You are here

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

Scheduling medicines and poisons

5 February 2018

Book pagination

1.7. Melanotan II

Referred scheduling proposal

An application was submitted to create a new entry in Schedule 10 for melanotan II in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

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

Schedule 10 – New Entry

MELANOTAN II for cosmetic or therapeutic use.

Index – New Entry

MELANOTAN II
cross reference α–MELANOCYTE STIMULATING HORMONE

Schedule 10

The applicant's reasons for the request are:

  • Melanotan II is a synthetic analogue of the α-melanocyte stimulating hormone (α-MSH). α-MSH is a melanocortin I receptor agonist which has a role in human pigmentation by stimulating production of eumelanin. Melanotan II was originally developed as a treatment for sexual dysfunction. However, the proposal was abandoned when development of the metabolite bremelanotide was established.
  • Melanotan II is being abused as an injectable subcutaneous lifestyle drug for the purposes of sunless tanning, appetite suppression and sexual stimulation.
  • Melanotan II has reported toxicity effects from therapeutic and overdose exposures including: renal dysfunction, rhabdomyolysis, sympathomimetic overdrive, change in size and pigmentation of pre-existing moles, rapid increase in the number of new moles associated with causing melanomas, posterior reversible encephalopathy syndrome, refractory priapism, stretching and yawning syndrome, shortness of breath, chest pain, abdominal cramping and pain, dizziness and lethargy. XXXXXX alone has received 28 calls about melanotan II since 2006.
  • The therapeutic dose is considered to be 0.01 mg/kg. However, reports from XXXXXX show that overdose appears to be relatively common, and hospitalisation is usually required.
  • Quality, safety and efficacy data for this product has not been established. There is also an unknown infection risk and case reports have detailed positive testing on these products for microbial contaminants.
  • Post reconstitution, vials are marketed for multiple uses for up to a few weeks, which could compound the infection risk and additionally, raises the issue of stability.
  • The unregulated nature of these products may falsely lead consumers to believe that these products are safe, in the absence of any detailed risk analysis.
  • There is no clinical safety and efficacy data and the side effects and toxicity profile greatly outweigh any benefits of use. Restricting the sale, possession or supply of this substance is in the public health's best interests.
Current scheduling status and relevant scheduling history

Melanotan II is not specifically scheduled. Therefore a scheduling history is not available.

Schedule 4

AFAMELANOTIDE.[38]

ADRENOCORTICAL HORMONES except when separately specified in these Schedules.

CORTICOTROPHIN.

Scheduling history of related substances:

Afamelanotide

In December 2010, the delegate made a delegate only decision to include afamelanotide (also known as melanotan I) with a cross-reference to melanocyte stimulating hormone (MSH) for inclusion into the current Poisons Standard. It was noted that afamelanotide should not be confused with a similar substance commonly known as Melanotan-II, which is a cyclic lactam synthetic analogue of α-MSH. It was noted that melanotan-II was under investigation for treating sexual dysfunction, although this has been abandoned due to side effects associated with the immune and cardiovascular systems. Its metabolite, bremelanotide, is under investigation for treating haemorrhagic shock.

Adreno-corticotrophic hormone

In January 1955, adreno-corticotrophic hormone (ACTH) was included in the very first Poisons Schedules. It was included in Schedule 4, Part A, which is equivalent to the current Schedule 4 of the Poisons Standard. Provisions for a repeated script must be authorised by an authorised prescriber, including general practitioners, veterinarian or dentist (if required for the purposes of the dental profession or are permitted to be prescribed by a dentist).

Corticotrophin

In May 1956, corticotrophin and other pituitary hormones for parenteral use in humans were included in Schedule 4 of the Draft Uniform Poisons Schedules.

Australian regulatory information

Melanotan II 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
New Zealand (NZ)

The European Medicines Agency granted orphan designation to α-melanocyte stimulating hormone for the treatment of erythropoietic porphyria.

Multiple European governing authorities including Danish Medicines Agency, Norwegian Medicines Agency, Swedish Medical Products Agency, United Kingdom Medicines and Healthcare products Regulatory agency have issued warnings on the sale and use of melanotan products.

United States of America (USA)

According to the USA Food and Drugs Administration (FDA) website, melanotan I, melanotan II and bremalanotide are unapproved injectable drugs in the USA.

In September 2007, the FDA issued a public notice advising consumers to stop using melanotan II as it was an unapproved drug with no safety or efficacy data for the advertised indications. Furthermore, the FDA issues a warning notice to a company owner that was illegally selling and marketing the product via a website. This led to subsequent indictment.

European Union (EU)

The European Medicines Agency granted orphan designation to α-melanocyte stimulating hormone for the treatment of erythropoietic porphyria.

Multiple European governing authorities including Danish Medicines Agency, Norwegian Medicines Agency, Swedish Medical Products Agency, United Kingdom Medicines and Healthcare products Regulatory agency have issued warnings on the sale and use of melanotan products.

