Guidelines for the unlicensed use of Melatonin for the Treatment of Sleep Disorders in children with Visual Impairment/Blindness, Attention Deficit Hyperactivity Disorder (ADHD), Autism, Emotional/ Behavioural

Difficulties or Attachment Disorder

Version number Month Year

Policy TitleState previous title where relevant.

Guidelines for the unlicensed use of Melatonin for the Treatment of Sleep Disorders in children Visual Impairment/Blindness, Attention Deficit Hyperactivity Disorder (ADHD), Autism, Emotional/ Behavioural Difficulties or Attachment Disorder

State if Policy New or Revised NewPolicy StrandOrg, HR, Clinical, H&S, Infection Control, FinanceFor clinical policies only - state index category

Clinical

Links to National Regulatory Standards:Care Quality Commission(CQC)NHS Litigation Authority (NHSLA)National Institute for Health & Clinical Excellence (NICE)Policy Lead/AuthorJob titles only Chief Pharmacist

ConsultationState year and the individuals, groups, committees, service users, working partners etc. you have consulted with

Medicines Management Committee 2015

RatificationState ratified by whom - Policy Ratification Group, Executive Committee or Director

Medicines Management Committee 2015

Equality Impact Assessment

Implementation PlanMedicines Management NewsletterPrescribing Update memo to prescribersPublish to Intranet

Month/year policy first developed October 2015

Months/years policy reviewedKeep review dates in chronological order

Next review due October 2018

Review detailsRevisions made, changes etc include page numbers and paragraphs

New Policy

For Corporate Executive Support use

Date Policy First Uploaded to Intranet

Date Policy Revised & Reloaded to Intranet

Ref. Contents Page

1.0 Introduction

2.0 Purpose

3.0 Objectives

4.0 Definitions

5.0 Duties

6.0 Committee/Group Responsible for Approval of this Policy

7.0 Process

8.0 Monitoring Compliance

9.0 Standards/Key Performance Indicators

10.0 Equality Impact Assessment

11.0 Training

12.0 Data Protection Act and Freedom of Information Act

13.0 References

13.1 Legislation

14.0 Links to other Policies and Procedures

Appendices

Appendix 1 Melatonin Effective Shared Care Agreement

Appendix 2 Melatonin Leaflet

Review and Amendment Log

Version Reason Status Date Description of Change

1.0 Introduction Sleep disorder is a common symptom in childhood. The underlying causes may be behavioural, psychological or related to underlying mood disorders.

V1.1 October 2015 2

Guidelines for the unlicensed use of Melatonin for the Treatment of Sleep Disorders in children with Visual Impairment/Blindness, Attention Deficit Hyperactivity Disorder (ADHD),

Autism, Emotional/ Behavioural Difficulties or Attachment Disorder

All forms of sleep disorders are more common in children with learning and behavioural difficulties, autism, ADHD and sensory impairments (particularly visual).

Although behavioural interventions should be the primary intervention and has robust evidence base, exogenous melatonin is the ‘first-line’ medication prescribed for childhood insomnia and sleep disorders.

Current guidance and published data around the use of Melatonin is lacking in children. The Children’s BNF states that clinical experience suggests that ‘melatonin may be of value for treating sleep onset insomnia and delayed sleep phase syndrome in children with conditions such as visual impairment, cerebral palsy, ADHD, autism and learning difficulties. The NICE Evidence Summary for unlicensed or off-label medicine relating to melatonin use in children reports that there are ‘no high-quality studies’ to provide evidence for efficacy of the UK-licensed prolonged release product used off-label in children with sleep disorders of ADHD, but there is limited evidence for unlicensed products.

Only one form of melatonin (Circadin® 2mg prolonged-release tablets) is currently licensed in the UK for the short term treatment of primary insomnia, characterised by poor quality of sleep, in adults who are aged 55 years or over. Under the license treatment is limited to a fixed dose of 2mg daily for up to 13 weeks. Additional melatonin products are available from special-order manufacturers or specialist importing companies however the costing and quality of such products is variable.

The Medicines and Healthcare Products Regulatory Authority (MHRA) recognises that melatonin use spans a wider remit than the licensed indication for Circadin® with regard to client group and formulation. For a given clinical indication, where a product is licensed for use in that indication it should be used in preference to any product that does not hold a product license for use in that indication. Where there’s no licensed product for a specific clinical indication, the use of appropriate licensed product outside of its license (off-label) is preferred to the use of a product that does not hold any product license.

