1.1. Interim decision in relation to phenpromethamine

1. Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #27, June 2019)

1.1. Interim decision in relation to phenpromethamine

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 amend the current Poisons Standard in relation to phenpromethamine as follows:

Proposed date of effect of the proposed amendment

1 February 2020

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

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Australian regulations | International regulations | Substance summary | Summary of pre-meeting public submissions | Summary of ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to create a Schedule 10 entry for phenpromethamine was considered.

The Applicant's proposed amendments to the Poisons Standard were:

The Applicant's main points provided in support of the proposed amendments were as follows:

• Phenpromethamine is considered a primary analogue of methamphetamine (structural isomers) as per section 301.9 of the Criminal Code Act 1995. Phenpromethamine is a stimulant; it is chemically and structurally related to amphetamine, its derivatives (e.g. methamphetamine) and analogues.
• Phenpromethamine is a substance prohibited from sport by the World Anti-Doping Agency (WADA).
• Phenpromethamine is currently controlled by the German regulator Betäubungsmittelgesetz (BtMG) and is classified as Anlage I, non-tradeable substances available only by special permission of the authorities, which is granted for scientific or other public interest purposes.
• Phenpromethamine has been reported to the Early Warning Advisory on New Psychoactive Substances of the United Nations Office on Drugs and Crime (UNODC).
• Article 10 of the UNESCO International Convention against Doping in Sport obliges State Parties (including the Australian Government) to encourage producers and distributors of nutritional supplements to establish best practices in the marketing and distribution of nutritional supplements, including information regarding their analytic composition and quality assurance. The marketplace supplies thousands of products claiming to provide nutritional support for athletes. However, there are growing concerns about the prevalence and quality control of these supplements. This is because supplements may contain substances that are prohibited from sport and/or it is often unknown what a supplement actually contains. Athletes cannot be sure if a supplement contains substances that are prohibited from sport or understand the potential health Current scheduling status

Current scheduling status

Phenpromethamine is not specifically scheduled in the current Poisons Standard and has not been previously considered for scheduling. Therefore a scheduling history is not available.

Australian regulations

• Phenpromethamine is not listed on the TGA Ingredient Database.
• There are no medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[1] that contain phenpromethamine as an active ingredient.
• Phenpromethamine is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2019.[2]
• The Database of Adverse Event Notifications (DAEN)[3] contains no reports of adverse events for products containing phenpromethamine as an active ingredient.
• There are no products containing phenpromethamine listed on the Public Chemical Registration Information System Search (PUBCRIS).[4]

International regulations

• Phenpromethamine is prohibited from sport under the 'S6: Stimulants' of the WADA List of Prohibited Substances and Methods as a result of its purported stimulant properties due to its structural relationship to amphetamine, its derivatives (e.g. methamphetamine) and analogues (WADA 2019).
• Phenpromethamine is currently controlled in Germany by the Betäubungsmittelgesetz (BtMG) and is classified as Anlage I, non-tradeable substances available only by special permission of the authorities, which is granted only for scientific or other public interest purposes (BtMG 2019).
• The European Chemicals Agency (ECHA) hazard classification for phenpromethamine is, 'Danger! According to the classification provided by companies to ECHA in CLP notifications this substance is harmful if swallowed, causes serious eye damage, causes skin irritation and may cause respiratory irritation'.

Substance summary

Table 1: Chemical information for phenpromethamine

Property	Phenpromethamine
Chemical structure
Molecular formula	C10H15N
Molecular weight	149.23 g/mol
CAS name	N-methyl-2-phenylpropan-1-amine
CAS number	93-88-9
IUPAC and/or common and/or other names	N-methyl-2-phenylpropylamine (IUPAC), benzeneethanamine, N,beta-dimethyl- (9CI), N,beta-dimethylphenethylamine, N,beta-dimethyl, 1-methylamino-2-methyl-2-phenylethane, 1-methylamino-2-phenylpropane, 1-phenyl-1-methyl-2-methylamino-ethan, 1-phenyl-1-methyl-2-ethylaminoethane, fenprometamina, phenpromethaminum. phenylpropylmethylamine, vonedrine, N,beta-dimethylphenethylamine, phenpromethadrinum

Summary of pre-meeting public submissions

Two (2) submissions were received in response to the notice published under regulation 42ZCZK advising of the proposed amendment. Both were in support of the proposed amendment.

The main points in support of the proposed amendment were:

• Phenpromethamine is a member of the phenethylamine family which acts as a central nervous system stimulant.
• Phenpromethamine is prohibited by the World Anti-Doping Agency (WADA) as a stimulant.
• There has been an increase in calls to the NSW Poisons Information Centre (PIC) regarding exposures to weight-loss and body building products in the past 5 years and most of these calls required medical attention (57%).