United Kingdom (UK)

In November 2008, the UK Medicines and Healthcare products Regulatory Agency (MHRA) warned the public against melanotan use stating it was an unlicensed medicine that may not be safe. As such, it is illegal to market or supply this product in the UK due to its unlicensed nature. Additionally the MHRA warned 18 companies about selling or advertising the product and closed down 72 websites involving melanotan. By 2013, the MHRA had received 18 reports of 74 separate reactions to the products and reactions have involved stomach and heart problems, as well as blood and eye disorders.

In February 2009, the Irish Medical Board (IMB) indicated that they had detected the presence of microbial contamination in the water vial supplied with melanotan which poses a risk of serious infection. Further the IMB stated that this product is not authorised for use in the EU due to no guarantees as to quality, safety or efficacy.

Substance summary
Table 1.7.1: Chemical information of melanotan II
Property Melanotan II
CAS name Melanotan II acetate salt
CAS number 121062-08-6
IUPAC and/or common and/or other names

(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-9-benzyl-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide (IUPAC);

Chemical structure
Molecular formula C50H69N 15O9
Molecular weight 1024.2 g/mol

Melanotans include melanotan I (afamelanotide) and melanotan II. Both melanotan I and II are widely abused to obtain a cosmetic tan. The melanotans are potent, non-selective melanocortin receptor agonists affecting MC1, MC3, MC4 and MC5 receptors. These receptors are responsible for many physiological systems including: pigmentation, energy, sexual function, immune system, inflammation and the cardiovascular system.

Melanotan II is a synthetic analogue of the α-melanocyte stimulating hormone (α-MSH). α-MSH is a melanocortin I receptor agonist which has a role in human pigmentation by stimulating production of eumelanin. As melanotan II is a non-specific melanocortin receptor agonist, it has been reported to cause toxicity effects involving the many physiological systems affected by the receptors.

Melanotan II was originally developed as a treatment for sexual dysfunction. However, this was abandoned when the metabolite bremelanotide was developed instead for treatment of haemorrhagic shock. Melanotan II is usually injected subcutaneously for the purposes of sunless tanning, appetite suppression, inducing sexual desire and penile erection and other conditions such as rosacea and fibromyalgia. There are also dose forms available for nasal administration. The therapeutic dose is considered to be 0.01 mg/kg.

Toxicity

Toxicity effects of melanotan II from therapeutic and overdose exposures include renal dysfunction, rhabdomyolysis, sympathomimetic overdrive, change in size and pigmentation of pre-existing moles, rapid increase in the number of new moles, associated with causing melanomas, posterior reversible encephalopathy syndrome, refractory priapism, stretching and yawning syndrome, shortness of breath, chest pain, abdominal cramping and pain, dizziness and lethargy.

XXXXXX experience shows overdose appears to be relatively common, with the most frequent observation being a 10 fold overdose error resulting in toxicity symptoms and some have required hospitalisation.

Stability and contamination

There are reports that these products have tested positive for microbial contaminants. After reconstitution, these vials are marketed for multiple uses for up to a few weeks, which pose a stability issue and further increase the infection risk issue.

Current use pattern in Australia

Melanotan II tanning injections have received media attention over the past few years and have been dubbed the "barbie drug" by XXXXXX. The XXXXXX website states that all products are manufactured and compounded in pharmacies in Australia and, pending the satisfactory completion of a short medical assessment, will express post products to a nominated shipping address. The XXXXXX website also states that melanotan II is defined as a 'more potent peptide' when compared to melanotan I, offering a greater density in peptide chain with noticeable results in a shorter timeframe. There are also claims of enhancing male libido, sexual performance, curing erectile dysfunction and as an appetite suppressant.

Pre-meeting public submissions

No submissions were received.

Summary of ACMS advice to the delegates

The committee recommended that a new Schedule 4 entry, along with cross referencing to alpha-melanocyte stimulating hormone in the Index, be created for melanotan II.

Schedule 4 – New Entry

MELANOTAN II.

