Guidance for use of melatonin in children and young people with

Datix Ref: 1855-66193

Guidance for use of melatonin in children and young people with severe

sleep disorders

Document Details

Title

Guidance for use of MELATONIN for children with severe

sleep disorders

Trust Ref No

1855-66193

Local Ref (optional)

Main points the document

covers

Guidance for use of MELATONIN for children with severe

sleep disorders

Who is the document

aimed at?

Clinicians working within Children, Young People and Families

Service

Author

Dr. Janet Butterworth

Approval process

Approved by

(Committee/Director)

Clinical Policies Group

Approval Date

11/01/2021

Initial Equality Impact

Screening

Yes

Full Equality Impact

Assessment

Lead Director

Steve Gregory, Director of Nursing and Operations

Category

Clinical

Sub Category

Review date

11/01/2024

Distribution

Who the policy will be

distributed to

Clinicians with Children’s’, Young People and Families Service

Method

Via website

Document Links

Required by CQC

Yes

Required by NHLSA

Keywords

Melatonin, sleep disorder

Amendments History

Date

Amendment

29/07/2013

Version 1

22/10/2015

Version 2

01/07/2020

Version 3: Change in layout

Product availability and local formulary updated

Datix Ref: 1855-66193

Contents

1. Introduction…………………………………………… ……………… 2

2. Purpose…………………………………………………………........... 3

3. Definitions / Glossary................................................................... 3

4. Duties ............................................................................................. 4

4.1 Chief Executive………………….................................... 4

4.2 Director of Nursing & Medical Director.......................... 4

4.3 Service Managers ......................................................... 4

4.4 All Clinical Staff ............................................................ 4

5. Management of Poor Sleep in Children

5.1 Indication of Therapy..................................................... 4

5.2 Treatment Aims ...........................................................4

5.3 Non-pharmalogical Therapy............................................4

5.4 Pharmalogical Treatment with Melatonin………………..5

5.4.1 Dosage........................................................... 5

5.4.2 Contra-indications……............................ 6

5.5. Cautions.........................................................................6

5.5.1 Side Effects.................................................... 6

5.5.2 Interactions.................................................... 6

5.5.3 Pregnancy and Lactation............................... 7

5.6 Monitoring .................................................................... 7

5.6.1 Toxicity........................................................... 7

6. Review and Compliance Monitoring.......................................... 8

7. Consultation................................................................................. 8

8. Dissemination and Implementation............................................ 8

9. References ................................................................................... 8

10. Useful Patient Resources

10.1 10 Steps to a Quiet Night…………................................9

10.2 Good Sleep Habits Booklet ..........................................9

10.3 What is enough sleep? Leaflet .....................................9

10.4–BNFC Leaflet on melatonin……………….……………..9

10.5 Melatonin Information ...................................................9

11. Appendices

Appendix 1 – What is enough sleep?......……………………..9

Appendix 2 – Shared Care Agreement……………………….10

Appendix 3 – Circadin MR tablets (Melatonin)………………11

Melatonin Guidelines Jan21 1

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1. Introduction

Background

Sleep disturbance in children and young person is common, especially in those with

neurological and/or behavioural disorders (Lin-Dyken and Dyken 2002, Ross, Davies,

Whitehouse 2007). Chronic sleep loss causes poor emotional processing, impaired cognition

(difficulties with executive function, attention, working memory and long term memory.). It

results in poor motor performance, an increased risk of general health problems and a

poorer quality of life generally. (www.innerdrive.co.uk)

Sleep disturbance may include delayed onset of sleep, frequent waking, early morning

waking or day-night reversal of sleep pattern (Jan, Espezel, and Appleion, 2008). The

resulting daytime sleepiness and associated cognitive impairment affects learning, behaviour

and emotional regulation, it also adds considerably to the burden of care.

Melatonin is a hormone secreted by the pineal gland which has an important role in the

regulation of circadian rhythm. Administration of synthetic melatonin promotes the onset of

sleep and has been used for the management of sleep difficulties in adults and children.

