Advisory Committee on Medicines Scheduling (ACMS #22)

Summary of delegate's final decisions

Substance	Interim Decision
Hyaluronic acid	Schedule 4 - Amend Entry HYALURONIC ACID AND ITS POLYMERS in preparations for injection or implantation. The proposed implementation date is 1 June 2018.
Cardarine	Schedule 10 - New Entry CARDARINE. Index – New Entry CARDARINE Schedule 10 The proposed implementation date is 1 June 2018.
Stenabolic (SR9009)	Schedule 4 - New Entry # STENABOLIC (SR9009) and other synthetic REV-ERB agonists. Appendix D, Part 5 - New Entry STENABOLIC (SR9009) and other synthetic REV-ERB agonists. Index – New Entry STENABOLIC (SR9009) and other synthetic REV-ERB agonists cross reference: SR9011, GSK2945, GSK0999, GSK5072, GSK2667 Schedule 4 Appendix D, Part 5 The proposed implementation date is 1 June 2018.
Ibutamoren	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.
alpha-Pyrrolidinovalerophenone (alpha-PVP) and related substances methylone and synthetic cathinones	Schedule 9 - New Entry ALPHA-PYRROLIDINOVALEROPHENONE *(ALPHA-PVP). Schedule 9 - New Entry METHYLONE *(MDMC). Schedule 9 - Amend Entry CATHINONES except when separately specified in these Schedules. Index - Amend Entry CATHINONES cross reference: SYNTHETIC CATHINONES The proposed implementation date is 1 June 2018.
Ibuprofen	The delegate’s interim decision is that the current scheduling of ibuprofen remains appropriate
Melanotan II	Schedule 4 - New Entry MELANOTAN II. Index - New Entry MELANOTAN II cross reference: α–MELANOCYTE STIMULATING HORMONE Schedule 4 The proposed implementation date is 1 June 2018.
Orphenadrine	The delegate’s interim decision is that the current scheduling of ibuprofen remains appropriate.
Clotrimazole	The delegate’s interim decision is that the current scheduling of ibuprofen remains appropriate.

Advisory Committee on Medicines Scheduling (ACMS #22)

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Scheduling history | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

A delegate from the Therapeutic Goods Administration (TGA) has referred the substance hyaluronic acid for consideration to amend the Schedule 4 entry to include the subclause 'for intra-articular injection' in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

This was a delegate initiated application. The delegate's proposed amendments to the Poisons Standard are:

Schedule 4 – Amend Entry

The delegate's reasons for the request are:

• The use of a product containing hyaluronic acid intended to be used for intra-articular injection for symptomatic treatment of knee osteoarthritis is not specifically noted in the Schedule 4 entry for hyaluronic acid.
• Based on the current schedule entry for hyaluronic acid in the Poisons Standard and on its scheduling history (particularly noting the June 2003 National Drugs and Poisons Schedule Committee (NDPSC) meeting – see Scheduling History below), hyaluronic acid in a registered product appears to be exempt from scheduling and does not require a prescription.
• According to the Australian Register of Therapeutic Goods (ARTG), the product is a medical device. According to the Appendix A entry for medical devices, medical devices are generally exempt from scheduling. However, this exemption does not extend to the product as it is intended to be used for intra-articular injection for symptomatic treatment of knee osteoarthritis. (See subclause) of the Appendix entry below:

Appendix A

MEDICAL DEVICES classified as Class III by the classification rules set out in Schedule 2 to the Therapeutic Goods (Medical Devices) Regulation 2002 except:

1. injectable tissue reconstructive, augmentation and restoration materials, including collagen;
2. medical devices which include anticoagulants;
3. artificial tears;
4. urinary catheters; or
5. intra-articular fluids.
• Sponsors of devices are obliged to ensure that the devices they supply in Australia meet the Australian Essential Principles. Essential Principle 1 of the Medical Devices Regulations 2002 states that:
• A medical device is to be designed and produced in a way that ensures that:

"(a) the device will not compromise the clinical condition or safety of a patient, or the safety and health of the user or any other person, when the device is used on a patient under the conditions and for the purposes for which the device was intended and, if applicable, by a user with appropriate technical knowledge, experience, education or training;"

• Schedule 1, Part 2, subsection 13 states that the information supplied with the device (instructions for use) must identify how to use the device safely including having regard to the training and knowledge of potential users of the device. This means that the device itself, or the supplied instructions for use must clearly state that the device is intended to only be used by an authorised physician.
• The intent of the Medical Devices Regulations 2002 is that the kinds of devices that should only be used by certain health care professionals are only marketed and supplied to these people. XXXX is such a device, as (according its ARTG entry):

XXXX is intended to be used for intra-articular injection for symptomatic treatment of knee osteoarthritis.

Functional description:

XXXX is presented in a glass syringe with a rigid tip cap and plunger stopper. The syringe is assembled with a luer lock adapter, finger grip and plunger rod. XXXX is injected into the synovial joint by an authorised person experienced in intra-articular injections following an aseptic technique using an 18 to 22 gauge needle (not supplied). XXXX provides mechanical joint lubrication to the injected joint.

• Prescriptions are not used for these types of devices, as the product is not supplied directly to the patient but rather to a health care professional who would then directly administer it to the patient. This is unlike a medicine supplied through a prescription, which the patient would obtain themselves using a prescription and then administer it themselves.
• The sponsor of this device (or their agent) should not be marketing this device to a pharmacy that would then supply to the general public.
• The intention of Schedule 4, part c) 'for the treatment of animals' was to allow for the use of hyaluronic acid via intra-articular injection in animals (see June 2003 NDPSC meeting – see Scheduling History below). The Schedule 4 entry currently excludes this use in humans.

Current scheduling status

Hyaluronic acid and its polymers are in Schedule 4 of the current Poisons Standard as follows:

Scheduling history

The relevant scheduling history of hyaluronic acid is as follows:

May 1986 National Drugs and Poisons Schedule Committee (NDPSC)

In May 1986, the NDPSC agreed to include hyaluronic acid in preparations for injection in Schedule 4, on the grounds that the product containing hyaluronic acid was used to treat a serious condition requiring veterinary intervention.

May 2000 National Drugs and Poisons Schedule Committee (NDPSC)

In May 2000, the committee were made aware that certain products that contained hyaluronic acid may have been overlooked at the time of registration and were classified as a device.

February 2001 National Drugs and Poisons Schedule Committee (NDPSC)

In February 2001, the NDPSC considered a background paper on hyaluronic acid use in devices. The committee had become aware that many products classified as devices for registration purposes, contained scheduled substances. The committee also considered the Trans-Tasman Harmonisation Working Party (TTHWP) recommendation that New Zealand adopt the existing Schedule 4 entry for hyaluronic acid. Additionally, the committee considered a request that the Schedule 4 entry for hyaluronic acid in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP) be reviewed, to exempt certain products, containing hyaluronic acid manufactured by bacterial fermentation.

This was deferred until the next meeting to allow assessment of the appropriateness and feasibility of scheduling substances that are either included in products, or are products, regulated as medical devices.

May 2001 National Drugs and Poisons Schedule Committee (NDPSC)

In May 2001, the NDPSC agreed that for clarity, the entry for hyaluronic acid in the SUSDP be amended to include its polymers. However, the committee did not agree that injectable products containing hyaluronic acid should not be exempt from scheduling but that these should be subject to the requirements of Schedule 4. The committee agreed to include the entry 'HYALURONIC ACID and its polymers, in preparations for injection.' in Schedule 4 of the SUSDP, and an entry for intraocular viscoelastic products in Appendix A.

August 2001 National Drugs and Poisons Schedule Committee (NDPSC)

In August 2001, the NDPSC considered hyaluronic acid when in intraocular viscoelastic products and confirmed that the Appendix A entry for viscoelastic products remained appropriate.

February 2002 National Drugs and Poisons Schedule Committee (NDPSC)

In February 2002, NDPSC considered a proposal to amend the existing entry for hyaluronic acid to read, 'HYALURONIC ACID AND ITS POLYMERS in preparations for injection.' Members agreed that the proposed amendment to change 'hyaluronic acid and its polymers' to upper case letters would ensure a consistent interpretation of the entry across the jurisdictions. The committee decided that such an amendment would be appropriate given that there is no regulatory impact expected as a result of the amendment.

February 2003 National Drugs and Poisons Schedule Committee (NDPSC)

In February 2003 the NDPSC amended the Schedule 4 entry for hyaluronic acid to include preparations for implantation. The committee agreed to clarify the intent of Schedule 4 entries for substances used in tissue augmentation or cosmetic use (including collagen, hyaluronic acid and polylactic acid), to encompass preparations for injection or implantation. The Schedule 4 hyaluronic acid amendment was made as follows:

June 2003 National Drugs and Poisons Schedule Committee (NDPSC)

In June 2003 the NDPSC agreed that the to the Schedule 4 entry amendment for hyaluronic acid inadvertently excluded 4 veterinary products containing sodium hyaluronate for the treatment of non-infectious joint diseases (synovitis) of horses. The committee recognised that the unintended regulatory impact on the Schedule 4 veterinary products and noted that the products required veterinary intervention so should remain in Schedule 4. The committee agreed that the Schedule 4 entry for hyaluronic acid should be amended to include 'c) for the treatment of animals'. The Schedule 4 hyaluronic acid amendment was made as follows:

Australian regulatory information

According to the TGA Ingredient Database, hyaluronic acid is permitted to be used as an:

• Excipient ingredient in Biologicals, Export Only, Listed Medicines, Over the Counter and Prescription Medicines; and
• Active ingredient in Biologicals, Export Only and Prescription Medicines.

Hyaluronic acid is not currently used in proprietary ingredient (PI) formulation.

Hyaluronic acid is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017 as an excipient in topical medicines for dermal applications.

In the last 30 years, there has been one adverse event reported in the Database of Adverse Event Notifications – Medicines with hyaluronic acid listed as a single suspected medicine. The reported adverse effect was hypoaesthesia.

There are 2 products on the ARTG containing hyaluronic acid:

• APVMA has 8 products registered for use in horses containing sodium hyaluronate. No adverse events were recorded from January 1995 to December 2013.

International regulations

Canada

In Canada, hyaluronic acid for intra articular use is regulated as class III or class IV medical devices and sold as pre-filled single use syringes.

Hyaluronic acid is also permitted for intra-articular use in horses.

United States of America

In the USA, hyaluronic acid is permitted for use in intra articular injections, and approved dermal fillers.

Hyaluronic acid is also permitted for intra articular use in horses, subject to conditions of use related to the dosage and treatment regime.

European Union (EU)

In the EU, there are no apparent restrictions on the use of hyaluronic acid.

New Zealand

In NZ, hyaluronic acid is considered prescription only for injections or implants for tissue augmentation or cosmetic use, and for general sale for all other uses.

Substance summary

Hyaluronic acid in its natural form is a linear unbranched (no isomerisation) biological polymer found in all animals, some plants and some bacteria (particularly gram positive). It is a glycosaminoglycan. The hyaluronic acid polymer is composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine disaccharide units.

Table 1.1.1: Chemical properties of hyaluronic acid

Property	Hyaluronic acid
CAS number	9004-61-9
IUPAC and/or common and/or other names	(2S,4S,5R,6S)-6-[(2S,3R,5S,6R)-3-acetamido-2-[(3S,4R,5R,6R)-6-[(3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid (IUPAC); Hyaluronan; Hyvisc; Luronit; Vitrax, Amp
Chemical structure
Molecular formula	Polymer: (C14H21NO11)n Monomer: C28H44N2O23, n = 2
Molecular weight	776.7 g/mol (monomer)

N-Acetyl-D-glucosamine is a component of connective tissue, skin, vitreous humour, umbilical cord, synovial fluid and the capsule of certain microorganisms contributing to adhesion, elasticity, and viscosity of extracellular substances. It is also found as small saccharides in the tissue due to enzymatic digestion and chemical breakdown.

