Approval of funding for modified-release melatonin for insomnia in children and adolescents with neurodevelopmental disorders

13 June 2017

Medicines Decision

PHARMAC is pleased to announce the approval of a proposal to fund modified-release melatonin for children and adolescents with insomnia secondary to neurodevelopmental disorders through an agreement with Aspen, from 1 July 2017.

This proposal was the subject of a consultation letter dated 8 May 2017. The proposal was approved as consulted on with some minor changes that are outlined below.

In summary, the effect of the decision is that:

melatonin 2 mg modified-release tablets (Circadin) will be funded in the community from 1 July 2017 via Special Authority for the treatment of secondary insomnia in children and adolescents up to the age of 18 years with neurodevelopmental disorders (an off-label indication);
the Circadin brand of melatonin 2 mg modified-release tablets will be listed on the Hospital Medicines List (HML) from 1 July 2017;
the HML restrictions for melatonin will be widened to include the treatment of secondary insomnia in children and adolescents up to the age of 18 years with neurodevelopmental disorders;
four of the unregistered presentations of melatonin currently listed on the HML (tab 1 mg and 2 mg, and cap 2 mg and 3 mg) will be delisted on 1 January 2018;
the tab 3 mg unregistered presentation of melatonin currently listed on the HML will remain listed for in-hospital use for extemporaneous compounding purposes only.

More information

We acknowledge that the use of melatonin in children and adolescents with neurodevelopmental disorders is an off-label indication and, as such, there is limited information available in New Zealand about the use of melatonin in this patient group. A copy of the August 2015 issue of Best Practice Journal is attached to this letter which contains information on the use of melatonin, including off-label use.

This can also be found online at: https://www.bpac.org.nz/BPJ/2015/August/melatonin.aspx(external link)

PHARMAC’s website has been updated to provide information on the administration of Circadin to children and adolescents with neurodevelopmental disorders, including suggestions about how to use Circadin in situations where patients may have difficulty swallowing [link no longer available].

Further background information on melatonin funding applications including links to previous clinical advice and consultation/notification documents can be found on the Application Tracker on PHARMAC’s website at: https://connect.pharmac.govt.nz/apptracker/s/global-search/melatonin(external link).

Details of the decision

Melatonin (Circadin) tab modified-release 2 mg will be listed in Section B and in Part II of Section H (the HML) of the Pharmaceutical Schedule from 1 July 2017 at a price and subsidy of $28.22 per pack of 30 (ex-manufacturer, excluding GST).
A confidential rebate will apply to Circadin that will reduce its net price to the Funder.
Melatonin tab modified-release 2 mg will be subject to the following Special Authority restrictions in Section B of the Pharmaceutical Schedule from 1 July 2017:

Special Authority for Subsidy

Initial application only from a psychiatrist, paediatrician, neurologist or respiratory specialist, or medical practitioner on the recommendation of a psychiatrist, paediatrician, neurologist or respiratory specialist. Approvals valid for 12 months for applications meeting the following criteria:

All of the following:

Patient has been diagnosed with persistent and distressing insomnia secondary to a neurodevelopmental disorder (including, but not limited to, autism spectrum disorder or attention deficit hyperactivity disorder)*; and
Behavioural and environmental approaches have been tried and were unsuccessful, or are inappropriate; and
Funded modified-release melatonin is to be given at doses no greater than 10 mg per day; and
Patient is aged ≤18 years*.

Renewal only from a psychiatrist, paediatrician, neurologist or respiratory specialist, or medical practitioner on the recommendation of a psychiatrist, paediatrician, neurologist or respiratory specialist. Approvals valid for 12 months for applications meeting the following criteria:

All of the following:

Patient is aged ≤18 years*; and
Patient has demonstrated clinically meaningful benefit from funded modified-release melatonin (clinician determined); and
Patient has had a trial of funded modified-release melatonin discontinuation within the past 12 months and has had a recurrence of persistent and distressing insomnia; and
Funded modified-release melatonin is to be given at doses no greater than 10 mg per day.

Note: Indications marked with * are Unapproved Indications.