Index – New Entry

MELANOTAN II.
cross reference: α–MELANOCYTE STIMULATING HORMONE

Schedule 4

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: Advertising is currently leading consumers to purchase the product for lifestyle purposes, e.g. sunless tanning and appetite suppression, sexual stimulation. There is potential for numerous adverse events and toxicity, microbial contamination and unsafe needle and syringe handling.
  • Melanotan II can be of unknown quality and subject to contamination and stability concerns with use of multi-dose vials. There is no experience with the product other than through unregulated channels. There are health risks from the substance itself and its route of administration – documented in medical literature, case reports as well as reports from NSW PIC.
  • Benefits: There is no body of evidence demonstrating therapeutic benefits of melanotan II.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Used by consumers, after purchase through unregulated online sites, for lifestyle enhancement/cosmetic purposes, e.g. sunless tanning, sexual enhancement and appetite suppression; these claims are unproven.
    • The melanotan II product seems to be attractive to many consumers based on blogs and internet discussions.
    • There have been warnings from regulators that a large numbers of unlicensed product suppliers have been closed (MHRA, FDA warnings).
    • Not assessed for quality, safety and efficacy.
    • Extent of use is unregulated and unquantified.
  • the toxicity of a substance:
    • Melanotan II has a vast range of adverse effects related to therapeutic and overdose exposures. Toxicity data is limited.
    • Toxicity is largely based on case reports and reports from the regulatory authorities (NSW PIC also submitted reports).
    • Toxicity includes renal dysfunction, rhabdomyolysis, sympathomimetic overdrive, change in size and pigmentation of new moles, with one report of melanoma associated with use of melanotan II. Other case reports include posterior reversible encephalopathy syndrome (consisting of seizures, visual disturbance, confusion, headache, vomiting); refractory priapism, stretching and yawning syndrome; shortness of breath, chest pain, abdominal cramping & pain, dizziness and lethargy.
    • There are also concerns with overdoses and infection risk from dosing errors, contamination, stability of multi-dose vials and poor injection technique. Most issues of use resolve and are reversible although some are serious and require hospitalisation.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Product is supplied as a vial for reconstitution with water for injections.
    • Injection – for SC use using an insulin-type needle. Unreferenced therapeutic dosage is thought to be 0.01 mg/kg. Dosing errors seem common.
    • There are concerns with product quality, unregulated packaging, labelling, formulation and presentation. Concerns exist with unregulated product and perception of safety based on advertising.
  • the potential for abuse of a substance:
    • Melanotan II is currently being used for unapproved and/or unregistered indications in an unregulated setting. Reports that the substance is abused for appetite suppression and sexual stimulation are limited.
  • any other matters that the Secretary considers necessary to protect public health
    • Other comparable regulators have issued warnings about its use.
    • Possible public health issues in relation to claims on supplier websites that this substance can protect skin from sun damage.
    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

    The delegate’s interim decision is to include melanotan II in Schedule 4. The proposed Schedule entry is:

    Schedule 4 – New Entry

    MELANOTAN II for cosmetic or therapeutic use.

    Index – New Entry

    MELANOTAN II
    cross reference α–MELANOCYTE STIMULATING HORMONE

    Schedule 4

    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: Advertising is currently leading consumers to purchase the product for lifestyle purposes, e.g. sunless tanning and appetite suppression, sexual stimulation. There is potential for numerous adverse events and toxicity, microbial contamination and unsafe needle and syringe handling.
    • The product can be of unknown quality and subject to contamination and stability concerns with use of multi-dose vials. There is no experience with the product other than through unregulated channels. There are health risks from the substance itself and its route of administration – documented in medical literature, case reports as well as reports from NSW PIC.
    • Benefits: There is no body of evidence demonstrating therapeutic benefits of melanotan II.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Used by consumers, after purchase through unregulated online sites, for lifestyle enhancement/cosmetic purposes, e.g. sunless tanning, sexual enhancement and appetite suppression; these claims are unproven.
    • The melanotan II product seems to be attractive to many consumers based on blogs and internet discussions.
    • There have been warnings from regulators that a large numbers of unlicensed product suppliers have been closed (MHRA, FDA warnings).
    • Not assessed for quality, safety and efficacy.
    • Extent of use is unregulated and unquantified.
  • the toxicity of a substance:
    • Melanotan II has a vast range of adverse effects related to therapeutic and overdose exposures. Toxicity data is limited.
    • Toxicity is largely based on case reports and reports from the regulatory authorities (NSW PIC also submitted reports).
    • Toxicity includes renal dysfunction, rhabdomyolysis, sympathomimetic overdrive, change in size and pigmentation of new moles, with one report of melanoma associated with use of melanotan II. Other case reports include posterior reversible encephalopathy syndrome (consisting of seizures, visual disturbance, confusion, headache, vomiting); refractory priapism, stretching and yawning syndrome; shortness of breath, chest pain, abdominal cramping & pain, dizziness and lethargy.
    • There are also concerns with overdoses and infection risk from dosing errors, contamination, stability of multi-dose vials and poor injection technique. Most issues of use resolve and are reversible although some are serious and require hospitalisation.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Product is supplied as a vial for reconstitution with water for injections.
    • Injection – for SC use using an insulin-type needle. Unreferenced therapeutic dosage is thought to be 0.01 mg/kg. Dosing errors seem common.
    • There are concerns with product quality, unregulated packaging, labelling, formulation and presentation. Concerns exist with unregulated product and perception of safety based on advertising.
  • the potential for abuse of a substance:
    • Melanotan II is currently being used for unapproved and/or unregistered indications in an unregulated setting. Reports that the substance is abused for appetite suppression and sexual stimulation are limited.
  • any other matters that the Secretary considers necessary to protect public health
    • Other comparable regulators have issued warnings about its use.
    • Possible public health issues in relation to claims on supplier websites that this substance can protect skin from sun damage.

    Footnotes

    1. Also known as melanotan I; cross referenced to MELANOCYTE STIMULATING HORMONE in the index

    Book pagination