Hyaluronan is a commonly term for salts of hyaluronic acid (usually Na, but exists in the tissues as various salts and complexes) but is also used interchangeably with the acid. Hyaluronic acid and its cross-linked derivatives are also used in tissue augmentation and visco-supplementation. Although the cross-linked forms have better residence time, resist enzymatic degradation and could have superior rheological properties in some applications. In literature, the term hylan is used to describe hyaluronic acids cross-linked with highly reactive chemicals (e.g. divinyl sulfone, imides or dialdehyde).

Pharmacology and Biochemistry

Hyaluronic acid is similar to a substance that occurs naturally in the joints. It may act as a lubricant and shock absorber in the joint, helping the joint to move smoothly.

Drug indication

Hyaluronic acid is used to treat knee pain in patients with joint inflammation (osteoarthritis). It is usually used in patients who have not responded to other treatments such as paracetamol, exercise, or physical therapy. Hyaluronic acid may also be used in plastic surgery to reduce wrinkles on the face or as a filler in other parts of the body. It may be used in ophthalmology to assist in the extraction of cataracts, the implantation of intraocular lenses, corneal transplants, glaucoma filtration, retinal attachment and in the treatment of dry eyes and is also used to coat the bladder lining in treating interstitial cystitis.

Drug warnings

Hyaluronic acid is considered to be non-immunogenic and is frequently used for the correction of facial lines. It is believed that hyaluronic acid injection fillers are safe and have no occurrence of serious adverse reactions or allergic reactions. However, publications have documented the rate of intermittent swelling and severe granulomatous allergic reactions that evolved into abscesses. Literature describes a clinical case of a 54-year-old patient.^[1] After injection of hyaluronic acid in the treatment of nasolabial folds, palpable painful erythematous nodules evolved into abscesses several months after injection. Surgical treatment and correction of the lesions after the hyaluronic acid injection of the nasolabial folds and histological findings of the erythematous nodules were described. Histological and clinical examination documented intermittent swelling and severe granulomatous allergic reactions that may render the use of hyaluronic acid unacceptable. The reference recommends that patients should be informed of the potential complications when treating facial lines with hyaluronic acid gel.

Non-animal hyaluronic acid gel was developed for soft tissue augmentation and volume expansion and has been reported to offer several advantages in comparison to other augmentation materials. There are rare reports of adverse events believed to be secondary to trace amounts of proteins in the hyaluronic acid raw material. Data from an estimated 144,000 patients treated in 1999 indicated the major reaction to injectable hyaluronic acid was localised hypersensitivity reactions, occurring in approximately 1 of every 1400 patients treated. In 1999, there was an adverse event reported for 1 of every 650 patients (0.15%) treated. These were temporary events that included redness, swelling, localised granulomatous reactions, bacterial infection, as well as acneiform and cystic lesions. In 2000, there was an estimated 262,000 patients treated with hyaluronic acid gel. The total number of adverse events was 144, corresponding to one adverse event for every 1800 patients (0.06%) treated. The major adverse event was again hypersensitivity, occurring in 1 of every 5000 patients treated. According to the reported worldwide adverse events data, hypersensitivity to non-animal hyaluronic acid gel is the major adverse event and is most likely secondary to impurities of bacterial fermentation. According to data from 2000, the incidence of hypersensitivity appears to be declining after the introduction of a more purified hyaluronic acid raw material.^[2]

Absorption, distribution and excretion

Hyaluronic acid is absorbed and diffuses slowly out of the injection site. It is eliminated via the canal of Schlemm and is degraded by hyaluronidase enzymes.

Mechanism of action

Hyaluronic acid functions as a tissue lubricant and is thought to play an important role in modulating the interactions between adjacent tissues. Hyaluronic acid is a polysaccharide which is distributed widely in the extracellular matrix of connective tissue. It forms a viscoelastic solution in water which makes it suitable for aqueous and vitreous humor in ophthalmic surgery. Mechanical protection for tissues (iris, retina) and cell layers (corneal, endothelium, and epithelium) are provided by the high viscosity of the solution. Elasticity of the solution assists in absorbing mechanical stress and providing a protective buffer for tissues. This viscoelasticity enables maintenance of a deep chamber during surgical manipulation since the solution does not flow out of the open anterior chamber. In facilitating wound healing, it is thought that it acts as a protective transport vehicle, taking peptide growth factors and other structural proteins to a site of action. It is then enzymatically degraded and active proteins are released to promote tissue repair. Hyaluronic acid is being used intra-articularly to treat osteoarthritis. Cell receptors that have been identified for hyaluronic acid fall into three main groups: CD44, Receptor for Hyaluronan-mediated motility (RHAMM) and intracellular adhesion molecule-1 (ICAM-1). CD44 mediates cell interaction with hyaluronic acid and the binding of the two functions as an important part in various physiologic events, such as cell aggregation, migration, proliferation and activation; cell-cell and cell-substrate adhesion; endocytosis of hyaluronic acid, which leads to hyaluronic acid catabolism in macrophages; and assembly of petircellular matrices from hyaluronic acid and proteoglycan. CD44 has two important roles in skin, regulation of keratinocyte proliferation in response to extracellular stimuli and the maintenance of local hyaluronic acid homeostasis. ICAM-1 is known mainly as a metabolic cell surface receptor for hyaluronic acid, and this protein may be responsible mainly for the clearance of hyaluronic acid from lymph and blood plasma, which accounts for perhaps most of its whole-body turnover. Ligand binding of this receptor, thus, triggers a highly coordinated cascade of events that includes the formation of an endocytotic vesicle, its fusion with primary lysosomes, enzymatic digestion to monosaccharides, active transmembrane transport of these sugars to cell sap, phosphorylation of GlcNAc and enzymatic deacetylation. ICAM-1 may also serve as a cell adhesion molecule, and the binding of hyaluronic acid to ICAM-1 may contribute to the control of ICAM-1-mediated inflammatory activation.

Pre-meeting public submissions

No submissions were received.

Summary of ACMS advice to the delegates

The committee recommended that the Schedule 4 entry for hyaluronic acid in the Poisons Standard be amended as follows:

The committee also recommends 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; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

1. the risks and benefits of the use of a substance:
• Risks: Hyaluronic acid presents very little risk when used in accordance with TGA-approved Product Information.
• Benefits: The potential benefits are for people not responding to other standard treatments for knee osteoarthritis and also those awaiting joint replacements, etc. Additionally, it is a one-off treatment lasting for 6-9 months rather than having to take increased quantities of pain medication daily. The associated risks of this are especially so in the older population.
2. the purposes for which a substance is to be used and the extent of use of a substance:
• For the symptomatic treatment of knee osteoarthritis
• Potential for misuse
• The ailments or symptoms that hyaluronic acid is used for require medical intervention.
3. the toxicity of a substance:
• Very low risk of allergy, toxicity or systemic adverse events in humans.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
• Packaged as an injectable.
• The use of hyaluronic acid requires a specialised medicine delivery device.
5. the potential for abuse of a substance:
• Nil
6. any other matters that the Secretary considers necessary to protect public health:
• Appropriate that hyaluronic acid be administered under a health practitioner’s supervision.

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 amend the Schedule 4 entry for hyaluronic acid. The proposed Schedule entry is:

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; 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: Hyaluronic acid presents very little risk when used in accordance with TGA-approved Product Information.
• Benefits: The potential benefits are for people not responding to other standard treatments for knee osteoarthritis and also those awaiting joint replacements, etc. Additionally, it is a one-off treatment lasting for 6-9 months rather than having to take increased quantities of pain medication daily. The associated risks of this are especially so in the older population.
2. the purposes for which a substance is to be used and the extent of use of a substance:
• For the symptomatic treatment of knee osteoarthritis.
• Potential for misuse.
• The ailments or symptoms that hyaluronic acid is used for require medical intervention.
• Any use as of an injection or implant requires medical practitioner use.
3. the toxicity of a substance:
• Very low risk of allergy, toxicity or systemic adverse events in humans.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
• Packaged as an injectable.
• The use of hyaluronic acid requires a specialised medicine delivery device.
5. the potential for abuse of a substance:
• Nil
6. any other matters that the Secretary considers necessary to protect public health
• Appropriate that hyaluronic acid be administered under a health practitioner’s supervision.

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Footnotes

1. Honig JF et al.,; J Craniofac Surg 14 (2): 197-200 (2003)
2. Friedman PM et al.,; Dermatol Surg 28 (6): 491-4 (2002)

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Current use pattern in Australia |Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

An application was submitted to create a new entry for cardarine in Schedule 9 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 9 – New Entry

The applicant’s reasons for the request are:

• Cardarine is known for its experimental status and it is not being approved for human use.
• Cardarine is readily available for purchase in Australia through online suppliers, based in Australia and overseas. It is also available through compounding pharmacies and anti-ageing clinics.
• The lack of regulation allows suppliers to advertise these substances freely and make unproven assertions about the efficacy and safety of the substances. They are administered without reliable advice on appropriate dosage, frequency of administration, and exact content. The products are being positioned as a cutting-edge alternative to steroids on bodybuilding forums and black-market sites.
• The substances are being used by athletes and gym users for the enhancement of sporting performance and aesthetics.
• Scheduling these substances aims to protect public health from the potential adverse impacts of these unapproved substances. The unregulated supply poses potentially serious health concerns. They are administered without reliable advice on appropriate dosage, frequency of administration, and exact content.
• Cardarine may be a potential carcinogen and its effect on humans has not been systematically investigated.
• The Australian Sports Anti-Doping Authority (ASADA) has advised that cardarine has been seized at the border by the Australian Border Force as a prohibited import on multiple occasions.
• If cardarine was marketed, it would require careful regulatory scrutiny. Therefore, in an open, unregulated illicit market, cardarine warrants a listing in the Poisons Standard.
• Cardarine has been identified as a substance of abuse with potential carcinogenic effects, and should be considered for a Schedule 9 entry.

Current scheduling status and relevant scheduling history

Cardarine is has not previously been considered for scheduling. Therefore, a scheduling history is not available.

Australian regulatory information

Cardarine 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)

Cardarine (GW501516) is a Peroxisome Proliferator Activated Receptor δ (PPARδ) agonist. WADA added PPARδ agonists to the Prohibited List in January 2009. In 2011, cardarine was placed in the class M3, 'gene doping', based on the following annotation:

In 2012, cardarine was moved to class S4, "hormone and metabolic modulators". WADA has undertaken an unprecedented decision to advise athletes about cardarines toxicity. WADA's aim is to ensure complete awareness of the potential health risks, thus preventing athletes from surrendering to temptation of assuming cardarine for performance improvement.

In March 2013, the WADA published on its website a warning concerning health risks associated with the use of cardarine. It stated that this substance, once a developmental drug, was withdrawn from research and terminated when serious toxicities were discovered in animal subjects (WADA alert, 2013). This was not triggered by new safety data, but by the fact that it was being marketed as a supplement advertised to complement endurance training. As a result, there had been several positive doping tests.

Canada

In April 2017, Health Canada issued a warning to consumers about unauthorised drugs sold online, including cardarine. The warning states:

Substance summary

Table 1.2.1: Chemical properties of cardarine (GW-501516)

Property	Cardarine (GW-501516)
CAS number	317318-70-0
IUPAC and/or common and/or other names	2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid (IUPAC);GW-501516, GW501516, endurobol, GSK 516
Chemical structure
Molecular formula	C21H18F3NO3S2
Molecular weight	453.5 g/mol

Cardarine (GW501516) is a metabolic activator that selectively targets the peroxisome proliferator-activated receptor δ (PPARδ) with high affinity and potency thereby rendering it as a PPARδ agonist. Other marketed drugs in that class include the thiazolidinediones for treatment of type 2 diabetes mellitus, some of which have had post-marketing safety problems.

