ASK DIS: Safety of Benzyl Alcohol in Children

Many product contains benzyl alcohol as a preservative.
The preservative benzyl alcohol has been associated with serious adverse events, including the “gasping syndrome”, and death in pediatric patients.
A number of neonatal deaths and severe respiratory and metabolic complications in low-birth-weight premature infants have been associated with use of this agent in bacteriostatic saline intravascular flush and endotracheal tube lavage solutions

Reference Levels

a subchronic oral reference dose of 1 mg/kg/day for adult was derived based on the no observed adverse effect level of 200 mg/kg found in a 13 weeks rat study.
A chronic oral reference dose of 0.3 mg/kg/day for adult was derived based on the LOAEL of 200 mg/kg found in a 2 years carcinogenicity study
no animal toxicological data for parenteral or topical use of benzyl alcohol. However, oral absorption is close to 100%, hence recommendations for oral use are considered applicable for other routes of administration
oral juvenile studies, only one short-term study has been performed in juvenile rats, which established a NOAEL of 300 mg/kg/day which is close to the adult. There are no juvenile animal toxicity studies related to long-term use.
Benzyl alcohol can cross the placenta

Benzyl Alcohol Toxicity (“Gasping Syndrome”)

Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known.
The risk of benzyl alcohol toxicity depends on the quantity administered and the hepatic capacity to detoxify the chemical.
Premature and low birth weight infants may be more likely to develop toxicity.

Metabolic Acidosis (commonly associated with NS alcohol flush)

Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid.
However, this metabolic pathway may not be well developed in premature infants.
The benzyl alcohol may therefore have been metabolized to benzoic acid, which could not be conjugated by the immature liver but accumulated, causing metabolic acidosis

Usage in Pediatrics

current recommendations are incomplete and too strict, as they contra-indicate benzyl alcohol for children up to 3 years old (European Medicines Agency).
While this excipient should not be used in neonates, it may be used for children aged older than 4 weeks with caution(European Medicines Agency).
Retrospective studies have now demonstrated a significant decline in mortality and other adverse events after discontinuation of use of a benzyl alcohol-containing solution to flush intravascular catheters or reconstitution of drugs for delivery through these catheters in the newborn population
No specific cut off points is available for Benzyl alcohol administered intravenously, however in the range of 100 to 200 mg/kg/day has been linked to the “gasping syndrome” in several pre-term newborns with metabolic acidosis that resulted in deterioration of the neurological status, cardio-vascular failure and haematological anomalies .
Premature infants receiving low doses in medications were found to have peak benzoic acid levels 10 times higher than those in term infants but without evidence of toxicity.
Two studies noting the striking decrease in kernicterus after removal of benzyl alcohol did not reveal a dose–response relationship and could not exclude the possibility that other advances in therapy were responsible

Recommendations

At low doses, such as those present when medications preserved with benzyl alcohol are administered, benzyl alcohol is safe for newborns
Content of benzyl alcohol as preservatives in IV medications are generally at lower levels than given safety levels (consult pharmacists for individual agents)
Avoid in Premature, low birth weight babies and liver impairment

References:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm403291.htm
http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm
Questions and Answers on Benzyl alcohol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00). European Medicines Agency, 2014 (Draft)
http://pediatrics.aappublications.org/content/99/2/268

ASK DIS