2.0 Purpose

The aim of this document is to provide prescribers with: Guidelines to manage sleep disorders in children with Visual

Impairment/Blindness, Attention Deficit Hyperactivity Disorder (ADHD), Autism, Emotional/ Behavioural Difficulties or Attachment Disorder.

Recommendations on prescribing melatonin cost-effectively by considering the brand and formulation choices available

Guidelines on the transfer of melatonin prescribing from consultant to GP in primary care as part of an Effective Shared Care Arrangement (ESCA).

3.0 Objectives

These guidelines are intended to:

V1.1 October 2015 3

ensure the appropriate prescribing of melatonin in the treatment of sleep disorders in children with visual impairment/blindness, ADHD, autism, emotional/ behavioural difficulties or attachment disorder

ensure cost-effective prescribing of melatonin support the prescribing of melatonin across the health economy via an ESCA.

4.0 Definitions

Melatonin – the hormone of the pineal gland is normally made in response to dropping light levels and after morning exposure to daylight. When given to humans it has a rapid half-life of half to one hour, producing a transient, mild sleep inducing effect. It lowers alertness, body temperature and performance during the three or four hours after a low dose has been administered.

MHRA – Medicines and Healthcare Regulatory Agency

NICE – National Institute of Clinical Excellence

Specials Manufacturing – ‘Specials’ are products which have been specially manufactured or imported for the treatment of an individual patient after being ordered by a doctor, dentist, nurse independent prescriber, pharmacist independent prescriber, supplementary prescriber.

ESCA – Effective Shared Care Agreement

5.0 Duties

Adherence to this policy is the responsibility of all staff who are involved in the prescribing of medication to children in mental health services.

6.0 Committee/Group Responsible for Approval of this Policy

The Medicines Management Committee is responsible for approval of this policy.

7.0Process

7.0 Management of Poor Sleep in Children

V1.1 October 2015 4

7.1 Non-pharmacological Therapy

Consider the use of a sleep diary; sleep information and advice sheet prior to the use of any drug treatment. Traditional, non-pharmacological sleep hygiene methods must have been tried and failed; such as:

Behavioural interventions - Advice on good sleep habits and behavioural techniques for managing sleep difficulties can give good effects and should always be tried prior to starting medication.

Cognitive behavioural therapy may be more effective than hypnotics in improving sleep in the long term. CBT has been shown to improve sleep quality, reduce hypnotic drug use and improve health related quality of life among long term hypnotic users with chronic sleep difficulties.

Self-help strategies (DVDs, audio-CDs) have a small but potentially worthwhile benefit.

Non-pharmacological strategies may have limited application where a patient’s condition is impaired.

Measurement and documentation of effectiveness of Intervention (clinician and patient/carer reports)

Parents should keep a sleep diary both prior to commencing medication and once medication is started. Review of the diary should occur at follow-up to inform decisions regarding dosage and continuation. Effectiveness of interventions should be documented in the clinical notes at review.

7.2 Pharmacological Treatment with Melatonin

Consider initiating treatment with melatonin when non-pharmacological sleep hygiene methods have been tried and failed.

Dose:- The usual starting dose of melatonin for sleep disorders is 1-2 mg in children

above the age of two. - The dose may be doubled if there is insufficient benefit after 1-2 weeks. - Maximum Dose - doses higher than 10 mg are not considered to be of

greater efficacy. - If no benefit is seen after 2 weeks, then melatonin should be stopped.

Contraindications:- Hypersensitivity to active substances or excipients (see Circadin SPC).

V1.1 October 2015 5

Cautions in use:- The manufacturer of Circadin® advises caution in patients with renal disorders

and not to use melatonin patients with liver disorders.- No evidence of safety in pregnancy or breastfeeding. - The frequency of seizures should be monitored in children or adolescents with

epilepsy given melatonin. - The manufacturer of Circadin® advises melatonin should not be used in

patients with autoimmune and some rare hereditary glucose tolerance disorders.

- Not to be used by children under one year of age.

Adverse effects:- Melatonin is generally well tolerated.- In clinical studies the most common adverse events were headache,

dizziness, drowsiness, pharyngitis, back pain and fatigue. These occurred at a similar frequency to placebo.

- There was no evidence of withdrawal effects following treatment discontinuation.