Melatonin

Melatonin, the hormone of the pineal gland, is normally made in response to dropping light

levels at night and after morning exposure to daylight. Production is affected by light

exposure detected by the retina; it is thought that this rhythm is disturbed in children with

brain damage, neurodevelopmental disorders such as autism or visual disturbance.

When given to humans it has a rapid half-life of half to one hour, producing transient, mild

sleep inducing effects (Wassmar and Whitehouse 2006). It lowers alertness, body

temperature and performance during the three or four hours after a low dose has been

given. Correctly timed, it is able to shift the internal ‘body clock’ both to later and earlier times

(BNF for Children 2015).

Children with Smith-Magenis syndrome have a reverse day night sleep pattern due to

abnormal melatonin secretion (Boudreau et al 2009)

Children with autism have lower melatonin levels (Rossignol et al 2014)

Melatonin is a hormone reported to improve the onset and duration of sleep in people with

Learning Disabilities, in particular those with cortical blindness (Antonia et Al 2017)

Although the evidence base for Melatonin is limited, it is actually more substantial than that

available to support the use of any alternative hypnotic (London New Drugs Group 2008).

Melatonin brand / formulary choices

Until 2019 there were no licensed melatonin preparations in the UK for use in children.

Slenyto is licenced for use in children with an Autism Spectrum Disorder and Smith- Magenis

Syndrome. It is a prolonged release formulation with a tiny 3mm tablet which is easy to

swallow for the paediatric population, however is not recommended to be prescribed within

Shropshire as it has not been authorised by Shropshire Area Prescribing Committee.

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A licensed modified release melatonin 2mg tablet (Circadin®) has been available since June

2008. Circadin® is only licensed for patients aged 55years and over, and in response to

guidance issued by MHRA on melatonin in 2008, its use in children is off-licence.

A melatonin 1mg/ml oral solution licensed for short-term treatment of jet lag in adults was

also released in 2019, however safety concerns regarding its excipients mean it should not

be prescribed off-license in children and young people.

Several strengths of melatonin capsules, tablets and liquids are available via Specials

manufacturers. These products are unlicensed and should not be prescribed if there is

licensed or off-license alternative (GMC)

MHRA guidance

MHRA stated that many non-pharmaceutical grade products of melatonin are being imported

from countries where melatonin is classed as a food supplement and so are not required to

be manufactured to the Good Manufacturing Practice (GMP) standard. The MHRA stated

that there should be a special clinical need should be submitted by the imported to MHRA if

imported melatonin was used, but if there was a licensed product available in the UK then

that should be prescribed.

If the dosage or formulation of Circadin® is not appropriate then a melatonin product that

does meet the GMP manufacturing standard could be used, but would be unlicensed.

Liquid preparations should only be prescribed for selected patients that cannot tolerate solid

dosage form, have swallowing difficulties, or because of the drug release characteristics.

Shropshire melatonin formulary

Melatonin formulary choices within Shropshire are;

 First line: Circadin MR 2mg Tablets - off-license

 Second line: melatonin 10mg/5ml oral solution - unlicensed

2. Purpose

The purpose of these guidelines is to provide clinicians with

 Guidance to the medical management of children and young people aged 2-18 years

old with sleep disorders within Shropshire Community Health Trust (SCHT).

 Recommendations on the cost-effective, evidence based prescribing of melatonin by

considering product formulations and brand.

3. Definitions and Glossary

BNFC

British National Formulary for Children

CAMHS

Child and Adolescent Mental Health Services

CHM

Commission on Human Medicines

CYP

Cytochrome P450

MHRA

Medicine and Healthcare Products Regulatory Agency

Off-licence

A licensed medication has been assessed for efficacy, safety

and quality and is manufactured to appropriate quality

standards. Age-appropriate formulations are difficult to

develop so are used off-licence. (www.gov.uk)

SCHT

Shropshire Community Health Trust

SPC

Summary of Product Characteristics

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4. Duties

4.1 Chief Executive

The Chief Executive has ultimate accountability for the strategic and operational

management of the Trust, including ensuring there are effective and appropriate processes

in place for the medical management of children.

