Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Education & Practice Online First, published on August 21, 2014 as 10.1136/archdischild-2013-305671 PHARMACY UPDATE
Ethanol exposure through medicines commonly used in paediatrics Nanna Christiansen Correspondence to Nanna Christiansen, Pharmacy Department, Barts Health NHS Trust, 80 Newark Street, London E1 2ES, UK; nanna.christiansen@bartshealth. nhs.uk Received 17 January 2014 Revised 18 June 2014 Accepted 28 July 2014
To cite: Christiansen N. Arch Dis Child Educ Pract Ed Published Online First: [ please include Day Month Year] doi:10.1136/archdischild2013-305671
INTRODUCTION Medicines for children provide many challenges for paediatricians, pharmacists and other healthcare professionals. Many drug preparations available are not specifically adapted for administration in children, resulting in a lack of suitable dosage forms and formulations available. Excipients used when formulating drug preparations have often only been evaluated for safety in the adult population and, in some cases, may be harmful in neonates and children. Although the European Union (EU) Paediatric Regulation came into place in 2006 with the aim of improving the availability of licensed medicines for children, many drugs prescribed for neonates and children are still not licensed in these age groups. As a result, the use of unlicensed and off-label medication is common1 and manufacturers have little incentive to ensure that the preparations and their excipients can be safely given to children. The aim of this article is to explain the role of alcohol as an excipient and assess the information available on the impact of alcohol as an excipient on babies and children. It will also look at what medicines are particularly problematic, where information on alcohol content can be found and look at work in progress to address the issues around excipient use in paediatric formulations. EXCIPIENTS USED Excipients are constituents of a pharmaceutical form that are not the active substance and are supposedly inert. Medicines usually contain a wide range of excipients in their formulations for a variety of reasons; they are used as colouring, antioxidants, preservatives, stabilisers, thickeners, emulsifiers, solubilisers, permeation enhancers and flavouring. As well as the active drug in a medicine, the use of excipients is also regulated.2
The Committee for Medicinal Products for Human Use guideline on excipients states that the ‘excipients to be used in formulations for the paediatric population should be selected with special care and possible sensitivities of the different age groups should be taken into consideration’.2 Despite this many paediatric preparations that where licensed prior to the new EU Paediatric Regulation contain excipients that are no longer recommended for use in children.3 4 Similar findings have been described in the USA.5 An additional problem is that the available safety data for excipients are often drawn from adult data,3 and, therefore, information pertaining to suitability and safety of excipients for neonates and children is often missing.6 This is important as babies and children are particularly vulnerable to adverse reactions owing to organ immaturity and differences in pharmacokinetic and pharmacodynamic profiles compared with adults. The toxicity of excipients may, therefore, differ between adult and paediatric patients as well as across the paediatric subset. A study in hospitalised neonates concluded that 97% of neonatal patients received at least one medicine containing a potentially or known to be harmful excipient.3 Similar results were found in two other studies; patients were receiving a wide range of potentially harmful excipients, such as ethanol, propylene glycol (PG), sorbitol, benzyl alcohol and others, through their medicine.7 4 Poly-pharmacy increases the probability of common excipients exceeding safe threshold levels potentially putting patients at an increased risk. ETHANOL AS AN EXCIPIENT AND ITS EFFECTS IN THE NEONATE AND CHILD One of the excipients understood to be harmful, particularly in neonates, is ethanol.
Christiansen N. Arch Dis Child Educ Pract Ed 2014;0:1–4. doi:10.1136/archdischild-2013-305671 1 Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.
Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Pharmacy update It is found in many oral liquid preparations and is incorporated for technical reasons as it acts as a solvent and a preservative. Three enzymes are attributed to metabolise ethanol in adults: alcohol dehydrogenase (ADH), microsomal ethanol oxidising system and catalase with ADH being the predominant pathway. Little data are available in regards to neonates and children. Available data suggest that the ADH content in perinatal neonates is significantly lower than in adults with catalase activity in some cases being higher and possibly having some compensatory effect.8 The harmful effects of maternal alcohol consumption resulting in severe central nervous system (CNS) abnormalities and neurodevelopmental impairments, known as foetal alcohol syndrome, are well understood;9 however, little data on the neurodevelopmental impact of alcohol exposure are available for preterm or term neonates. Effects of alcohol ingestion through breastmilk have been investigated in infants and a detrimental effect on psychomotor function has been reported.10 However, these findings could not be replicated in a later study.11 For children, the toxicity data for chronic and acute ethanol exposure are very limited. There are data to suggest that clearance in acutely intoxicated children is similar to adults,12 but adverse reactions are expected to appear at much lower concentrations.13 Regrettably, no data are available on the effect of chronic alcohol exposure in children. EXPOSURE TO ETHANOL THROUGH DRUG FORMULATIONS Published information on exposure of ethanol in neonates and children through medicines is limited. Two studies in Italy found14 15 many commercially available preparations that have the potential to deliver significant amounts of alcohol. With respect to the UK, two studies were conducted in neonatal services. Whittaker et al4 examined the exposure with eight oral liquid formulations and found that infants were exposed to 20 different excipients. Ethanol was found in several of the medications including commonly used ones such as iron and furosemide. This resulted in a significant ethanol exposure to infants, ranging from 0.11 to 0.70 g/kg/week, equivalent to 1–7 units in a 70 kg adult. For adults, the recommended safe weekly limit for ethanol is currently 14 units for women and 21 units for man. Another study16 that looked solely at alcohol exposure through medication in neonates found that 14 formulations routinely stocked on the neonatal intensive care unit contained alcohol. Two of these contained around 10% v/v of ethanol, furosemide and ranitidine liquid preparations. The most commonly encountered were chlorothiazide and ranitidine liquid preparations. Ethanol exposure ranged from 6 to 280 mg/kg/week. This would be equivalent to a 70 kg adult receiving up to 2.5 units/week. The study also looked at possible
2
alternative preparations; however, for most drugs, it was not possible to find suitable alternative preparations. A similar picture emerges from a study undertaken on a paediatric intensive care unit in the UK,17 which included patients up to the age of 15 years. Here ethanol exposure ranged from 0.07 units to 15.2 units per week calculated as adult equivalent with a median of 1.4 units/week. The most frequently prescribed alcohol containing formulations were liquid preparations of nystatin, ranitidine, furosemide and morphine. Again, it was not possible to find commercially available alcohol-free alternatives for most of these. In addition to the effects of alcohol alone, there has also been a report by the US Food and Drug Administration around the serious health problems that have been caused in neonates following the administration of Kaletra oral solution.18 This preparation contains both ethanol and PG, resulting in reduced PG clearance and hence increased toxicity. All of this only paints a small picture of the overall problem, and it is reasonable to assume that similar problems exist in other countries. Although healthcare professionals need to be aware and acknowledge the risks associated with prescribing preparations containing alcohol, uncertainty continues to surround the identification of safe limits for children and neonates. In 1984, the American Academy of Paediatrics published an article highlighting the importance of removing alcohol from paediatric formulations19 and in cases where this was not possible to provide information explaining the risks. It stipulated that a child’s blood alcohol concentration should not exceed 0.25 g/L after the administration of a single dose. Although these figures were based on adult data and therefore hypothetical for children, it did succeed in persuading many manufacturers to voluntarily reduce the alcohol content in their products.20 The Food and Drug Agency subsequently issued guidance on the alcohol content of oral over the counter (OTC) medication, providing clear guidance on maximum alcohol concentrations for different age groups. For adults and children over 12 years, the maximum alcohol concentration is 10%, for under 12 and under 6 year olds, 5% and 0.5%, respectively.21 This regulation had the aim of reducing unnecessary alcohol exposure to paediatric patients, as well as reducing potential misuse of OTC medicines for their alcohol content.20 The regulation also requires the alcohol content to be prominently shown on the principal display panel. In the UK, this information is not necessarily provided on the packaging but can in some cases be found in the British National Formulary for children, in the patient information leaflet or in the Summaries of Product Characteristics. These are available through the electronic medicines compendium at http://www. medicines.org.uk.