- Vivid dreams and nightmares have been reported - Some reports suggest melatonin improves seizure control when used in

patients with epilepsy; others indicate that it may worsen seizure control. When used in patients with epilepsy, it is important to closely monitor the effect of melatonin on seizure frequency.

- No robust large controlled clinical studies have been conducted in children and adults with learning disabilities and epilepsy taking melatonin, so its safety in this group has not been established.

- Many of the children who have received melatonin in the published RCTs had developmental problems. The scope for detecting subtle adverse effects in this population was limited. Common side effects reported included: headache, depression, restlessness, confusion, nausea, tachycardia and pruritis.

Drug Interactions:- Melatonin’s metabolism is mainly mediated via CYP1A enzymes. Therefore

interactions may occur between melatonin and other drugs affecting or metabolised by CYP1A enzymes e.g. fluvoxamine, cimetidine, ciprofloxacin and other quinolones, carbamazepine, omeprazole, oestrogens (oral contraceptives and HRT), rifampicin, theophylline and. Increase in blood pressure with nifedipine and reduced prothrombin with warfarin have been reported.

- There is a large amount of data in the literature regarding the effect of adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressant medicinal products, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenous melatonin secretion. Whether or not these active substances interfere with the dynamic or kinetic effects of Circadin or vice versa has not been studied.

V1.1 October 2015 6

- Alcohol should not be taken with melatonin, because it reduces the effectiveness of melatonin on sleep.

- Melatonin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone.

- Circadin has been co-administered in studies with thioridazine and imipramine, active substances which affect the central nervous system. No clinically significant pharmacokinetic interactions were found in each case. However, Circadin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy-headedness” compared to thioridazine alone.

7.3Continuation of behavioural interventions in combination with medication is more effective than medication alone.

7.4Melatonin Brand/Formulation choices

In August 2008 the MHRA issued guidance on the use of melatonin. Many non-pharmaceutical grade products of melatonin are being imported from countries where melatonin products are classed as food supplements, not medicines, they are not required to be manufactured to the standard of Good Manufacturing Practice (GMP) normal for pharmaceuticals. It is believed that at least 50 melatonin preparations are being imported into, or manufactured in the UK. To encourage the use of melatonin manufactured according to GMP the MHRA advised that if imported melatonin was used then the special clinical need should be provided to the importer for submission to the MHRA. Melatonin 2 mg prolonged release (Circadin®) is now licensed as monotherapy for the short term treatment of primary insomnia in adults aged 55 years and over. The MHRA advised … ‘It is therefore important to ensure that the licensed product available in the UK is used where possible.”

If this dosage or formulation of Circadin® is not appropriate a melatonin product manufactured according to GMP should be used, although this will be an unlicensed product.

First line –The licensed product Melatonin 2 mg MR (Circadin®) for an unlicensed indication, if the dose is appropriate.

It is recommended that melatonin be given on an empty stomach, since the absorption may be delayed when taken with large meals. It should be taken one to two hours before bedtime.

Please note patients who experience difficulties in swallowing the tablet, breaking or sub-division and crushing the tablet alters the release characteristics approximate to an immediate release dose form. The in-vitro release from a crushed or powdered tablet is expected to provide an immediate release profile similar to that from an unlicensed immediate release tablet or (unlicensed) oral solution and as such provides a viable

V1.1 October 2015 7

alternative to either of these options. However, to the extent that Circadin® is a licensed product, its use outside of licence (in so far as the tablet is broken or crushed) is considered preferable to an unlicensed presentation of melatonin.

If an unlicensed product is clinically indicated, rather than the licensed product, e.g. because of swallowing difficulties with tablets, or because of the release characteristics, then a number of Specials Manufacturing Companies are able to supply melatonin capsules or liquid that are manufactured in the UK according to GMP. Further information and advice is available from the Trust’s pharmacy department.

Liquid preparations should only be prescribed for selected patients that truly cannot tolerate solid oral preparations. If only a liquid preparation is suitable, ensure this is prescribed as per the Drug Tariff version i.e. Melatonin 5mg/5ml oral solution x 200ml. Patients prescribed other non-tariff strengths (i.e. 2.5mg/5ml or 10mg/5ml) or formulations (i.e. suspension), should be changed (with equivalent volume of dose amendment) to the tariff listed strength and formulation.