Cardarine was primarily developed to treat obesity, diabetes, lipid strain, and heart health problems. Cardarine activates AMP-activated protein kinase, glucose uptake and fatty acid oxidation in skeletal muscle (see Figure 1.2.1). Cardarine may reverse metabolic abnormalities in obese and pre-diabetic individuals by stimulating fatty acid oxidation, burning fat and increasing glucose uptake in skeletal muscle tissue, which changes the body’s metabolism to burn fat for energy instead of muscle or carbohydrates.^[3]

Cardarine was initially developed in 1992 by Ligand Pharmaceuticals and GlaxoSmithKline (GSK) as a metabolic agent with potential anti-cancer, anti-obesity and cardiovascular applications. Phase I trials of cardarine for the treatment of hyperlipidaemia began in 2000 followed by phase I/II in 2002. Further development of cardarine was abandoned in 2007 for safety reasons when preclinical toxicology showed that it caused various cancers ^[4]

A few clinical trials have been performed on cardarine and its effects on lipid and lipoprotein metabolism. In contrast to the animal toxicity studies, no significant adverse effects were reported in any of the human studies, which may reflect the considerably lower doses administered (up to 10 mg/day) for much shorter periods of time (up to 12 weeks). However, the available clinical data on cardarine’s safety is insufficient to claim it is safe for humans. Long-term consequences have not been determined due to the low number of clinical trials performed.

Cardarine has a substantial following in sporting circles. It is also on the WADA Prohibited List under the category S4 ‘Hormone and Metabolic Modulators’ and appears increasingly in the list of drugs linked to anti-doping rule violations ^[5]

There are no known side effects associated with cardarine use to date. Unlike most fat loss drugs in use, cardarine does not stimulate the nervous system .There were no side-effects reported in the human studies performed, which may be due to short study durations. It may also be due to the small doses used in humans. The side-effects of cardarine from animal studies including its carcinogenicity potential were based on large doses of the drug.

Limited Human Studies

A few clinical trials have been performed on cardarine (GW501516) and its effects on lipid and lipoprotein metabolism. In contrast to the animal toxicity studies, no significant adverse effects were reported in any of the human studies, which may reflect the considerably lower doses administered (up to 10 mg/day) for much shorter periods of time (up to 12 weeks). However, the available clinical data on GW501516 safety is insufficient to assess the long-term health risks associated with its intake by human subjects. Long-term consequences have not been discovered yet due to the low number of clinical trials performed.

Summary of clinical trials

Various clinical trials with cardarine (GW501516) during early drug development are detailed below:

• Phase 1 trial (Clinical trials id NCT00388180)

  This was a randomised, double-blind, parallel group study to evaluate the effect of 12-week treatment with GW590735X (20 µg) or GW501516X (10 mg) relative to placebo on measures of adiposity and inflammation in overweight and obese healthy volunteers.

• Phase 1 trial (Clinical trials id NCT00318617)

  This was a two part study to separately evaluate the effect of 4-week treatment with GW501516X relative to placebo on cardiac energetics in a randomised, single-blind, repeat dose, parallel group design in healthy male subjects

  This phase I trial was terminated without disclosing the reasons for termination.

• Phase 2 trial (Clinical trials id NCT00158899)

  This was a multi-centre, three-staged with interim analyses, parallel, randomised, double-blind, fenofibrate-and placebo-controlled proof of concept and dose-response evaluation of the safety, tolerability, and effects on plasma high-density lipoprotein cholesterol (HDLc) and triglycerides of eight weeks treatment with GW501516 in otherwise healthy patients with low HDLc, mildly to moderately elevated triglycerides, and normal low-density lipoprotein cholesterol (LDLc)

• Phase 4 trial (Clinical trials id NCT00841217)

  This was a double-blind randomised crossover trial of 6 week intervention periods to determine whether PPAR-delta agonists (GW5015156) had favorable effects on lipoprotein metabolism (2.5 mg/day).

This clinical trial was conducted in Australia (April 2003 to December 2008). The authors concluded that GW501516 increased the hepatic removal of VLDL particles, which might have resulted from decreased apoC-III concentration. GW501516 increased apoA-II production, resulting in an increased concentration of LpA-I: A-II particles. This study elucidates the mechanism of action of this PPARδ agonist on lipoprotein metabolism and supports its potential use in treating dyslipidemia in obesity. All these results were achieved without any significant alteration in body weight or insulin resistance. No adverse events were observed ^[6]

Eric J. Olson et al., (2012) ^[7]

Cardarine (GW501516) (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. The doses used were found to be safe with regard to safety outcomes assessed.

Dennis L. Sprecher et al., (2007) ^[8]

Healthy volunteers were allocated placebo (n=6) or PPARδ agonist (GW501516) at 2.5 mg (n=9) or 10 mg (n=9), orally, once-daily for 2 weeks while hospitalised and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vivo and evaluated for lipid-related gene expression and fatty acid oxidation (FAO). Serum TG trended downwards (P=0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (P=0.02). HDLc was enhanced in both treatment groups (2.5 mg P=0.004, 10 mg P<0.001) when compared with the decrease in the placebo group (−11.5±1.6%, P=0.002). These findings complimented in vivo cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression. No adverse events were identified.

Reproductive toxicity studies

Nishimura K, et al., (2013) ^[9]

Nishimura et al., 2013 conducted a study in Japan to evaluate the foetal and placental developmental toxicity due to cardarine (GW501516) administration to pregnant rats.

In the first experiment, Sprague-Dawley pregnant rats were administered 0, 30 or 100 mg/kg daily dose of GW501516 by gavage from gestational day (GD) 6-17. The current results indicated that maternal oral administration of GW501516 at a dose of 100 mg/kg/day during GD 6 to 17 caused the suppression of maternal body weight and food consumption, and increased foetal death ratio. Placental malformation was also induced by administration of GW501516 at a dose of 100 mg/kg/day. In those placentae, cystic structure was observed in the basal zone. Although the rate of placental malformation was very high (72.2%), placental weight was not affected.

In the second experiment, GW501516 was administered as a single dose of 0, 275 or 350 mg/kg to pregnant rats at gestational days 7, 8,9,10, or 11. One female rat died on GD 9 that was exposed to 350 mg/kg GW501516. Rate of post-implantation loss was significantly higher in the 275 and 350 mg/kg GW501516 groups on GD 9, and 350 mg/kg GW501516 group on GD 10. Single oral administration of GW501516 at a dose of 275 and/or 350 mg/kg on GD 8, 9, 10, or 11 induced placental malformation.

In the third experiment, female Sprague–Dawley rats were administered a single dose of 275mg/kg of GW501516 on gestational day 10. Fetal poor growth was observed. Single oral administration of GW501516 on GD 10 induced cystic degeneration associated with cellular lysis of glycogen cells started from GD 15 in the basal zone.

All results indicate that GW501516 administration is associated with high frequency of placental malformations. GW501516 administration at various dose levels had detrimental effect on foetal survivability and growth.

Carcinogenicity

In two abstracts published in The Toxicologist, it was shown that when rats and mice were given the drug for two years, there was a significantly increased risk of developing a range of cancers. These carcinogenicity studies were performed as part of the drug approval process.

L. E. Geiger et al., (2009) ^[10]

Carcinogenic potential of cardarine (GW501516) was assessed in male and female Han Wistar rats by daily administration of GW501516 for 104 weeks. Male rats were given a daily dose of 0,5,15 or 30 mg/kg/day for first six months and 0, 5, 20 or 40 mg/kg/day for rest of the study. Female rats were given a daily dose of 0, 3, 10 or 20 mg/kg/day for the entire duration of study.

Neoplastic changes were noted in multiple tissues at all dose levels. Increased mortality was noted in female rats at all dose levels and uterine endometrial carcinoma was the major cause of death in female rats. Other neoplasms related to GW501516 are as follows:

List of neoplasms effects relating to GW501516 in male and female rats.

Organ	Neoplasm	Dose level (in mg/kg/day)
Liver	Hepatocellular adenoma	10 mg/kg/day
Urinary bladder	Transitional cell carcinoma	20 and 40 mg/kg/day
Thyroid Gland	Follicular cell adenoma	3 mg/kg/day
Thyroid Gland	Follicular cell carcinoma in male rats	20 mg/kg/day
Tongue	Squamous cell papilloma of tongue in male rats	5 and 40 mg/kg/day
Stomach	Squamous cell papilloma in male rats	5 mg/kg/day
	Squamous cell papilloma of stomach in female rats	20 mg/kg/day
	Squamous cell carcinoma of stomach in male rats	40 mg/kg/day
	Squamous cell carcinoma of stomach in female rats	3 mg/kg/day
Skin	Inverted squamous cell papilloma of skin in male rats	5 mg/kg/day
	Inverted squamous cell papilloma of skin in female rats	3 or 20 mg/kg/day
Harderain glands	Adenoma of harderian glands in male rats	5 mg/kg/day
	Adenocarcinoma of harderian glands in male rats	40 mg/kg/day
Testis	Interstitial cell adenoma of testis in male rats	40 mg/kg/day
Ovaries	Sertoli cell adenoma of ovaries in female rats	10 mg/kg/day
Uterus	Polyp and endometrial adenocarcinoma of uterus in female rats	3 mg/kg/day

The authors concluded that some of the tumour types observed in this study have not been reported with either PPARα or PPARγ agonists and may reflect tumour promotion mediated through PPARδ agonism.

S. J. Newsholme et al., (2009) ^[11]

Carcinogenic potential of cardarine (GW501516) was assessed in CD1 mice by daily administration of GW501516 for 104 weeks. The mice were administered a daily dose of 0, 10, 30, 60 or 80 mg/kg/day. Neoplastic changes were noted in multiple tissues at all dose levels. Neoplasms related to GW501516 identified in this study are as follows:

• Hepatocellular carcinoma of liver (dose level 30 mg/kg/day);
• Hepatocellular adenoma of liver (dose level 10 mg/kg/day);
• Squamous cell carcinoma of stomach at all doses; and
• Combined squamous cell tumours i.e. squamous cell papilloma and carcinoma and keratoacanthoma at all dose levels.

The results from this study did not support a role of PPARδ in colon carcinogenesis, but these results demonstrated an increase in proliferation of certain epithelial cell populations e.g. Squamous cell tumours.

Rajnish A Gupta et al., (2004) ^[12]

Gupta et al., 2004 assessed the carcinogenic potential of cardarine (GW501516) by administering it to Apcmin mice. Exposure of Apcmin mice to the PPARδ ligand GW501516 resulted in a significant increase in the number and size of intestinal polyps. The most prominent effect was on polyp size; mice treated with the PPARδ activator had a fivefold increase in the number of polyps larger than 2 mm. The results implied PPARδ in the regulation of intestinal adenoma growth. To test the effects of PPARδ activation on polyp growth, Apcmin mice were either given vehicle or 10 mg/kg of GW501516. Treatment was limited to 6 weeks.

The control Apcmin mice developed an average of 30 small intestine polyps and 1.4 colonic polyps. In contrast, GW501516 treatment led to a twofold increase in polyp number in the small intestine, with no change in the large bowel. The authors concluded that PPARδ activation promotes the growth of intestinal adenomas in Apcmin mice.