4.2 Director of Nursing & Medical Director

The Director of Nursing & Medical Director has responsibility for ensuring that

Children are offered appropriate medical management.

4.3 Service Managers

Service Managers are responsible for the day-to-day operational management

and coordination of the medical management.

4.4 All Clinical Staff

Clinical staffs are key members in ensuring that children with sleep difficulties are managed

appropriately. All clinical staff who prescribe Melatonin are required to comply with this

guideline and report any adverse care related issues to their line manager and report any

adverse reactions.

5 Management of poor sleep in Children

5.1 Indications for Therapy

Randomized-controlled trials and clinical experience suggests that it may be of value for

treating sleep onset insomnia and delayed sleep phase syndrome in children with conditions

such as visual impairment, cerebral palsy, attention deficit hyperactivity disorder, epilepsy,

autism, and learning difficulties.

Melatonin will only be initiated where standard non pharmacological behavioural modification

methods have failed, and other medical causes of sleep disturbance such as sleep apnoea,

have been excluded i.e., Patients should first receive sleep hygiene advice.

5.2 Treatment Aims

The aim of treatment is to establish a regular nocturnal sleep pattern. This treatment is of

particular benefit when behavioural modification has been unsuccessful or very difficult to

achieve, especially in children with severe sleep disturbance.

5.3 Non-pharmacological Therapy

Non-pharmacological measures take precedence in the management of most disorders.

These interventions stated below should be initiated by the clinician before considering any

form of medication to treat the sleep difficulties.

Before starting melatonin treatment consider the use of a sleep diary; the use of sleep diary

is crucial in establishing the sleep routine and in determining the pattern of sleep difficulties.

Signposting to the relevant sleep management websites for Information regarding sleep is

essential. Parents should be provided with sleep information and advice sheets and

signposting to the children sleep charity website www.childrensleepcharity.org.uk See

Patient resources.

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Traditional non pharmacological sleep hygiene methods must have been tried and failed;

 Behavioural interventions like good sleeping hygiene and behavioural techniques for

managing sleep difficulties. See Patient resources.

 Cognitive behavioural therapy (CBT)may be more effective than hypnotics in

improving sleep in the longer term. Reduced hypnotic use and improved quality of

sleep has been shown with CBT.

5.4 Pharmacological Treatment with Melatonin

Consider initiating treatment with Melatonin when non-pharmacological measures have

failed. Behavioural therapies should be continued alongside medication as the combination

has been found to be more effective than medication alone.

Problems with sleep initiation

Standard release melatonin is indicated for children and adolescents who have problems

with sleep initiation. The starting dose is usually 2mg mg given 30-60 minutes before

bedtime. If there is no response or insufficient response after a minimum of 3 days therapy

the dose is increased to 6mg. In certain circumstances the dose can be increased up to a

maximum dose of 10mg.

Problems with both sleep initiation and sleep maintenance/fragmental sleep/early morning

awakening

Ideally Circadin tablets should be swallowed whole when their long acting properties will be

at their best Circadin can be crushed .This reduces its delayed absorption.

They can however be cut in half and swallowed without chewing, which will cause them to

retain their slow release characteristics.

A time period of 7-14 days is usually sufficient to determine if a specific dose is

effective, and if ineffective, melatonin can be stopped without the need for gradual

withdrawal

5.4.1 Dosage (by mouth)

Child 1 month–18 years:

 Initially 2 mg

 Dose may be doubled after 1-2 weeks of insufficient benefit

 Maximum daily dose 10 mg

 If no benefit is seen after 2 weeks, melatonin treatment should be stopped

The dose should be given 30-60 minutes prior to bedtime.

In sleep phase disorders, lower doses (0.5 to 1.0 mg) may be employed initially.