Changing from immediate release melatonin to prolonged release melatonin When the dose of melatonin capsules is equivalent to a dose of Circadin then this can be changed to the same dose e.g. 6mg of unlicensed melatonin capsules to 3 x 2mg of Circadin. For patients not on an equivalent dose, this can be changed to the next nearest dose e.g. 2.5mg capsules to 2mg tablets or 3mg capsules to 2 x 2mg Circadin. Patients who have difficulty swallowing tablets or who open capsules should not be changed.

7.5DocumentationThe off-label or unlicensed use of melatonin is documented in the patient’s clinical notes recording that it has been discussed with the patient’s carers in line with the guidance provided in the Unlicensed Medication Policy. Appropriate consent should be obtained and filed in the patient’s notes. Patient information leaflets are available on the Trust intranet – See Appendix 2.

7.6Effective Shared Care Agreement

Once stabilised, shared care is appropriate, in accordance with the ESCA (see appendix 1).

7.7 Review of therapy

It is recommended that the patients are followed up two weeks after initiation to assess benefit of treatment and then every six months to ensure continuing benefit of melatonin.

Standard monitoring of growth and sexual development is recommended when treating children i.e. height, weight and pubertal development progress.

V1.1 October 2015 8

Monitoring of side effects should be done on a regular basis and reviewed at each appointment. GPs should also be involved in the review of side effects and this information be relayed back to the consultant.

Length of trial for effectiveness

The aim is to establish healthy sleep habits with the lowest effective dose. At least six months of an improved sleep pattern should elapse before withdrawal takes place.

Drug holidays if tolerance is suspected

Tolerance is characterised by the administration of a drug in higher doses to achieve the same effect. It is not listed on the Summary of Product Characteristics (SPC) for Circadin®. However, some clinical experience from the National Child and Adolescent Learning Disability Psychiatry Network suggests that the efficacy may be lost if melatonin is prescribed for longer than two years. It suggests that if the melatonin is withdrawn prior to this, sensitivity may be re-established and melatonin successfully re-introduced at a lower dose.

Withdrawal of treatment

Withdrawal may occur over a period of 3-4 weeks. However, for some children if withdrawal is not successful treatment may be necessary long term.

8.0Monitoring compliance

To ensure that the MHRA guidance is adhered to, the safe prescribing of melatonin in children will be reviewed every six months by analysing prescribing data available from e-PACT.

9.0 Equality Impact Assessment

The Black Country Partnership NHS Foundation Trust is committed to ensuring that the way we provide services and the way we recruit and treat staff reflects individual needs, promotes equality and does not discriminate unfairly against any particular individual or group. The Equality Impact Assessment for this policy has been completed and is readily available on the Intranet. If you require this in a different format e.g. larger print, Braille, different languages or audio tape, please contact the Equality & Diversity Team on 0121-612-8067 or email EqualityImpact.assessment@bcpft.nhs.uk.

10.0 TrainingTraining on this policy should be given to all new members of staff who are expected to work under it. Staff should ensure they maintain a working knowledge of this policy and

V1.1 October 2015 9

read as often as required to ensure competence under it. Staff should be re-trained on this policy when an incident occurs. Where specific training needs are identified, please contact the CAMHS manager.

11.0 Data Protection Act and Freedom of Information Act

All staff have a responsibility to ensure that they do not disclose information concerning the Trust’s activities or about service users in its care to unauthorised individuals. This responsibility applies whether you are currently employed or after your employment ends and in certain aspects of your personal life e.g. use of social networking sites etc. The Trust seeks to ensure a high level of transparency in all its business activities but reserves the right not to disclose information where relevant legislation applies.

12.0 References

1 Wassmer E and Whitehouse WP. Melatonin and sleep in children with neurodevelopmental disabilities and sleep disorders. Current Paediatrics;2006:16:132-8

2 Arendt J. Melatonin. British Medical Journal 1996;312:1242-33 Melatonin in paediatric sleep disorders. London New Drugs Group

September 20084 BNF for Children 2011-125 Prescribing Guidelines: Melatonin. South Staffs and Shropshire

Healthcare Foundation Trust6 Regional Drug and Therapeutics Centre. Melatonin for sleep disorders

in adults. New Drug Evaluation No. 90 June 20087 National Children and Adolescent Learning Disability Psychiatry

Network. 20088 Alder Hey Royal Liverpool Children’s NHS Trust. Guidelines on

melatonin. 20009 Drug Procurement Advise. Restrictions on the import of unlicensed

melatonin products following the grant of a marketing authorisation for Circadin® 2mg tablets. MHRA August 2008

