title: Metamizole (dipyrone)-associated agranulocytosis. An analysis of German spontaneous reports 1990-2012.
abstract: OBJECTIVE
  In 1986, the risk of agranulocytosis prompted German authorities to restrict the indications for metamizole use. After an initial decline, prescriptions increased from <20 million defined daily doses in 1990 to >140 million in 2012. Concurrently, spontaneous reports of agranulocytosis increased from about 10 in 1990 to >50 in 2012. In this study, reports were analyzed to identify targets for risk minimization measures.
  
  
  METHODS
  Reports of suspected metamizole-induced agranulocytosis (neutrophils < 0.5 × 10(9) cells/l) between 1990 and 2012 were identified in the German spontaneous reporting database. Cases for which original reporting documents were available were eligible for analysis. Patient characteristics, indication, clinical course, and outcome were assessed.
  
  
  RESULTS
  One hundred sixty-one reports were analyzed. The mean age of the patients was 56.8 years (11-93) and 64.6 % were female. Off-label use was identified in about 25 % of cases. Neutrophils fell below 100/μl in 63 and intercurrent infections developed in 109 cases. Thirty-eight patients (23.6 %) died. In two thirds of the cases, agranulocytosis occurred within 6 weeks of permanent or intermittent metamizole treatment, in 30.5 % within 7 days, including 18 cases of immediate onset after the first or second administration.
  
  
  CONCLUSIONS
  The reported cases show severe clinical courses and are, to some extent, a result of off-label use. Due to the absence of individual risk factors and presence of variable onset patterns, risk minimization measures should focus on restricting use to defined clinical situations and providing concise risk information for patients and healthcare professionals.
authors.affiliation: Drug Commission of the German Medical Association (DCGMA), Herbert-Lewin-Platz 1, 10623, Berlin, Germany, thomas.stammschulte@akdae.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stammschulte
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Ludwig
authors.forename: Bernd
authors.initials: B
authors.lastname: Mühlbauer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bronder
authors.forename: Ursula
authors.initials: U
authors.lastname: Gundert-Remy
mesh_terms: D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D000380:Agranulocytosis / Q000139:chemically induced*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D002648:Child; D004177:Dipyrone / Q000009:adverse effects*; D004363:Drug Utilization / Q000639:trends; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use / Q000706:statistics & numerical data; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004177:Dipyrone