Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, November 2016

Scheduling medicines and poisons

Book pagination

2 February 2017

3.2 Melatonin

Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)

3. Advisory Committee on Medicines Scheduling (ACMS #19)

3.2 Melatonin

Referred scheduling proposal

An application was submitted to exempt melatonin for human use in preparations containing 1 mg or less of melatonin.

Scheduling application

This was a general application. The Applicant's proposed amendment to the Poisons Standard is as follows:

Schedule 4 - Amend Entry

MELATONIN for human use except when in preparations containing 1 mg or less of melatonin.

The applicant's reasons for the request are:

  • Melatonin can currently only be used as an active ingredient for biologicals, export only and prescription medicines and homeopathic formulation in Australia. It is freely sold as a food supplement in USA, Europe and other countries across the globe.
  • The applicant provided information that there were products currently being sold in Australia containing melatonin in various strengths and forms. There is also a large market of importation of melatonin via online channels from international retailers, raising concerns that there is a risk to consumers when buying such products from unverified sources some of which are in high dosage strengths of up to 10 mg.
  • In general, animal and human studies documented that short-term use of melatonin is safe, even in extreme doses. Only mild adverse effects, such as dizziness, headache, nausea and sleepiness have been reported. No studies have indicated that exogenous melatonin should induce any serious adverse effects. Similarly, randomized clinical studies indicate that long-term melatonin treatment causes only mild adverse effects comparable to placebo.
  • Down-scheduling of melatonin will have little or no adverse impact on public health.
Current scheduling status

Melatonin for human use is currently in Schedule 4 of the Poisons Standard as follows:

Schedule 4

MELATONIN for human use.

Relevant scheduling history

In February 1987, the DPSC considered melatonin in a veterinary medicine to synchronise oestrous in ewes. Members agreed to include melatonin in Appendix B.

In February 1997, the NDPSC was advised of the compounding of melatonin capsules by a pharmacist, although the product had not been evaluated or registered by the TGA.

In May 1997, the NDPSC considered responses and information provided following the pre-meeting gazette notice advising it was its intent to consider the scheduling of melatonin at the May 1997 meeting. The NDPSC noted some of melatonin's current popularity related to its benefits in alleviating the symptoms of 'jet lag' and also to claims that it had anti-oxidant, anticancer and anti-aging effects. It was noted that New Zealand had scheduled melatonin as a prescription only medicine, in the absence of adequate data on safety and efficacy being provided to the regulators. The NDPSC considered that insufficient information was available on the safety of melatonin to allow it to remain exempt from scheduling for human therapeutic use and that it should not be available without prescription.

In November 2001, the NDPSC decided that where an entry existed in the Schedules for a particular use/s, no entry should be made in Appendix B; subsequently melatonin was deleted from the Appendix B listing.

Substance summary

Melatonin (Figure 3.2) is a naturally occurring hormone, which is normally produced by the brain's pineal gland. It is involved in co-ordinating the body's sleep cycle by acting on cells in specific areas of the brain and helping to bring about sleep. Blood levels normally increase after the onset of darkness and peak in the middle of the night.

Structure of melatonin

Figure 3.2: Structure of melatonin

Table 3.2: General information for melatonin
Property Melatonin
INN/BAN/AAN Melatonin
CAS No. 73-31-4
IUPAC name N-[2-(5-methoxy-1H-indol-3-yl)ethyl]; N-[2-(5-methoxyindol-3-yl)ethyl]acetamide
Chemical name N-acetyl-5-methoxy tryptamine
Molecular formula 232.3
Molecular Weight C13H16N2O2
Pre-meeting public submissions

Seven (7) public submissions were received. Two (2) submissions supported the proposal.

The main points in support were:

  • Global relevance of safety as supported by decisions from comparable Regulatory Authorities. Melatonin was reclassified from prescription-only to Natural Health Product (NHP) status under the Health Canada Natural and Non-prescription Health Products Directorate (NNHPD) in 2003. Melatonin has been available for over 20 years in the US dietary supplement market, where it is used by approximately 5% of the population. In 2011 the European Food Safety Authority (EFSA) considered the scientific opinion on the substantiation of a health claim related to melatonin and reduction of sleep onset latency (time taken to fall asleep), which found melatonin to be sufficiently characterised.
  • Rescheduling is supported based on the safety profile of melatonin when used as directed on the medicine label and in the context of its proposed indication(s).
  • Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in patients who are over 55 with primary insomnia.
  • Melatonin seems to be safe when used for up to 6 months and there is some evidence melatonin can be used safely for up to 2 years in some patients.
  • Melatonin available without a prescription in Canada and OTC in the USA.
  • Helps increase the total sleep time (aspect of sleep quality) in people suffering from sleep restriction or altered sleep schedule, e.g. shift-work and jet lag.
  • Melatonin is a safe and effective hormone used to alleviate the symptoms of jetlag. It helps to prevent and/or reduce the effects of jet lag (e.g. daytime fatigue, sleep disturbance) for people travelling by plane easterly across two or more time zones.
  • Helps to reduce the time it takes to fall asleep (sleep onset latency aspect of sleep quality) in people with delayed sleep phase disorder.
  • Helps re-set the body's sleep-wake cycle (aspect of the circadian rhythm).
  • The EFSA recommended 1 mg close to bed time.
  • Risk mitigation should include:
    • Appropriate health warnings: e.g. consumption with alcohol, other medications or natural health products with sedative properties is not recommended.
    • Directions when taking other medications to consult a health care practitioner prior to use: anticoagulant, anticonvulsant, blood pressure medications, immunosuppressive medications, sedative, hypnotic or psychotropic medications, or steroids.
    • Directions for certain medical conditions, consult a health care practitioner prior to use: asthma, cardiovascular disease, chronic kidney disease, depression, diabetes or hypoglycaemia, hormonal disorder, immune system disease, liver disease, migraine, or seizure disorders.
    • Sleep restriction/altered sleep schedule; delayed sleep phase disorder; sleep-wake cycle: If symptoms persist continuously for more than 4 weeks (chronic insomnia), directions for referral to health care practitioner.
    • Contraindication(s): If you are pregnant or breastfeeding, do not use this product.
    • Known Adverse Reaction(s): Mild gastrointestinal symptoms (nausea, vomiting, or cramping) have been known to occur in which case, discontinue use.
    • Rare allergic reactions have been known to occur in which case, discontinue use.
  • Appropriate packaging, dosage, formulation and labelling is necessary.
  • Health Canada recommends 3 mg daily for 4 weeks to increase REM sleep in adults.
  • Adverse events:
    • There have been 65 reports of mild adverse events, of those 53 where indicated as the single medicine suspected of causing a reaction such as dizziness, nausea and insomnia.
    • Adverse events for Melatonin are low and comparable between Circadin (2 mg) and placebo. There were no treatment-related deaths or serious Adverse Events recorded.
    • Administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature.
  • The effects of melatonin on sleep are modest but do not appear to dissipate with continued melatonin use.
  • The absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, however melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents.
  • Lack of side-effects compared to other prescription sleep aids.
  • There is no medical requirement for it to remain scheduled due to the lack of any risk at the concentrations proposed.
  • It should be removed from the Schedule at concentrations of 5 mg or less. Its removal at concentrations of 1 mg or less as per the application should be considered the bare minimum for action.

Five (5) submissions did not support the proposal.

The main points opposed were:

  • Creating a scheduling exemption directly from Schedule 4 is inconsistent with Australia’s scheduling system and Scheduling Policy Framework.
  • While the maximum dosage for melatonin that would be exempt from scheduling under this proposal is half that of the prescription dosage, there is no proposal for limitation on pack sizes.
  • There are no restrictions on the number of packs that can be purchased in a single transaction when medicines are sold outside pharmacy.
  • Risks in relation to inadvertent excessive or inappropriate intake of melatonin are magnified in non-pharmacy settings with no increased benefit to consumers.
  • If products containing melatonin are sold online or in general retail, consumers could purchase these products without any oversight from a health professional to treat what is potentially a serious health condition. It may also encourage patients who are currently under the care of a doctor to abandon their treatment plan as under this scheduling proposal they will not require a prescription for these medicines.
  • Lack of clinical evidence regarding use in children.
  • The proposal does not define whether the 1 mg referred to is the strength per dose unit or total amount per container (e.g. for a homoeopathic remedy) - assumes the application is based on the New Zealand 1 mg per dose unit application.
  • Risks of down-scheduling outweigh the benefits. Potential risk relating to use while pregnant or breastfeeding, and interactions with other substances. Avoidance of the product in pregnancy or women intending to become pregnant; women who are breast-feeding due to lack of direct clinical data; people with auto-immune disorders, and use with fluvoxamine (which can increase bioavailability by 17-fold).
  • Long-term toxicity is unknown. Not aware of any recent more comprehensive data on the use of melatonin that would demonstrate or clarify long term safety.
  • Misuse potential for inappropriate use, e.g. long-term use in children for sleep conditions more appropriately managed in other ways (e.g. behavioural interventions such as sleep hygiene and stimulus controls) and shift workers, exams, or inappropriate use without first investing in other methods of improving sleep hygiene.
  • Increasing patient access to unregistered (dietary supplement melatonin) without healthcare professional oversight could lead to short and long-term health consequences and inappropriate use with considerable safety risks.
  • There are risks of underlying conditions not being diagnosed or managed appropriately, of long-term use in certain adults, and in children (for which the safety is unknown), and for dosing with a tablet rather than the first-line behavioural changes recommended to manage insomnia.
  • The purposes for which the product would be used are not appropriate for unscheduled supply.
  • Melatonin is available as prescription-only in Australia, New Zealand, the United Kingdom and much of Europe. The availability of melatonin in Australia has been determined by the rationale for use based on the role of melatonin in sleep and circadian rhythm regulation and the age-associated decrease in endogenous levels. This is clearly reflected in the parameters of the approved indication of the currently registered melatonin-containing product.
  • Melatonin is indicated for primary insomnia, a condition that should be treated and managed by health professionals. Sends wrong message that patients can self-treat insomnia. Insomnia varies in individuals and may be serious underlying condition requiring pharmacist or GP intervention.
  • The pharmacokinetic profile of the medicinal product, which has been proven to mimic the endogenous profile, is profoundly different from that of any immediate release preparations. The plasma profile of the melatonin peak following ingestion of 1 mg immediate release preparation is entirely different from the normal endogenous profile of the hormone, leading to an imbalance between the melatonin release and the nocturnal period.
  • Efficacy: Only the prolonged release 2 mg melatonin studies have been sufficiently robust to provide appropriate evidence for registration as a medicine. It is not possible to extrapolate the efficacy nor the safety data generated from prolonged release melatonin 2 mg product.
Summary of ACMS advice to the delegate

