Assessing the potential for drug interactions and long term safety of melatonin for the treatment of insomnia in children with autism spectrum disorder

ABSTRACT

Introduction

Melatonin preparations are emerging first-line pharmacotherapy for insomnia in children and adolescents with autism spectrum disorder (ASD), but quality, formulation, consistency, dosing, and limited long-term safety data are of concern. The recent approval of pediatric-appropriate prolonged-release melatonin (Ped-PRM) addresses these aspects.

Areas covered

A systematic search of PubMed and web of science for prospective, randomized, and controlled trials (RCTs) of melatonin preparations vs placebo in children and adolescents with ASD and the European public assessment report on Ped-PRM was conducted.

Expert opinion

Melatonin is rapidly absorbed and undergoes first pass hepatic metabolism by cytochrome CYP1A2; over 80% is excreted in the urine as 6-sulfatoxymelatonin (inactive). Immediate-release melatonin (IRM) is short-acting (3–4 h), whereas PRM provides therapeutic levels throughout the night. Drugs interacting with CYP1A2 are likely to slow-down melatonin metabolism. High variability in bioavailability among subjects calls for dose optimization. Melatonin was essentially safe for short-term use (up to 3 months). Long-term data available for Ped-PRM demonstrate fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%) with no evidence of effects on height, BMI, or pubertal development, tolerance or withdrawal effects following long-term use of this product. Studies on long-term safety of IRM and oversight of melatonin supplement manufacture are warranted.

KEYWORDS:

• Immediate release melatonin
• prolonged-release melatonin
• insomnia
• autism spectrum disorder
• drug interactions
• safety
• child
• adolescent

Article highlights

• Melatonin is considered first choice treatment in children and adolescents with ASD and insomnia who fail behavioral intervention.

• Most melatonin formulations are unlicensed and special attention must be given to their composition and quality.

• A pediatric-appropriate prolonged-released melatonin (PedPRM) has been recently licensed for the treatment of insomnia in children and adolescents with ASD providing the first in-license drug for this indication.

• Drug interactions of melatonin are mostly with inhibitors and enhancers of CYP1A2 resulting in the increase in the decrease in melatonin bioavailability, namely, the amount which reaches the systemic circulation and becomes available at the site of drug action.

• Due to large inter-individual variability in bioavailability of melatonin, a dose titration approach is recommended for optimal efficacy.

• Melatonin appears safe for the short-term treatment if there are no contaminants.

• Long-term safety data are available for PedPRM, 2-10 mg but prospective, rigorous studies on long-term safety of IRM for insomnia in children and adolescents with ASD are still missing.

Declaration of interest

N Zisapel is the founder and Chief Scientific Officer of Neurim Pharmaceuticals, the company that developed and produces Circadin® and Slenyto®. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This paper was not funded.