  Year	Calls to NSW PIC on body building/weight-loss products
  2014	57
  2015	66
  2016	68
  2017	79
  2018	59
  Jan-April 2019	30

• There is often little detail of the contents of weight-loss and body building products. However, once ingested, they commonly show signs of stimulant toxicity.
• Entry of phenpromethamine in Schedule 10 will minimise the opportunity of it being included in weight-loss and bodybuilding products.

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that a Schedule 10 entry for phenpromethamine be created as follows:

The Committee also recommended an implementation date as soon as practicable.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) 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; (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; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

1. risks and benefits of the use of a substance:
   • Side effects of phenpromethamine are expected to be similar to other stimulants such as methamphetamine (cardiovascular side effects of most concern).
   • Member of the phenethylamine family and primary analogue of methamphetamine; phenpromethamine has the potential to cause harm based on its chemical profile.
   • Limited research informs the risk or benefits (no current registered therapeutic product in use).
   • Preclinical studies (in cats) have demonstrated a pressor effect.
2. the purpose for which a substance is to be used and the extent of use:
   • No currently established therapeutic use.
   • Used by the broader community as a stimulant in 'pre-workout' sports supplements/stimulants typically ingested before physical activity.
   • Stated purpose for use of sports supplements (in general) is to provide a stimulant effect, to improve athletic performance, and to increase weight loss, though the ingredient is not listed on products.
3. the toxicity of a substance:
   • Limited peer-reviewed studies assessing toxicity in humans; plausible toxicity based on its structural analogues (methamphetamine) and stimulant properties.
   • It is a non-approved drug with little information about its safety.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • There are currently no ARTG registered products containing phenpromethamine as an active ingredient and it is not permitted to be included in listed medicines.
   • There are also no veterinary products containing this substance.
5. the potential for abuse of a substance:
   • Phenpromethamine is considered to have a potential for abuse due to its stimulant properties arising from its structural relationship to amphetamine, its derivatives and analogues.
6. any other matters that the Secretary considers necessary to protect public health:
   • There are broader concerns related to the manufacture, labelling, ingredients and use of sports supplements that go beyond the concerns with phenpromethamine, but are relevant to consider in the context of public health.
   • Scheduling is important to avoid inadvertent consumption and related harms given it has been identified in products where it was not labelled.
   • Phenpromethamine is considered to be a new psychoactive substance which may pose increasing and serious harms to public health.
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   • Available information suggests this segment of the sports supplement industry is considerably expanding in Australia.

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to phenpromethamine;
• Advisory Committee on Medicines Scheduling's advice;
• The public submissions received before the first closing date;
• Section 52E of the Therapeutic Goods Act 1989, in particular: (a) 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; and (f) any other matters that the Secretary considers necessary to protect public health;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• The Australian Health Ministers' Advisory Council's Scheduling Handbook (V 1.0, January 2018).

Reasons for the interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (a) 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; and (f) any other matters that the Secretary considers necessary to protect public health.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the scheduling factors for Schedule 8, Schedule 9 and Schedule 10.

I have made a decision to amend the current Poisons Standard by creating a new Schedule 10 entry for phenpromethamine and I have set out my reasons below.

Having considered the SPF 2018, it is my view that phenpromethamine meets some of the Schedule 9 scheduling factors on the grounds that 'The substance has no currently established therapeutic value and is likely to present a high risk of dependency, abuse, misuse or illicit use'. However, in my view, these are minor considerations as the evidence for these harms have been extrapolated from analogues and are based on its stimulant properties. Further, whilst phenpromethamine is a structural analogue of methamphetamine (which is a Schedule 8 substance) and given the lack of evidence to support its therapeutic use, I do not believe it meets the scheduling factors for Schedule 8.

In making my decision, I considered the scheduling factors for inclusion in Schedule 10, particularly 'the substance poses such a high public health risk, including potential risk, that its sale, supply and/or use require very strict control, with access generally being prohibited'. Phenpromethamine is a phenethylamine, a class of substances with documented psychoactive and stimulant health effects and I find that the risk of cardiovascular outcomes following use of phenpromethamine to be a significant potential risk to public health.

I have considered that inclusion in Schedule 10 is a public health measure, given that it XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX, is banned by the World Anti-Doping Agency (WADA) and that minimal evidence exists for its use in humans. I have also had regard for the potential risk of inadvertent use in unlabelled sports supplements and the related harms. Placing phenpromethamine in Schedule 10 would mitigate such risks. I note that scheduling phenpromethamine in Schedule 10 is consistent with the scheduling of similar substances such as 1,3-dimethylamylamine (DMAA).

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