Drug-Drug Interactions Between ADHD and Cardiometabolic Medications: a Pharmacovigilance Study

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Hypothesis generation (including signal detection)

  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Case-control

Study drug and medical condition

• Name of medicine, other:
  ADHD medications including methylphenidate, amfetamine, dexamfetamine, lisdexamfetamine, atomoxetine and guanfacine.

Population studied

• Short description of the study population:
  In the first step, we screened for drug–drug interaction (DDI) signals from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the European Medicines Agency’s EudraVigilance database.; In the second step, we examined the prevalence of concurrent ADHD and cardiometabolic medication use with potential DDIs among ADHD medication users in Australia (residents in the state of New South Wales, MedIntel Data Platform), Denmark and Sweden (linkage of national health registers), as well as the US (federated EHR from the TriNetX Research Network database).
• Age groups:
  • Paediatric Population (< 18 years)

    • Neonate

      • Preterm newborn infants (0 – 27 days)
      • Term newborn infants (0 – 27 days)
    • Infants and toddlers (28 days – 23 months)
    • Children (2 to < 12 years)
    • Adolescents (12 to < 18 years)
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)

Study design details

• Main study objective:
  First, we screened for drug–drug interaction (DDI) signals from the FAERS and the EudraVigilance database.; Second, we examined the prevalence of concurrent ADHD and cardiometabolic medication use with potential DDI among ADHD medication users in four countries.
• Data analysis plan:
  We analyzed individual case safety reports (ICSRs) from two pharmacovigilance databases: FAERS (2004-2024) and EudraVigilance (2002-2024). Both systems collect post-marketing reports submitted by healthcare professionals, patients, and marketing authorization holders. The reference set comprised reports that included at least one ADHD medication during the study period. ADHD medication was defined using WHO ATC codes and included methylphenidate (N06BA04), amphetamine (N06BA01), dexamfetamine (N06BA02), and lisdexamfetamine (N06BA12), atomoxetine (N06BA09) and guanfacine (C02AC02). Cardiometabolic medications were defined as agents within ATC groups C (cardiovascular system), A10 (drugs used in diabetes), and B01 (antithrombotic agents). Serious outcomes were defined in FAERS as: death; life-threatening event; hospitalization (initial or prolonged); disability; congenital anomaly; required intervention to prevent permanent impairment or damage; and other medically important condition. In EudraVigilance, serious outcomes included: death; life-threatening event; hospitalization (initial or prolonged); disability; congenital anomaly; and other medically important condition. Potential DDI signals were screened using three disproportionality methods—reporting odds ratio (ROR), proportional reporting ratio (PRR), and the Bayesian confidence propagation neural network (BCPNN) - computed independently in each database.; We applied a common, preregistered protocol to assess the real-world prevalence of the identified DDI pairs in four countries (Australia, Denmark, Sweden, and the United States). For each calendar year, we calculate the prevalence of concurrent use of ADHD and cardiometabolic medication associated with DDIs identified in the first step among ADHD medication users.