From 1 July 2017, the restrictions applying to melatonin in the HML will be replaced with the following, which adds the secondary insomnia indication:

Restricted

Initiation – insomnia secondary to neurodevelopmental disorder

Psychiatrist, paediatrician, neurologist or respiratory specialist

Re-assessment required after 12 months

All of the following:

Patient has been diagnosed with persistent and distressing insomnia secondary to a neurodevelopmental disorder (including, but not limited to, autism spectrum disorder or attention deficit hyperactivity disorder); and
Behavioural and environmental approaches have been tried or are inappropriate; and
Funded modified-release melatonin is to be given at doses no greater than 10 mg per day; and
Patient is aged ≤18 years.

Continuation – insomnia secondary to neurodevelopmental disorder

Psychiatrist, paediatrician, neurologist or respiratory specialist

Re-assessment required after 12 months

All of the following:

Patient is aged ≤ 18 years; and
Patient has demonstrated clinically meaningful benefit from funded modified-release melatonin (clinician determined); and
Patient has had a trial of funded modified-release melatonin discontinuation within the past 12 months and has had a recurrence of persistent and distressing insomnia; and
Funded modified-release melatonin is to be given at doses no greater than 10 mg per day.

Initiation – insomnia where benzodiazepines and zopiclone are contraindicated

Both:

Patient has insomnia and benzodiazepines and zopiclone are contraindicated; and
For in-hospital use only.

Four of the unregistered presentations of melatonin currently listed on the HML (tab 1 mg and 2 mg, and cap 2 mg and 3 mg) will be delisted from the HML on 1 January 2018.
The tab 3 mg unregistered presentation of melatonin currently listed on the HML will remain listed on the HML subject to restrictions that limit its use to hospital in-patients for extemporaneous compounding (tab 3 mg) purposes.

Feedback received

PHARMAC appreciates all of the feedback received and acknowledge the time people took to respond. All consultation responses received by 1 June 2017 were considered in their entirety in making a decision on the proposed changes. Most responses were supportive of the proposal, and the following issues were raised in relation to specific aspects of the proposal.

