Overview

Parenteral nutrition (PN) is indicated in paediatric and adult patients who cannot be fully fed or are fed enterally due to medical conditions such as severe intestinal failure, malabsorption and short bowel syndrome.¹

In Malaysia, there are currently 11 registered PN products containing amino acids and/or lipids which are approved for use in paediatric patients less than 2 years of age.

Background of the safety issue

The European Medicines Agency (EMA) has reviewed the risk of toxic degradations of ingredients in PN products exposed to light, which may lead to adverse outcomes in neonates and children below 2 years of age.²

Studies have shown that exposure of PN products to light induces generation of peroxides and other degradation by-products, which are quantifiable in experimental PN solutions, animals and neonates.³ PN containing vitamins and/or lipids may be most affected. Ambient light, environmental light and particularly phototherapy could contribute to the formation of peroxides in PN products. High concentrations of photo degradation by-products may lead to oxidative stress, which disrupts cell structures such as DNA, lipids and proteins.⁴

Newborns and premature neonates are especially more vulnerable to oxidative stress due to multiple risk factors including oxygen therapy, phototherapy, weak immune system and inflammatory response with reduced oxidant defense.^3,5 Oxidative stress has been shown to play a role in many neonatal complications, including respiratory distress syndrome, bronchopulmonary dysplasia (BPD), periventribular leukomalacia (PVL), and retinopathy of prematurity (ROP).⁴ While evidence of harm mainly concerns newborn and premature neonates, as a precautionary measure it is advised that light protection should be provided for PN products in neonates and children below 2 years.³

Considering all available evidence, EMA has required all registration holders of the products involved to update their product information with the recommendations on light protection when the solution is to be used in these population groups.

Adverse Drug Reaction (ADR) Reports:

To date, NPRA has received seven (7) reports with 13 adverse events suspected to be related to parenteral nutrition products containing amino acids and/or lipids which are approved for use in paediatric patients less than 2 years of age. However, no event that could be linked to oxidative stress due to photo degradation by-products of PN has been reported locally.⁶

Advice for Healthcare Professionals:

• Be alert that light exposure of PN products containing amino acids and/or lipids, especially after admixture with trace elements and/or vitamins may lead to the formation of high concentration of peroxides in these products.
• Be informed that exposures to photo degradation by-products could lead to oxidative stress related adverse outcomes such as respiratory distress syndrome, bronchopulmonary dysplasia and periventribular leukomalacia particularly in paediatric patients less than 2 years of age.
• PN products containing amino acids and/or lipids (in bags and administration sets) should be protected from light until administration is completed when used in in paediatric patients less than 2 years of age.
• Report all suspected adverse events associated with parenteral nutrition products to NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (6)] has been issued for registration holders to update the local package inserts of parenteral nutrition products containing amino acids and/or lipids approved for use in paediatric patients less than 2 years of age.

References:

1. Pharmaceutical Services Division, Ministry of Health Malaysia. Pharmacist’s Handbook of Parenteral Nutrition: In Neonates and Paediatrics. 1^st 2015.
2. European Medicines Agency. PRAC recommendations on signals adopted at the 8-11 July 2019 PRAC meeting [Internet]. 5 August 2019 [Cited on 2020 August 12]. EMA/PRAC/347675/2019.
3. Medicines and Healthcare Products Regulatory Agency. Direct healthcare professional communication: parenteral nutrition products - light protection required to reduce the risk of serious adverse effects in premature neonates [Internet]. 2019 September 2 [Cited 2020 Aug 12]. Available from: https://www.gov.uk/drug-safety-update/letters-and-drug-alerts-sent-to-healthcare-professionals-in-september-2019
4. Ozsurekci Y, Aykac K. Oxidative stress related diseases in newborns. Oxidative medicine and cellular longevity [Internet]. 2016 Oct [Cited on 2020 August 12]. Available from: https://doi.org/10.1155/2016/2768365
5. Gitto E, Pellegrino S, Gitto P, Barberi I, Reiter RJ. Oxidative stress of the newborn in the pre‐and postnatal period and the clinical utility of melatonin. Journal of pineal research [Internet]. 2009 March [Cited on 2020 August 12]. 46(2):128-39. Available from: https://doi.org/10.1111/j.1600-079X.2008.00649.x
6. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2020 [cited 2020 Aug 12]. Available from: https://www.npra.gov.my

DISCLAIMER:

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.