Safe Excipient Exposure in Neonates and Small ChildreN

Pediatric Clinical Trial

— SEEN  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02545712
• Other study ID #: BBH-KSV-01
• Status: Active, not recruiting
• Phase: N/A
• First received: September 3, 2015
• Last updated: February 4, 2017
• Start date: January 2016

Study information

• Verified date: February 2017
• Source: Bispebjerg Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 630
• Est. primary completion date: April 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 5 Years

Eligibility

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

Related Conditions & MeSH terms

• Excipient Exposure
• Neonatal
• Pediatric

Intervention

Other:
• Exposure to ethanol
The drug source(s) and amount administered daily are noted.
• Exposure to propylene glycol
The drug source(s) and amount administered daily are noted.
• Exposure to benzyl alcohol
The drug source(s) and amount administered daily are noted.
• Exposure to acesulfam potassium
The drug source(s) and amount administered daily are noted.
• Exposure to aspartame
The drug source(s) and amount administered daily are noted.
• Exposure to glycerol
The drug source(s) and amount administered daily are noted.
• Exposure to sorbitol
The drug source(s) and amount administered daily are noted.
• Exposure to methyl-p-hydroxybenzoate
The drug source(s) and amount administered daily are noted.
• Exposure to propanyl-p-hydroxybenzoate
The drug source(s) and amount administered daily are noted.
• Exposure to polysorbate-80
The drug source(s) and amount administered daily are noted.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Bispebjerg Hospital	Rigshospitalet, Denmark

References & Publications (14)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

Lass J, Käär R, Jõgi 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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Concentration (mg/kg/day) of benzyl alcohol in the patient		Single day
Primary	Concentration (mg/kg/day) of acesulfam potassium in the patient		Single day
Primary	Concentration (mg/kg/day) of aspartame in the patient		Single day
Primary	Concentration (mg/kg/day) of glycerin in the patient		Single day
Primary	Concentration (mg/kg/day) of sorbitol in the patient		Single day
Primary	Concentration (mg/l) of methyl-p-hydroxybenzoate in the patient		Single day
Primary	Concentration (mg/kg/day) of propyl-p-hydroxybenzoate in the patient		Single day
Primary	Concentration (mg/kg/day) of polysorbate-80 in the patient		Single day
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   European Medical Agency. Guideline on pharmaceutical development of medicines for paediatric use. [accessed August 27th 2015].
•   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