10 Summary of Product Characteristics (SPC) – Circadin, Flynn Pharmaceuticals. http://www.medicines.org.uk/emc/medicine/25643/SPC/

11 ESUOM2: Sleep disorders in children and young people with attention deficit hyperactivity disorder: melatonin

12 In-vitro Release (Dissolution) of Circadin® from Intact, Divided and Crushed Melatonin Tablets. Data on File. Flynn Pharmaceuticals

13 Dudley and Walsall Mental Health Trust: Guidance on The Prescribing of Melatonin in Children for the Treatment of Sleep Disorders

13.0 Links to other Policies and Procedures

V1.1 October 2015 10

BCPFT Unlicensed Medicines policyBCPFT Medicines Policy

Appendix 1

V1.1 October 2015 11

Effective Shared Care Agreement for MelatoninFor the treatment of sleep disorders in children with visual impairment or blindness, attention deficit hyperactivity disorder, autism (Unlicensed Use). Melatonin is licensed for the short term treatment of insomnia in patients age over 55 years.

Patient’s Name: NHS Number:

Date of Birth: Date Treatment Started:

Name of drug:

(Add Date)

One copy of information leaflet given to patient

One copy of agreement sent to general practitioner

One copy filed in patients notes

Name of Initiating Doctor:

Consultant:

Speciality:

Fax Number:

PRIMARY CARE SECTION TO BE COMPLETED BY GENERAL PRACTITIONER

I agree*/don’t agree* to enter into a shared care arrangement for the treatment of the above patient with this medicine (*delete as appropriate)

GP Name:

Signature: Date:

Once signed please detach this sheet and fax to the number shown above.

V1.1 October 2015 12

ADVICE AND SUPPORT (Please contact the specialist who initiated the treatment)

Contact details Telephone No.Specialist:Consultant Psychiatrist – CAMHS (West Bromwich) 0121 612 6620Consultant Psychiatrist – CAMHS (Wolverhampton) 01902 444021

Other:Prescribing and Medicines Management Team (West Bromwich)

0121 612 2802

Prescribing and Medicines Management Team, Wolverhampton 01902 575209Chief Pharmacist at Black Country Partnership NHS Foundation Trust

0121-612-8609

Effective Shared Care Agreement for Melatonin

V1.1 October 2015 13

For the treatment of sleep disorders in children with visual impairment or blindness, attention deficit hyperactivity disorder, autism (Unlicensed Use). Melatonin is licensed for the short term treatment of insomnia in patients age over 55 years.

Patient’s Name: NHS Number:

Date of Birth: Date treatment commenced:

Name of drug, form and dosage:

AREAS OF RESPONSIBILITY FOR THE SHARING OF CAREThis shared care agreement outlines suggested ways in which the responsibilities for managing the prescribing of melatonin can be shared between the specialist and general practitioner (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 for the diagnosed condition remains with the specialist. Sharing of care assumes communication between the specialist, GP and patient. The intention to share care is usually explained to the patient by the specialist prescriber initiating treatment. It is important that patients/carers are consulted about treatment and are in agreement with it.

The prescriber of the medication legally assumes clinical responsibility for the drug and the consequences of its use.

RESPONSIBILITIES and ROLESSpecialist Responsibilities

1. Initiate melatonin and stabilise patient on a maintenance dose, selecting appropriate product and providing patient with appropriate formulation. (See BCFPT Guidance: The Prescribing of Melatonin in Children for the Treatment of Sleep Disorders.

2. Discuss the benefits and side effects of treatment with the patient, including that the medication is unlicensed.

3. Transfer all appropriate information of the treatment to the GP for effective continuity of care.

4. Ensure that the patient has enough medication, at least two weeks supply during transfer of care. Clearly indicate the name, strength and formulation of the chosen melatonin preparation and any future dose changes in the letter to the patient’s GP. The recommended brand is Circadin® 2mg MR tablet.

5. Have a mechanism in place for regular review treatment to monitor the parameters as listed below and patient’s response to the medication (see paragraph 4 below).

6. Inform GP on the outcomes of medication review.7. Report adverse events to the CSM and GP.8. Ensure that clear backup arrangements exist for GPs to obtain advice and

support.

