In the 1980s, ten neonatal gasping syndrome and death were reported in a study as a result of toxicity of benzyl alcohol (preservative) used in intravenous solutions [5]. Parabens, ethanol and propylene glycol are other examples of excipients having harmful effects in neonates [1]. Therefore, this study was conducted to assess types and amount of exposure to excipients among neonates in neonatal intensive care unit (NICU).

This prospective observational study was conducted in the NICU of a tertiary care teaching hospital in Bangalore for duration of 2.5 years (January, 2017 to June, 2019) after approval from institutional human ethics committee. Valid consent was given by the parents/guardians of included study subjects who received at least one drug. Neonates dying within 24 hours of birth were excluded. Demographic details (gestational age, birthweight, gender, date of birth, post natal age), length of stay, daily clinical progress of neonates, information about prescribed medicines for all neonates (indication, dose, frequency, route of administration, dosage form and brand names) were recorded. Diagnoses were classified according to ICD-10 (International statistical classification of diseases and related health problems, 10th revision, 2016). Administered drugs were classified according to WHO Anatomical Therapeutic and Chemical (ATC) classification system.

Lists of excipients and their quantities present in each prescribed formulation were collected by referring to package insert leaflets (PIL) of drugs or contacting the manufacturers. Excipients were categorized into four groups as per Lass, et al. [1] viz., (a) known to be harmful to neonates (adverse reactions reported in neonates); (b) potentially harmful (adverse reactions reported); (c) no safety data found (no data found in the literature on human exposure and toxicity); and (d) description of the excipient in PIL non-specific (description does not allow a specific literature search).

Statistical analyses: Daily exposure to excipients (mg/kg/day) were calculated based on available data on quantity of excipients in formulations, and were compared with acceptable daily intake (ADI) [6-8] for those which data of ADI was available.

Of the 790 cases admitted to NICU during the study period, 41 were excluded as they had received only phototherapy (no medications), and 3 babies died within 24 hours of birth. The baseline characteristics of 746 included neonates are described in Table I. The most frequent diagnoses were respiratory distress of newborn, neonatal sepsis and congenital heart disease.

Table I Characteristics of Neonates (N=746)

The total number of prescribed drugs was 5535, and 77 different drugs were given. Systemic anti-infectives, blood and blood forming organs, and alimentary tract and metabolism class were the most commonly prescribed classes of drugs. Intravenous (49, 63.6%) and oral (18, 23.3%) were the most common routes of administration.

The qualitative and quantitative information on excipients were available only for 35 and 15 drugs, respectively. Total of 27 different excipients were identified. Of all excipients, 4 (14.8%) and 10 (37%) were grouped under category a and category b, respectively. These excipients were present in 26% (20/77) of prescribed formulations, details of which, including safety concerns [1,6,9], are given in Table III. It was found that the highest proportion of above mentioned excipient were present in systemic anti-infectives.

Table II Amount of Exposure to Excipients in Neonates (N=746)*

Emulsifier 472 C was the only identified excipient of category c. Remaining excipients (8, 29.6%) including yellow and red oxides of iron, caramel colour and flavours were classified under category d. Daily exposure to excipients of 8 injections (vitamin K, adrenaline, amikacin, gentamicin, dexamethasone, heparin, midazolam and ranitidine), oxymetazoline hydrochloride nasal solution and paracetamol syrup were assessed and compared to ADI (table II).

Table III Classification of Excipients to Which Neonates were Exposed*

This study on qualitative and quantitative excipient exposure among hospitalized neonates in India found that 86.9% and 53.8% of neonates were exposed to at least one excipient known to be harmful or potentially harmful, respectively. Previous studies conducted in Brazil and Estonia found that almost all neonates were prescribed drugs containing at least one harmful excipient [1,3]. We found that harmful and potentially harmful excipients were present in formulations that were administered frequently and simultaneously. Hence neonates could be at greater risk of toxic effects. Similarly, Fister, et al. [10] reported that 51.6% of added excipients in formulations were potentially harmful and harmful ones.

Coloring agents (ponceau 4R, sunset yellow FCF, erythrosine and titanium dioxide) present in oral dosage forms were included in potentially harmful category. Regulatory status on colorants in different countries are not similar; in the European union, medicines containing sunset yellow and ponceau 4R must carry warning label concerning possible allergic reactions [6]. In our study, Ponceau 4R was most frequently observed colorant, though its use is banned in some countries due to its effect on neurocognitive development and behavior [2].

The use of category a or b excipients in intravenous/oral formulations was much lesser in our study than findings of Lass, et al. [1]. However, in another study carried out in Spain [11], 32% of intravenous formulations and 62% of oral formulations contained at least one harmful excipient. These differences can be explained by the availability of information of excipients present in formulations in different countries. We found high rates of exposure (higher than ADI) to sodium metabisulphite and sunset yellow FCF. Similar findings were reported by Akinmboni, et al. [12] that 11% of neonates were exposed to a higher amount of an excipient than the FDA/WHO recommended adult dose.

Daily exposure to phenol (in ranitidine injection) was within the adult ADI range. However, literatures show that use of ranitidine in very low birth weight neonates can increase incidence of necrotizing enterocolitis, mortality and infection [13]. Safety concern regarding use of ranitidine was reported to the neonatologist. Daily exposure to benzyl alcohol did not exceed the adult ADI. However, as per FDA recommendation and label of the heparin injection, benzyl alcohol containing formulations should not be used for neonates and premature infants due to risk of fatal toxic syndrome in neonates [6,14-16]. Unfortunately, 14.5% of neonates were exposed to benzyl alcohol containing formulations. For 12.5% of exposures, alternative preservative free formulation with the same concentration of heparin sodium injection and similar cost was available, which were suggested to the neonatologist. Another study conducted in Netherlands showed that oral liquid medicines without potentially harmful excipient were available for 22% of medicines [17].

An important limitation of the present study was the lack of data on neonatal ADI of excipients due to barriers to conduct such studies. Another limitation was lack of information about list of excipients and their quantities present in each formulation. So, we could not assess the extent of exposure to all excipients of formulations. However, our findings with limited available data show that exposure to harmful excipients is high, and awareness regarding their risks needs to be raised.

Substitution of those medications with excipient (harmful) free formulations, at least in high risk conditions, will avoid unwanted risks. It is also important that manufacturers disclose detailed qualitative and quantitative information of excipients of formulations to clinicians and clinical pharmacists, for risk/benefit assessment of selection of drugs for neonates.

Ethical clearance: VIPS Human Ethics Committee; IEC/2016-14 dated December 09, 2016.

Contributors: SN: collected the data, analyzed the data and wrote the manuscript; NKM: designed, monitored and supervised the study and approved the final manuscript; SB: was the neonatologist who co-supervised the study.

Funding: None; Competing interest: None stated.

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