Elizabeth E. Girroir et al., (2007) ^[13]

Girroir et al., 2007 examined the effect of ligand activation of PPARδ on cell growth of two human cancer cell lines, MCF7 (breast cancer) and UACC903 (melanoma) in the presence or absence of serum using two highly specific PPARδ ligands, GW0742 or cardarine (GW501516). Culturing cells in the presence of either GW0742 or GW501516 caused up-regulation of the known PPARδ target gene angiopoietin-like protein 4 (ANGPTL4). Inhibition of cell growth was observed in both cell lines cultured in the presence of either GW0742 or GW501516, and the presence or absence of serum had little influence on this inhibition. The authors concluded that ligand activation of PPARδ inhibits the growth of both MCF7 and UACC903 cell lines and provide further evidence that PPARδ ligands are not mitogenic in human cancer cell lines.

Holly Hollingshead et al., (2007) ^[14]

Hollingshead et al., 2007 examined the effect of two different PPARδ ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS–174T, HepG2 and HuH7) cultured in the presence or absence of serum and compared in vivo analysis with in vivo analysis. Neither PPARδ ligand increased cell growth nor phosphorylation of Akt and no increase in the expression of VEGF or COX-2 were detected in any cancer cell line in the presence or absence of serum. Similarly, liver, colon and colon polyps from mice administered these PPARδ ligands in vivo did not exhibit changes in these markers.

Claire B. Pollock et al., (2010) ^[15]

Pollock et al., 2010 described a gastric tumour mouse model that is dependent on the potent and highly selective PPARδ agonist cardarine (GW501516) following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the fore-stomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARδ expression in tumours correlated with increased PDK1, Akt, β-catenin, and S100A9 expression. It is important to note that the dose of GW501516 used in the present study is equivalent to daily oral doses of 3–10 mg/kg that were previously shown to specifically enhance PPARδ-dependent fatty acid oxidation in mice in previous studies. In addition, PPARδ agonist GW7042, which is almost identical to GW501516 in structure, potency, and specificity, was inactive in inducing gene expression in PPARδ knockout mice.

Current use pattern in Australia

An internet search for “GW501516” or “cardarine” indicates that cardarine is sold online as oral liquid, capsule or powder for performance enhancement.

Labels indicate the following:

• Relevant identified uses: "For research purposes only", "SARM (Selective Androgen Receptor Modulator", "For laboratory and research use only", "Dietary supplement", "Promotes lean mass" "Anabolic enhancement agent", "Increases endurance" "CardioCapacity boost" "AMPk booster" "Works with or without exercise" "Endurance enhancer" "Melts body fat" "Weight loss/Endurance";
• Population: It should ONLY be used by men and women over 21 years old. It is NOT meant for children, teenagers, and pregnant or nursing women;
• Formulation: liquid and powder;
• Route: Oral;
• Dosage: 10-30 mg/day; and
• Intended duration of use: 4-8 weeks taking at least 4 weeks off in between cycles.

Medical Use

Cardarine was developed to treat obesity, diabetes, lipid strain, and heart health problems. It has been reported to reverse metabolic abnormalities in obese and pre-diabetics by stimulating fatty acid oxidation. Burning fat by increasing glucose uptake in skeletal muscle tissue, this changes metabolism to burn fat for energy instead of muscle or other carbohydrates.

Performance-enhancing use

Concerns were raised prior to the 2008 Beijing Olympics that cardarine could be used by athletes as an ergogenic performance-enhancing drug that was not then controlled by regulations or detected by standard tests. Consequently, a urine test to detect cardarine was developed and made available to the International Olympic Committee. The World Anti-Doping Agency (WADA) developed a test for cardarine and other related PPARδ modulators, and added such drugs to the prohibited list in 2009.

Cardarine has been promoted on bodybuilding and athletics websites. In 2011 it was reported to cost $1000 for 10 g. In 2012, WADA re-categorised cardarine from a gene doping compound to a "hormone and metabolic modulator".

A number of athletes have tested positive for cardarine in the last few years.

Pre-meeting public submissions

One (1) submission was received that opposed the proposal for cardarine, instead suggesting that a Schedule 9 entry may be more appropriate. The main points opposed to a Schedule 4 entry and in support of a Schedule 9 entry were:

• These medicines are used to alter gene expression and can be used as a physical performance enhancer.
• Clinical evidence of purported health outcomes such as reduced obesity and diabetes through altering gene expression is scant, of low quality and only produced in mice subjects.^[16] Human studies of this medicine have not been published.

The public submission will be made available on the TGA website.

Summary of ACMS advice to the delegates

The committee recommended that new entries in Schedule 10 and in the index be created for cardarine as follows:

The committee also recommends 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 included:

1. the risks and benefits of the use of a substance:

• Risks: Cardarine is banned from use as a performance enhancement substance in sports. Demonstrated risks based on the results of animal toxicological studies include carcinogenicity. Development of the drug was abandoned based on the results of toxicological data from animal studies. It has no approved or regulated use. There is very little data available on long-term use in humans. There is reported misuse and inappropriate use by athletes/fitness/gym users, some of whom access cardarine through “black market” channels.
• Benefits: There have been no clearly substantiated benefits based on clinical data or scientific evidence. Cardarine was initially trialled in a small number of early phase trials for potential uses in dyslipidaemia, obesity and diabetes. Limited data show that cardarine has an effect on PPARδ receptors, with effects on skeletal muscle, fat and glucose metabolism.

the purposes for which a substance is to be used and the extent of use of a substance:

• Cardarine was developed as a therapeutic agent and abandoned due to toxicity issues most likely related to its mechanism of action.
• Nil approved uses – there are no products registered on the ARTG containing cardarine. There is no established therapeutic value.
• Various websites claim that cardarine can enhance athletic performance, hence the marketing of cardarine to gyms and the bodybuilding scene. Athletes use it as an endurance booster based on its limited clinical and experimental data. Presently, its use appears to be limited to internet purchases, anti-ageing clinics and compounding pharmacies; possible availability through gyms etc.
• Cardarine is on the WADA prohibited list.

the toxicity of a substance:

• Cardarine is associated with a higher rate of numerous cancers and a high frequency of reproductive toxic effects in preclinical settings.
• Toxicity has been evaluated in long-term animal studies, showing an increase in tumour formation. These animal studies (usually performed in parallel with early clinical development) resulted in termination of the clinical development program.
• The increase in tumour development was not replicated in the early human studies, which used lower doses and shorter study duration, so long-term effects in humans are unknown.

the dosage, formulation, labelling, packaging and presentation of a substance:

• Nil approved products or accepted dosages.
• Cardarine is available via internet purchase. It is frequently referred to as “Endurobol” and is available as oral liquid, capsule or powder for performance enhancement. Dosage is reported to be 10-30 mg/day and intended for use in cycles of 4-8 weeks on and at least 4 weeks off between cycles.

the potential for abuse of a substance:

• There is evidence of abuse in ergogenic settings, based on its pharmacological properties, to assist with weight loss and endurance. There are no known documented reports of dependence.
• Its use has been detected following testing of athletes.

any other matters that the Secretary considers necessary to protect public health

• Cardarine satisfies SPF factors of a Schedule 10:

1. Cardarine poses a potential public health risk as a result of its sale, possession or supply that requires management. The potential health risk does not include potential for abuse, diversion into illicit products or other factors which would warrant inclusion in Schedule 9.
2. Cardarine has a public health risk that substantially outweighs the benefit to the extent that no schedule would provide appropriate public access to any proposed or known products.

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)

Delegate's interim decision

The delegate’s interim decision is to include cardarine in Schedule 10. The proposed Schedule entry is:

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: Cardarine is banned from use as a performance enhancement substance in sports. Demonstrated risks based on the results of animal toxicological studies include carcinogenicity. Development of the drug was abandoned based on the results of toxicological data from animal studies. It has no approved or regulated use. There is very little data available on long-term use in humans. There is reported misuse and inappropriate use by athletes/fitness/gym users, some of whom access cardarine through “black market” channels.
• Benefits: There have been no clearly substantiated benefits based on clinical data or scientific evidence. The substance was initially trialled in a small number of early phase trials for potential uses in dyslipidaemia, obesity and diabetes. Limited data show that cardarine has an effect on PPARδ receptors, with effects on skeletal muscle, fat and glucose metabolism.

the purposes for which a substance is to be used and the extent of use of a substance:

• Cardarine was developed as a therapeutic agent and abandoned due to toxicity issues most likely related to its mechanism of action.
• Nil approved uses – there are no products registered on the ARTG containing cardarine. There is no established therapeutic value.
• Various websites claim that cardarine can enhance athletic performance, hence the marketing of cardarine to gyms and the bodybuilding scene. Athletes use it as an endurance booster based on its limited clinical and experimental data. Presently, its use appears to be limited to internet purchases, anti-ageing clinics and compounding pharmacies; possible availability through gyms etc.
• Product is on the WADA prohibited list.

the toxicity of a substance:

• Cardarine is associated with a higher rate of numerous cancers and a high frequency of reproductive toxic effects in preclinical settings.
• Toxicity has been evaluated in long-term animal studies, showing an increase in tumour formation. These animal studies (usually performed in parallel with early clinical development) resulted in termination of the clinical development program.
• The increase in tumour development was not replicated in the early human studies, which used lower doses and shorter study duration, so long-term effects in humans are unknown.

the dosage, formulation, labelling, packaging and presentation of a substance:

• Nil approved products or accepted dosages.
• Cardarine is available via internet purchase. It is frequently referred to as “Endurobol” and is available as oral liquid, capsule or powder for performance enhancement. Dosage is reported to be 10-30 mg/day and intended for use in cycles of 4-8 weeks on and at least 4 weeks off between cycles.

the potential for abuse of a substance:

• There is evidence of abuse in ergogenic settings, based on its pharmacological properties, to assist with weight loss and endurance. There are no known documented reports of dependence.
• Its use has been detected following testing of athletes.

any other matters that the Secretary considers necessary to protect public health

• Cardarine satisfies SPF factors of a Schedule 10:
• Cardarine poses a potential public health risk as a result of its sale, possession or supply that requires management. The potential health risk does not include potential for abuse, diversion into illicit products or other factors which would warrant inclusion in Schedule 9.
• Cardarine has a public health risk that substantially outweighs the benefit to the extent that no schedule would provide appropriate public access to any proposed or known products.

