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Scheduling delegates' interim decisions and invitation for further comment: ACCS/ACMS, November 2017

Scheduling medicines and poisons

5 February 2018

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1.4. Ibutamoren

Referred scheduling proposal
Scheduling application

This was a general application. The applicant’s proposed amendments to the Poisons Standard are:

Schedule 4 – New Entry

# IBUTAMOREN.

Appendix D – New Entry

IBUTAMOREN.

The applicant’s reasons for the request are:

  • Ibutamoren is an experimental drug that has not been systematically investigated beyond clinical trials.
  • Ibutamoren is currently sold online as a'fountain of youth'-type drug for muscle gain as well as other anecdotal effects. This highlights the potential for misuse and abuse by the sporting community and general public.
  • Ibutamoren is a growth hormone secretagogue. It is captured under the broad class entry in Schedule 4 of the Poisons Standard for growth hormone secretagogues in. However, ibutamoren should be considered for an individual entry in Schedule 4 and Appendix D due to its potential for misuse and abuse in sports doping.
Current scheduling status

Ibutamoren is currently captured by the Growth Hormone Secretagogues (GHSs) listing in Schedule 4 and Appendix D, Part 5 of the Poisons Standard. These and other Performance and Image Enhancing Drugs (PIEDs) are listed as follows:

Schedule 4

# CJC-1295 (CAS No. 863288-34-0).

# PRALMORELIN ((GROWTH HORMONE RELEASING PEPTIDE-2) (GHRP-2)).

# GROWTH HORMONE RELEASING PEPTIDE-6 (GHRP-6).

# GROWTH HORMONE RELEASING HORMONES *(GHRHs).

# GROWTH HORMONE RELEASING PEPTIDES *(GHRPs).

# GROWTH HORMONE SECRETAGOGUES* (GHSs).

# HEXARELIN.

# IPAMORELIN.

# THYMOSIN BETA 4 (THYMOSIN β4).

# TB-500.

# FIBROBLAST GROWTH FACTORS.

Appendix D, Part 5

All the substances above are also in Appendix D, Part 5 (as indicated by the #).

Scheduling history

In November 2014, the Advisory Committee on Medicines Scheduling (ACMS) considered a proposal to include new entries for the following performance and image enhancing drugs in Schedule 4 and Appendix D:

  • Growth Hormone Releasing Hormones and Analogues (GHRHs);
  • Growth Hormone Secretagogues (GHSs);
  • Growth Hormone Releasing Peptides (GHRPs); and
  • Growth Hormone Variants:
    • CJC-1295 (CAS No. 863288-34-0);
    • Ipamorelin;
    • pralmorelin (growth hormone releasing peptide-2 (GHPR-2);
    • growth hormone releasing peptide-6 (GHRP-6);
    • Hexarelin; and
    • AOD-9604 (CAS No. 221231-10-3).

In March 2015, the ACMS recommended, and the delegate confirmed, that the currently scheduled substances should be included in Schedule 4 and in Appendix D, Item 5 in the Poisons Standard. The reasons for the recommendation were due to several points of safety. These include the long-term safety of PIEDs is not established and their potential adverse effects may include those associated with administration of growth hormones and the potential for downstream health effects such as adverse cardiovascular and hormonal effects. The limited safety data on AOD-9604 do not provide evidence that repeated intravenous or subcutaneous injections are safe or that long term use of oral doses in excess of those used in the clinical trials are safe. Scheduling of the substances would help ensure there is appropriate medical supervision of use and may make the substances more difficult to obtain without a lawful purpose. There is also evidence of involvement of organised crime in supply of the substances. The substances are offered for sale via the internet. Suppliers are making unproven assertions about the efficacy and safety of the substances.