Theme	Comment
Responders requested funding of presentations of melatonin they considered more suitable for the proposed patient group, specifically immediate-release (IR) tablets and an oral liquid.	There is only one registered presentation of melatonin in New Zealand: Circadin 2 mg MR tablets. Given the availability of a registered presentation and our clinical advice that supports the use of the MR presentation in the proposed patient group (see below), PHARMAC considers that funding an unregistered presentation of melatonin in the community would undermine the Medsafe registration process. We are not proposing to fund any unregistered presentations of melatonin in the community. Advice from PHARMAC’s main clinical advisory committee, the Pharmacology and Therapeutics Advisory Committee (PTAC) is that there are no clinical situations where only the IR presentation could be used and the Committee has advised that the available evidence suggests that both IR and MR presentations would provide similar therapeutic effects. The full advice is appended to this notification letter. The August 2015 BPJ(external link) article also provides advice on timing of administration of MR versus IR. Advice from PTAC is that crushing the MR tablets would remove the modified-release properties. This could be an option for situations where an IR effect is required. Information on this can be found in the August 2015 BPJ article. PHARMAC staff (registered pharmacists) have crushed Circadin MR tablets, and found them easy to crush with no palatability issues (being fairly tasteless and mildly sweet). Further, PTAC’s advice is that crushing the registered MR presentation would be preferable to funding an unregistered IR presentation given the lack of quality controls for the unregistered presentations (including a lack of controls around whether or not the product contains the stated quantity of melatonin). PTAC has advised that as there are no regulatory, safety, efficacy, or quality controls for IR melatonin, it would be preferable to only fund in the community, and list on the HML, the registered brand of melatonin.
DHB hospital pharmacists noted that there is an extemporaneous compounding formula for melatonin oral liquid available on the eMixt (www.pharminfotech.co.nz(external link)) website that is based on 3 mg IR tablets and there is no such known stability data for a compounded formulation using the 2 mg modified-release (MR) tablets. They also noted that a 1 mg IR tablet would be useful for titration purposes.	PHARMAC staff are not aware of any (unregistered) proprietary oral liquid presentations available in New Zealand; however, based on the feedback it appears that an extemporaneously compounded formulation is currently being used in hospitals. The compounding formula on the eMixt website (www.pharminfotech.co.nz(external link)) uses a specific brand of unregistered 3 mg IR tablets compounded with Ora-Plus and Ora-Sweet. Given that DHB hospitals already use this formulation (as the 3 mg IR tablets are listed on the HML), including for uses other than the currently proposed indication, and the DHB hospital paediatric pharmacists have identified issues with removal of this option, we have decided to maintain the listing of this presentation on the HML, for compounding purposes only. We consider that splitting the 2 mg MR tablet should be sufficient for titration purposes. We are aware of a study investigating the dissolution/release profile of Circadin when divided or crushed. This showed that the MR profile is largely maintained when Circadin is halved. The publication is available to download from www.ncbi.nlm.nih.gov/pmc/articles/PMC4810078/(external link)We would be pleased to consider funding another presentation of melatonin should one become registered in New Zealand.
Responders requested that melatonin be funded for other patient groups, including secondary insomnia in blind or visually impaired children (in the absence of a neurodevelopmental disorder); children with conditions other than neurodevelopmental disorders; primary insomnia in all children; and primary insomnia in adults.	Of these indications, the only one we have assessed is for funding is primary insomnia in adults aged >55 years. PTAC recommended that the application be declined, primarily because of lack of evidence of benefits over the funded comparator, zopiclone. We would be pleased to re-assess this application should new information be provided to address PTAC’s concerns. Links to information about this funding application can be found in the Application Tracker record for melatonin at: https://connect.pharmac.govt.nz/apptracker/s/global-search/melatonin(external link) All other indications raised in feedback have not been assessed for funding and PHARMAC would require further information to progress such an assessment. We would encourage respondents to submit funding application(s) providing additional information. Information about how to submit a funding application, including the application form for clinicians and consumers, can be found on PHARMAC’s website at:https://www.pharmac.govt.nz/medicines/how-medicines-are-funded/new-funding-applications/