---

Footnotes

3. Gupta R A, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN(2004) Activation of nuclear hormone receptor peroxisome proliferator–activated receptor-δ accelerates intestinal adenoma growth. Nat Med 10(3):245-247.
4. Geiger LE, Dunsford WS, Lewis DJ, Brennan C, Liu KC, Newsholme SJ (2009). PS 895 - Rat carcinogenicity study with GW501516, a PPAR delta agonist (PDF). 48th Annual Meeting of the Society of Toxicology. Baltimore: Society of Toxicology. p. 105.
5. Sobolevsky T, Dikunets M, Sukhanova I, Virus E, Rodchenkov G. Detection of PPARδ agonists GW1516 and GW0742 and their metabolites in human urine. Drug Test Anal. 2012 Oct;4(10):754-60. Epub 2012 Sep 13. PubMed PMID: 22977012.
6. Ooi, E.M., Watts, G.F., Sprecher, D, Chan, C.F., Barrett, H.H. (2011), 'Mechanism of Action of a Peroxisome Proliferator-Activated Receptor (PPAR)- Agonist on Lipoprotein Metabolism in Dyslipidemic Subjects with Central Obesity', Journal of Clinical Endocrinology and Metabolism, 96, 10, pp. E1568-E1576.
7. Olson EJ, Pearce GL, Jones NP, Sprecher DL. Lipid effects of peroxisome proliferator-activated receptor-d agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome. Arterioscler Thromb Vasc Biol 2012; 32: 2289-2294.
8. Sprecher DL, Massien C, Pearce G, Billin AN, Perlstein I, Willson TM, Hassall DG, Ancellin N, Patterson SD, Lobe DC, Johnson TG. Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist. Arterioscler Thromb Vasc Biol. 2007;27:359–365.
9. Nishimura K, Nakano N, Chowdhury VS, Kaneto M, Torii M, Hattori M-A, Yamauchi N, Kawai M. Effect of PPARβ/δ agonist on the placentation and embryo-fetal development in rats. Birth Defects Res B Dev Reprod Toxicol 2013;98:164–9.
10. Geiger LE, Dunsford WS, Lewis DJ, Brennan C, Liu KC, Newsholme SJ (2009). PS 895 - Rat carcinogenicity study with GW501516, a PPAR delta agonist (PDF). 48th Annual Meeting of the Society of Toxicology. Baltimore: Society of Toxicology. p. 105.
11. Newsholme SJ, Dunsford WS, Brodie T, Brennan C, Brown M, Geiger LE (2009).PS 896 - Mouse carcinogenicity study with GW501516, a PPAR delta agonist. (PDF). 48th Annual Meeting of the Society of Toxicology. Baltimore: Society of Toxicology. p. 105
12. Gupta R A, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN(2004) Activation of nuclear hormone receptor peroxisome proliferator–activated receptor-δ accelerates intestinal adenoma growth. Nat Med 10(3):245-247.
13. Girroir EE, Hollingshead HE, He P, Billin, A.N., Willson,T.M, Roberston GP, Sharma, A.K., Amin, S., Gonzalez, F.J., Peters, J.M.(2007) Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines. Toxicology Volume 243, Issues 1–2, 14 January 2008, Pages 236–243.
14. Hollingshead, H.E., Killins, R.L., Girroir, E.E., Billin, A.N., Willson,T.M., Sharma, A.K., Amin, S., Gonzalez, F.J., Peters, J.M., 2007a.Peroxisome proliferator-activated receptor(PPARδ) ligands do not potentiate growth of human cancer cell lines. Carcinogenesis (2007) 28 (12): 2641-2649
15. Pollock C B, Rodriguez O, Martin P L, Albanese C, Li X, Kopelovich L, Glazer R I(2010) Induction of Metastatic Gastric Cancer by Peroxisome Proliferator-Activated Receptorδ Activation PPAR Res. 2010; 2010: 571783.
16. Sprecher DL. (2007). Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta. Am. J.Cardiol. 100 (11 A): n20–4.

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

An application was submitted to include stenabolic (SR9009) and synthetic REV-ERB agonists in Schedule 9 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 9 – New Entry

The applicant's reasons for the request are:

• Apply for a grouped REV-ERB agonists schedule entry to cover all related compounds, including SR9011, GSK2945, GSK0999, GSK5072 and GSK2667. These substances should be considered as Schedule 9 poisons due to their potential to produce toxic side-effects and potential for misuse and abuse in sports doping.
• Stenabolic (SR9009) (and its related compounds) has not been widely tested for safety in humans. Much of the available research to date is in pre-clinical animal models. These studies suggest that SR9009 and other synthetic REV-ERB agonists can alter the circadian rhythm in rodents (and likely to do this in humans) which has implications for sleep, metabolic issues and potentially mental health problems.
• Scheduling of stenabolic aims to protect public health from the potential adverse impacts of these unapproved substances. The supply of stenabolic products poses health concerns as they are being administered without appropriate trials in humans, without guidelines for the appropriate dosages and frequency of dosages and without knowledge of the exact contents of the product being administered.
• SR9009 and is related compounds are currently sold online as 'workout in a pill' type drugs and other derivatives. It has the potential to enter the Australian market in this space.
• Despite the experimental status of these products they are readily available for purchase in Australia through online suppliers, based in Australia and overseas, and through compounding pharmacies and anti-ageing clinics.
• The lack of regulation allows suppliers to advertise products with stenabolic freely and make unproven assertions about the efficacy and safety of the substances. On bodybuilding forums and black-market sites, stenabolic is being positioned as a cutting-edge alternative to steroids.
• The substances are being used by athletes and gym users for the enhancement of sporting performance and aesthetics.
• Stenabolic may be a potential carcinogen and its effect on humans has not been systematically investigated.
• The Australian Sports Anti-Doping Authority (ASADA) has advised that stenabolic has been seized at the border by the Australian Border Force as prohibited imports on multiple occasions.
• Stenabolic is also prohibited under the World Anti-Doping Agency (WADA) Prohibited List category S4 'Hormone and Metabolic Modulators'.

Current scheduling status and relevant scheduling history

Stenabolic has not previously been considered for scheduling. Therefore, a scheduling history is not available.

Australian regulatory information

Stenabolic 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)

Stenabolic is also prohibited under the World Anti-Doping Agency (WADA) Prohibited List category S4 Hormone and Metabolic Modulators.

According to a respected endocrinologist, Stenabolic is captured as a prohibited substance under WADA’s Prohibited List category S4 Hormone and Metabolic Modulators and its potent and diverse pharmacological effects warrant its listing on the Poisons Standard. Direct inquiries with WADA regarding prohibited status have been less definitive. WADA advised that this will be a specific item of consideration for the prohibited list expert group on 24-25 August 2017, where further advice will be provided. Regardless of this further consideration, and as other derivatives have the potential to enter the Australian market, it is requested that a class entry for synthetic REV-ERB agonists be considered for Schedule 9 with additional separate entries for SR9011, GSK2945, GSK0999, GSK5072 and GSK2667.

United States of America

Substance summary

Table 1.3.1: Chemical properties of synthetic REV-ERBs

Chemical	CAS number	IUPAC and/or common and/or other names	Structure
Stenabolic	1379686-30-2	ethyl 3-[[(4-chlorophenyl)methyl-[(5-nitrothiophen-2-yl)methyl]amino]methyl]pyrrolidine-1-carboxylate (IUPAC); 1S/C20H24ClN3O4S/c1-2-28-20(25)23-10-9-16(13-23)12-22(11-15-3-5-17(21)6-4-15)14-18-7-8-19(29-18)24(26)27/h3-8,16H,2,9-14H2,1H3 (InChI); SR9009
SR9011	1379686-29-9	3-[[(4-chlorophenyl)methyl-[(5-nitrothiophen-2-yl)methyl]amino]methyl]-N-pentylpyrrolidine-1-carboxamide (IUPAC); 1S/C23H31ClN4O3S/c1-2-3-4-12-25-23(29)27-13-11-19(16-27)15-26(14-18-5-7-20(24)8-6-18)17-21-9-10-22(32-21)28(30)31/h5-10,19H,2-4,11-17H2,1H3,(H,25,29) (InChI);
GSK2945	1438071-12-5	N-[(4-chloro-2-methylphenyl)methyl]-1-(4-chlorophenyl)-N-[(5-nitrothiophen-2-yl)methyl]methanamine (IUPAC); 1S/C20H18Cl2N2O2S/c1-14-10-18(22)7-4-16(14)12-23(11-15-2-5-17(21)6-3-15)13-19-8-9-20(27-19)24(25)26/h2-10H,11-13H2,1H3 (InChI);
GSK0999	N/A	N/A
GSK5072	1438071-23-8	5-[[(4-chlorophenyl)methyl-(pyridin-3-ylmethyl)amino]methyl]thiophene-2-carbonitrile (IUPAC); 1S/C19H16ClN3S/c20-17-5-3-15(4-6-17)12-23(13-16-2-1-9-22-11-16)14-19-8-7-18(10-21)24-19/h1-9,11H,12-14H2 (InChI);
GSK2667	N/A	N/A	N/A

Stenabolic (SR9009) was developed as an orally active REV-ERBα ligand acting on a heme regulated, nuclear receptor. A non‐exclusive list of its pharmacological actions of SR9009 and other synthetic REV-ERB agonists suggests they alter the circadian rhythm in rodents (and likely to do this in humans), which has implications for sleep, metabolic issues and potentially mental health problems^[17]

Stenabolic and its related compounds have not been widely tested for safety in humans. Despite this lack of testing, it is being sold online with a wide range of unsupported health claims.

Stenabolic is an agonist of the orphan receptors REV-ERBα and REV-ERBβ^[18] The alpha isoform is encoded by the complementary DNA/RNA strand of the ERBA oncogene, while the beta isoform is encoded by the template strand within the same chromosome. These receptors are constitutive repressors of transcription through their binding to co-repressors (e.g. nuclear receptor co-repressor 1).

REV-ERB co-repressor binding activity leads to repression of target chromosomal sequences via DNA response elements through histone deacetylation and chromatin condensation. Heme is an endogenous ligand required for REV-ERB recruitment of the co-repressor, with the redox state of the iron centre and diatomic gases such as nitric oxide influencing co-repressor binding and hence downstream activity.

REV-ERB receptors are widely expressed throughout the body and have a circadian pattern of expression that reflects their role in circadian transcription regulation. The expression of REV-ERBs and the transcription activator ‘retinoic acid receptor-related orphan receptor’ (ROR) are 12 hours out of phase with one another, with their influence on transcription of the core mammalian circadian proteins ‘brain and muscle ARNT-like 1’ (BMAL1) and ‘circadian locomotor output cycles protein kaput’ (CLOCK) reinforcing core circadian oscillation. REV-ERBα expression is itself regulated by BMAL1-CLOCK dimers interacting with an E box DNA response element in the promoter region of the REV-ERB sequence.

Circadian rhythms are linked to metabolic regulation, with REV-ERBs consequently playing a crucial role in lipid metabolism. REV-ERB has been demonstrated in mice to be central to regulation of genes involved in fatty acid/lipid absorption, energy expenditure and muscle lipogenesis. REV-ERBβ is also central in hepatic glucose metabolism. It regulates expression of gluconeogenetic enzymes to modulate blood glucose levels and insulin sensitivity. REV-ERBβ is additionally involved in regulating oxidative capacity of skeletal muscle, ensuring adequate mitochondria and oxidative function are maintained. REV-ERBα also appears to have increased expression during adipogenesis, with degradation of the protein at later stages to allow for efficient fat cell development.

REV-ERBα appears to have a role in immune function, demonstrating a regulatory action on macrophage production and release of the pro-inflammatory interleukin-6. As REV-ERBs and RORs typically have opposing roles, it is proposed that REV-ERBs may suppress T_H17 cell development. Gene knockdown studies have indicated REV-ERB is a key player in the development of atherosclerotic lesions through increasing the development of anti-inflammatory M2 macrophages.

In vitro studies

Stenabolic is 3-4x fold more potent as an agonist than GSK4112, with a 3x fold greater efficacy in repressing a reporter gene in a luciferase assay (REV-ERBα/β IC₅₀ of 670/800 nM). Stenabolic was found to have high specificity for the REV-ERB receptors over 46 other members of the human nuclear receptor superfamily^[19].

In explants from a transgenic mouse model, stenabolic inhibited activity of the hypothalamic suprachiasmatic nucleus circadian clock, as well as the circadian cycle in fibroblasts, supressing the amplitude of the circadian oscillations without affecting the period.

In vivo studies

Only two REV-ERB agonists appear to have been tested in vivo: stenabolic & the structurally-related SR9011.

Both stenabolic and SR9011 affect circadian expression of several core clock genes in the hypothalamus of murine subjects (suppression of cryptochrome 2; enhancement of period circadian clock 2; phase shift in BMAL1 and CLOCK expression; and complete elimination of circadian expression of the neuronal PAS domain-containing protein2). Dose-dependent suppression of the REV-ERB target plasminogen activator inhibitor 1 gene was observed in the liver in response to treatment of mice with various doses over 6 days. Observations obtained when mice were kept under light:dark (12 h:12 h) conditions or complete darkness indicated that the effect of light on the circadian oscillator had a significant effect on the drug action.

In white adipose tissue of mice, a suppression of the circadian expression of genes involved in lipid storage was observed following stenabolic administration, with diglyceride acyltransferases 1 and 2, monoacylglycerol acyltransferase, perilipin 1 and hormone sensitive lipase all suppressed. The related compound SR9011 elicited amplification of the circadian expression of genes in skeletal muscle that are involved in fatty acid oxidation and glycolysis.

