title: Profiles of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolone antibacterials: experience from large cohorts from the Drug Safety Research Unit Prescription-Event Monitoring database.
abstract: OBJECTIVE
  To investigate how frequently serious dysrhythmic cardiovascular, and hepatotoxic events are reported during routine clinical use of fluoroquinolones (quinolones) in general practice.
  
  
  METHODS
  Cohorts prescribed quinolones (cohort sizes: ciprofloxacin 11 477; enoxacin 2790; ofloxacin 11 033 and norfloxacin 11 110; mean age in each cohort of 48.6 to 57.0 years) were selected from the Drug Safety Research Unit's Prescription-Event Monitoring (PEM) database. The monitoring periods were November 1988 to January 1989 for ciprofloxacin; April 1989 to January 1991 for enoxacin; May 1991 to December 1991 for ofloxacin and October 1990 to October 1991 for norfloxacin. Data collected over the total PEM surveillance period on selected gastrointestinal events were extracted and reviewed to identify possible hepatic events, together with selected cardiovascular events associated with dysrhythmias. For each quinolone, times to onset of the event and patient-months of observation (denominator values) were calculated. The analysis was based on two observation periods: rate of event during the first 7 days following dispensing of a prescription for each drug (W(1)), and rate of event during the second to sixth week inclusive (W(2)).
  
  
  RESULTS
  Scrutiny of original green forms revealed no evidence of drug-induced hepatic dysfunction within 42 days of drug administration for any of the quinolones monitored. No evidence was found of drug-induced dysrhythmic events associated with enoxacin within 42 days of drug administration. Of the other quinolones, 'atrial fibrillation' was reported most often within 42 days following ciprofloxacin administration, with no change in event rate over that time, crude relative risk (CRR)[W(1)/W(2)] 1.0 [95% confidence interval (CI) 0.02 to 8.92]. Other less serious events associated with dysrhythmia were reported with varying incidence within 42 days of quinolone administration. The crude rate of palpitation did not change significantly over that time for ciprofloxacin, ofloxacin and norfloxacin: CRR 0.83 (95% CI 0.02 to 6.86), 2.00 (95% CI 0.19 to 12.20) and 4.99 (95% CI 0.06 to 391.94), respectively. Syncope and tachycardia were also reported for ofloxacin [CRR 9.99 (95% CI 0.52 to 589.49 for both events)] and ciprofloxacin [1.0 (95% CI 0.02, 8.92)] and 2.50 (95% CI 0.04, 47.96) for syncope and tachycardia, respectively].
  
  
  CONCLUSIONS
  It cannot be ruled out that some rare hepatic and dysrhythmic events associated with quinolones may be drug related. The primary purpose of PEM is signal generation. Compared with the other quinolones, ciprofloxacin was associated with the highest number of reports of dysrhythmic cardiovascular events occurring within 42 days of administration. This requires further investigation by other types of epidemiological study.
authors.affiliation: Drug Safety Research Unit, Bursledon Hall, Southampton, UK.
authors.forename: D W
authors.initials: DW
authors.lastname: Clark
authors.forename: D
authors.initials: D
authors.lastname: Layton
authors.forename: L V
authors.initials: LV
authors.lastname: Wilton
authors.forename: G L
authors.initials: GL
authors.lastname: Pearce
authors.forename: S A
authors.initials: SA
authors.lastname: Shakir
mesh_terms: D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury; D002939:Ciprofloxacin / Q000009:adverse effects; D015331:Cohort Studies; D016208:Databases, Factual; D016903:Drug Monitoring / Q000379:methods; D004739:England / Q000453:epidemiology; D015365:Enoxacin / Q000009:adverse effects; D005194:Family Practice; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009643:Norfloxacin / Q000009:adverse effects; D015242:Ofloxacin / Q000009:adverse effects; D011358:Product Surveillance, Postmarketing / Q000379:methods; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D015365:Enoxacin; D002939:Ciprofloxacin; D015242:Ofloxacin; D009643:Norfloxacin