Table 1.

A summary of studies comparing adverse reactions to acetaminophen and ibuprofen in children

Reference	Type and Aim of the study	Methods	Keys results	Adverse events
Southey ER, 2009 [7]	Systematic review and meta- analysis of the clinical safety and tolerability of ibuprofen compared with acetaminophen in pediatric pain and fever	MEDLINE, Embase, Cochrane library	24 RCT examinated either ibuprofen and acetaminophen versus placebo for AE data. No significant difference between two group	Hepatic injury, gastrointestinal symptoms
AIFA Pediatric working group. 2010 [8]	Recommendations by the pediatric working group of AIFA on caution to use NSAID in children		About ibuprofen, the reports the reporting rate of RA reached 1.7 × 100,000 pediatric packages in 2010.	Acute renal failure (interstitial nephritis), rash, enterorrhages, GI bleeding
Bianciotto M, 2012 [9]	A case-control study on drug use and upper gastrointestinal complications in children	This study is part of a large Italian prospective multicentre study. The study population included children hospitalised for acute conditions through the emergency departments of eight clinical centres. Patients admitted for UGIC	Paracetamol showed a lower risk (adjusted OR 2.0, 95% CI 1.5 to 2.6) compared to ibuprofen (adjusted OR 3.7, 95% CI 2.3 to 5.9	NSAIDs, oral steroids and antibiotics, even when administered for a short period, were associated with an increased risk of UGIC.
Lee WJ, 2014 [10]	Observational study to describe the suspected medications and their AEs in children	All cases FDA adverse event reporting system (FEARS)	AEs report of the top 20 drugs: ibuprofen 72,3%, acetaminophen 68.8%	Gastrointestinal symptoms
Playne R, 2018 [11]	A randomized, single-blind, parallel group trial to evaluate safety of a paracetamol/ibuprofen fixed-dose combination in children	multicenter, randomized, single-blind, parallel group trial, 251 children aged 2–12 years undergoing day‐stay (adeno)tonsillectomy were randomized to two dose groups of the fixed-dose combination	The combination was well tolerated by both groups.	The most common adverse events were vomiting and nausea.
Tan E, 2020 [12]	Systematic review and meta- analysis to compare acetaminophen and ibuprofen for treatment of fever and pain in children younger than 2 years	All published studies from any health care setting or country that compared use of acetaminophen and ibuprofen in children with pain or fever	Very low rates of adverse events reported across all studies (kidney impairment, hepatotoxicity, asthma)	Uncomon. Acetaminophen and ibuprofen have similar serious adverse event profiles. Equivalent safety
Martinelli M. 2021 [13]	A national survey among Italian pediatricians about indications and adverse events of ibuprofen in children	Specific questionnaire-form regarding the management of ibuprofen therapy in children was distributed among a sample of pediatricians all over the Italian territory	Sixty-three (35%) out of 181 participating pediatricians reported 191 adverse events during ibuprofen administration.	GI bleeding being reported in 15.7%, epigastric pain in 15.1%, non-specified abdominal pain in 11.1% and nausea/vomiting in 11%. Severe adverse events including kidney damage (3.1%), complicated infections (0.5%), pneumonia associated empyema (0.5%), soft tissue infection (0.5%) and disseminated intravascular coagulation (0.5%)
Quaglietta L,2021 [14]	A narrative review in the era of COVID-19 pandemic on serious infectious events and ibuprofen administration in pediatrics	A literature search was performed including Medline- PubMed database	Ibuprofen should not be recommended for chickenpox management. Due to possible higher risks of complicated pneumonia, we suggest caution on its use in children with respiratory symptoms	Acute renal failure (interstitial nephritis), rash, enterorrhages, GI bleeding
Paul IM, 2021 [15]	Narrative review on acetaminophen and ibuprofen in the treatment of pediatric fever	Pubmed and Embase literature database to identify relevant articles.	Antypiretic effects of ibuprofen and acetaminophen are similar	No significant differences in rates of AEs between both group
Pelliccia V, 2022 [16]	Observational study to evaluate the ADRs of acetaminophen and ibuprofen over 15 years	Reporting database by AIFA (Pharmacolovigilance of the italian Drug Agency)	Acetaminophen ADRs in children were 15% of cases. Ibuprofen Pediatric ADRs were 26%	Skin and soft tissue in 63% of cases, gastrointestinal tract 47,5%, liver and kidney injury (6,7% and 2.3%)
Ziesenitz V.C. 2022 [17]	A comprehensive review of the literature of the past 20 Years on efficacy and safety of NSAIDs in infants	Summarizes the current knowledge on the safety and efficacy of various NSAIDs used in infants for which data are available,	Adverse drug reactions may be renal, gastrointestinal, hematological, or immunologic. even in young infants.
Marano M. 2023 [18]	Retrospective study to analyze all the patients who contacted pediatric poison control center (PPCC) OPBG in Rome after exposure to acetaminophen and ibuprofen	Retrospectively reported the clinical data of children with accidental or intentional intake of inappropriate doses of acetaminophen/ibuprofen	Adverse event in 10% of cases with similar incidence in both group. A higher frequency of moderate intoxication in patient who took acetaminophen.	Neausea end vomiting most commonly reported.
Leitzen S,2023 [19]	Study to Compare Reports Collected in a Pharmacovigilance Project Versus Spontaneously Collected ADR Reports about ADR drug in children	systematically collected ADRs in the KiDSafe project and the spontaneous reports from EudraVigilance,	Reports from both data sources contributed to the identification of ADRs and dedicated issues related to drug therapy.
Parri N. 2023 [20]	To evaluate the ADR to combination of paracetamol and ibuprofen in children		Safety profile is good	Nausea, vomiting, GI bleeding 4,4%
Castagno E, 2024 [21]	Paracetamol and ibuprofen combination for the management of acute mild‑to‑moderate pain in children: expert consensus using the Nominal Group Technique (NGT)	An investigation using the Nominal Group Technique was carried out between May and August 2022	The board achieved a final consensus on a better analgesic power of paracetamol and ibuprofen in fixed- dose combination as compared to monotherapy, without compromising safety.	no