Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Melatonin

Generic name
Melatonin
Brand name
ATC Code
N05CH01

Pharmacokinetics in children

Source Goldman 2014
immediate-release melatonin 		 SmPC Melatonine Tiofarma  SmPC Slenyto
Prolonged release
 Age 3-8 years (n=9) 3-12 years

 7-15 years
Cmax (pg/ml) 2,5 – 11,6 NR NR
Tmax (hour) 0,6 – 0,7 NR NR
t1/2 (hour) 1,0-1,3 0,7-1,3 3,5-4 (terminal t½)
Cl (ml/hour/kg) 12,6-14,2 2-14 NR
Vd (ml/kg) 17,0-28,8 2,3-38 NR

NR= not reported

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

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Available formulations

No information is present at this moment.

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Dosages

Sleep initiation disorder associated with delayed sleep-wake-phase disorder (with or without autism spectrum disorder or neurogenetic disorders or ADHD)
  • Oral
    • 1 month up to 2 years
      • Maximum chronobiotic effect (phase advance): 0.1 - 0.5 mg/day in 1 dose

      • Administer 4-6 hours before bedtime.
Insomnia in children with autism spectrum disorders and/or neurogenetic disorders
  • Oral
    • Extended release tablet
      • 2 years up to 18 years
        • Initial dose: 2 mg/day in 1 dose
        • Maintenance dose: If the response is insufficient, the dose should be increased to 5 mg/day in 1 dose. Max: 10 mg/day.
        • Directions for administration:

          0.5-1 hour before going to sleep, with or after food.

          • Administer 30-60 minutes before bedtime.
          • After at least 3 months of treatment, the  treatment effect should be evaluated  and stopping treatment should be considered if no clinically relevant treatment effect is seen. If a lower treatment effect is seen after titration to a higher dose, a down-titration to a lower dose should be considered first, before deciding on a complete discontinuation of treatment.
      • 2 years up to 18 years
        [11]
        • Initial dose: 2 mg/day in 1 dose
        • Maintenance dose: If the response is insufficient, the dose should be increased to 5 mg/day in 1 dose. Max: 10 mg/day.
        • Directions for administration:

          0.5-1 hour before going to sleep, with or after food.

          • Administer 30-60 minutes before bedtime.
          • After at least 3 months of treatment, the  treatment effect should be evaluated  and stopping treatment should be considered if no clinically relevant treatment effect is seen. If a lower treatment effect is seen after titration to a higher dose, a down-titration to a lower dose should be considered first, before deciding on a complete discontinuation of treatment.
Procedural sedation for EEG
  • Oral
    • 1 month up to 6 months
      • 0.2 - 0.3 mg/kg/day, once only.
    • 6 months up to 18 years and < 10 kg
      • 0.2 - 0.3 mg/kg/dose, once only. If necessary, administer a 2nd dose of 0.1-0.15 mg/kg/dose if the child does not sleep after 45 minutes. Maximal cumulative dose: 10 mg.
    • 6 months up to 18 years and 10 up to 15 kg
      • 2 - 3 mg/dose, once only. If necessary, administer a 2nd dose of 1-1,5 mg/dose if the child does not sleep after 45 minutes. Maximal cumulative dose: 10 mg.
    • 6 months up to 18 years and ≥ 15 kg
      • 4 - 6 mg/dose, once only. If necessary, administer a 2nd dose of 2-3 mg/dose if the child does not sleep after 45 minutes. Maximal cumulative dose: 10 mg.

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Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

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The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Enuresis, diarrhea and hypothermia [Bruni 2015].

1-10%: somnolence, fatigue, mood swings, headache, irritability, aggression and hangover occurring in 1:100-1:10 children.(Epar Slenyto, Maras 2018)

Frequency unknown, during off-label use of adult formulation: epilepsy, visual impairment, dyspnoea, epistaxis, constipation, decreased appetite, swelling face, skin lesion, feeling abnormal, abnormal behaviour and neutropenia (2 mg prolonged-release). Depression, nightmares, agitation and abdominal pain (2-6 mg, ASD and neurogenetic children).(Maras 2018)

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The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Convulsions have been reported in children with epilepsy with severe neurological impairments. There is no data on the long-term effects in children.

When melatonin is used for the treatment of a delayed sleep phase syndrome, always combine with behavioral treatment, with attention for sleeping hygiene, the use of strict bed times, and optimum light exposure in the morning.

The optimal time of administration depends on the child's own melatonin production. This can be estimated based on sleep-awake calendars, actigraphy or DLMO determination.

In order to advance the moment of falling asleep, the administration time can be gradually expedited. On average, the rhythm shifts by 30 minutes every 2-3 days. Melatonin should be taken approximately 3 hours before the desired time to fall asleep.

There is no evidence that long-acting preparations have an advantage over short-acting preparations.

For long-term use: discontinue treatment once a year after a normal sleep cycle has been achieved (preferably in the summer) to determine if melatonin use is still indicated.

If the effect dimishes after an initial good effect: be alert for melatonin accumulation, this can already occur at low doses. The advice is then to stop for a few days and to restart in a lower dose or to give it intermittently.
Melatonin as a hypnotic should be used as short as possible. With each visit to the prescribing physician, consideration should be given to whether the use is still indicated or can be replaced by behavioral treatment.