As part of the above considerations, the ACMS also recommended that new Schedule 4 and Appendix D, Item 5 be created for Thymosin Beta 4, TB-500 and fibroblast growth factors. The delegate agreed with the committee and made a final decision on 17 March 2016. Reasons for the delegate’s decision include: no form of Thymosin Beta 4 was approved for human therapeutic use anywhere in the world; the substances are considered experimental in humans and are increasingly being used as a performance or image enhancing agent, thus have potential for misuse or abuse; toxicity is unknown due to the experimental nature of the medication but they have potential side effects including carcinogenicity and cardiovascular problems.

Australian regulatory information

Ibutamoren is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017, and is not an excipient or active in any medicines on the ARTG.

International regulations
World Anti-Doping Agency (WADA)

Ibutamoren is prohibited from sport under the category S2 Peptide hormones, growth factors, related substances and mimetics.

United States of America

On 19 June 2017, the USA Food and Drug Administration granted Orphan Drug Designation for ibutamoren mesylate (MK-0677) for the treatment of growth hormone deficiency.

European Union (EU)

On 20 June 2017, the European Commission granted orphan designation (EU/3/17/1882) for ibutamoren mesilate (also known as MK-0677) for the treatment of growth hormone deficiency.

New Zealand

In NZ, ibutamoren is currently unclassified.

Substance summary

Ibutamoren is a potent, orally active small molecule (non‐peptide) ghrelin analogue which is exploited pharmacologically as a growth hormone (GH) secretagogue. Though there was some interest to market this drug, like virtually all other congeners in this class, their marketing campaigns were mostly abandoned failed due to inadequate efficacy (short‐term benefits in GH stimulation and increases in muscle and bone mass proved ill‐sustained in longer term studies) and safety concerns.

Ibutamoren is an orally-available growth hormone secretagogue that is functionally indistinguishable both in vitro and in vivo from the Schedule 4 and Appendix D substance growth hormone-releasing peptide 6 (GHRP-6).[26] The substance was developed as an investigational drug for use in animal models only.

Ibutamoren is a ghrelin receptor agonist. Agonists of the ghrelin receptor are known as growth hormone secretagogues, a class of compounds that resides within Schedule 4 of the Poisons Standard. This receptor leads to stimulation of growth hormone secretion in the same manner as elicited by ghrelin.[27]

Table 1.4.1: Chemical information of ibutamoren
Property Ibutamoren
CAS name MK-677
CAS number 159634-47-6
IUPAC and/or common and/or other names

2-amino-2-methyl-N-[(2R)-1-(1-methylsulfonylspiro[2H-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide (IUPAC);

Ibutamoren (INN);

Common names: Nutrobal; L-163,191; GH pep; Propanamide; crescendo

Chemical structure
Molecular formula C27H36N4O5S
Molecular weight 528.7 g/mol
Pre-meeting public submissions

No submissions were received.

Summary of ACMS advice to the delegates

The committee recommended that new Schedule 4 and Appendix D entries be created for ibutamoren in the Poisons Standard, along with a cross reference to similar compounds in the index, as follows:

Schedule 4 – New Entry

# IBUTAMOREN.

Appendix D, Part 5 – New Entry

IBUTAMOREN

Index – New Entry

IBUTAMOREN
cross reference: MK-677, Nutrobal

Schedule 4
Appendix D, Part 5

The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.

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 comprised the following:

