title: Clozapine-associated neutropenia and agranulocytosis in Argentina (2007-2012).
abstract: The risks of severe leukopenia and agranulocytosis have varied over time and among geographical regions and cultures, with little information available on South American populations. Accordingly, we reviewed and analyzed data from a 6-year experience monitored by an Argentine national registry to which reporting of adverse events reports is required. We analyzed data for 2007-2012 from the pharmacovigilance program of the Argentine drug-regulatory agency (ANMAT) using standard bivariate and multivariate statistical methods and survival analysis. We identified 378 cases of adverse hematological events over 6 years among an average of 12 305 individuals/year treated with clozapine (308±133 mg/day) to estimate the mean annualized rates of leukopenia [0.19 (95% confidence interval [CI] 0.11-0.27)], neutropenia [0.38 (95% CI 0.34-0.43)], and agranulocytosis [0.05 (95% CI 0.02-0.08)] % per year [median latency 2 (95% CI 1.3-2.1) months]; fatalities related to agranulocytosis averaged 4.2 (95% CI 0.0-9.2) per 100 000 treated individuals/year. Factors associated significantly and independently with agranulocytosis were female sex, older age, and use of other drugs in addition to clozapine. With monitoring by international standards, recent risks of clozapine-associated agranulocytosis in Argentina were lower, but fatality rates were higher than that in other regions of the world. Risk factors include the use of multiple psychotropic drugs, female sex, and older age.
authors.affiliation: aAdministración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT), Avenida de Mayo 869 (C1084AAD) bInstituto de Efectividad Clínica y Sanitaria (IECS), Dr Emilio Ravignani 2024 cSecretaría de Política Económica, Ministerio de Economía y Finanzas Públicas dIII Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor eConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina fInternational Consortium for Bipolar & Psychotic Disorders Research, McLean Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: María V
authors.initials: MV
authors.lastname: Balda
authors.forename: Osvaldo U
authors.initials: OU
authors.lastname: Garay
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Papale
authors.forename: Inés
authors.initials: I
authors.lastname: Bignone
authors.forename: Viviana G
authors.initials: VG
authors.lastname: Bologna
authors.forename: Andrés
authors.initials: A
authors.lastname: Brandolini
authors.forename: Cintia R
authors.initials: CR
authors.lastname: Prokopez
authors.forename: Juan I
authors.initials: JI
authors.lastname: Balasini
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Baldessarini
authors.forename: Federico M
authors.initials: FM
authors.lastname: Daray
mesh_terms: D000328:Adult; D017677:Age Distribution; D000380:Agranulocytosis / Q000139:chemically induced / Q000453:epidemiology* / Q000401:mortality; D014150:Antipsychotic Agents / Q000009:adverse effects; D001118:Argentina / Q000453:epidemiology; D003024:Clozapine / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000453:epidemiology*; D012042:Registries; D012307:Risk Factors
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine