Safe Excipient Exposure in Neonates and Small ChildreN (SEEN)

Safe Excipient Exposure in Neonates and Small ChildreN - a Retrospective, Descriptive Study Off the Amount of Ethanol, Propylene Glycol, Benzyl Alcohol, Parabens, Acesulfam k, Aspartame, Glycerol, Sorbitol and Polysorbate-80 Exposed to Pediatric Patients

The purpose of this study is to explore the quantity of excipient exposure in neonatal and young pediatric patients in a Danish Hospital. The focus will be on the preservatives ethanol, propyl glycol, benzyl alcohol, methyl-p-hydroxybenzoate and propanyl-p-hydroxybenzoate and the artificial sweeteners acesulfam potassium, aspartame, glycerol and sorbitol.

Study Overview

• Status: Unknown
• Conditions: Pediatric; Neonatal; Excipient Exposure
• Intervention / Treatment: Other: Exposure to ethanol; Other: Exposure to propylene glycol; Other: Exposure to benzyl alcohol; Other: Exposure to acesulfam potassium; Other: Exposure to aspartame; Other: Exposure to glycerol; Other: Exposure to sorbitol; Other: Exposure to methyl-p-hydroxybenzoate; Other: Exposure to propanyl-p-hydroxybenzoate; Other: Exposure to polysorbate-80

Detailed Description

Studies have previously examined whether or not neonatal nor pediatric patients are exposed to excipients and what excipients they are possibly exposed to. They have shown that practically all neonatal patients receive one or more drug containing an excipient, known to be harmful. This observational study will look at both registered drugs and extemporaneous pharmaceuticals as possible sources of excipients. Based on information provided by the manufacturer (ex. the index-list), the investigator will calculate the amounts of excipients administered to the patient a week after hospitalisation. The investigator will calculate the blood alcohol content when the neonatal patient are exposed to ethanol and/or propylene glycol.

By grouping the patients according to age and subgrouping according to diagnosis/affected organ system and compare the amount of excipient exposure in each group, the study aims at identifying the most vulnerable neonatal and/or pediatric patients in terms of the amount and identity of excipients accumulated in the patient.

The study will use a descriptive, parametric statistic analysis to identify

• an average exposure rate (concentration i mg/l or amount in mg) of each of the listed excipients
• how much the average patient in each age-group is exposed to each excipient
• how much the average patient in each "affected organ system"-subgroup is exposed to each excipient

• Study Type: Observational
• Enrollment (Actual): 630

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Neonatal patients and pediatric patients (≤ 5 years) who, at one point, have been/are being treated at the "Neonatalklinikken" (units 5021, 5023, 5024) or "BørneUngeklinikken" (units 5061, 5062, 5054, 4144) of Rigshospitalet, Denmark. To be included in the study, the patients must receive

• 2 or more different drugs if < 28 days old
• 3 or more different drugs if 28 day ≤ 5 years old

Description

Inclusion Criteria:

• if < 28 days: must receive 2 or more prescriptions a day
• if 28 days ≤ 5 years: must receive 3 or more prescriptions a day
• must have been/be submitted and treated at the neonatal department (units 5021, 5023, 5024) or pediatric department (units 5061, 5062, 5054, 4144) of Rigshospitalet

Exclusion Criteria:

• no up-dated weight is listed
• > 5 years old

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Neonatal patients; Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.	Other: Exposure to ethanol; The drug source(s) and amount administered daily are noted.; Other Names: Ethyl achohol; Other: Exposure to propylene glycol; The drug source(s) and amount administered daily are noted.; Other: Exposure to benzyl alcohol; The drug source(s) and amount administered daily are noted.; Other: Exposure to acesulfam potassium; The drug source(s) and amount administered daily are noted.; Other Names: Acesulfame-K; Other: Exposure to aspartame; The drug source(s) and amount administered daily are noted.; Other: Exposure to glycerol; The drug source(s) and amount administered daily are noted.; Other Names: Glycerol; Other: Exposure to sorbitol; The drug source(s) and amount administered daily are noted.; Other: Exposure to methyl-p-hydroxybenzoate; The drug source(s) and amount administered daily are noted.; Other Names: including sodium-methyl-p-hydroxybenzoate; Other: Exposure to propanyl-p-hydroxybenzoate; The drug source(s) and amount administered daily are noted.; Other Names: including sodium-propanyl-p-hydroxybenzoate; Other: Exposure to polysorbate-80; The drug source(s) and amount administered daily are noted.
Pediatric patients (28 days ≤ 5 years); Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.	Other: Exposure to ethanol; The drug source(s) and amount administered daily are noted.; Other Names: Ethyl achohol; Other: Exposure to propylene glycol; The drug source(s) and amount administered daily are noted.; Other: Exposure to benzyl alcohol; The drug source(s) and amount administered daily are noted.; Other: Exposure to acesulfam potassium; The drug source(s) and amount administered daily are noted.; Other Names: Acesulfame-K; Other: Exposure to aspartame; The drug source(s) and amount administered daily are noted.; Other: Exposure to glycerol; The drug source(s) and amount administered daily are noted.; Other Names: Glycerol; Other: Exposure to sorbitol; The drug source(s) and amount administered daily are noted.; Other: Exposure to methyl-p-hydroxybenzoate; The drug source(s) and amount administered daily are noted.; Other Names: including sodium-methyl-p-hydroxybenzoate; Other: Exposure to propanyl-p-hydroxybenzoate; The drug source(s) and amount administered daily are noted.; Other Names: including sodium-propanyl-p-hydroxybenzoate; Other: Exposure to polysorbate-80; The drug source(s) and amount administered daily are noted.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood alcohol content measured in per mille (grams of ethanol and propylene glycol pr. kilograms of blood) in the patient	Both concentrations of ethanol and propylene glycol are included in the calculations. with propylene glycol 1/3 as intoxicating as ethanol.	Single day
Concentration (mg/kg/day) of benzyl alcohol in the patient		Single day
Concentration (mg/kg/day) of acesulfam potassium in the patient		Single day
Concentration (mg/kg/day) of aspartame in the patient		Single day
Concentration (mg/kg/day) of glycerin in the patient		Single day
Concentration (mg/kg/day) of sorbitol in the patient		Single day
Concentration (mg/l) of methyl-p-hydroxybenzoate in the patient		Single day
Concentration (mg/kg/day) of propyl-p-hydroxybenzoate in the patient		Single day
Concentration (mg/kg/day) of polysorbate-80 in the patient		Single day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of patient group (according to age-interval) most vulnerable to excipient exposure (measured in number of excipients)	The excipients (ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerol, polysorbate-80 and sorbitol) will be ranked according to which excipient is most often present in the medicine administered to the patients.	During the participants hospitalization, an expected average of 2 months
Identification of patient group (according to age-interval) most vulnerable to excipient exposure (amounts of each excipient measured in (mg/l))	The excipients (ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerol, polysorbate-80 and sorbitol) will be ranked according to which excipient is most often present in the medicine administered to the patients.	During the participants hospitalization, an expected average of 2 months
Identification of patient group (according to affected organ system) most vulnerable to excipient exposure (measured in number of excipients)	The excipients (ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerol, polysorbate-80 and sorbitol) will be ranked according to which excipient is most often present in the medicine administered to the patients.	During the participants hospitalization, an expected average of 2 months
Identification of patient group (according to affected organ system) most vulnerable to excipient exposure (amounts of each excipient measured in (mg/l))	The excipients (ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerol, polysorbate-80 and sorbitol) will be ranked according to which excipient is most often present in the medicine administered to the patients.	During the participants hospitalization, an expected average of 2 months
Identification of number of patient exposed to ethanol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of ethanol to daily tolerance limit	Single day
Identification of number of patient exposed to propylene glycol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of proplyene glycol to daily tolerance limit	Single day
Identification of number of patient exposed to benzyl alcohol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of benzyl alcohol to daily tolerance limit	Single day
Identification of number of patient exposed to methyl-p-hydroxy-benzoate levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of methyl-p-hydroxy-benzoate to daily tolerance limit	Single day
Identification of number of patient exposed to propyl-p-hydroxy-benzoate levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of propyl-p-hydroxy-benzoate to daily tolerance limit	Single day
Identification of number of patient exposed to sodium-propyl-p-hydroxy-benzoate levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of sodium-propyl-p-hydroxy-benzoate to daily tolerance limit	Single day
Identification of number of patient exposed to sodium-methyl-p-hydroxy-benzoate levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of sodium-methyl-p-hydroxy-benzoate to daily tolerance limit	Single day
Identification of number of patient exposed to acesulfame potassium levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of acesulfame potassium to daily tolerance limit	Single day
Identification of number of patient exposed to aspartame levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of aspartame to daily tolerance limit	Single day
Identification of number of patient exposed to glycerol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of glycerol to daily tolerance limit	Single day
Identification of number of patient exposed to sorbitol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of sorbitol to daily tolerance limit	Single day
Identification of number of patient exposed to polysorbate-80 levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Comparison of each patient daily exposure rate of polysorbate-80 to daily tolerance limit	Single day

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Collaborators: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Kristine Svinning Valeur, MS, Bispebjerg Frederiksberg Hospital

Publications and helpful links

General Publications

• Nellis G, Metsvaht T, Varendi H, Toompere K, Lass J, Mesek I, Nunn AJ, Turner MA, Lutsar I; ESNEE consortium. Potentially harmful excipients in neonatal medicines: a pan-European observational study. Arch Dis Child. 2015 Jul;100(7):694-9. doi: 10.1136/archdischild-2014-307793. Epub 2015 Apr 8.
• Souza A Jr, Santos D, Fonseca S, Medeiros M, Batista L, Turner M, Coelho H. Toxic excipients in medications for neonates in Brazil. Eur J Pediatr. 2014 Jul;173(7):935-45. doi: 10.1007/s00431-014-2272-z. Epub 2014 Feb 6.
• Marek E, Kraft WK. Ethanol pharmacokinetics in neonates and infants. Curr Ther Res Clin Exp. 2014 Oct 22;76:90-7. doi: 10.1016/j.curtheres.2014.09.002. eCollection 2014 Dec.
• Nguyen KA, Claris O, Kassai B. Unlicensed and off-label drug use in a neonatal unit in France. Acta Paediatr. 2011 Apr;100(4):615-7. doi: 10.1111/j.1651-2227.2010.02103.x. Epub 2010 Dec 17. No abstract available.
• Jacqz-Aigrain E. Drug policy in Europe Research and funding in neonates: current challenges, future perspectives, new opportunities. Early Hum Dev. 2011 Mar;87 Suppl 1:S27-30. doi: 10.1016/j.earlhumdev.2011.01.007. Epub 2011 Jan 26.
• Allegaert K. Neonates need tailored drug formulations. World J Clin Pediatr. 2013 Feb 8;2(1):1-5. doi: 10.5409/wjcp.v2.i1.1. eCollection 2013 Feb 8.
• Bellis JR, Kirkham JJ, Thiesen S, Conroy EJ, Bracken LE, Mannix HL, Bird KA, Duncan JC, Peak M, Turner MA, Smyth RL, Nunn AJ, Pirmohamed M. Adverse drug reactions and off-label and unlicensed medicines in children: a nested case-control study of inpatients in a pediatric hospital. BMC Med. 2013 Nov 7;11:238. doi: 10.1186/1741-7015-11-238.
• Nahata MC. Safety of "inert" additives or excipients in paediatric medicines. Arch Dis Child Fetal Neonatal Ed. 2009 Nov;94(6):F392-3. doi: 10.1136/adc.2009.160192. No abstract available.
• Whittaker A, Currie AE, Turner MA, Field DJ, Mulla H, Pandya HC. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009 Jul;94(4):F236-40. doi: 10.1136/adc.2008.146035. Epub 2009 Jan 21.
• Saiyed MM, Lalwani T, Rana D. Is off-label use a risk factor for adverse drug reactions in pediatric patients? A prospective study in an Indian tertiary care hospital. Int J Risk Saf Med. 2015;27(1):45-53. doi: 10.3233/JRS-150642.
• Collison KS, Makhoul NJ, Zaidi MZ, Al-Rabiah R, Inglis A, Andres BL, Ubungen R, Shoukri M, Al-Mohanna FA. Interactive effects of neonatal exposure to monosodium glutamate and aspartame on glucose homeostasis. Nutr Metab (Lond). 2012 Jun 14;9(1):58. doi: 10.1186/1743-7075-9-58.
• Ornoy A, Ergaz Z. Alcohol abuse in pregnant women: effects on the fetus and newborn, mode of action and maternal treatment. Int J Environ Res Public Health. 2010 Feb;7(2):364-79. doi: 10.3390/ijerph7020364. Epub 2010 Jan 27.
• Lass J, Kaar R, Jogi K, Varendi H, Metsvaht T, Lutsar I. Drug utilisation pattern and off-label use of medicines in Estonian neonatal units. Eur J Clin Pharmacol. 2011 Dec;67(12):1263-71. doi: 10.1007/s00228-011-1072-x. Epub 2011 Jun 11.
• Fister P, Urh S, Karner A, Krzan M, Paro-Panjan D. The prevalence and pattern of pharmaceutical and excipient exposure in a neonatal unit in Slovenia. J Matern Fetal Neonatal Med. 2015;28(17):2053-61. doi: 10.3109/14767058.2014.976549. Epub 2015 Sep 4.
• Valeur KS, Hertel SA, Lundstrom KE, Holst H. Safe excipient exposure in neonates and small children - protocol for the SEEN project. Dan Med J. 2017 Feb;64(2):A5324.

Helpful Links

• European Medical Agensy. Questions and Answers on Ethanol in the context of the 5 revision of the guideline on 'Excipients in the label and 6 package leaflet of medicinal products for human use' [accessed September 3rd 2015]
• Isaac R, Khan I, Langley C. Ethanol intake of paediatric intensive care patients. Arch Dis Child 2013;98:e1 doi:10.1136/archdischild-2013-303935a.21

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Anticipated): April 1, 2017

Study Registration Dates

• First Submitted: September 3, 2015
• First Submitted That Met QC Criteria: September 9, 2015
• First Posted (Estimate): September 10, 2015

Study Record Updates

• Last Update Posted (Estimate): February 7, 2017
• Last Update Submitted That Met QC Criteria: February 4, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Ethanol; Patients; Propylene glycol; Sorbitol; Benzyl alcohol; Acesulfam potassium; Aspartame; Glycerin; Methyl-p-hydroxybenzoate; Propanyl-p-hydroxybenzoate
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Gastrointestinal Agents; Protective Agents; Anesthetics, Local; Cathartics; Cryoprotective Agents; Ethanol; Sorbitol; Glycerol; Benzyl Alcohol
• Other Study ID Numbers: BBH-KSV-01