These effects are all consistent with the REV-ERB agonist effect of stenabolic.

Single-dose toxicity

The only data akin to a single-dose toxicity study derives from the study in C57Bl6 mice performed under non-OECD conditions (i.e. total darkness). A total blood count was performed at the end of the study following a single i.p. dose of 100 mg/kg¹.There was no significant difference between control and test subjects (24 per group) for the parameters measured. However, it is noted that for several parameters (white blood cell count, lymphocyte count, monocyte count, haematocrit, mean corpuscular volume and platelet count) the average for one or both groups was below the lower end of historical 95% confidence interval (CI), bringing the validity of methodology for this blood count into question.^[20]

Genotoxicity

The structures of many known synthetic REV-ERB agonists, including stenabolic, contain a 2 nitrothiophene moiety, which is a potential toxicological liability due to carcinogenicity concerns. While specific genotoxicity studies have not been performed on these ligands themselves, there is substantial literature that suggests nitrothiophenes present a carcinogen risk. Only the related REV ERB agonists GSK5072 and GSK2667 lack the, 5-nitro group on the thiophene, replacing it with a 5-cyano group.

Drugs with the nitrothiophene or similar groups are uncommon due to their toxicity. Furazolidone is an example of a drug containing the similar moiety nitrofuran, which in Australia is typically prescribed only to patients with refractory Helicobacter infections through the Special Access Scheme.

A 1975 study on the mutagenicity of nitro- and aminoheterocycles that did not meet the OECD 471 guideline on the bacterial reverse mutation test but used similar techniques provides useful data on the likelihood of genotoxicity of these compounds.^[21] All nitroheterocycles, including 2-acetyl-5-nitrothiophene; 2-acetoxime-5-nitrothiophene; 2-thiazolyl derivatives of 5-nitrothiophene; 2 quinazolyl derivatives of 5-nitrothiophene; and 2-thiazolyl derivatives of 4-nitrothiophene were mutagenic in Salmonella typhimurium Strain TA100.

2-acetyl-5-nitrothiophene; 2-formylamino-4-(5-nitro-2-thienyl)thiazole; 1,2-dihydro-2-(5-nitro-2-thienyl)quinazolin-4(3H)-one; 4-morpholino-2-(5-nitro-2-thienyl)quinazoline; 2-amino-4-(4-nitro-2-thienyl)thiazole; and 2-formylamino-4-(4-nitro-2-thienyl)thiazole were also mutagenic in strain TA98, highlighting that regardless of the nitro substituent being ortho- or meta- to the heteroatom, mutagenic potential was apparent.

Carcinogenicity

Several 2-quinazolyl derivatives of 5-nitrothiophene studied by Wang, Muraoka & Bryan (1975) were found to be carcinogenic in rats prior to this subsequent experimentation.^[22]

Cohen, Erturk & Bryan (1976) also found that 2-heterocyle-substituted 5-nitorthiophenes induced benign and malignant mammary tumours and intestinal tract sarcomas in Sprague-Dawley rats.^[24]

Auer, Nabholz & Baetcke (1990) validates the presumption that the 5-nitrothiophenyl group contained in most known synthetic REV-ERB agonists is a toxicological liability, specifically using this moiety as an example on the assessment of chemical hazards in the presence of limited data.^[24]

Pre-meeting public submissions

One (1) submission was received that opposed the proposal for stenabolic and other synthetic REV ERB agonists, instead suggesting that a Schedule 9 entry may be more appropriate. The main points opposed to a Schedule 4 entry and in support of a Schedule 9 entry were:

• These medicines are used to alter gene expression and can be used as a physical performance enhancer.
• Clinical evidence of purported health outcomes such as reduced obesity and diabetes through altering gene expression is scant, of low quality and only produced in mice subjects.^[25] Human studies of this medicine have not been published.

The public submission will be made available on the TGA website.

Summary of ACMS advice to the delegates

The committee recommended that stenabolic (SR9009) and other REV-ERB agonists be included in Schedule 4 and Appendix D, along with cross referencing to similar compounds in the index, as follows:

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; and (e) the potential for abuse of a substance.

The reasons for the advice comprised the following:

1. the risks and benefits of the use of a substance:

• Risks: Currently no human safety data for stenabolic and synthetic REV-ERB agonists.
• Benefits: no current benefits.

the purposes for which a substance is to be used and the extent of use of a substance:

• Currently no established therapeutic use.

the toxicity of a substance:

• Potentially carcinogenic, however details of toxicity are yet to be fully established as there has been no marketing experience in Australia.
• Stenabolic and synthetic REV-ERB agonists have a range of potent pharmacological effects.

the dosage, formulation, labelling, packaging and presentation of a substance:

• Sold as capsules (5-20 mg) or oral liquid (20 mg/mL).
• Currently no guidelines for the appropriate dosages and frequency of dosages.

the potential for abuse of a substance:

• Stenabolic and synthetic REV-ERB agonists are being illicitly marketed to athletes and gym users as an alternative to steroids and as an anti-aging, fat-reducing agent.

any other matters that the Secretary considers necessary to protect public health

• Nil.

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)

Delegate's interim decision

The delegate’s interim decision is to include stenabolic (SR9009) and other synthetic REV-ERB agonists in Schedule 4 with an Appendix D (Part 5) entry. The proposed Schedule entry is:

Schedule 4 – New Entry

# STENABOLIC (SR9009) and other synthetic REV-ERB agonists.

Appendix D, Part 5 – New Entry

STENABOLIC (SR9009) and other synthetic REV-ERB agonists.

Index – New Entry

STENABOLIC (SR9009) and other synthetic REV-ERB agonists
cross reference: SR9011, GSK2945, GSK0999, GSK5072, GSK2667

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; and (e) the potential for abuse of a substance.

The reasons for the recommendation comprised the following:

1. the risks and benefits of the use of a substance:

• Risks: Currently no human safety data for stenabolic and synthetic REV-ERB agonists.
• Benefits: no current benefits.

the purposes for which a substance is to be used and the extent of use of a substance:

• Currently no established therapeutic use.

the toxicity of a substance:

• Potentially carcinogenic, however details of toxicity are yet to be fully established as there has been no marketing experience in Australia.
• Stenabolic and synthetic REV-ERB agonists have a range of potent pharmacological effects.

the dosage, formulation, labelling, packaging and presentation of a substance:

• Sold as capsules (5-20 mg) or oral liquid (20 mg/mL).
• Currently no guidelines for the appropriate dosages and frequency of dosages.

the potential for abuse of a substance:

• Stenabolic and synthetic REV-ERB agonists are being illicitly marketed to athletes and gym users as an alternative to steroids and as an anti-aging, fat-reducing agent.

any other matters that the Secretary considers necessary to protect public health

• Nil.

---

Footnotes

17. Solt, L. A., Wang, Y., Banerjee, S., Hughes, T., Kojetin, D. J., Lundasen, T., Shin, Y., Liu, J., Cameron, M. D., Noel, R., Yoo, S.-H., Takahashi, J. S., Butler, A. A.,Kamenecka, T. M. & Burris, T. P. (2012). Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists. Nature, 485(7396), 62-68 (and Supplementary Material).
18. Kojetin, D. J. & Burris, T. P. (2014). REV-ERB and ROR nuclear receptors as drug targets. Nature Reviews Drug Discovery, 13(3), 197-216.
19. Solt, L. A., Wang, Y., Banerjee, S., Hughes, T., Kojetin, D. J., Lundasen, T., Shin, Y., Liu, J., Cameron, M. D., Noel, R., Yoo, S.-H., Takahashi, J. S., Butler, A. A.,Kamenecka, T. M. & Burris, T. P. (2012). Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists. Nature, 485(7396), 62-68 (and Supplementary Material).
20. Charles River Laboratories International Inc. (2012). C57BL/6 Mouse Haematology.
21. Wang, C. Y., Muraoka, K. & Bryan, G. T. (1975). Mutagenicity of Nitrofurans, Nitrothiophenes, Nitropyrroles, Nitroimidazole, Aminothiophenes, and Aminothiazoles in Salmonella typhim urium. Cancer Research, 35, 3611-3617.
22. Wang, C. Y., Muraoka, K. & Bryan, G. T. (1975). Mutagenicity of Nitrofurans, Nitrothiophenes, Nitropyrroles, Nitroimidazole, Aminothiophenes, and Aminothiazoles in Salmonella typhim urium. Cancer Research, 35, 3611-3617.
23. Cohen, S. M., Erturk, E. & Bryan, G. T. (1976). Comparative carcinogenicity of 5-nitrothiophenes and 5-nitrofurans in rats 23. Journal of the National Cancer Institute, 57(2), 277-282 (Abstract only) https://doi.org/10.1093/jnci/57.2.277.
24. Auer, C. M., Nabholz, J. V. & Baetcke, K. P. (1990). Mode of Action and the Assessment of Chemical Hazards in the Presence of Limited Data: Use of Structure-Activity Relationships (SAR) under TSCA, Section 5. Environmental Health Perspectives, 87, 183-197.
25. Sprecher DL. (2007). Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta. Am. J. Cardiol. 100 (11 A): n20–4.

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

Scheduling application

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

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:

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:

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

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

26. 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.
27. 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.

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

Scheduling application

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

Schedule 9 – New Entries

The delegate’s reasons for the request are:

• Synthetic cathinones (also known as substituted cathinones or cathinone derivatives) are derivatives of cathinone, a monoamine alkaloid found in the khat plant (Catha edulis), which are often referred to colloquially as "bath salts". Synthetic cathinones elicit a variety of amphetamine-like and/or 3,4-methylenedioxy-methamphetamine (MDMA)-like physiological, subjective, and behavioural effects.
• Synthetic cathinones act predominantly as central nervous system stimulants. Stimulants mediate the actions of dopamine, norepinephrine and/or serotonin, mimicking the effects of traditional drugs such as cocaine, amphetamine, methamphetamine and ecstasy.
• Cathinone and its related substances have the potential to be misused and abused. Synthetic cathinones include alpha-PVP and methylone.
• Synthetic cathinones are the β-keto (βk) analogues of a corresponding phenethylamine. Cathinone itself is β-keto (βk) amphetamine, 2-aminopropiophenone or, more formally, 2-amino-1-phenyl-1-propanone (IUPAC systematic name). The group includes several substances that have been used as active pharmaceutical ingredients (API) of medicinal products, e.g. amfepramone (diethylpropion).
• Use of synthetic cathinones has been associated with sympathomimetic toxidrome.
• Most of the unregulated cathinone derivatives (synthetic cathinones) that have been marketed in are ring-substituted and first appeared in drug markets in the mid-2000s. The most prevalent of which appears to be mephedrone (4-methylmethcathinone).^[28] In 2005, methylone, an analogue of MDMA, was the first synthetic cathinone reported to the European Monitoring Centre on Drugs and Drug Addiction (EMCDDA). In 2007, reports of 4-methylmethcathinone (mephedrone, currently in Schedule 9) use emerged, first in Israel and then in other countries and regions, including Australia, Scandinavia, Ireland and the United Kingdom.^[29] Mephedrone was reportedly first synthesised in 1929.^[30]
• The most commonly available cathinones sold on the recreational market in the period up to 2010 appear to be mephedrone (captured under the Schedule 9 entry, 4-methylmethcathinone) and methylone (unscheduled). These products are usually encountered as highly pure white or brown powders. Ring-substituted cathinone derivatives are claimed to have effects similar to those of cocaine, amphetamine or 3,4-methylenedioxymethamphetamine (MDMA/ecstasy), but little is known of their detailed pharmacology.
• Methylone (unscheduled) is one of the most popular products with stimulant effects. Methylone is a synthetic cathinone and an alternative of MDMA. Methylone in most cases is taken orally or by insufflation. Methylone is also part of a party liquid.
• Synthetic cathinones were associated with nearly 23,000 emergency department visits in the United States in 2011,^[31] and have been implicated in multiple deaths.^[32]

Current scheduling status

Cathinone

alpha-Pyrrolidinovalerophenone (alpha-PVP)

alpha-PVP, also known as alpha-pyrrolidinopentiophenone, is not specifically listed in the Poisons Standard. It is structurally related to, but not captured by, pyrovalerone (Schedule 4), prolintane (Schedule 4), 3,4-methylenedioxypyrovalerone (MDPV, Schedule 9) and cathinone (Schedule 9).