No long-term effects of exogenous melatonin were found on mental development or adolescence (Boss 2023)

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Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

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Barbiturates, plain
N05CA01
Aldehydes and derivatives
N05CC01
Benzodiazepine derivatives
N05CD08
N05CD02
N05CD07
Other hypnotics and sedatives
N05CM18
N05CM21

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References

  1. Van der Heijden KB, et al, Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia, J Am Acad Child Adolesc Psychiatry, 2007, Feb;46(2), 233-41
  2. Tjon Pian Gi CV, et al, Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study, Eur J Pediatr, 2003, Jul;162(7-8), 554-5
  3. Weiss MD, et al, Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia, J Am Acad Child Adolesc Psychiatry, 2006, May;45(5), 512-9
  4. Wasdell MB, et al, A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities, J Pineal Res, 2008, Jan;44(1), 57-64
  5. Garstang J, et al, Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems, Child Care Health Dev, 2006, Sep;32(5), 585-9
  6. Hancock E, et al, Effect of melatonin dosage on sleep disorder in tuberous sclerosis complex, J Child Neurol, 2005, Jan;20(1), 78-80
  7. Braam W, et al, Melatonin decreases daytime challenging behaviour in persons with intellectual disability and chronic insomnia, J Intellect Disabil Res., 2010, Jan 1;54(1), 52-9
  8. Coppola G, et al, Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial., Brain Dev., 2004, Sep;26(6):, 373-6
  9. Dodge NN, et al, Melatonin for treatment of sleep disorders in children with developmental disabilities, J Child Neurol., 2001, Aug;16(8), 581-4
  10. Medice, SmPC Circadin 2mg Retardtablette (EU/1/07/392/001-004), 07/2015
  11. RAD Neurim Pharmaceuticals EEC Limited, SmPC Slenyto (EU/1/18/1318/001-004) `Rev 11, 19-02-2024, www.ema.europa.eu
  12. Bruni O, et al., Current role of melatonin in pediatric neurology: clinical recommendations, Eur J Paediatr Neurol, 2015, 19, 122-33
  13. Goldman SE, et al, Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep, J Autism Dev Disord, 2014, Oct;44(10), 2525-35
  14. RAD Neurim Pharmaceuticals EEC, SmPC Slenyto 1 mg/5 mg Retardtabletten (EU/1/18/1318/001, EU/1/18/1318/002, EU/1/18/1318/003, EU/1/18/1318/004, EU/1/18/1318/005), 01/2019
  15. RAD Neurim Pharmaceuticals EEC, SmPC Slenyto 1 mg/5 mg Retardtabletten (EU/1/18/1318/001, EU/1/18/1318/002, EU/1/18/1318/003, EU/1/18/1318/004, EU/1/18/1318/005), 01/2019
  16. RAD Neurim Pharmaceuticals EEC, SmPC Slenyto 1 mg/5 mg Retardtabletten (EU/1/18/1318/001, EU/1/18/1318/002, EU/1/18/1318/003, EU/1/18/1318/004, EU/1/18/1318/005), 01/2019
  17. Jalilolghadr S, et al., The effect of treatment with melatonin on primary school aged children with difficulty in initiation and maintenance of sleep., Turk J Pediatr., 2022, 64(6), 993-1000
  18. Maras A, et al., Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder., J Child Adolesc Psychopharmacol, 2018, 28(10), 699-710
  19. European Medicins Agency, European Public Assessment Report (EPAR) Slenyto , www.ema.europa.eu, 2018
  20. Ahmed J, et al., Melatonin for non-operating room sedation in paediatric population: a systematic review and meta-analysis., Arch Dis Child., 2022, 107(1), 78-85
  21. Tiofarma BV, SmPC Melatonine (RVG 120771) 22-04-2021, www.geneesmiddeleninformatiebank.nl
  22. Rolling J, et al., Melatonin Treatment for Pediatric Patients with Insomnia: Is There a Place for It?, Nat Sci Sleep, 2022, 14, 1927-44
  23. Wei S, et al., Efficacy and safety of melatonin for sleep onset insomnia in children and adolescents: a meta-analysis of randomized controlled trials., Sleep medicine, 2020, 68, 1-8
  24. Mombelli S, et al., Non-pharmacological and melatonin interventions for pediatric sleep initiation and maintenance problems: A systematic review and network meta-analysis. , Sleep Med Rev., 2023, 70, 101806
  25. Lalwani S, et al., Efficacy and tolerability of Melatonin vs Triclofos to achieve sleep for pediatric electroencephalography: A single blinded randomized controlled trial., Eur J Paediatr Neurol., 2021, 34, 14-20
  26. Boss M., Aanbevelingen voor het juiste gebruik van melatonine in de klinische praktijk; Praktisch handvat en expert opinion., 2023, version 1.1.
  27. European Medicins Agency, European Public Assessment Report (EPAR) Slenyto, www.ema.europa.eu, 2018
  28. Mombelli S, et al., Non-pharmacological and melatonin interventions for pediatric sleep initiation and maintenance problems: A systematic review and network meta-analysis., Sleep Med Rev., 2023, 70, 101806

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Changes

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