A responder noted that the proposal is for an unregistered indication for melatonin and Medsafe has not assessed the safety and efficacy of melatonin in healthy children or children with neurodevelopmental disorders. The responder also highlighted a December 2015 Health Canada review (attached in Appendix 7) of the safety of melatonin in children and adolescents following concerns about a possible risk of neurological side effects. The review can be found at:https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/summary-safety-review-melatonin-acetyl-methoxytryptamine-review-safety-melatonin-children-adolescents.html(external link)	We acknowledge that the proposal is for an unregistered indication for melatonin and this is clearly stated on the Special Authority criteria. The Pharmaceutical Schedule, Section A: General Rules, Part IV (Miscellaneous Provisions) rule 5.5 provides: 5.5 Practitioners prescribing unapproved Pharmaceuticals Practitioners should, where possible, prescribe Pharmaceuticals that are approved under the Medicines Act 1981. However, the access criteria under which a Pharmaceutical is listed on the Pharmaceutical Schedule may: a) in some cases, explicitly permit Government funded access to a Pharmaceutical that is not approved under the Medicines Act 1981 or for an Unapproved Indication; or b) not explicitly preclude Government funded access to a Pharmaceutical when it is used for an Unapproved Indication; Accordingly, if Practitioners are planning on prescribing an unapproved Pharmaceutical or a Pharmaceutical for an Unapproved Indication, Practitioners should: a) be aware of and comply with their obligations under sections 25 and 29 of the Medicines Act 1981, as applicable, and otherwise under that Act and the Medicines Regulations 1984; b) be aware of and comply with their obligations under the Health and Disability Commissioner's Code of Consumer Rights, including the requirement to obtain informed consent from the patient (PHARMAC recommends that Practitioners obtain written consent); and c) exercise their own skill, judgment, expertise and discretion, and make their own prescribing decisions with respect to the use of an unapproved Pharmaceutical or a Pharmaceutical for an Unapproved Indication. Practitioners should be aware that simply by listing a Pharmaceutical on the Pharmaceutical Schedule PHARMAC makes no representations about whether that Pharmaceutical has any form of approval or consent under, or whether the supply or use of the Pharmaceutical otherwise complies with, the Medicines Act 1981. Further, the Pharmaceutical Schedule does not constitute an advertisement, advertising material or a medical advertisement as defined in the Medicines Act or otherwise. The use of melatonin in the proposed indication has been reviewed by PTAC and PTAC has recommended funding melatonin for this indication, with a low priority.The Health Canada review concludes that the data relating to melatonin neurological side effects in children is limited and inconclusive. It encourages parents and caregivers to consult a healthcare professional before giving melatonin to children, particularly if they have medical conditions. PHARMAC’s Special Authority criteria will require patients to be seen by a relevant specialist in order to access funded melatonin, which is in line with Health Canada’s recommendation.
Responders requested various changes to the Special Authority criteria: (a) to remove the requirement for specialist initiation of treatment. (b) to reduce the approval periods from 12 to 6 months, noting that the New Zealand Formulary for Children recommends that melatonin should be reviewed every six months. (c) to add additional criterion to the Special Authority initial and renewal applications to require that the child does not have a history of sleep-disordered breathing or other primary sleep disorder, or if there is a history of a primary sleep disorder that this has been adequately investigated and/or treated. (d) to increase the maximum dose limit from 6 mg per day to 10 mg per day, in line with New Zealand Formulary for Children recommendations. (e) Request to remove the age limit.	(a) Given the feedback highlighting a possible risk of harm (see above), and the fact that the proposed funding is for an off-label indication, we consider that it remains appropriate for specialist overview of this treatment and this has been retained in the Special Authority. (b) We consider that a 6-month approval period could be unnecessarily costly and burdensome for patients and their doctors given that it would require specialist recommendation. We note that the approval period is for funding, as recommended by PTAC, and would not prevent patients from being clinically reviewed by their prescriber on a 6-monthly basis as needed. (c) It appears from the response that the reason for this request is to drive better/appropriate clinical practice rather than to ensure that funding is restricted to the intended patient population. We note that there is information about the diagnosis of primary sleep disorders in the August 2015 BPJ(external link) article. (d) We have increased the upper dose limit to 10 mg/day in the Special Authority criteria and HML restrictions. However, we note that PTAC’s advice that there was no evidence to suggest that doses of MR melatonin higher than 6 mg daily would provide greater efficacy than doses of 4–6 mg per day. The recommended dose range on the New Zealand Formulary for Children is 2–3 mg per day. (e) We acknowledge that it could be problematic to transition patients from melatonin to another treatment once they turn 19 years of age. However, the PTAC has advised that it would be reasonable to restrict funded access to melatonin to patients aged 18 years or under for fiscal reasons and because there are less expensive funded alternatives for older patients.PTAC’s advice is that there are a number of funded alternatives that can reasonably be tried in patients aged 19 years and older. PTAC also noted that PHARMAC has not received a funding application for melatonin in insomnia secondary to a neurodevelopmental disorder in patients aged 19 years or older, nor has PTAC assessed the evidence (if any) for melatonin in this age group. As such, PTAC considered that there was no basis for recommending melatonin over the funded alternatives in patients aged 19 years or older.A number of applicants raised this issue and some more recent references (that have not previously been considered by PTAC) were supplied. Given this, we now intend to seek further advice on this matter from PTAC at the next available meeting.