Change of formulation

If needing to change from immediate release (unlicensed) melatonin capsule to Circadin

Tablets then this can be done on a like for like basis

 3x2mg melatonin capsule = 3x2mg MR tablet (Ciracdin)

For patients not on an equivalent Circadin dose, the melatonin dose can be change to the

nearest dose

Melatonin Guidelines Jan21 4

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 2.5mg melatonin capsule = 2mg MR Circadin or 3mg MR Circadin (Circadin can be

halved whilst retaining slow release properties)

Swallowing difficulties or feeding tubes administration

Circadin

is a modified-release tablet, and is not licensed to be given through enteral feeding

tubes. However the manufacturers state that if necessary it can be crushed (note - this

would change it from a modified-release tablet to an immediate-release one) and mixed in

15-30mL of water for administration through enteral feeding tubes. The tube should be

flushed well after administration (NEWT guidelines, 2020).

Telford and Wrekin CCG have a PID (Prescribing information document) which we currently

use across the two CCGs

https://www.telfordccg.nhs.uk/your-health/medicines-management/shared-care-agreements-

prescribing-information-documents/central-nervous-system/central-nervous-system-prescribing-

information-documents/6400-melatonin-prescribing-information-dec-19/file

5.4.2 Contra-indications

Hypersensitivity to the active substance or excipients in each preparation

5.5 Cautions

There is no convincing evidence that melatonin adversely affects seizure control, indeed

improved sleep often improves common forms of However when used in patients with

epilepsy, it is important to monitor seizure frequency.

The manufacturer of the UK licensed product advises caution in patients with renal disorders

and not to use melatonin in patients with liver disorders some rare hereditary glucose

tolerance disorders (due to it containing lactose).

5.5.1 Side Effects

Melatonin is generally well-tolerated. Sedation and fatigue, headaches, skin disorders,

restlessness, increased pulse, itching and nausea have all been reported as side effects

associated with melatonin use.

Melatonin has no predictable effect upon seizure control (see above).

There is no safety data for long term use but it has been used in some patients with learning

disability throughout their childhoods. (P.Gringas et al 2012, 2017, A.Maras 2018)

The above details are not a complete list and the BNF and the summary of product

characteristics (SPC) remain authoritative. Full list of side effects is given in the Melatonin

(Circadin) SPC, available from Circadin - Summary of Product Characteristics (SmPC) - (emc)

(medicines.org.uk)

5.5.2 Interactions

Fluvoxamine and cimetidine has been shown to increase melatonin levels by inhibiting

cytochrome P450 (CYP), isozymes CYP1A2 and CYP 2D respectively and these

combinations should be avoided. There is a theoretical risk that any CYP1A2 inhibitors could

cause an increase in melatonin levels (e.g. oestrogens, quinolones).

CYP1A2 inducers such as carbamazepine and rifampicin may give rise to reduced plasma

concentrations of melatonin. Alcohol should be avoided as it reduces the effect of melatonin

on sleep.

Melatonin may enhance the effects of sedatives and hypnotics (e.g. benzodiazepines).

Melatonin Guidelines Jan21 6

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On initiation of melatonin the specialist will be responsible for checking interactions and

making necessary alterations in treatment.

The above details are not a complete list and the BNF and the SPC remain authoritative.

5.5.3 Pregnancy /Lactation

No clinical data on exposed pregnancies are available.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,

embryonic /foetal development, parturition or postnatal development. In view of the lack of

clinical data, use in pregnant women and by women intending to become pregnant is not

recommended.

Endogenous melatonin was measured in human breast milk thus exogenous melatonin is

probably secreted into human milk. There are data in animal models including rodents,

sheep, bovine and primates that indicate maternal transfer of melatonin to the foetus via the

placenta or in the milk. Breast-feeding is not recommended in women under treatment with

melatonin.

5.6 Monitoring

During initiation of treatment, sleep patterns should be documented in a sleep diary to

monitor efficacy.

In people with epilepsy, monitoring of seizure frequency is advised.

Review patients after four weeks to ensure that continued treatment with Melatonin is

appropriate and effective. Six monthly reviews should then take place to review the need for

ongoing treatment.

There should be at least an annual trial of cessation of treatment, a drug holiday of four to

six weeks, to assess if continued treatment is indicated. Timing of such a trial must take into

account individual circumstances where the impact of potential sleep disruption can be

minimised.