Methylone

Methylone is not specifically listed in the Poisons Standard. Methylone is structurally related to, but not captured by, the Schedule 9 entry for MDMA (differing only by a single beta-ketone). Methylone is also chemically related to several other cathinones and amphetamines already included in Schedules 9 and 8.

Related substances listed in the Poisons Standard

Scheduling history

alpha-PVP

alpha-PVP, also known as alpha-pyrrolidinopentiophenone, has not been previously considered for scheduling. Therefore, a scheduling history is not available.

Cathinone

In August 1986, the Drugs and Poisons Schedule Committee (DPSC) considered a Schedule 9 entry for cathinone in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP) under Psychotropic Substances. It was discussed after a notification from the Secretary-General from the United Nations.

In November 1986, after review of the States and Territories, the DPSC agreed to add cathinone into Schedule 9 of the SUSDP.

Methcathinone

In November 1998, the National Drugs and Poisons Schedule Committee (NDPSC) agreed to the inclusion of methcathinone in Schedule 9 due to its potential as a problem drug.

Methylone

Methylone has not been previously considered for scheduling. Therefore, a scheduling history is not available.

4-Methylmethcathinone (mephedrone)

In June 2010, the NDPSC decided to create a new entry in Schedule 9 for 4-methylmethcathinone (mephedrone). The committee agreed that 4-methylmethcathinone, as a derivative of methcathinone, is captured by the Schedule 9 entry for methcathinone. The committee further agreed that it would be appropriate to create a new entry for 4-methylmethcathinone in Schedule 9 to clarify that this substance is indeed a prohibited substance.

3,4-methylenedioxypyrovalerone (MDPV)

In October 2011, the Advisory Committee on Medicines Scheduling (ACMS) considered an application to include MDPV in Schedule 9 of the Poisons Standard due to it being structurally related to cathinone and MDMA. The ACMS recommended that MDPV be included in Schedule 9, with a cross-reference to 3,4-methylenedioxypyrovalerone, due to its potency and its associated dangers with heavy and repetitive use.

Australian regulatory information

Alpha-PVP, methylone and cathinone are not an excipient or active in any medicines on the ARTG.

According to the TGA Ingredient Database, prolintane is available for use as an:

• Active ingredient in biologicals, export only and prescription medicines;
• Excipient ingredient in biologicals, devices and prescription medicines; and

There are no recorded adverse event reports for any related substances on the Database of Adverse Events Notification (DAEN) - Medicines.

International regulations

United Nations (UN)

Cathinone and methcathinone are listed in Schedule I of the UN 1971 Convention on Psychotropic Substances. Amfepramone and pyrovalerone are in Schedule IV of that Convention, but other derivatives are not under international control. A few synthetic cathinones are controlled in some Member States under drug control or equivalent legislation, for example:

• Mephedrone (Belgium, Denmark, Germany, Estonia, Ireland, France, Italy, Lithuania, Romania, Sweden, Croatia and Norway);
• Methylone (Denmark, Ireland, Romania and Sweden);
• Butylone (Denmark, Ireland, Romania, Sweden and Norway);
• MDPV (Denmark, Ireland, Finland and Sweden); and
• Flephedrone (Denmark, Ireland and Romania).

Mephedrone is controlled under medicines legislation in Finland and the Netherlands. By Council Decision of 2 December 2010, 4-methylmethcathinone (mephedrone) was submitted to control measures in EU Member States (2010/759/EU).^[33]

United Kingdom (UK)

Generic control in the UK covers a wide group of cathinone derivatives. In the UK, the 31 March 2010 report of the UK Advisory Council on the Misuse of Drugs – Consideration of the cathinones indicated that the harms associated with mephedrone and related cathinones were commensurate with the amphetamines and the substances in Class B. This UK report, defines cathinone derivatives generically as follows:

1. by substitution in the phenyl ring to any extent with alkyl, alkoxy, alkylenedioxy, haloalkyl or halide substituents, whether or not further substituted in the phenyl ring by one or more other univalent substituents;
2. by substitution at the 3-position with an alkyl substituent;
3. by substitution at the nitrogen atom with alkyl or dialkyl groups, or by inclusion of the nitrogen atom in a cyclic structure.

Present UK controls include:

• Cathinone (Class C), methcathinone (Class B), diethylpropion (Class C) and pyrovalerone (Class C) are controlled under the Misuse of Drugs Act 1971. However, other derivatives and analogues are not presently controlled (including mephedrone).
• Although the paragraph 1(c) of Part 1 (Schedule 2) of the Misuse of Drugs Act 1971 offers some scope for the control of substances which are structurally related to the phenethylamine backbone, it is primarily concerned with ring-substituted amphetamine-like compounds. Specifically, no mention is made of the presence of any substituents (other than hydrogen) at the β-carbon of the phenethylamine backbone (cathinones all possess a β-ketone oxygen).
• Irrespective of whether controls for the cathinones are implemented under the Misuse of Drugs Act 1971, the rapidity and easy availability of mephedrone and other cathinones (including websites set up so that vendors that can deliver to individual addresses) does raise the question of whether other legislation and regulation should be available.

United States of America

In the USA, alpha-PVP (also known as alpha-pyrrolidinopentophenone) is reported by the US DEA to be a synthetic cathinone and was temporarily placed in the US Schedule 1 of controlled drug substances in March 2017. After consideration of the relevant matter presented as a result of public comment, the scientific and medical evaluations and accompanying recommendations of the Department of Health and Human Services (HHS), and the DEA's consideration of its own eight-factor analysis, the DEA finds that these facts and all other relevant data constitute substantial evidence of potential for abuse of 4-MEC, 4-MePPP, alpha-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and alpha-PBP. As such, the DEA is permanently scheduling them as controlled substances under the Controlled Substances Act.

See also the DEA warning in relation to synthetic cathinones.

Canada

Schedule I of the Controlled Drugs and Substances Act:

• Methylenedioxypyrovalerone (MDPV), its salts, derivatives, isomers and analogues and salts of derivatives, isomers and analogues

Table 1.5.1: Laws of Schedule I

Property	Punishment
Possession	Maximum 7 years imprisonment
Trafficking/possession for the purpose of	Maximum life imprisonment (mandatory minimum 1-year jail sentence for trafficking a Schedule I drug under 1 kg, 2 years if amount exceeds 2 kg)
Exportation/possession for the purpose of	Maximum life imprisonment
Production	Maximum life imprisonment

Schedule III of the Controlled Drugs and Substances Act:

• Cathinone ((-)-α-aminopropiophenone) and its salts
• Methcathinone (2–Methylamino–1–phenyl–1–propanone) and its salts

Table 1.5.2: Laws of Schedule III

Property	Punishment
Possession (requires a prescription to legally possess)	Maximum 10 years imprisonment
Trafficking/possession for the purpose of	Maximum 10 years imprisonment
Exportation/possession for the purpose of	Maximum 10 years imprisonment
Production	Maximum 10 years imprisonment

New Zealand

Table 1.5.3: Medicine classifications in New Zealand

Ingredient	Classification
Cathinone	Class B2 Controlled Drug
Methcathinone	Class B2 Controlled Drug
Monomethylpropion (synonym for methcathinone)	Class B2 Controlled Drug

Substance summary

Synthetic cathinones are chemically similar to cathinone, which comes from the khat plant (Catha edulis). Khat is a shrub grown in East Africa and southern Arabia, and people sometimes chew its leaves for their mild stimulant effects.

Synthetic cathinones are included in a group of drugs that concern public health officials called "new psychoactive substances" (NPS). NPS are unregulated psychoactive (mind-altering) substances that have become newly available on the market and are intended to copy the effects of illegal drugs. Some of these substances may have been around for years but have re-entered the market in altered chemical forms or due to renewed popularity.

The most well-known synthetic cathinone is mephedrone (4-MMC or meow meow), although there are several others, including methylone, alpha-PVP, methedrone, naphyrone, butylone and MDPV. These substances reportedly produce similar effects to methamphetamine and MDMA (ecstasy).^[34] Synthetic cathinones have only been used as street drugs since the 2000s.^[35]

Until recently, these drugs were available under the guise of 'research chemicals' or 'plant food', either online or in shops which sell legal highs.

Table 1.5.4: Chemical properties of cathinone and some synthetic cathinones

Chemical	CAS number	IUPAC and/or common and/or other names	Molecular structure and weight	Structure
Cathinone	42542-10-9	1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine (IUPAC); Mandy, MDMA, Molly, ecstasy;	C11H15NO2 193.2 g/mol
Mephedrone (4-methylmethcathinone)	1189805-46-6	2-(methylamino)-1-(4-methylphenyl)propan-1-one (IUPAC); M-CAT, HSB 7979, Meow Meow, Bounce, Bubbles;	C11H15NO 177.2 g/mol
Methylone	186028-79-5	1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (IUPAC); BK-MDMA, HSB 7997, M1;	C11H21NO
Pyrovalerone	3563-49-3	1-(4-methylphenyl)-2-pyrrolidin-1-ylpentan-1-one (IUPAC);	C16H23NO 245.4
Prolintane	493-92-5	1-(1-phenylpentan-2-yl)pyrrolidine (IUPAC); Catovit;	C15H23N 217.4 g/mol
3,4-methylenedioxypyrovalerone (MDPV)	687603-66-3	1-(1,3-benzodioxol-5-yl)-2-pyrrolidin-1-ylpentan-1-one (IUPAC); MDPV, MDPK;	C16H21NO3 275.3 g/mol
General chemical structure of a cathinone derivative showing substitution patterns

Cathinones act as central nervous system stimulants, although the potencies of the cathinones are generally lower than their amphetamine congeners. This may be due to the increased polarity conferred on a cathinone by the presence of a β-keto group reducing their ability to cross the blood-brain barrier.

Cathinone derivatives are the β-keto (βk) analogues of a corresponding phenethylamine. Synthetic variants of cathinone can be much stronger than the natural product and, in some cases, very dangerous.^[36]

Cathinone is structurally very similar to amphetamine (1-phenylpropan-2-amine), differing only in the functionality present at the β-carbon. Cathinone possesses a ketone oxygen at the β-carbon; cathinone can therefore be considered as the 'beta;-keto analogue' of amphetamine. The molecular architecture of 2-amino-1-phenyl propanone (cathinone) can be altered to produce a series of different compounds which are closely structurally related to cathinone. Together these are known as the 'cathinones', 'synthetic cathinones' or 'cathinone derivatives'.

The basic cathinone structure can be altered in a number of predictable ways, such as the inclusion of additional functionality to the aromatic ring (ring substitution, R₁), N-alkylation (or inclusion of the nitrogen atom in a ring structure, R₃ and R₄), and variation of the (typically alkyl) α-carbon substituent (R₂). Multiple modifications may be present in a single derivative. Cathinones are all usually N-alkylated (or the nitrogen is incorporated into a ring structure, typically pyrrolidine) and many also bear ring substituents.