Theme

Comment

Responders requested funding of presentations of melatonin they considered more suitable for the proposed patient group, specifically immediate-release (IR) tablets and an oral liquid.

There is only one registered presentation of melatonin in New Zealand: Circadin 2 mg MR tablets. Given the availability of a registered presentation and our clinical advice that supports the use of the MR presentation in the proposed patient group (see below), PHARMAC considers that funding an unregistered presentation of melatonin in the community would undermine the Medsafe registration process. We are not proposing to fund any unregistered presentations of melatonin in the community.

Advice from PHARMAC’s main clinical advisory committee, the Pharmacology and Therapeutics Advisory Committee (PTAC) is that there are no clinical situations where only the IR presentation could be used and the Committee has advised that the available evidence suggests that both IR and MR presentations would provide similar therapeutic effects. The full advice is appended to this notification letter.

The August 2015 BPJ(external link) article also provides advice on timing of administration of MR versus IR.

Advice from PTAC is that crushing the MR tablets would remove the modified-release properties. This could be an option for situations where an IR effect is required. Information on this can be found in the August 2015 BPJ article. PHARMAC staff (registered pharmacists) have crushed Circadin MR tablets, and found them easy to crush with no palatability issues (being fairly tasteless and mildly sweet).

Further, PTAC’s advice is that crushing the registered MR presentation would be preferable to funding an unregistered IR presentation given the lack of quality controls for the unregistered presentations (including a lack of controls around whether or not the product contains the stated quantity of melatonin).

PTAC has advised that as there are no regulatory, safety, efficacy, or quality controls for IR melatonin, it would be preferable to only fund in the community, and list on the HML, the registered brand of melatonin.

DHB hospital pharmacists noted that there is an extemporaneous compounding formula for melatonin oral liquid available on the eMixt (www.pharminfotech.co.nz(external link)) website that is based on 3 mg IR tablets and there is no such known stability data for a compounded formulation using the 2 mg modified-release (MR) tablets. They also noted that a 1 mg IR tablet would be useful for titration purposes.

PHARMAC staff are not aware of any (unregistered) proprietary oral liquid presentations available in New Zealand; however, based on the feedback it appears that an extemporaneously compounded formulation is currently being used in hospitals. The compounding formula on the eMixt website (www.pharminfotech.co.nz(external link)) uses a specific brand of unregistered 3 mg IR tablets compounded with Ora-Plus and Ora-Sweet. Given that DHB hospitals already use this formulation (as the 3 mg IR tablets are listed on the HML), including for uses other than the currently proposed indication, and the DHB hospital paediatric pharmacists have identified issues with removal of this option, we have decided to maintain the listing of this presentation on the HML, for compounding purposes only.

We consider that splitting the 2 mg MR tablet should be sufficient for titration purposes. We are aware of a study investigating the dissolution/release profile of Circadin when divided or crushed. This showed that the MR profile is largely maintained when Circadin is halved. The publication is available to download from www.ncbi.nlm.nih.gov/pmc/articles/PMC4810078/(external link)We would be pleased to consider funding another presentation of melatonin should one become registered in New Zealand.

Responders requested that melatonin be funded for other patient groups, including secondary insomnia in blind or visually impaired children (in the absence of a neurodevelopmental disorder); children with conditions other than neurodevelopmental disorders; primary insomnia in all children; and primary insomnia in adults.

Of these indications, the only one we have assessed is for funding is primary insomnia in adults aged >55 years. PTAC recommended that the application be declined, primarily because of lack of evidence of benefits over the funded comparator, zopiclone. We would be pleased to re-assess this application should new information be provided to address PTAC’s concerns. Links to information about this funding application can be found in the Application Tracker record for melatonin at: https://connect.pharmac.govt.nz/apptracker/s/global-search/melatonin(external link)

All other indications raised in feedback have not been assessed for funding and PHARMAC would require further information to progress such an assessment. We would encourage respondents to submit funding application(s) providing additional information. Information about how to submit a funding application, including the application form for clinicians and consumers, can be found on PHARMAC’s website at:https://www.pharmac.govt.nz/medicines/how-medicines-are-funded/new-funding-applications/

A responder noted that the proposal is for an unregistered indication for melatonin and Medsafe has not assessed the safety and efficacy of melatonin in healthy children or children with neurodevelopmental disorders.

The responder also highlighted a December 2015 Health Canada review (attached in Appendix 7) of the safety of melatonin in children and adolescents following concerns about a possible risk of neurological side effects.

The review can be found at:https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/summary-safety-review-melatonin-acetyl-methoxytryptamine-review-safety-melatonin-children-adolescents.html(external link)

We acknowledge that the proposal is for an unregistered indication for melatonin and this is clearly stated on the Special Authority criteria. The Pharmaceutical Schedule, Section A: General Rules, Part IV (Miscellaneous Provisions) rule 5.5 provides:

5.5 Practitioners prescribing unapproved Pharmaceuticals

Practitioners should, where possible, prescribe Pharmaceuticals that are approved under the Medicines Act 1981. However, the access criteria under which a Pharmaceutical is listed on the Pharmaceutical Schedule may:

a) in some cases, explicitly permit Government funded access to a Pharmaceutical that is not approved under the Medicines Act 1981 or for an Unapproved Indication; or

b) not explicitly preclude Government funded access to a Pharmaceutical when it is used for an Unapproved Indication;

Accordingly, if Practitioners are planning on prescribing an unapproved Pharmaceutical or a Pharmaceutical for an Unapproved Indication, Practitioners should:

a) be aware of and comply with their obligations under sections 25 and 29 of the Medicines Act 1981, as applicable, and otherwise under that Act and the Medicines Regulations 1984;

b) be aware of and comply with their obligations under the Health and Disability Commissioner's Code of Consumer Rights, including the requirement to obtain informed consent from the patient (PHARMAC recommends that Practitioners obtain written consent); and

c) exercise their own skill, judgment, expertise and discretion, and make their own prescribing decisions with respect to the use of an unapproved Pharmaceutical or a Pharmaceutical for an Unapproved Indication.