A drug holiday may also be indicated if melatonin stops working. Melatonin can then be

restarted at a lower dose after the wash out period.

Patients on long term treatment should be reviewed every 6 months to reduce the dose and

aim for withdrawal of treatment

5.6.1 Toxicity

It has been suggested that melatonin may affect the reproductive system by inhibiting the

hypothalamic-pituitary- gonadal axis. Growth and sexual development monitoring is

advisable, especially with long-term melatonin use.

This is primarily the responsibility of the Consultant clinician but any concerns from the

primary care clinician should be reported to the Consultant clinician.

(Melatonin is monitored intensively by the Commission on Human Medicines (CHM) and

MHRA - Please report any adverse reaction to the CHM, using the yellow card system

available online at Yellow Card Scheme - MHRA

6. Review and Compliance Monitoring

Compliance to guidelines can be audited through the audit cycle within the Children, Young

People and Families Service

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SCHT Medicines Management Team monitors all prescribing individuals within the trust via

ePact2.

Prescription costs are monitored within each department for as part of their budgeting

responsibilities.

7. Consultation

Consultation with Community Paediatric team; Dr M Ganesh, Dr S Buch, Dr G Minnaar, Dr S

Ogilvie, Dr S Postings, Dr D Short, Dr H Unsworth, Mrs N Kular Nurse consultant, and

Specialist Registrar Doctors.

Expert opinion from Diane Kitching (Lead Pharmacist for Children’s’ Community Services)

Susan Watkins (Chief Pharmacist))

8. Dissemination and Implementation

Dissemination to all Community Paediatric Clinicians who prescribe Melatonin within SCHT

9. References

BNF for children 2020

Jan, J.E., Espezel, H. and Appleion, R.E. (2008) ‘THE TREATMENT OF SLEEP

DISORDERS WITH MELATONIN’, Developmental Medicine & Child Neurology, 36(2), pp.

97–107.

Lin-Dyken, D.C. and Dyken, M.E. (2002) ‘Use of Melatonin in young children for sleep

disorders’, Infants & Young Children, 15(2), pp. 20–37.

Quera Salva, M., Hartley, S., Léger, D. and Dauvilliers, Y., 2017. Non-24-Hour Sleep–Wake

Rhythm Disorder in the Totally Blind: Diagnosis and Management. Frontiers in Neurology, 8.

London New Drugs Group. Melatonin in paediatric sleep disorders. APC/DTC Briefing.

London New Drugs Group. September 2008

Ross, C., Davies, P. and Whitehouse, W. (2007) ‘Melatonin treatment for sleep disorders in

children with neurodevelopmental disorders: An observational study’, Developmental

Medicine & Child Neurology, 44(5), pp. 339–344.

Wassmer, E. and Whitehouse, W.P. (2006) ‘Melatonin and sleep in children with

neurodevelopmental disabilities and sleep disorders’, Current Paediatrics, 16(2), pp. 132–

138.

A. Maras (2018) Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin

for Insomnia in Children with Autism Spectrum Disorder. Journal of Child and Adolescent

Psychopharmacology

P. Gringas (2012) Melatonin for sleep problems in children with Neurodevelopmental

disorders: randomised double masked placebo controlled trial. BMJ Research 5/11/12

P. Gringas et al.(2017 Efficacy and safety of Pediatric Prolonged –Release Melatonin for

Insomnia in children with Autistic Spectrum Disorder. Journal of American Academy of Child

and Adolescent Psychiatry. Vol 56 No11 November 2017

Prescribing unlicensed medicines - GMC (gmc-uk.org)

NEWT Guidelines 2020 [online] Available at NEWT Guidelines, www.newtguidelines.com

Melatonin Guidelines Jan21 7

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10. Useful patient resources

10 Steps to a Quiet Night available from “Ten Steps to a Quiet Night” (cchp.nhs.uk)

Healthy sleep tips for children www.nhs.uk/live-well/sleep-and-tiredness/healthy-sleep-tips-

for-children/

Taking Melatonin information leaflet download from medicines for children

https://www.medicinesforchildren.org.uk/melatonin-sleep-disorders

Sleep advice websites-www.cerebra.org.uk

www.thesleepcharity.co.uk

Good sleep habits booklet can be downloaded at:

www.autism.org.uk

11. Appendices

Appendix 1

What is enough sleep?

