Causality assessment of adverse drug reactions in neonates: a comparative study between Naranjo's algorithm and Du's tool.

BACKGROUND: Algorithms for causality assessment of adverse drug reactions (ADRs) in a neonatal intensive care unit (NICU) are important in the management of adverse events, however, it is inconclusive which tool best suits pharmacovigilance in neonates. AIM: To compare the performance of the algorithms of Du and Naranjo in determining causality in cases of ADRs in neonates in a NICU. METHOD: This observational and prospective study was conducted in a NICU of a Brazilian maternity school between January 2019 and December 2020. Independently, three clinical pharmacists used the algorithms of Naranjo and Du in 79 cases of ADRs in 57 neonates. The algorithms were evaluated for inter-rater and inter-tool agreement using Cohen's kappa coefficient (k). RESULTS: The Du algorithm showed greater ability to identify definite ADRs (≈ 60%), but had low reproducibility (overall k = 0.108; 95% CI 0.064-0.149). In contrast, the Naranjo algorithm showed a lower proportion of definite ADRs (< 4%), but had good reproducibility (overall k = 0.402; 95% CI 0.379-0.429). The tools showed no significant correlation regarding ADR causality classification (overall k = - 0.031; 95% CI - 0.049 to 0.065). CONCLUSION: Although the Du algorithm has a lower reproducibility compared to the Naranjo, this tool showed good sensitivity for classifying ADRs as definite, proving to be a more suitable tool for neonatal clinical routine.

Drug-drug interactions in neonatal intensive care: A prospective cohort study.

BACKGROUND: To characterize the prevalence and profile of drug-drug interactions (DDIs), the drugs most related to major DDIs and risk factors of their prescription in a neonatal intensive care unit (NICU). METHODS: Neonates admitted to a NICU who had at least one medication prescribed and a hospital stay >24 h were included in a prospective cohort study (August 2017 to July 2018). All medications prescribed during the hospitalization were collected from all neonates (n = 220), with the screening for DDIs. Prevalence and type of DDIs was identified. Network analysis was used to identify the drugs more implicated with DDIs. Logistic regression was used for the analysis of risk factors (p < 0.05). RESULTS: Over 70% of neonates were exposed to DDIs and 29% were exposed to major DDIs. The network analysis identified furosemide, fentanyl, aminophylline and fluconazole as most implicated with DDI, fentanyl was especially associated with major DDIs. The number of drugs (OR 1.60, p < 0.01), caesarean delivery (OR 2.68, p < 0.05), gestational age (OR 1.03, p < 0.01) and APGAR score (OR 0.78, p < 0.01) were identified as risk factors for exposure to DDI. CONCLUSION: Neonates in intensive care have a high exposure to DDIs and the occurrence of major DDIs is related specifically to the prescription of fentanyl. The number of prescribed drugs, gestational age, cesarean delivery and low APGAR score in the first minute were identified as risk factors for DDIs in NICU.

[Comparative assessment of off-label and unlicensed drug prescription in neonatal intensive care: FDA versus Brazilian guidelines]. / Evaluación comparativa de la prescripción off-label y unlicensed de fármacos en cuidados intensivos neonatales: Guías de la FDA versus guías brasileñas.

INTRODUCTION: Regulatory agencies are responsible for defining the use of off-label (OL) and unlicensed (UL) drug prescription in neonatal intensive care. However, these regulatory criteria may differ between agencies in different countries. The aim of this study was to establish the frequency of OL and UL drug prescription in a sample of patients in a neonatal intensive care unit applying the criteria of the Food and Drug Administration (FDA) of the United States and the Agência Nacional de Vigilância Sanitária (ANVISA) of Brazil, analysing the differences observed in the results based on the applied criteria. METHODS: Prospective cohort study in neonates admitted for more than 24hours to the neonatal intensive care unit (NICU) of a teaching maternity hospital between August 2017 and July 2018. We obtained information concerning the drugs included in the analysis of OL and UL prescriptions from the DrugDex-Micromedex® and official information on pharmaceutical products in Brazil. We used the kappa correlation coefficient to assess the agreement between the FDA and ANVISA criteria. We defined disagreement as a kappa value of less than 0.200. RESULTS: We evaluated 220 neonates admitted to the NICU and 17,421 items prescribed during the study period. We did not find a difference in the proportion of neonates in which at least 1 drug was prescribed under OL conditions applying the FDA versus the ANVISA criteria (96.4% vs. 98.6%). We found differences between the FDA and ANVISA in the OL classification based on the authorised age of use and indications for prescription, mainly in systemic antimicrobials and cardiovascular drugs. When we compared the prescribing information provided by the FDA and the ANVISA, we found that the criteria of the ANVISA were less specific. CONCLUSIONS: OL and UL drug prescription are frequent in neonatal intensive care applying the criteria of either agency, although the FDA has established more detailed criteria in terms of the ages and indications for which prescription is authorised.

