Dihydropyrimidine dehydrogenase deficiency related toxicities to fluorouracil and fluorouracil related substances containing medicinal products - EudraVigilance analysis and literature review

Study type

• Study topic:
  Human medicinal product

  Disease /health condition
• Study type:
  Non-interventional study
• Scope of the study:
  Other
• If ‘other’, further details on the scope of the study:
  Case series review of Pharmacovigilance Data
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Other
• Non-interventional study design, other:
  Case-series, Probabilistic phenotyping with Machine Learning

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  FLUOROURACIL

  CAPECITABINE

  TEGAFUR

  FLUCYTOSINE
• Medical condition to be studied:
  Dihydropyrimidine dehydrogenase deficiency
• Additional medical condition(s):
  Dihydropyrimidine dehydrogenase deficiency related toxicity

Population studied

• Short description of the study population:
  Case reports to fluorouracil and related substances in EudraVigilance that could have resulted from dihydropyrimidine dehydrogenase deficiency (DPD).
• Age groups:
  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)

  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:
  126890

Study design details

• Main study objective:
  To identify and describe case reports to fluorouracil and fluorouracil related substances and, To identify and characterise case reports to these products where dihydropyrimidine dehydrogenase deficiency (DPD) was also reported.
• Data analysis plan:
  Descriptive statistics was performed by substance, age, gender, indication for use, origin of reports, reaction and outcome for all case reports. Cases were highlighted according to whether they refer to a DPD patient or mention any term within the toxicity spectrum. Where feasible, boxplots of time to onset were plotted and stratified by product and indication for use. In addition, the proportion of cases with life-threatening or fatal reactions amongst DPD patients and those with DPD toxicity spectrum reactions was compared as were the proportions of cases with immediate (1 - 2 days), short (3 – 21 days) and long (> 21 days) time-to-onset for DPD patients and those with DPD toxicity spectrum reactions. To estimate the number of likely DPD related cases, machine learning models were be run deployed. These identify patterns in the terms reported to DPD patients and detect similar patterns in cases were DPD status is unknown.