Below are the approximate hours of sleep needed by children of different ages (How

much sleep do children need? - NHS (www.nhs.uk)).

Babies 4 to 12 months old

 12 to 16 hours including naps

Toddlers 1 to 2 years old

 11 to 14 hours including naps

Children 3 to 5 years old

 10 to 13 hours including naps

Children 6 to 12 years old

 9 to 12 hours

Teenagers 13 to 18 years old

 8 to 10 hours

Sleep hygiene in children and young people | Great Ormond Street Hospital (gosh.nhs.uk)

Melatonin Guidelines Jan21 8

Melatonin Guidelines Jan21 9

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Shared Care Agreement

Agreement to transfer of prescribing to GP

Patient details

Drug name, dose and manufacturer: (NB for unlicensed formulations please remember to

specify manufacturer – Special Products Ltd should be the first line choice):-

Drug: Circadin MR Dose: 2mgs Manufacturer:

This shared care agreement outlines suggested ways in which the prescribing responsibilities can be

shared between the specialist and GP. GPs are invited to participate. If the GP is not confident to

undertake these roles, then he or she is under no obligation to do so. In such an event, the total

clinical responsibility for the patient’s mental health remains with the specialist. If a specialist asks the

GP to prescribe, the GP should reply to this request as soon as practicable.

Sharing of care assumes communication between specialist, GP and patient. The prescriber of the

medication legally assumes clinical responsibility for the drug and the consequences of its

use.

Nuala O’Kane – Chair

Patricia Davies – Chief Executive

Consultant: Dr

Address: Coral House, Longbow Close,

Shrewsbury, SY1 3GZ

Contact number:

GP:

Email:

Contact number:

Main carer: parent/guardian

Name:

Contact number:

Agreement to shared care, to be

signed by GP and Consultant before

prescribing is transferred to GP

Consultant Signature:

Date:

GP Signature:

Date:

Name:

Address:

Date of Birth:

NHS number:

Melatonin Guidelines Jan21 10

Appendix 2

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Circadin MR tablets (melatonin)

Advice for crushing

Circadin tablets may require to be crushed for ease of consumption. If so, the following

advice may be beneficial.

1. Tablet can be crushed by the use of the tablet crusher or between two metal spoons.

2. The crushed border should be added to 15 to 30 ML of water and mixed well.

3. The mixed solution should be drawn into an oral syringe.

4. The dose can then be administered to the child.

5. The tablet crusher should be rinsed with water and this should also be administered.

Alternatively, powder may be mixed with soft food.

Tablets should not be crushed in plastic containers, other than commercially available tablet

crushers, due to the possibility of the medicine sticking to the plastic container.

Boiling water should not be used.

Medicine should not be left unattended in syringes.

Medicine which has been prepared by someone else must not be administered.

Tablet crushers are inexpensive and can be purchased from your local community

pharmacy. They can be washed and dried after use.

If using two metal spoons, two spoons of similar size should be taken, sitting one spoon

inside the one below.

A small gap must be made between the spoons, and one tablet must be placed between

these surfaces and the spoons should be gently squeezed together.

The tablet should break up without shooting out. Further crushing will make a finer powder.

Even if tablet is roughly crushed, it will offer “immediate release” characteristics as desired.

Information from the manufacturer states that crushing a Circadin® tablet will not damage

the active ingredient (melatonin). There are no safety concerns with crushing Circadin®,

however it will affect prolonged-release properties of the product.

As long as the tablet is swallowed whole, the prolonged-release properties are maintained.

The prolonged-release properties will be maintained to some extent if the tablet is halved or

divided into 4 quarters.

For further queries, please speak to your prescriber or pharmacist.

Ref: www.newtguidelines.com

Melatonin Guidelines Jan21 11

Appendix 3