Use of off-label and unlicensed medicines in neonatal intensive care.

PURPOSE: To evaluate the use of off-label and unlicensed medicines in a neonatal intensive care unit (NICU) of a teaching maternity hospital specialized in high risk pregnancy. METHODS: A prospective cohort study was conducted between August 2015 and July 2016. All newborns admitted to the NICU who had at least one medication prescribed and a hospital stay longer than 24 hours were included. The classification of off-label and unlicensed drugs for the neonatal population was done according to the information of Food and Drug Administration. RESULTS: A total of 17421 medication items were analyzed in 3935 prescriptions of 220 newborns. The proportion of newborns exposed to off-label drugs was 96.4%, and to unlicensed medicines was 66.8%. About one-half (49.3%) of the medication items were off-label and 24.6% were unlicensed. The main reason for off-label and unlicensed classification was, respectively, frequency of administration and the administration of adaptations of pharmaceutical forms. CONCLUSIONS: Although there are actions to encourage the development of pharmacological studies with neonates, this study observed a high rate of prescription and exposure of newborns to off-label and unlicensed drugs in NICUs and pointed out areas of neonatal therapy that require scientific investment.

Potential drug incompatibilities in the neonatal intensive care unit: a network analysis approach.

BACKGROUND: There is little information on the frequency of drug incompatibilities in neonatal intensive care units (NICU) and the agents most commonly involved in them. The objective of the study was to characterize potential Drug Incompatibilities (DI) in the NICU by frequency, type and combination of drugs. METHODS: Between August 2015 and December 2016, all neonates admitted for more than 24 h and who received any drug treatment were included in this cohort study conducted in the NICU of a teaching maternity hospital in Brazil. Patient data were collected from patient records and prescription orders, and the compatibilities of all drug pairs were classified using the Trissel's™ 2 IV Compatibility tool. Network analysis was performed in order to visualize the drug pairs commonly involved in potential DI. RESULTS: The study population consisted of 281 neonates with a median NICU length of stay of 11 days (range 2-184) and received 1343 intravenous medications. A total of 1114 potential DI were identified, 469 (42.1%) were restricted compatibilities, 348 (31.2%) unknown compatibilities and 297 (26.7%) documented incompatibilities. The incidence of documented incompatibilities in the NICU was 25.0% patient-days (95% confidence interval (CI) 19.4-30.7% patient-days). Incompatible potential DI affected 46.3% (95%CI 40.3-52.3%) of the neonates. Ampicillin (408 of 1114 pairs), gentamicin (216 of 1114 pairs) and aminophylline (197 of 1114 pairs) were the main medicines involved in potential DI. CONCLUSION: Potential DI are extremely common in NICU, with half of the population susceptible to simultaneous administration of incompatible medications. More research is needed to understand the actual drug incompatibilities and their clinical outcomes.

Oral exposure to cylindrospermopsin in pregnant rats: reproduction and foetal toxicity studies.

Cylindrospermopsin (CYN) induces toxicity in pregnant mice when administered intraperitoneally. This study investigated whether oral exposure to CYN (0.03, 0.3 and 3 µg/kg) during pregnancy causes toxic effects and impairs gestation in rats. The results of reproductive performance and teratology studies were similar between the control and experimental dams. Our findings suggest that CYN consumption within the guideline values for drinking water is not able to promote foetal toxicity or alterations in rat reproductive performance.