To the best of our knowledge this is the first study looking at the excipients in medicines given to an unselected group of hospitalised neonates. We describe the presence of over a hundred different excipients and demonstrate that almost all drugs used in neonates (including those licensed for neonates) contain at least one potentially harmful excipient. The safety of the majority of these excipients in neonates is not easily assessable as the information in the SPCs is scarce and published studies on the topic are rare. The fact that over a third of excipients present in medicines are known or suggested to be potentially harmful to neonates is even more worrisome.
As we are not aware of any validated classification of excipients in terms of neonatal safety and tolerability, we created a tentative classification for the study purposes in which all administered excipients were divided into the categories by conducting a literature search. As a result we show, that in addition to excipients known to cause harm (e.g. propylene glycol, ethanol etc.), many other excipients (e.g. sodium metabisulfite and colloidal anhydrous silica) could possess some safety concerns to neonates as they have been found to be harmful in older children and adults (Table
The proportion of medicines containing potentially harmful excipients in our study (68%) is higher than the one recently published by van Riet-Nales et al.
] in the Netherlands (52% of oral liquid formulations and 7% of all parenteral products). This difference is most likely explained by the methodological variations, regional characteristics in marketed product ranges and by differences in classifying excipients into the toxicity categories. In the Dutch study only “known to be toxic” excipients were taken into the analysis while in our study a very conservative approach was taken and the excipients were classified into the “potentially harmful” category even if only some data on human toxicity had been published (also when used as a substance) as one could not assure that the same agent does not cause any harm when used in small quantities as an excipient. However, we declare that all classifications without clear data from appropriately designed studies are hypothetical.
The use of excipients is unavoidable. Some can be found in food and WHO has set an acceptable daily intake for several of these. Nevertheless the amount of excipients in drug formulations is rarely reported in the SPCs making the evaluation of precise exposure and assessment of true harmfulness of these substances to neonates impossible. Investigators have requested information about exact excipient amounts from the manufacturers
], but this is very time-consuming and does not allow a large number of medicines to be investigated. Whilst the FDA provides an online database of excipient concentrations in licensed medicines, it does not identify the marketed medicinal products for confidentiality reasons (
; last accessed 14th
January 2012). The limits on data about excipients are exemplified by the 24 products (22% of the total used), which were not officially registered in Estonia or through the centralised EU mutual recognition agreement. These medicines were imported to Estonia according to the ad hoc
approval of the Estonian State Agency of Medicines. The list of these drugs included parenteral phenobarbital, petidine and sodium oxybutyrate. The SPCs of most of these products could not be accessed, as they did not have European SPCs. The lack of quantitative data despite considerable effort to obtain information from the manufacturers means that our results may underestimate the extent of excipient exposure in these patients. However, this does not affect our conclusions. We suggest that quantitative information about high-risk excipients should be made available to pharmacists and physicians working with neonates.
Despite the lack of quantitative information, it could be that even if the excipient is known to be harmful, the daily intake will not exceed the toxic threshold due to the small quantities used in drug formulations. For example, from using a parenteral gentamicin product, a premature infant weighting 500
g and receiving a daily dose of 2
mg gets a maximum of 0.1mcg of parabens (methyl- and propylparahydroxybenzoate, parenteral formulations contain up to 0.75% parabens). When comparing this value to the allowed daily intake of 10
mg/kg body weight in adults it is obvious that the quantities are far below the toxic threshold. However, the fact that in neonates organs and thus the PK pathways are not fully matured may change the situation drastically
]. Furthermore Allegaert et al
. showed recently that a short duration of unintended propylene glycol administration at a median dose of 34
mg/kg over 48
hours was well tolerated by (pre)term neonates
]. At the same time the authors stress that long-term safety of propylene glycol is still not established. We believe that the well-known toxic or potentially harmful excipients need careful safety assessment and determination of PK/PD profiles in neonates.
It has been stated that certain colouring and flavouring agents such as erythrosine (cherry-pink dye) need to be avoided in children
]. This study also found that the SPC description of 15 excipients was too unspecific to allow a safety evaluation. Many of these excipients were flavouring agents such as banana flavour, cherry aroma, strawberry, raspberry flavour etc. Without further information in the SPC the safety assessment and critical evaluation of the administration of these agents to neonates is impossible in clinical practice.
We found that the formulation of the most commonly used drug in Estonian neonates, gentamicin, contains well-known harmful excipients – parabens. However a paraben-free gentamicin product is also registered in Europe. With this our data are in line with van Riet-Nales et al.
] who also showed that for 22% of oral liquid paediatric medicines contain potentially harmful excipients an alternative formulation lacking such excipient was available with the same active chemical entity. This indicates that health professionals have a low awareness on safety of excipients. We recommend that when compiling a formulary for the treatment of vulnerable patients such as neonates attention should also be paid to the identification of excipients in medicines.
The most important limitation of our study is the lack of information on the exact amounts of excipients in medicines which precludes us making any conclusions on the real excipient exposure. This limitation was beyond our control because manufacturers do not disseminate this information. The other challenges are the use of a novel and non-validated classification system and restriction of the study to one country only. Also we did not collect information about dosage regimens since this would have been uninterpretable in the absence of quantitative information about the excipient content of the prescribed medicines. Another issue, possibly characteristic of other small markets, was the significant use (22%) of unlicensed medicines and thus unavailability of SPCs. In these cases the excipient content was recorded according to the package insert leaflets. Altough we appreciate that only excipients of intravenous, topical and opthalmic products and known to be toxic excipients have to be declared in the package leaflet, we assume that this will not significally affect our conclusions. Finally the study was conducted in a small country and thus these results cannot be generalised to other countries. These limitations do not undermine our findings that neonates are frequently exposed to a range of potentially harmful and known to be toxic excipients. Many of these limitations will be addressed in a recently commenced international research project, the European Study of Neonatal Excipient Exposure (ESNEE)
], which evaluates the neonatal excipient exposure of over 20 European countries. The aims of the project are to show which excipients are used in formulations given to neonates treated in European hospitals, to conduct a review of toxicological studies on excipients and to investigate excipient kinetics during treatment with commonly prescribed neonatal medicines.