Christiansen N. Arch Dis Child Educ Pract Ed 2014;0:1–4. doi:10.1136/archdischild-2013-305671
Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Pharmacy update More recently, recommendations on ethanol threshold in liquid formulation intended for paediatrics have been published in France. These require the ethanol concentration to be below 5% and/or that the amount of ethanol should not produce blood ethanol concentrations higher than 0.125 g/L after a single dose.13 Although this offers a useful reference point and may prompt the use and development of safer alternatives, it should be borne in mind that ethanol concentration in the range of 0.01–1 g/L has been associated with adverse effects on the CNS in children.22 In adults, impaired concentration and motor coordination have been observed with concentrations in the range of 0.15–0.3 g/L.13 Most recently in January 2014 the European Medicines Agency (EMEA) published a draft for the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’, proposing more detailed information on alcohol content in the patient information leaflet as well as alcohol content thresholds for different age groups.23 CONCLUSION Even though the use of excipients is regulated through the EMEA, babies and children are still exposed to potentially harmful excipients and adequate safety information on excipients used in the paediatric population is often missing. It has been shown that neonates and children in some cases are exposed to considerable amounts of alcohol through their medication. Although information on the effects of acute and chronic alcohol exposure in babies and children is scarce, it could be argued that they should be protected from any potentially harmful effects of alcohol and hence the amount of alcohol in drug formulations should be kept to a minimum. Guidance on maximum limits for ethanol content in paediatric drug formulations is increasing, both in the USA19 21 and the EU.13 23 Improved information about excipient content including alcohol would greatly help healthcare professionals in weighing up the risks and benefits of a medication. The proposed changes in respect to alcohol in the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’23 are a step in this direction and may also encourage manufacturers to reduce the alcohol content. However, given the high rate of unlicensed and offlabel usage of medication in paediatrics, this might only address a proportion of the preparations administered to children. Even with an increase in licensed medication in children following the EU Paediatric Regulation from 2006, the use of unlicensed and offlabel medication is likely to continue. Healthcare professionals will, therefore, continue to be presented with a conundrum: in seeking to provide care they will frequently find themselves in situations where the
only means of avoiding an excipient is to withdraw medication. To improve safety of drug formulations for children and to advance knowledge on the safety and toxicity of excipients in this vulnerable population will require collaboration between manufactures, researchers and healthcare professionals. Against this backdrop, the European Paediatric Formulation Initiative (EuPFI) was founded in 2007 by members from the pharmaceutical industries, hospital and academia interested in formulating better medicines for children. One of the key work streams of the EuPFI aims to address safety issues and problems associated with the excipients likely to be used in paediatric formulations, which is an exciting step forward for developing better paediatric drug formulations. Another Europe-wide project aims to address this problem in the youngest patients, the European Study of Neonatal Exposure to Excipients collaboration. This collaboration aims to develop a range of methodologies providing an integrated assessment of exposure among neonates in Europe to potentially toxic excipients contained in medicines.24
Learning Points ▸ Even though the use of excipients is regulated through the European Medicines Agency, babies and children are still exposed to potentially harmful excipients and adequate safety information on excipients used in the paediatric population is often missing. ▸ Commonly used liquid formulations containing ethanol are nystatin, ranitidine, furosemide, as well as some iron and morphine preparations. Often it is not possible to find commercially available ethanolfree alternatives.
Assessment questions 1. What is an excipient and what role does ethanol play in drug formulations? 2. Why are children more vulnerable to adverse reactions from excipients than adults? 3. What were the most frequently prescribed ethanolcontaining preparations? 4. Where can information on ethanol content of a medication be found? Answers are at the end of the references.
Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
Christiansen N. Arch Dis Child Educ Pract Ed 2014;0:1–4. doi:10.1136/archdischild-2013-305671
3
Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Pharmacy update REFERENCES 1 Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Paediatr 2005;164:552–8. 2 European Medicines Agency. Committee for Medicinal Product for Human Use (CHMP): Guideline on excipients in the dossier for application for marketing authorisation of a medicinal product 2007. CHMP/QWP/396951/2006. 3 Lass J, Naelapää K, Shah U, et al. Hosptialised neonates in Estonia commonly receive potentially harmful excipients. BMC Paediatr 2012;12:136. 4 Whittaker A, Currie AE, Turner MA, et al. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94:F236–40. 5 Strickley RG, Iwatra Q, Wu S, et al. Pediatric drugs—a review of commercially available oral formulations. J Pharm Sci 2008;97:1731–74. 6 European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP): Guideline on pharmaceutical development of medicines for paediatric use EMEA/CHMP/QWP/805880/2012 Rev. 2. 7 Shehab N, Lewis CL, Streetman DD, et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Paediatr Crit Care Med 2009;10:256–9. 8 Tran MN, Wu AHB, Hill DW. Alcohol dehydrogenase and catalase content in perinatal infant and adult livers: Potential influence on neonatal alcohol metabolism. Toxicol Lett 2007;169:245–52. 9 Riley EP, McGee CL. Fetal alcohol spectrum disorders: an overview ewith the emphasis on changes in brain and behaviour. Exp Biol Med 2005;230:357–65. 10 Little RE, Anderson KW, Ervin CH, et al. Maternal alcohol use during breast-feeding and infant mental and motor development at one year. N Engl J Med 1989; 321:425–30. 11 Little RE, Northstone K, Golding J; ALSPAC study Team. Alcohol, breastfeeding and development at 18 month. Paediatrics 2002;109:E72. 12 Simon HK, Cox JM, Sucov A, et al. Serum ethanol clearance in intoxicated children and adolescents presenting to the ED. Acad Emerg Med 1994;1:520–4. 13 European Medicine Agency. Committee on Herbal Medicinal Products (HMPC): Reflection paper on ethanol content in herbal medicinal products and traditional herbal medicinal products used in children. 2010, EMEA/HMPC/85114/2008. 14 Fiocchi A, Riva E, Giovannini M. Ethanol in medicines and other products intended for children: Commentary on a medical parardox. Nutr Res 1999;19:373–9. 15 Zuccotti GV, Fabiano V. Safety issues with ethanol as an excipient in drugs intended for pediatric use. Expert Opin Drug Saf 2011;10:499–502. 16 Jutley H, Christiansen N. Alcohol Exposure in Neonatal Intensive Care Patients. Proceedings of the 19th Neonatal and
4
17
18
19 20
21
22
23
24
Paediatric Pharmacist Group Conference; 8–10 November 2013, London, Great Britain. Issac R, Khan I, Langley C. Ethanol intake of paediatric intensive care patients. Proceedings of the 18th Neonatal and Paediatric Pharmacist Group Conference; 9–11 November 2012, Liverpool, Great Britain. FDA.gov [Internet]. Silver Spring: FDA; 2011 Aug. Drug Safety Communications: Serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution; 2011. [cited 2014 Jun 9]. http://www.fda.gov/Drugs/ DrugSafety/ucm246002.htm Pruitt AW, Anyan WRJ, Hill RM, et al. Ethanol in liquid preparations intended for children. Pediatrics 1984;73:405–7. Food and Drug Administration. Proposed rules—Over the counter drug products intended for oral ingestion that contain alcohol. Rockville, MD: Department of Health and Human Services (US), Food and Drug Administration; 1993. Oct (Federal Register; vol. 58, No202). Docket No.: 93N-0107. Food and Drug Administration. Over the counter drug products intended for oral ingestion that contain ethanol. 2013. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ CFRSearch.cfm?CFRPart=328&showFR=1 European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP): Reflection Paper: Formulations of choice for the paediatric population. EMEA/ CHMP/PEG/194810/2005. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP): Questions and answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medical products for human use.’ EMA/CHMP/507988/2013. Graham S, Turner M. European study of neonatal exposure to Excipients (ESNEE). Infant 2011;6(7):196–9.
Answers to the quiz on the previous page 1. An excipient is a supposedly inert constituent of a drug preparation. Excipients have various roles; in the case of ethanol, it acts as a solvent and preservative. 2. Babies and children are more vulnerable to adverse reactions due to organ immaturity and differences in pharmacokinetic as well as pharmacodynamic profiles of the excipients compared to adults. 3. In the UK these are commonly but not exclusively nystatin, ranitidine, furosemide, some morphine and iron liquid preparations. 4. In the UK, this information can be found in the patient information leaflet or in the Summaries of Product Characteristics and in some cases in the British National Formulary for children.
