et al. A web-based quantitative signal detection system on adverse drug reaction in China. Eur J Clin Pharmacol. 2009; 65:729–741.

15. Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf. 2009; 18:427–436.

16. Grundmark B, Holmberg L, Garmo H, Zethelius B. Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area. Eur J Clin Pharmacol. 2014; 70:627–635.

17. Cannon JP, Lee TA, Clark NM, Setlak P, Grim SA. The risk of seizures among the carbapenems: a meta-analysis. J Antimicrob Chemother. 2014; 69:2043–2055.

18. Chen Z, Wu J, Zhang Y, Wei J, Leng X, Bi J, et al. Efficacy and safety of tigecycline monotherapy vs. imipenem/cilastatin in Chinese patients with complicated intra-abdominal infections: a randomized controlled trial. BMC Infect Dis. 2010; 10:217.

19. Drusano GL, Standiford HC, Bustamante CI, Rivera G, Forrest A, Leslie J, et al. Safety and tolerability of multiple doses of imipenem/cilastatin. Clin Pharmacol Ther. 1985; 37:539–543.

20. Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E. Tigecycline 301 Study Group. Tigecycline 306 Study Group. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis. 2005; 41:Suppl 5. S354–S367.

21. Torres A, Bauer TT, León-Gil C, Castillo F, Alvarez-Lerma F, Martínez-Pellús A, et al. Treatment of severe nosocomial pneumonia: a prospective randomised comparison of intravenous ciprofloxacin with imipenem/cilastatin. Thorax. 2000; 55:1033–1039.

22. Ramasamy R, Murugaiyan SB, Gopal N, Shalini R. The prospect of serum magnesium and an electrolyte panel as an adjuvant cardiac biomarker in the management of acute myocardial infarction. J Clin Diagn Res. 2013; 7:817–820.

23. Bardai A, Lamberts RJ, Blom MT, Spanjaart AM, Berdowski J, van der Staal SR, et al. Epilepsy is a risk factor for sudden cardiac arrest in the general population. PLoS One. 2012; 7:e42749.

24. Lindquist M, Ståhl M, Bate A, Edwards IR, Meyboom RH. A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database. Drug Saf. 2000; 23:533–542.

25. Bandekar MS, Anwikar SR, Kshirsagar NA. Quality check of spontaneous adverse drug reaction reporting forms of different countries. Pharmacoepidemiol Drug Saf. 2010; 19:1181–1185.

26. Finkelsztejn A, Cabral L, Bragatti JA, Silva AV, Schuh AF. Imipenem-associated encephalopathy: alert to physicians. Arq Neuropsiquiatr. 2010; 68:137–139.

27. Gelband H, Miller-Petrie M, Pant S, Gandra S, Levinson J, Barter D. The State of the World's Antibiotics. 2015. accessed on 2015 September 18. Available at: http://cddep.org/publications/state_worlds_antibiotics_2015#sthash.RrXl4cFU.dpbs.

28. Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: past, present, and future. Antimicrob Agents Chemother. 2011; 55:4943–4960.

29. van Puijenbroek EP, Egberts AC, Meyboom RH, Leufkens HG. Signalling possible drug-drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole. Br J Clin Pharmacol. 1999; 47:689–693.

30. Lindquist M, Edwards IR, Bate A, Fucik H, Nunes AM, Ståhl M. From association to alert--a revised approach to international signal analysis. Pharmacoepidemiol Drug Saf. 1999; 8:Suppl 1. S15–S25.

31. World Health Organizaion-Uppsala Monitoring Centre. WHOART: Structure. accessed on 2015 September 9. Available at: http://www.umc-products.com/DynPage.aspx?id=73558&mn1=1107&mn2=1664&mn3=6043.

32. Alecu I, Bousquet C, Mougin F, Jaulent MC. Mapping of the WHO-ART terminology on Snomed CT to improve grouping of related adverse drug reactions. Stud Health Technol Inform. 2006; 124:833–838.