Neonatal Formulations and Additives

Allegaert, Karel; Turner, Mark A.; Anker, John N. van den

doi:10.1159/000365021

Cited by 3 publications

(3 citation statements)

References 67 publications

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“…The manufacturer is obliged to specify potentially problematic additives in the SmPC, 37 but it is ultimately up to the neonatologist to interpret the risk. Severe toxicity syndromes may occur due to the physiological immature clearance pathways in neonates 14,38,39 . In addition, the exact content of additives is rarely stated in the SmPC, just as threshold values are unknown for most additives 27,40 .…”

Section: Discussionmentioning

confidence: 99%

“…Severe toxicity syndromes may occur due to the physiological immature clearance pathways in neonates. 14,38,39 In addition, the exact content of additives is rarely stated in the SmPC, just as threshold values are unknown for most additives. 27,40 To make matters worse, there is great variation in the use of additives from manufacturer to manufacturer, and even within medicines products with origin from the same manufacturer, e.g.…”

Section: Potentially Pernicious Additivesmentioning

confidence: 99%

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Massive presence of off‐label medicines in Danish neonatal departments: A nationwide survey using national hospital purchase data

Gade

Trolle

Mørk

et al. 2022

Pharmacology Res & Perspec

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There is currently insufficient knowledge of gestational age dependent medicine disposition in neonates. Accordingly, the use of off-label medication, i.e., use of medicines outside its approved marketing authorization, is high in the neonatal departments. By using data from the Danish National Pharmaceutical Hospital Purchase Database, we identified the most commonly occurring medications and calculated the on/off-label ratios for premature and term neonates. Data was extracted on ATC level 5 and based on defined daily doses as per WHO. Data covered the 4 high-level NICUs and 10 of 13 of the intermediate/standard level Danish neonatal departments. Of the identified medication, 87% and 70% did not have approved marketing authorization for use in premature and full-term neonates, respectively. Furthermore, one-fifth of the top 100 medicines did not have a (Danish) marketing license. Overall, off-label medication was widespread covering virtually all ATC groups and no ATC group had an off-label level lower than 50% (range 50%-100%). Finally, in 21% of medications, additives from 8 different chemical groups with potential deleterious effects for neonates were identified. In conclusion, off-label medication in the Danish neonatal departments is widespread. The pharmaceutical industry is unlikely to solve this problem, and we may for a very long time be occasionally forced to use off-label medication. Practical solution must therefore come from multidisciplinary clinical and academic collaboration. Use of formulation list as guidance for prescriptions and NICU-friendly galenic formulations may mitigate the problem temporarily while waiting for definitive studies.

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Section: Discussionmentioning

confidence: 99%

Section: Potentially Pernicious Additivesmentioning

confidence: 99%

Massive presence of off‐label medicines in Danish neonatal departments: A nationwide survey using national hospital purchase data

Gade

Trolle

Mørk

et al. 2022

Pharmacology Res & Perspec

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“…O Álcool Benzílico pode ser usado tanto como solubilizante, como conservante; o Propilenoglicol é utilizado como solvente e umectante (Golightly et al, 2012); e o Etanol é usado como solvente e preservativo (Christiansen, 2015). Todos eles são considerados excipientes perigosos para a saúde do neonato, e, desta forma, é importante apontar para a necessidade do desenvolvimento de medicamentos sob medida para esta faixa de idade (Allegaert, Turner & Van Den Anker, 2015).…”

Section: Excipientes Alcoólicos Administrados a Neonatosunclassified

Medicamentos Com Excipiente Alcoólico Administrados a Neonatos No Sistema De Saúde Brasileiro

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The Cumulative Daily Tolerance Levels of Potentially Toxic Excipients Ethanol and Propylene Glycol Are Commonly Exceeded in Neonates and Infants

Valeur

Hertel

Lundstrøm

et al. 2018

Basic Clin Pharma Tox

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Polymedicated neonates and young infants may be at risk of harmful cumulative exposure to toxic excipients like ethanol, propylene glycol and benzyl alcohol during routine clinical care. The aim of this study was to calculate the cumulative daily alcohol exposure (mg/kg/day) in polymedicated neonates and infants and compare these levels to the tolerance limits found in guidelines published by European Medicines Agency (EMA). As part of the SEEN study, all medicinal products administered to neonates and infants were recorded. All included neonates received ≥2 medicinal products/day and infants ≥3 medicinal products/day. Daily excipient levels were calculated based on quantities obtained from manufacturers or databases. Excipient levels were compared to tolerance limits proposed by the EMA. Altogether, 470 neonates and 160 infants were included, recording 4207 prescriptions and 316 products. In total, 45% (n = 288) of patients were exposed to an alcohol of interest; 2% (n = 14) were exposed to benzyl alcohol (BA), 38% (n = 237) to ethanol and 23% (n = 146) to propylene glycol (PG). Of the total number of prescriptions involving ethanol-containing medicinal products (n = 334), 51% would alone exceed tolerance limit of 6 mg/kg/day. Of the total number of prescriptions involving PG-containing medicinal products (n = 174), 70% would alone exceed a maximum tolerance limit of 50 mg/kg/day. Maximal daily exposure to ethanol (1563 mg/kg/day) or PG (954 mg/kg/day) exceeded the tolerance limits recommended by EMA 260.5 and 19.1 times, respectively. Tolerance limits for ethanol and PG as proposed by the EMA are frequently exceeded in polymedicated neonates and infants due to the cumulative effect of these alcohols. Alternative formulations may minimize excipient exposure.

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Neonatal Formulations and Additives

Cited by 3 publications

References 67 publications

Massive presence of off‐label medicines in Danish neonatal departments: A nationwide survey using national hospital purchase data

Massive presence of off‐label medicines in Danish neonatal departments: A nationwide survey using national hospital purchase data

Medicamentos Com Excipiente Alcoólico Administrados a Neonatos No Sistema De Saúde Brasileiro

The Cumulative Daily Tolerance Levels of Potentially Toxic Excipients Ethanol and Propylene Glycol Are Commonly Exceeded in Neonates and Infants

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