The committee advised that the scheduling of melatonin remains appropriate.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) the risks and benefits of the use of a substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of a substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the advice comprised the following:

  • The identified risks of changing the scheduling of melatonin mainly involve patterns of use. Such risks included indiscriminate use/misuse by consumers, inadvertent excessive or inappropriate intake of melatonin, potential for underlying sleep conditions not being diagnosed or managed properly (especially in children) and potential for interaction with other drugs (e.g. fluvoxamine, which can increase bioavailability of melatonin by 17-fold). There is also potential that unscheduled melatonin could be used in children, which also poses a potential for misuse, e.g. for long term treatment or in children with behavioural/discipline issues.
  • There are concerns around the current Schedule 4 medicine and the wider indications of its use.
  • Melatonin is used to aid sleep or to re-set sleep rhythm. Uses of the existing 2 mg product, registered in 2009, seem to be limited to jet lag and for sleep disorders caused by stress and fatigue.
  • Acute use of melatonin appears to have low toxicity. However, chronic use data is lacking. Furthermore, although the frequency and type of adverse effects are not of particular concern, melatonin is a potent hormone and can produce significant effects on multiple body systems at relatively small doses, far less than the cut-off dose proposed. There is no persuasive evidence supplied in the application for the proposed scheduling cut-off dosage.
  • The dosage form of the current Schedule 4 medicine is a fast dissolving thin polymer film embedded with melatonin that melts and dissolves in oral cavity saliva. Studies on melatonin have shown no serious adverse events. There is concern about the broader ability of this formulation, in that it may be readily used in children.
  • Methods of deterring the increasing volume of personal imports, which are often inappropriate unregistered medicines, should be considered.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACMS advice
  • Public submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that the current scheduling for melatonin remains appropriate.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

  • The delegate acknowledges the committee's advice.
  • The identified risks of changing the scheduling of melatonin mainly involve patterns of use. Such risks included indiscriminate use/misuse by consumers, inadvertent excessive or inappropriate intake of melatonin, potential for underlying sleep conditions not being diagnosed or managed properly (especially in children) and potential for interaction with other drugs (e.g. fluvoxamine, which can increase bioavailability of melatonin by 17-fold). There is also potential that unscheduled melatonin could be used in children, which also poses a potential for misuse, e.g. for long term treatment or in children with behavioural/discipline issues.
  • Acute use of melatonin appears to have low toxicity. However, chronic use data is lacking. Furthermore, although the frequency and type of adverse effects are not of particular concern, melatonin is a potent hormone and can produce significant effects on multiple body systems at relatively small doses, far less than the cut-off dose proposed. There is no persuasive evidence supplied in the application for the proposed scheduling cut-off dosage.
  • The dosage form of the current Schedule 4 medicine is a fast dissolving thin polymer film embedded with melatonin that melts and dissolves in oral cavity saliva. Studies on melatonin have shown no serious adverse events. There is concern about the broader ability of this formulation, in that it may be readily used in children.

Book pagination