Metamizole and risk of agranulocytosis

Study type

• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Secondary data collection

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine, other:
  Metamizole; other analgesics / anti-inflammatories (Ibuprofen, diclofenac, naproxen, dexketoprofen and the rest of ATC M01A, single drug; or paracetamol, codeine or tramadol as single drugs and in fixed dose combinations or simultaneous prescription
• Study drug International non-proprietary name (INN) or common name:
  CODEINE

  DICLOFENAC

  IBUPROFEN

  PARACETAMOL

  TRAMADOL
• Anatomical Therapeutic Chemical (ATC) code:
  (M01A) ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS, NON-STEROIDS

  (N02AA79) codeine, combinations with psycholeptics

  (N02AJ06) codeine and paracetamol

  (N02AJ13) tramadol and paracetamol

  (N02AX02) tramadol

  (N02BB02) metamizole sodium

  (N02BB52) metamizole sodium, combinations excl. psycholeptics

  (N02BB72) metamizole sodium, combinations with psycholeptics

  (N02BE01) paracetamol

  (N02BE51) paracetamol, combinations excl. psycholeptics

  (N02BE51) paracetamol, combinations excl. psycholeptics
• Medical condition to be studied:
  Agranulocytosis

  Idiopathic neutropenia

Population studied

• Short description of the study population:
  Patients aged ≥2 years in 2005-2022 new users (i.e. 1st dispensation after ≥6 months without prescription) of metamizole, NSAID or opiates-paracetamol. Patients diagnosed with any of the conditions where severe neutropenia is a common manifestation were excluded (i.e. lymphoma, leukaemia, myelodysplastic syndromes, bone marrow metastasis, cyclic neutropenia, familiar neutropenia, myelofibrosis, AIDS, recent –6 months- use of cytotoxic or immunosuppressant drugs or radiotherapy, aplastic or megaloblastic anaemia, hypersplenism or prior non-idiosyncratic neutropenia). Patients with prior idiosyncratic neutropenia or agranulocytosis were also included, which were considered as confounders.
• Age groups:
  Children (2 to < 12 years)

  Adolescents (12 to < 18 years)

  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Estimated number of subjects:
  7000000

Study design details

• Study design:
  Patients aged ≥2 years in 2005-2022 were followed from the day after their 1st metamizole or NSAID dispensation up to the end of the first continuous treatment period (i.e. having <30 days without supply) to identify hospitalizations due to idiosyncratic agranulocytosis.
• Main study objective:
  The objective of this proposal is the estimation of the risk of agranulocytosis associated with the use of metamizole compared to other analgesics / anti-inflammatories with similar use profile, in the BIFAP population.
• Setting:
  Primary care and linked hospital records in Spain.
• Comparators:
  - Non-steroidal anti-inflammatory drugs-NSAID. ; - Opiates-paracetamols as negative control.
• Outcomes:
  The outcome of interest is idiosyncratic agranulocytosis which is clinically defined as a reduction in the peripheral ANC to <500 cells/mm3 plus compatible symptomatology. To identify all incident cases of agranulocytosis during treatment periods, idiosyncratic neutropenias recorded in hospital discharge registries were captured. Then, agranulocytosis cases were identified through manual review of patients' clinical histories blinded to drug used.
• Data analysis plan:
  As internal validation of the outcome, potential cases identified will be manually reviewed (blinded to drug use) in order to confirm the diagnosis record. Baseline characteristics will be summarized as means and standard deviations or proportions where appropriate. Two survival analyses with Cox proportional hazard regression models will be applied to estimate the risk of agranulocytosis (crude and adjusted hazard ratios, HR) during metamizole treatment episode: ; 1. versus NSAID as reference cohort ; 2. versus Opioid- paracetamol as a negative control ; ; An STATA v15 procedure using automatic backward stepwise selection of potential confounders will be performed. Analyses will be stratified by sex, age and the possible effect modifiers.
• Summary results:
  Overall, 26 hospitalised agranulocytosis occurred, 5 in the 1st week (and so removed in main analysis) and 21 thereafter. ; ; IR of agranulocytosis was 14.20 (N=5 cases) and 8.52 (N=3), 1.95 (N=6) and 1.62 (N=5) and 4.29 (N=15) and 3.72 (N=13) per 107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. ; ; Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. ; ; Adjusted HR of agranulocytosis associated with metamizole was 7.20 [1.92-26.99] and 4.40 [95% CI: 0.90-21.57] versus NSAID, and 3.31 (1.17-9.34) and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID.

Documents

Study, other information

Abstract Results_MTZ_AGRA_EMA catalog.pdf