V1.1 October 2015 14

General Practitioner Responsibilities1. Reply to the request for shared care as soon as possible (within two weeks).2. Prescribe melatonin within the dose ranges and period of treatment specified or

recommended. Adjust the dose as advised by the specialist.3. Report to and seek advice from the specialist on any aspect of patient care that is

of concern and may affect treatment with melatonin.4. Refer patients to the specialist if their condition deteriorates.5. Liaise with the patient’s nominated community pharmacy, if required, regarding

supply.6. Stop treatment on the advice of the specialist or immediately if an urgent need to

stop treatment arises.7. Report adverse events to the specialist and CSM.8. Inform specialist of all relevant medical information regarding the patient and any

changes to the patient’s medication irrespective of indication.

Patient's / Carer’s Role1. Inform specialist or GP of any other medication being taken, including over-the-

counter products.2. Report to the specialist or GP if he or she does not have a clear understanding of

the treatment.3. Share any concerns in relation to the treatment with melatonin and report any

adverse effects or problems to the specialist or GP.4. Attend appointments for review of treatment arranged by the specialist or GP.

SUPPORTING INFORMATION

1. Therapeutic UseMelatonin is a hormone that is produced by the pineal gland in the brain. Melatonin is produced naturally by the body during the hours of darkness and is involved in the promotion of sleep. It is used in the treatment of sleep disorders in children with visual impairment or blindness, cerebral palsy, attention deficit hyperactivity disorder, autism, epilepsy and in the treatment of sleep disorders in patients with learning disabilities or dementia. Treatment must be initiated by or under the supervision of a physician with appropriate knowledge and experience of childhood behavioural disorders or learning disabilities. It may be used in short courses of a few weeks to help re-establish a good sleep routine, or as a continuous medication. For some patients where it appears to lose its effect after a while, it should be given for blocks of a few weeks with a few days break before restarting

2. Choice of products and NHS Cost.Only one brand of melatonin is licensed in the UK (Circadin® - Melatonin 2mg prolonged-release tablets). Licensed preparation is to be preferred over an unlicensed one and use in many circumstances may be “off-label”. Prescribers should always consider licensed preparation first and unlicensed products are restricted to where there is need for dose titration or when patients are not be able to take solid dosage. Liquid preparations should only be prescribed for selected patients that truly cannot tolerate solid oral preparations.

V1.1 October 2015 15

Prescriptions should state the drug, strength, form, frequency and quantity to be supplied e.g. Melatonin MR 2mg tablets, one at night crushed and mixed with water, 28 tablets.

The MHRA advice is to prescribe in the following order of preference:

I. If there is a licensed product available it should be used, even if it is for an unlicensed use. This means Circadin® 2mg sustained release tablets. These are in packs of 21, not 28, so prescribe quantities with care. This should be the preparation of choice unless there are clear reasons why it will be inappropriate.

II. Liquid preparations If only a liquid preparation is suitable, ensure this is prescribed as per the drug tariff version i.e. Melatonin 5mg/5ml oral solution x 200ml. Patients prescribed other non-tariff strengths (i.e. 2.5mg/5ml or 10mg/5ml) or formulations (i.e. suspension), should be changed (with equivalent volume of dose amendment) to the tariff listed strength and formulation.

3. Dose and Administration See BCPFT Guidance: Guidelines for the unlicensed use of Melatonin for the Treatment of Sleep Disorders in children with Visual Impairment/Blindness, Attention Deficit Hyperactivity Disorder (ADHD), Autism, Emotional/ Behavioural Difficulties or Attachment Disorder

Changing from immediate release melatonin to prolonged release melatonin When the dose of melatonin capsules is equivalent to a dose of Circadin® then this can be changed to the same dose e.g. 6mg of unlicensed melatonin capsules to 3 x 2mg of Circadin®. For patients not on an equivalent dose, this can be changed to the next nearest dose e.g. 2.5mg capsules to 2mg tablets or 3mg capsules to 2 x 2mg Circadin® or 1 x 2mg Circadin®. Patients who have difficulty swallowing tablets or who open capsules should not be changed. If in doubt seek advice from the specialist who initiated treatment.

4. Monitoring Requirements: The need to continue melatonin therapy should be reviewed every 6 months.

5. Side EffectsMelatonin appears to have very few adverse effects such as worsening of seizures and exacerbation of asthma, so should be used with caution in patients with a history of seizures and respiratory disorders. Other reported side effects include headaches, dizziness, nausea and excessive drowsiness. There is limited information about the long term adverse effects, so routine screening for side effect is recommended. All suspected reactions (including those considered not to be serious and even where the causal link is uncertain) should be reported to the CSM.

