1.3. Melatonin

1 Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #29 March 2020)

1.3. Interim decision in relation to melatonin

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to down-schedule melatonin in modified release formulations from Schedule 4 to Schedule 3 by amending the current Poisons Standard as follows:

Proposed date of effect of the proposed amendment

1 October 2020

Reasons for the interim decision (including findings on material questions of fact)

In making this interim decision, the Delegate considered the following material:

• The application to amend the current Poisons Standard with respect to melatonin;
• Advisory Committee on Medicines Scheduling's advice;
• The public submissions received in response to the pre-meeting consultation;
• Section 52E of the Therapeutic Goods Act 1989, in particular (a) the risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance;
• Scheduling handbook: Guidance for amending the Poisons Standard; and
• Scheduling Policy Framework (SPF 2018).

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended the down-scheduling of melatonin to Schedule 3 in the Poisons Standard as follows:

The Committee recommended the following Required Advisory Statements for Medicine Labels (RASML) statement to the Over the Counter Evaluations Section at the Over-the-Counter Medicines Evaluation Section at the TGA:

1. Do not use this product if you have impaired liver function or autoimmune disease or taking other medications. Consult your doctor or pharmacist.
2. Do not use if you are pregnant or breastfeeding. Consult your doctor.
3. Do not use in children and adolescent under 18 years of age.
4. Do not use if you are allergic to melatonin. If you get an allergic reaction, stop taking and seek medical advice immediately.
5. Consumption with alcohol, other medications or natural health products with sedative properties is not recommended.
6. This product may cause drowsiness

The Committee also recommended an implementation date of 1 October 2020.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) the risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance.

The reasons for the advice included:

1. the risks and benefits of the use of a substance
   • Benefits:
     • Well tolerated and offers a safer alternative to benzodiazepines, sedating anti-depressants and over the counter sedating antihistamines to treat insomnia patients over 55 years of age.
   • Risks:
     • Hypersensitivity reactions, hepatic impairment, autoimmune diseases, drug interactions e.g. fluvoxamine, cigarette smoking, hypnotics, alcohol, pregnancy, use in lactation.
     • The risks associated with melatonin can be adequately managed including during patient-pharmacist counselling and use of Cautionary Advisory Labels.
2. the purposes for which a substance is to be used and the extent of use of a substance
   • The TGA-approved indication is for 'Monotherapy for the short term treatment of primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over.'
3. the toxicity of a substance
   • Mild side effects have been reported with higher doses including drowsiness, daytime sleepiness, headaches and nausea.
   • No evidence suggests that people develop tolerance to melatonin or dependency or withdrawal effects or rebound insomnia
   • Established safety profile when used for up to 6 months and there is some evidence that melatonin can be used safely for up to 2 years in some patients.
   • TGA approved Product Information indicates administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature. If overdose occurs, drowsiness is to be expected.
4. the dosage, formulation, labelling, packaging and presentation of a substance
   • The dosage of the slow release formulation is 2 mg once daily 1-2 hours before bedtime and after food. This dosage may be continued for up to thirteen weeks.
5. the potential for abuse of a substance
   • The potential for abuse of this medication is limited. It is not a drug of addiction and it has no euphoric effect.
   • It cannot be converted into another more active substance for illicit use.

Reasons for interim decision

I have made an interim decision to down-schedule melatonin in modified release formulations to Schedule 3 of the Poison Standard with restrictions on age and pack size. The reasons for my decision are set out below.

Melatonin is currently approved for monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over. In my opinion, the risk profile of melatonin is well defined and the adverse effects, interactions and contraindications are known, identifiable and manageable by a pharmacist. I have not identified any compelling evidence, which establishes that melatonin can be safety supplied to consumers, by a pharmacist, outside the current approved indications.

I am satisfied that melatonin, when supplied in accordance with the current approved indications, meets the Scheduling Factors for Schedule 3. Insomnia does not require medical diagnosis or only requires initial medical diagnosis, and the consumer does not require close medical management. I find that consumer consultation with a pharmacist is necessary to reinforce and/or expand on aspects of the safe use and appropriate supply in line with the approved indications. The use of melatonin is not expected to produce dependency at either the established therapeutic dose or at supra-therapeutic doses. There may be potential for harm if melatonin is used inappropriately, however, I am satisfied that it is substantially safe with pharmacist intervention. Where risk of misuse, abuse or illicit use is identified, again, I am satisfied that the risk can be minimised through pharmacist-consumer consultation.

I have made a decision not to include melatonin in Appendix M. I am satisfied that melatonin meets the Scheduling Factors under a Schedule 3 classification and that additional controls through inclusion in Appendix M are not necessary.

Having considered the matters set out in the Guidelines for advertisements for medicines containing Schedule 3 substances, I have deliberated on the potential sedating effects of melatonin and its suitability for inclusion in Appendix H. I am satisfied that daytime sedation effects are small and in comparison to other Schedule 3 sedatives, the potential for melatonin-induced sedation is milder and less common. It is my understanding that melatonin has a very short half-life of 20 to 50 minutes. The evidence demonstrates that the sedative effects of melatonin are not likely to impact on safety to drive or cognition more generally while under the effect of melatonin or the following day.

It is my view that melatonin has a better safety profile than the existing over the counter options for insomnia, especially in older people i.e. the 55 years and over age group, who are more sensitive to the anticholinergic side effects of sedating antihistamines. For many older patients, melatonin would represent a better option in preference to long-term use of benzodiazepines or the non-benzodiazepines used for insomnia. I have considered that there may be public health benefit in increasing awareness of the Schedule 3 availability of melatonin for use within the permitted indication. On the balance of evidence, I find that melatonin is appropriate for inclusion in Appendix H to allow it to be advertised for the approved indication.

I have not made a decision on the RASML statements, as they are not relevant to the matters, which I must consider under section 52E of the Therapeutic Goods Act 1989. Accordingly, I have not given any weight to the ACMS recommendation insofar as it relates to the RASML statements and they were not material to my decision.

I agree with the Committee's finding that the relevant provisions of section 52E of the Therapeutic Goods Act 1989 are (a) the risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance.

Implementation date

I have decided the appropriate implementation date is 1 October 2020.