Practitioners should be aware that simply by listing a Pharmaceutical on the Pharmaceutical Schedule PHARMAC makes no representations about whether that Pharmaceutical has any form of approval or consent under, or whether the supply or use of the Pharmaceutical otherwise complies with, the Medicines Act 1981. Further, the Pharmaceutical Schedule does not constitute an advertisement, advertising material or a medical advertisement as defined in the Medicines Act or otherwise.

The use of melatonin in the proposed indication has been reviewed by PTAC and PTAC has recommended funding melatonin for this indication, with a low priority.The Health Canada review concludes that the data relating to melatonin neurological side effects in children is limited and inconclusive. It encourages parents and caregivers to consult a healthcare professional before giving melatonin to children, particularly if they have medical conditions. PHARMAC’s Special Authority criteria will require patients to be seen by a relevant specialist in order to access funded melatonin, which is in line with Health Canada’s recommendation.

Responders requested various changes to the Special Authority criteria:

(a) to remove the requirement for specialist initiation of treatment.

(b) to reduce the approval periods from 12 to 6 months, noting that the New Zealand Formulary for Children recommends that melatonin should be reviewed every six months.

(c) to add additional criterion to the Special Authority initial and renewal applications to require that the child does not have a history of sleep-disordered breathing or other primary sleep disorder, or if there is a history of a primary sleep disorder that this has been adequately investigated and/or treated.

(d) to increase the maximum dose limit from 6 mg per day to 10 mg per day, in line with New Zealand Formulary for Children recommendations.

(e) Request to remove the age limit.

(a) Given the feedback highlighting a possible risk of harm (see above), and the fact that the proposed funding is for an off-label indication, we consider that it remains appropriate for specialist overview of this treatment and this has been retained in the Special Authority.

(b) We consider that a 6-month approval period could be unnecessarily costly and burdensome for patients and their doctors given that it would require specialist recommendation. We note that the approval period is for funding, as recommended by PTAC, and would not prevent patients from being clinically reviewed by their prescriber on a 6-monthly basis as needed.

(c) It appears from the response that the reason for this request is to drive better/appropriate clinical practice rather than to ensure that funding is restricted to the intended patient population. We note that there is information about the diagnosis of primary sleep disorders in the August 2015 BPJ(external link) article.

(d) We have increased the upper dose limit to 10 mg/day in the Special Authority criteria and HML restrictions. However, we note that PTAC’s advice that there was no evidence to suggest that doses of MR melatonin higher than 6 mg daily would provide greater efficacy than doses of 4–6 mg per day. The recommended dose range on the New Zealand Formulary for Children is 2–3 mg per day.

(e) We acknowledge that it could be problematic to transition patients from melatonin to another treatment once they turn 19 years of age. However, the PTAC has advised that it would be reasonable to restrict funded access to melatonin to patients aged 18 years or under for fiscal reasons and because there are less expensive funded alternatives for older patients.PTAC’s advice is that there are a number of funded alternatives that can reasonably be tried in patients aged 19 years and older. PTAC also noted that PHARMAC has not received a funding application for melatonin in insomnia secondary to a neurodevelopmental disorder in patients aged 19 years or older, nor has PTAC assessed the evidence (if any) for melatonin in this age group. As such, PTAC considered that there was no basis for recommending melatonin over the funded alternatives in patients aged 19 years or older.A number of applicants raised this issue and some more recent references (that have not previously been considered by PTAC) were supplied. Given this, we now intend to seek further advice on this matter from PTAC at the next available meeting.

If you have any questions about this decision, you can email us at enquiry@pharmac.govt.nz or call our toll free number (9 am to 5 pm, Monday to Friday) on 0800 66 00 50.