Christiansen N. Arch Dis Child Educ Pract Ed 2014;0:1–4. doi:10.1136/archdischild-2013-305671
Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Ethanol exposure through medicines commonly used in paediatrics Nanna Christiansen Arch Dis Child Educ Pract Ed published online August 21, 2014
Updated information and services can be found at: http://ep.bmj.com/content/early/2014/08/21/archdischild-2013-305671
These include:
References
This article cites 14 articles, 3 of which you can access for free at: http://ep.bmj.com/content/early/2014/08/21/archdischild-2013-305671 #BIBL
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Topic Collections
Articles on similar topics can be found in the following collections Child health (281) Neonatal health (28) Infant health (44)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Education & Practice Online First, published on August 21, 2014 as 10.1136/archdischild-2013-305671 PHARMACY UPDATE
Ethanol exposure through medicines commonly used in paediatrics Nanna Christiansen Correspondence to Nanna Christiansen, Pharmacy Department, Barts Health NHS Trust, 80 Newark Street, London E1 2ES, UK; nanna.christiansen@bartshealth. nhs.uk Received 17 January 2014 Revised 18 June 2014 Accepted 28 July 2014
To cite: Christiansen N. Arch Dis Child Educ Pract Ed Published Online First: [ please include Day Month Year] doi:10.1136/archdischild2013-305671
INTRODUCTION Medicines for children provide many challenges for paediatricians, pharmacists and other healthcare professionals. Many drug preparations available are not specifically adapted for administration in children, resulting in a lack of suitable dosage forms and formulations available. Excipients used when formulating drug preparations have often only been evaluated for safety in the adult population and, in some cases, may be harmful in neonates and children. Although the European Union (EU) Paediatric Regulation came into place in 2006 with the aim of improving the availability of licensed medicines for children, many drugs prescribed for neonates and children are still not licensed in these age groups. As a result, the use of unlicensed and off-label medication is common1 and manufacturers have little incentive to ensure that the preparations and their excipients can be safely given to children. The aim of this article is to explain the role of alcohol as an excipient and assess the information available on the impact of alcohol as an excipient on babies and children. It will also look at what medicines are particularly problematic, where information on alcohol content can be found and look at work in progress to address the issues around excipient use in paediatric formulations. EXCIPIENTS USED Excipients are constituents of a pharmaceutical form that are not the active substance and are supposedly inert. Medicines usually contain a wide range of excipients in their formulations for a variety of reasons; they are used as colouring, antioxidants, preservatives, stabilisers, thickeners, emulsifiers, solubilisers, permeation enhancers and flavouring. As well as the active drug in a medicine, the use of excipients is also regulated.2
The Committee for Medicinal Products for Human Use guideline on excipients states that the ‘excipients to be used in formulations for the paediatric population should be selected with special care and possible sensitivities of the different age groups should be taken into consideration’.2 Despite this many paediatric preparations that where licensed prior to the new EU Paediatric Regulation contain excipients that are no longer recommended for use in children.3 4 Similar findings have been described in the USA.5 An additional problem is that the available safety data for excipients are often drawn from adult data,3 and, therefore, information pertaining to suitability and safety of excipients for neonates and children is often missing.6 This is important as babies and children are particularly vulnerable to adverse reactions owing to organ immaturity and differences in pharmacokinetic and pharmacodynamic profiles compared with adults. The toxicity of excipients may, therefore, differ between adult and paediatric patients as well as across the paediatric subset. A study in hospitalised neonates concluded that 97% of neonatal patients received at least one medicine containing a potentially or known to be harmful excipient.3 Similar results were found in two other studies; patients were receiving a wide range of potentially harmful excipients, such as ethanol, propylene glycol (PG), sorbitol, benzyl alcohol and others, through their medicine.7 4 Poly-pharmacy increases the probability of common excipients exceeding safe threshold levels potentially putting patients at an increased risk. ETHANOL AS AN EXCIPIENT AND ITS EFFECTS IN THE NEONATE AND CHILD One of the excipients understood to be harmful, particularly in neonates, is ethanol.
Christiansen N. Arch Dis Child Educ Pract Ed 2014;0:1–4. doi:10.1136/archdischild-2013-305671 1 Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.
Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Pharmacy update It is found in many oral liquid preparations and is incorporated for technical reasons as it acts as a solvent and a preservative. Three enzymes are attributed to metabolise ethanol in adults: alcohol dehydrogenase (ADH), microsomal ethanol oxidising system and catalase with ADH being the predominant pathway. Little data are available in regards to neonates and children. Available data suggest that the ADH content in perinatal neonates is significantly lower than in adults with catalase activity in some cases being higher and possibly having some compensatory effect.8 The harmful effects of maternal alcohol consumption resulting in severe central nervous system (CNS) abnormalities and neurodevelopmental impairments, known as foetal alcohol syndrome, are well understood;9 however, little data on the neurodevelopmental impact of alcohol exposure are available for preterm or term neonates. Effects of alcohol ingestion through breastmilk have been investigated in infants and a detrimental effect on psychomotor function has been reported.10 However, these findings could not be replicated in a later study.11 For children, the toxicity data for chronic and acute ethanol exposure are very limited. There are data to suggest that clearance in acutely intoxicated children is similar to adults,12 but adverse reactions are expected to appear at much lower concentrations.13 Regrettably, no data are available on the effect of chronic alcohol exposure in children. EXPOSURE TO ETHANOL THROUGH DRUG FORMULATIONS Published information on exposure of ethanol in neonates and children through medicines is limited. Two studies in Italy found14 15 many commercially available preparations that have the potential to deliver significant amounts of alcohol. With respect to the UK, two studies were conducted in neonatal services. Whittaker et al4 examined the exposure with eight oral liquid formulations and found that infants were exposed to 20 different excipients. Ethanol was found in several of the medications including commonly used ones such as iron and furosemide. This resulted in a significant ethanol exposure to infants, ranging from 0.11 to 0.70 g/kg/week, equivalent to 1–7 units in a 70 kg adult. For adults, the recommended safe weekly limit for ethanol is currently 14 units for women and 21 units for man. Another study16 that looked solely at alcohol exposure through medication in neonates found that 14 formulations routinely stocked on the neonatal intensive care unit contained alcohol. Two of these contained around 10% v/v of ethanol, furosemide and ranitidine liquid preparations. The most commonly encountered were chlorothiazide and ranitidine liquid preparations. Ethanol exposure ranged from 6 to 280 mg/kg/week. This would be equivalent to a 70 kg adult receiving up to 2.5 units/week. The study also looked at possible
2
alternative preparations; however, for most drugs, it was not possible to find suitable alternative preparations. A similar picture emerges from a study undertaken on a paediatric intensive care unit in the UK,17 which included patients up to the age of 15 years. Here ethanol exposure ranged from 0.07 units to 15.2 units per week calculated as adult equivalent with a median of 1.4 units/week. The most frequently prescribed alcohol containing formulations were liquid preparations of nystatin, ranitidine, furosemide and morphine. Again, it was not possible to find commercially available alcohol-free alternatives for most of these. In addition to the effects of alcohol alone, there has also been a report by the US Food and Drug Administration around the serious health problems that have been caused in neonates following the administration of Kaletra oral solution.18 This preparation contains both ethanol and PG, resulting in reduced PG clearance and hence increased toxicity. All of this only paints a small picture of the overall problem, and it is reasonable to assume that similar problems exist in other countries. Although healthcare professionals need to be aware and acknowledge the risks associated with prescribing preparations containing alcohol, uncertainty continues to surround the identification of safe limits for children and neonates. In 1984, the American Academy of Paediatrics published an article highlighting the importance of removing alcohol from paediatric formulations19 and in cases where this was not possible to provide information explaining the risks. It stipulated that a child’s blood alcohol concentration should not exceed 0.25 g/L after the administration of a single dose. Although these figures were based on adult data and therefore hypothetical for children, it did succeed in persuading many manufacturers to voluntarily reduce the alcohol content in their products.20 The Food and Drug Agency subsequently issued guidance on the alcohol content of oral over the counter (OTC) medication, providing clear guidance on maximum alcohol concentrations for different age groups. For adults and children over 12 years, the maximum alcohol concentration is 10%, for under 12 and under 6 year olds, 5% and 0.5%, respectively.21 This regulation had the aim of reducing unnecessary alcohol exposure to paediatric patients, as well as reducing potential misuse of OTC medicines for their alcohol content.20 The regulation also requires the alcohol content to be prominently shown on the principal display panel. In the UK, this information is not necessarily provided on the packaging but can in some cases be found in the British National Formulary for children, in the patient information leaflet or in the Summaries of Product Characteristics. These are available through the electronic medicines compendium at http://www. medicines.org.uk.