6. Drug InteractionsMelatonin’s metabolism is mainly mediated via CYP1A enzymes. Therefore interactions may occur between melatonin and other drugs affecting or metabolised by CYP1A enzymes e.g. fluvoxamine, cimetidine, ciprofloxacin and other quinolones, carbamazepine, omeprazole, oestrogens (oral contraceptives and HRT), rifampicin, theophylline and. Increase in blood pressure with nifedipine and reduced prothrombin with warfarin have been reported.

V1.1 October 2015 16

Parameter Frequency of monitoring ActionHeight 6 monthly By SpecialistWeight 6 monthly By Specialist

Pubertal development 6 monthly By Specialist

There is a large amount of data in the literature regarding the effect of adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressant medicinal products, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenous melatonin secretion. Whether or not these active substances interfere with the dynamic or kinetic effects of Circadin or vice versa has not been studied.

Alcohol should not be taken with melatonin, because it reduces the effectiveness of melatonin on sleep.

Melatonin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone.

Circadin has been co-administered in studies with thioridazine and imipramine, active substances which affect the central nervous system. No clinically significant pharmacokinetic interactions were found in each case. However, Circadin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy-headedness” compared to thioridazine alone.

References

BNF for children. 2014-2015 NHS Quality Improvement Scotland. Evidence Note. No. 14. Dec 2006 Regional Drug and Therapeutics Centre: Drug Update. No. 44. November 2005. Great Manchester Interface Prescribing Group. Shared Care Guideline for Melatonin for Sleep

Disorder LNDG review: Melatonin in paediatric sleep disorders (Sep 2008)

http://www.nelm.nhs.uk/en/NeLMArea/ Evidence/Drug-Specific-Reviews/Melatonin-in-paediatric-sleep-disorders/?query=melatonin&rank=4

Dudley and Walsall Mental Health Trust. Guidance on The Prescribing of Melatonin in Children for the Treatment of Sleep Disorders

BCPFT Guidance: Guidelines for the unlicensed use of Melatonin for the Treatment of Sleep Disorders in children with Visual Impairment/Blindness, Attention Deficit Hyperactivity Disorder (ADHD), Autism, Emotional/ Behavioural Difficulties or Attachment Disorder

Version Control

Version Date of Issue Author/s Brief Description of Changes

1.0 September 2015

V1.1 October 2015 17

Appendix 2 - Melatonin LeafletMelatonin for children

What is melatonin? Melatonin is a natural hormone that regulates the sleep/wake cycle. When children have a disturbed sleep cycle, melatonin can help restore a more natural sleep pattern. Melatonin work best in combination with good night-time routines and is not intended to be a long-term treatment.

Who needs melatonin? Melatonin is mainly used for children with cerebral palsy, Attention Deficit Hyperactivity Disorder (ADHD), autism, learning disabilities or visual impairment.

Who can prescribe melatonin? Only specialist paediatricians and psychiatrists can initiate treatment and prescribe for the first few months of treatment. Initially you may be given a liquid version of melatonin to help find the best dose to treat your child. Once the most effective dose has been found, your child will be transferred to tablets. The prescribing responsibility may then be shared with your GP. The specialist will review the continued need for melatonin every six months. Attempts will be made to wean your child off melatonin once a good sleep routine is established or if melatonin is no longer considered effective.

What form of melatonin will be supplied? Melatonin is available as a modified-release tablet called Circadin™. However, this is licensed for use only in people aged over 55. This does not mean that it is unsafe to use Circadin™ in younger people, just that the manufacturer has not applied to the Medicines Healthcare Products Regulatory Agency for a licence. Many medicines are not licensed for use in children but are considered safe and effective. There is evidence to support the use of melatonin in younger people available at NICE Evidence Summary for melatonin in children and young people.

How will melatonin be prescribed? Once the most effective dose for your child has been found, the specialist will give you a prescription for Circadin™ which can be taken to your usual chemist. Repeat prescriptions for Circadin™ will continue to be supplied by the specialist until such time as it is considered appropriate for your GP to take over the prescribing.

How does my child take melatonin? Circadin™ tablets should normally be swallowed whole with a glass of water one to two hours before bedtime. This is because they are a modified (slow) release tablet; this means that the melatonin is released over a period of time. Depending on the dose prescribed, you may need to cut the tablets in half. Tablet-cutters are available from your chemist.

V1.1 October 2015 18