Manfred Hauben1,2, Stephen Bai3, Eric Hung4, Kasia Lobello5, Charles Tressler5, Vincent P Zucal5. 1. Worldwide Safety and Regulatory, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA. manfred.hauben@Pfizer.com. 2. Department of Medicine, NYU Langone Health, 550 First Avenue, New York, NY, 10016, USA. manfred.hauben@Pfizer.com. 3. Clinical Pharmacology, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA. 4. Worldwide Safety and Regulatory, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA. 5. Safety Surveillance and Risk Management, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA.
Abstract
PURPOSE: Acetaminophen (APAP) is available over-the-counter and widely regarded as safe for use in pregnancy. APAP has been used to close a persistently patent ductus arteriosus. Fetal constriction/closure of the ductus arteriosus (FCCDA), of public health interest given the drug's widespread use during pregnancy, is being monitored globally, including by the European Medicines Agency Pharmacovigilance Risk Assessment Committee. Our objective was to share a comprehensive signal evaluation of FCCDA with in utero APAP exposure to determine if the totality of evidence is sufficiently more consistent with one of the following two possibilities: (1) APAP never contributes to FCCDA (null hypothesis or HO) versus (2) APAP may in some cases be at least a contributory cause of in utero DA narrowing (alternative hypothesis or HA) to justify risk communication. METHODS: To assess the relative support for HO versus HA, we synthesize and interpret within an Austin Bradford Hill criteria framework a comprehensive, cross-disciplinary set of published information and de novo analysis, including toxicology, epidemiology, clinical pharmacology, and clinical and quantitative pharmacovigilance analysis of spontaneous reports. RESULTS: While residual uncertainty remains, the totality of information is more compatible with HA than H0, to the extent that it is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA. CONCLUSION: It is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA, and this should therefore be communicated to stakeholders. TRIAL REGISTRATION: CLINICALTRIALS. GOV REGISTRATION: NOT APPLICABLE.
PURPOSE:Acetaminophen (APAP) is available over-the-counter and widely regarded as safe for use in pregnancy. APAP has been used to close a persistently patent ductus arteriosus. Fetal constriction/closure of the ductus arteriosus (FCCDA), of public health interest given the drug's widespread use during pregnancy, is being monitored globally, including by the European Medicines Agency Pharmacovigilance Risk Assessment Committee. Our objective was to share a comprehensive signal evaluation of FCCDA with in utero APAP exposure to determine if the totality of evidence is sufficiently more consistent with one of the following two possibilities: (1) APAP never contributes to FCCDA (null hypothesis or HO) versus (2) APAP may in some cases be at least a contributory cause of in utero DA narrowing (alternative hypothesis or HA) to justify risk communication. METHODS: To assess the relative support for HO versus HA, we synthesize and interpret within an Austin Bradford Hill criteria framework a comprehensive, cross-disciplinary set of published information and de novo analysis, including toxicology, epidemiology, clinical pharmacology, and clinical and quantitative pharmacovigilance analysis of spontaneous reports. RESULTS: While residual uncertainty remains, the totality of information is more compatible with HA than H0, to the extent that it is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA. CONCLUSION: It is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA, and this should therefore be communicated to stakeholders. TRIAL REGISTRATION: CLINICALTRIALS. GOV REGISTRATION: NOT APPLICABLE.
Entities:
Keywords:
Acetaminophen; Drug exposure; Fetal ductus arteriosus closure; In utero; Signal evaluation
Authors: Marc Gewillig; Stephen C Brown; Luc De Catte; Anne Debeer; Benedicte Eyskens; Veerle Cossey; Dominique Van Schoubroeck; Chris Van Hole; Roland Devlieger Journal: Eur Heart J Date: 2009-04-23 Impact factor: 29.983