Christiansen N. Arch Dis Child Educ Pract Ed 2014;0:1–4. doi:10.1136/archdischild-2013-305671
Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Pharmacy update More recently, recommendations on ethanol threshold in liquid formulation intended for paediatrics have been published in France. These require the ethanol concentration to be below 5% and/or that the amount of ethanol should not produce blood ethanol concentrations higher than 0.125 g/L after a single dose.13 Although this offers a useful reference point and may prompt the use and development of safer alternatives, it should be borne in mind that ethanol concentration in the range of 0.01–1 g/L has been associated with adverse effects on the CNS in children.22 In adults, impaired concentration and motor coordination have been observed with concentrations in the range of 0.15–0.3 g/L.13 Most recently in January 2014 the European Medicines Agency (EMEA) published a draft for the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’, proposing more detailed information on alcohol content in the patient information leaflet as well as alcohol content thresholds for different age groups.23 CONCLUSION Even though the use of excipients is regulated through the EMEA, babies and children are still exposed to potentially harmful excipients and adequate safety information on excipients used in the paediatric population is often missing. It has been shown that neonates and children in some cases are exposed to considerable amounts of alcohol through their medication. Although information on the effects of acute and chronic alcohol exposure in babies and children is scarce, it could be argued that they should be protected from any potentially harmful effects of alcohol and hence the amount of alcohol in drug formulations should be kept to a minimum. Guidance on maximum limits for ethanol content in paediatric drug formulations is increasing, both in the USA19 21 and the EU.13 23 Improved information about excipient content including alcohol would greatly help healthcare professionals in weighing up the risks and benefits of a medication. The proposed changes in respect to alcohol in the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’23 are a step in this direction and may also encourage manufacturers to reduce the alcohol content. However, given the high rate of unlicensed and offlabel usage of medication in paediatrics, this might only address a proportion of the preparations administered to children. Even with an increase in licensed medication in children following the EU Paediatric Regulation from 2006, the use of unlicensed and offlabel medication is likely to continue. Healthcare professionals will, therefore, continue to be presented with a conundrum: in seeking to provide care they will frequently find themselves in situations where the
only means of avoiding an excipient is to withdraw medication. To improve safety of drug formulations for children and to advance knowledge on the safety and toxicity of excipients in this vulnerable population will require collaboration between manufactures, researchers and healthcare professionals. Against this backdrop, the European Paediatric Formulation Initiative (EuPFI) was founded in 2007 by members from the pharmaceutical industries, hospital and academia interested in formulating better medicines for children. One of the key work streams of the EuPFI aims to address safety issues and problems associated with the excipients likely to be used in paediatric formulations, which is an exciting step forward for developing better paediatric drug formulations. Another Europe-wide project aims to address this problem in the youngest patients, the European Study of Neonatal Exposure to Excipients collaboration. This collaboration aims to develop a range of methodologies providing an integrated assessment of exposure among neonates in Europe to potentially toxic excipients contained in medicines.24
Learning Points ▸ Even though the use of excipients is regulated through the European Medicines Agency, babies and children are still exposed to potentially harmful excipients and adequate safety information on excipients used in the paediatric population is often missing. ▸ Commonly used liquid formulations containing ethanol are nystatin, ranitidine, furosemide, as well as some iron and morphine preparations. Often it is not possible to find commercially available ethanolfree alternatives.
Assessment questions 1. What is an excipient and what role does ethanol play in drug formulations? 2. Why are children more vulnerable to adverse reactions from excipients than adults? 3. What were the most frequently prescribed ethanolcontaining preparations? 4. Where can information on ethanol content of a medication be found? Answers are at the end of the references.
Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
Christiansen N. Arch Dis Child Educ Pract Ed 2014;0:1–4. doi:10.1136/archdischild-2013-305671
3
Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Pharmacy update REFERENCES 1 Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Paediatr 2005;164:552–8. 2 European Medicines Agency. Committee for Medicinal Product for Human Use (CHMP): Guideline on excipients in the dossier for application for marketing authorisation of a medicinal product 2007. CHMP/QWP/396951/2006. 3 Lass J, Naelapää K, Shah U, et al. Hosptialised neonates in Estonia commonly receive potentially harmful excipients. BMC Paediatr 2012;12:136. 4 Whittaker A, Currie AE, Turner MA, et al. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94:F236–40. 5 Strickley RG, Iwatra Q, Wu S, et al. Pediatric drugs—a review of commercially available oral formulations. J Pharm Sci 2008;97:1731–74. 6 European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP): Guideline on pharmaceutical development of medicines for paediatric use EMEA/CHMP/QWP/805880/2012 Rev. 2. 7 Shehab N, Lewis CL, Streetman DD, et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Paediatr Crit Care Med 2009;10:256–9. 8 Tran MN, Wu AHB, Hill DW. Alcohol dehydrogenase and catalase content in perinatal infant and adult livers: Potential influence on neonatal alcohol metabolism. Toxicol Lett 2007;169:245–52. 9 Riley EP, McGee CL. Fetal alcohol spectrum disorders: an overview ewith the emphasis on changes in brain and behaviour. Exp Biol Med 2005;230:357–65. 10 Little RE, Anderson KW, Ervin CH, et al. Maternal alcohol use during breast-feeding and infant mental and motor development at one year. N Engl J Med 1989; 321:425–30. 11 Little RE, Northstone K, Golding J; ALSPAC study Team. Alcohol, breastfeeding and development at 18 month. Paediatrics 2002;109:E72. 12 Simon HK, Cox JM, Sucov A, et al. Serum ethanol clearance in intoxicated children and adolescents presenting to the ED. Acad Emerg Med 1994;1:520–4. 13 European Medicine Agency. Committee on Herbal Medicinal Products (HMPC): Reflection paper on ethanol content in herbal medicinal products and traditional herbal medicinal products used in children. 2010, EMEA/HMPC/85114/2008. 14 Fiocchi A, Riva E, Giovannini M. Ethanol in medicines and other products intended for children: Commentary on a medical parardox. Nutr Res 1999;19:373–9. 15 Zuccotti GV, Fabiano V. Safety issues with ethanol as an excipient in drugs intended for pediatric use. Expert Opin Drug Saf 2011;10:499–502. 16 Jutley H, Christiansen N. Alcohol Exposure in Neonatal Intensive Care Patients. Proceedings of the 19th Neonatal and
4
17
18
19 20
21
22
23
24
Paediatric Pharmacist Group Conference; 8–10 November 2013, London, Great Britain. Issac R, Khan I, Langley C. Ethanol intake of paediatric intensive care patients. Proceedings of the 18th Neonatal and Paediatric Pharmacist Group Conference; 9–11 November 2012, Liverpool, Great Britain. FDA.gov [Internet]. Silver Spring: FDA; 2011 Aug. Drug Safety Communications: Serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution; 2011. [cited 2014 Jun 9]. http://www.fda.gov/Drugs/ DrugSafety/ucm246002.htm Pruitt AW, Anyan WRJ, Hill RM, et al. Ethanol in liquid preparations intended for children. Pediatrics 1984;73:405–7. Food and Drug Administration. Proposed rules—Over the counter drug products intended for oral ingestion that contain alcohol. Rockville, MD: Department of Health and Human Services (US), Food and Drug Administration; 1993. Oct (Federal Register; vol. 58, No202). Docket No.: 93N-0107. Food and Drug Administration. Over the counter drug products intended for oral ingestion that contain ethanol. 2013. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ CFRSearch.cfm?CFRPart=328&showFR=1 European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP): Reflection Paper: Formulations of choice for the paediatric population. EMEA/ CHMP/PEG/194810/2005. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP): Questions and answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medical products for human use.’ EMA/CHMP/507988/2013. Graham S, Turner M. European study of neonatal exposure to Excipients (ESNEE). Infant 2011;6(7):196–9.
Answers to the quiz on the previous page 1. An excipient is a supposedly inert constituent of a drug preparation. Excipients have various roles; in the case of ethanol, it acts as a solvent and preservative. 2. Babies and children are more vulnerable to adverse reactions due to organ immaturity and differences in pharmacokinetic as well as pharmacodynamic profiles of the excipients compared to adults. 3. In the UK these are commonly but not exclusively nystatin, ranitidine, furosemide, some morphine and iron liquid preparations. 4. In the UK, this information can be found in the patient information leaflet or in the Summaries of Product Characteristics and in some cases in the British National Formulary for children.
Christiansen N. Arch Dis Child Educ Pract Ed 2014;0:1–4. doi:10.1136/archdischild-2013-305671
Downloaded from http://ep.bmj.com/ on February 27, 2015 - Published by group.bmj.com
Ethanol exposure through medicines commonly used in paediatrics Nanna Christiansen Arch Dis Child Educ Pract Ed published online August 21, 2014
Updated information and services can be found at: http://ep.bmj.com/content/early/2014/08/21/archdischild-2013-305671
These include:
References
This article cites 14 articles, 3 of which you can access for free at: http://ep.bmj.com/content/early/2014/08/21/archdischild-2013-305671 #BIBL
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Topic Collections
Articles on similar topics can be found in the following collections Child health (281) Neonatal health (28) Infant health (44)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