  1. the risks and benefits of the use of a substance:
  • Risks: long term safety of ibutamoren has not been established but some safety signals have been detected in clinical trials.
  • Benefits: theoretical benefits on muscle and bone accrual have not been confirmed in clinical trials. There are no long-term safety data. At least one well designed Phase IIb trial of ibutamoren was terminated early due to a signal of congestive heart failure (Adunsky A et al., Arch Gerontol Geriatr 2011).
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Ibutamoren is widely promoted for uses other than what it had been originally trialled, i.e. for acute illness, post-op and hip fracture recovery.
    • Ibutamoren is used illicitly to increase muscle mass, predominantly in the context of athletic and aesthetic pursuits.
  • the toxicity of a substance:
    • Toxicity of ibutamoren remains unknown, but concerns exist (see point (a)).
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Ibutamoren is available online as an oral powder. There are also capsules and liquid formulations apparently available.
  • the potential for abuse of a substance:
    • Ibutamoren is advertised online as an ‘anti-ageing’, ‘fountain of youth’ product.
    • Potential for abuse and misuse in sports doping is high.
  • any other matters that the Secretary considers necessary to protect public health
    • Evidence that ibutamoren products are marketed as a safe, oral alternative to other performance enhancing drugs.
    • Oral presentation may have a lower barrier to use than agents requiring injection.
    • This substance is already covered by the group entry of Growth Hormone Secretagogues. However, a specific entry is required to ensure clarification of its scheduling status.
    Delegate's considerations

    The delegate considered the following in regards to this proposal:

    • Scheduling proposal
    • ACMS advice
    • Section 52E of the Therapeutic Goods Act 1989
    • Scheduling Policy Framework (SPF 2015)
    Delegate's interim decision

    Schedule 4 – New Entry

    # IBUTAMOREN.

    Appendix D, Part 5 – New Entry

    IBUTAMOREN.

    Index – New Entry

    IBUTAMOREN
    cross reference: MK-677, NUTROBAL

    Schedule 4
    Appendix D, Part 5

    The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.

    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:

    1. the risks and benefits of the use of a substance:
    • Risks: long term safety of ibutamoren has not been established but some safety signals have been detected in clinical trials.
    • Benefits: theoretical benefits on muscle and bone accrual have not been confirmed in clinical trials. There are no long-term safety data. At least one well designed Phase IIb trial of ibutamoren was terminated early due to a signal of congestive heart failure (Adunsky A et al., Arch Gerontol Geriatr 2011).
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Ibutamoren is widely promoted for uses other than what it had been originally trialled, i.e. for acute illness, post-op and hip fracture recovery.
    • Ibutamoren is used illicitly to increase muscle mass, predominantly in the context of athletic and aesthetic pursuits.
  • the toxicity of a substance:
    • Toxicity of ibutamoren remains unknown, but concerns exist (see point (a)).
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Ibutamoren is available online as an oral powder. There are also capsules and liquid formulations apparently available.
  • the potential for abuse of a substance:
    • Ibutamoren is advertised online as an ‘anti-ageing’, ‘fountain of youth’ product.
    • Potential for abuse and misuse in sports doping is high.
  • any other matters that the Secretary considers necessary to protect public health
    • Evidence that ibutamoren products are marketed as a safe, oral alternative to other performance enhancing drugs.
    • Oral presentation may have a lower barrier to use than agents requiring injection.
    • This substance is already covered by the group entry of Growth Hormone Secretagogues. However, a specific entry is required to ensure clarification of its scheduling status.

    Footnotes

    1. Patchett, A. A.; Nargund, R. P., Tata, J. R., Chen, M.-H., Barakat, K. J., Johnston, D. B.R., Cheng, K., Chan, W. W.-S., Butler, B., Hickey, G., Jacks, T., Schleim, K., Pong,S.-S., Chaung, L.-Y. P., Chen, H. Y., Frazier, E., Leung, K. H., Chiu, S.-H. L. & Smith, R. G. (1995). Design and biological activities of L-163,191 (MK 0677): A potent, orally active growth hormone secretagogue. Proceedings of the National Academy of Sciences of the USA, 92, 7001-7005.
    2. Cassoni, P., Papotti, M., Ghe, C., Catapano, F., Sapino, A., Graziani, A., Deghenghi, R., Reissmann, T., Ghigo, E. & Muccioli, G. (2001). Identification, Characterization, and Biological Activity of Specific Receptors for Natural (Ghrelin) and Synthetic Growth Hormone Secretagogues and Analogs in Human Breast Carcinomas and Cell Lines. Journal of Clinical Endocrinology and Metabolism, 86(4), 1738-1745.

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