Pre-meeting public submissions

Three (3) public submissions were received that opposed the proposal for for alpha-PVP and related substances (cathinones and methylone), instead suggesting that a Schedule 9 entry may be more appropriate. The main points opposed to a Schedule 4 entry and in support of a Schedule 9 entry were:

• Methylone (MDMC) and alpha-pyrrolidinovalerophenone (alpha-PVP) are synthetic psychostimulants associated with overdoses, suicides and illicit use.
• The poisons information centres and clinical toxicology units around Australia continue to be contacted for advice on poisonings from these agents. Features of these poisonings include agitation, tachycardia, hypertension and in severe cases delirium, aggressive behaviour, hallucinations, hyperthermia, cardiac dysrhythmias and seizures. Deaths have occurred due to alpha-PVP toxicity.
• Cathinones, MDMC and alpha-PVP have no currently established therapeutic value and have demonstrated high risks of dependency, abuse, misuse and illicit use; and possess a significant toxicity profile which fits the criteria for inclusion in Schedule 9. Schedule 4 and Appendix D are not appropriate.
• Cathinones are illegal in many other countries such as the United States of America, the United Kingdom, Sweden and New Zealand.

The public submissions will be made available on the TGA website.

Summary of ACMS advice to the delegates

The committee recommended that new Schedule 9 entries be created for alpha-PVP and methylone in the Poisons Standard, and the current Schedule 9 cathinone entry be amended as follows:

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: These classes of substances collectively are associated with considerable toxic effects as evidenced by reports of mortality and poisons data. Risks of consumption by humans are significant.
• Benefits: There was no benefit of use found.

the purposes for which a substance is to be used and the extent of use of a substance:

• No established therapeutic purpose or use (except cathinone-structure medicines are already included in Schedule 4). There is evidence these substances are used as recreational drugs worldwide, including in Australia, with consequent significant public health harm.
• Readily available in internet and retail stores.

the toxicity of a substance:

• Significant stimulant and psychoactive effects. Human use has resulted in death.
• Toxic effects include agitation, tachycardia, hypertension, delirium, aggression, hyperthermia, cardiac arrhythmias and seizures. There has been reported mortality in Australia and internationally. With mephedrone in particular, there are deaths reported in England, Scotland, Wales and Sweden.

the dosage, formulation, labelling, packaging and presentation of a substance:

• N/A – generally 'white powders'.
• Doses of MDPV reported as 5 mg or less, mephedrone as 200 mg or more with repeated redosing up to 1-2 g per 'session'.

the potential for abuse of a substance:

• Animal studies indicate many cathinone substances have addiction potential.

any other matters that the Secretary considers necessary to protect public health

• Alpha-PVP, methylone and some synthetic cathinones are already controlled through misuse of drugs legislation across Australia.
• Increasingly, there are similar controls internationally.

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)

Delegate's interim decision

The delegate’s interim decision is create a new Schedule 9 entries for alpha-pyrrolidinovalerophenone and methylone, as well as amend the Schedule 9 entry for cathinone. The proposed Schedule entries are:

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 advice comprised the following:

1. the risks and benefits of the use of a substance:

• Risks: These classes of substances collectively are associated with considerable toxic effects as evidenced by reports of mortality and poisons data. Risks of consumption by humans are significant.
• Benefits: There was no benefit of use found.

the purposes for which a substance is to be used and the extent of use of a substance:

• No established therapeutic purpose or use (except cathinone-structure medicines are already included in Schedule 4). There is evidence these substances are used as recreational drugs worldwide, including in Australia, with consequent significant public health harm.
• Readily available in internet and retail stores.

the toxicity of a substance:

• Significant stimulant and psychoactive effects. Human use has resulted in death.
• Toxic effects include agitation, tachycardia, hypertension, delirium, aggression, hyperthermia, cardiac arrhythmias and seizures. There has been reported mortality in Australia and internationally. With mephedrone in particular, there are deaths reported in England, Scotland, Wales and Sweden.

the dosage, formulation, labelling, packaging and presentation of a substance:

• N/A – generally 'white powders'.
• Doses of MDPV reported as 5 mg or less, mephedrone as 200 mg or more with repeated redosing up to 1-2 g per 'session'.

the potential for abuse of a substance:

• Animal studies indicate many cathinone substances have addiction potential.

any other matters that the Secretary considers necessary to protect public health

• Alpha-PVP, methylone and some synthetic cathinones are already controlled through misuse of drugs legislation across Australia.
• Increasingly, there are similar controls internationally.

---

Footnotes

28. The Europe Monitoring Centre for Drugs and Drug Addiction – Synthetic cathinones drug profile.
29. Kelly, J.P. "Cathinone derivatives: A review of their chemistry, pharmacology and toxicology", Drug Testing and Analysis 3 (2011): 439-453.
30. Saem de Burnaga Sanchez, J. “Sur un homologue de l’ephedrine”, Bulletin de la Société Chimique de France 45 (1929): 284-86. [4] Meyer, M.R., Wilhelm, J., Peters, F.T., Maurer, H.H. "Beta-ketone amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone and methylone" in urine using gas chromatography-mass spectrometry, Analytical and Bioanlytical Chemistry 396 (2010):1225–1233.
31. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality Drug Abuse Warning Network (DAWN). (2013). "Bath salts" were involved in over 20,000 drug-related emergency department visits in 2011.
32. Maskell et al., "Mephedrone (4-Methylmethcathinone)-Related Deaths", Journal of Analytical Toxicology 35(2011)188-191.
33. The Europe Monitoring Centre for Drugs and Drug Addiction – Synthetic cathinones drug profile

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

An application was submitted to amend the Schedule 2 to and Schedule 3 entries 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:

On 29 June 2017, the delegate decided to amend the Schedule 3 entry to include a modified release dosage form of ibuprofen. As a result, the secretariat has amended the proposed entry for consistency with the delegate's decision, which came into effect on 1 October 2017:

The applicant's reasons for the request are:

• Over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used pharmacological agents worldwide to treat mild to moderate pain. Ibuprofen is the most commonly used NSAID.
• Ibuprofen is currently the only oral NSAID exempt from scheduling that can be sold in general retail with no access to professional advice regarding appropriate use. The current maximum pack size of 100 dosage units is also significantly larger than other type of oral NSAID listed in Schedule 2.
• Several recent major international studies have highlighted the increased risk of heart failure associated with NSAIDs at OTC doses. Additionally, clearer warnings regarding the use of NSAIDs during preconception and pregnancy have been adopted as per recommendation by the Therapeutic Goods Administration (TGA). Noted in the 2014 TGA safety review of NSAIDs:

'NSAIDs are among the most commonly used pharmacological agents worldwide due to their efficacy as non-addictive analgesics and their anti-inflammatory properties. Hence, even a small absolute risk of serious cardiovascular effects associated with these drugs could produce a significant health burden in a given population.'

• The proposed amendments to the Schedule 2 listing for ibuprofen are a prudent response to the recent and mounting evidence regarding the risks associated with NSAIDs. The proposed changes will mitigate these risks and facilitate access to these medicines so that patients will gain optimal health outcomes.
• Low levels of consumer health literacy regarding the safe maximum daily dose of ibuprofen warrants tighter controls on the supply of ibuprofen. This applies particularly to outlets where there are no restrictions on the number of packs that can be purchased by consumers and no access to professional advice or administration under professional health care supervision and guidance.
• This application should also be viewed in the context of the deletion of Schedule 2 and Schedule 3 entries for codeine, taking effect on 1 February 2018. From this date, many consumers who were previously taking Schedule 3 codeine medicines (specifically combination analgesics containing codeine) will likely seek alternatives that may include ibuprofen either as a single active ingredient or in combination with paracetamol. This will likely lead to increased use of ibuprofen, which will further exacerbate these risks.
• Providing consumer access to information via hand-outs or labelling is not sufficient to address the concerns raised. Facilitating access to professional advice for the prescribing and supply of medicines is the best way to maintain safe and cost-effective access to medicines. Consumers need advice on the correct and proper way to use medicines. This is best achieved with supply from a pharmacist through a community pharmacy and when necessary, referral to a general practitioner or appropriate health care professional.
• Large packs of ibuprofen for longer term use should only be available as a Schedule 3 medicine. The mandatory intervention of a pharmacist will determine whether a larger pack size is therapeutically appropriate and will facilitate discussions regarding pain management. Recommendations on potentially more suitable medicines and referral to other health practitioners can be made as required.

Current scheduling status

Ibuprofen is currently listed in Schedules 2, 3 and 4 and Appendix F, Part 3 and Appendix H of the Poisons Standard as follows:

Schedule 2

IBUPROFEN in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen:

1. in liquid preparations when sold in the manufacturer’s original pack containing 8 g or less of ibuprofen; or
2. b) in divided preparations, each containing 200 mg or less of ibuprofen, in packs of not more than 100 dosage units except when:
1. as the only therapeutically active constituent (other than phenylephrine or when combined with an effervescent agent);
2. packed in blister or strip packaging or in a container with a child-resistant closure;
3. in a primary pack containing not more than 25 dosage units;
4. compliant with the requirements of the Required Advisory Statements for Medicine Labels;
5. not labelled for the treatment of children 6 years of age or less; and
6. not labelled for the treatment of children under 12 years of age when combined with phenylephrine.

Schedule 3

IBUPROFEN:

1. in divided preparations, each containing 400 mg or less of ibuprofen in a primary pack containing not more than 50 dosage units, when labelled:
1. with a recommended daily dose of 1200 mg or less of ibuprofen; and
2. not for the treatment of children under 12 years of age; or
2. in a modified release dosage form, each containing 600 mg of ibuprofen in a primary pack containing not more than 32 dosage units, when labelled:
1. with a recommended daily dose of 1200 mg or less of ibuprofen; and
2. not for the treatment of children under 12 years of age,

except when included in or expressly excluded from Schedule 2.

Schedule 4

IBUPROFEN except:

1. when included in or expressly excluded from Schedule 2 or 3; or
2. in preparations for dermal use.

Appendix F, Part 3

Warning Statements: 101, 104

Appendix H

IBUPROFEN.

Scheduling history

In November 1985, the National Health and Medical Research Council (NHMRC) considered a request to amend the scheduling of ibuprofen from Schedule 4 to Schedule 2 as ibuprofen was not scheduled in Victoria. It was agreed there were anaphylactic problems with people sensitive to aspirin. It was decided not to alter the scheduling.

In November 1987 the NHMRC considered a request to move ibuprofen from Schedule 4 to Schedule 2 with pack size restrictions. The committee was of the opinion that there was a place for ibuprofen outside Schedule 4. Recommendation for a new Schedule 3 entry with pack size restrictions of less than 50 tablets or capsules (200 mg).

In May 1995, the NDPSC considered proposal for a new Schedule 2 entry for ibuprofen and agreed to a new entry. Schedule 4 entry amended. New Schedule 2 for ibuprofen in divided preparations for oral use containing 200mg or less with a recommended dose of 1200mg or less.

In November 1998, the NDPSC considered an application for ibuprofen liquid suspension 100 mg/5 mL to be rescheduled from Schedule 4 to Schedule 2. Overall, the committee considered that a Schedule 3 classification was more appropriate for this formulation, and agreed that the Poisons Standard be amended accordingly. The committee agreed that a maximum daily dose should be stipulated, but because the proposed pack size was 200 mL (maximum of 4 g ibuprofen) a restriction on total content was not required for this classification. A new entry for Schedule 3 was agreed in undivided preparations for oral use when labelled with a recommended daily dose of not more than 1200 mg of ibuprofen.

In May 2000, the NDPSC considered a proposal to amend the Schedule 2 entry for ibuprofen to include oral liquid preparations containing more than 20 mg/1 mL. The committee considered the safety profile of ibuprofen and that Schedule 2 is appropriate when used in analgesic dose for minor and temporary ailments for short periods. The committee was seeking consistency with divided dose formulations.

In June 2003, the NDPSC considered a proposal to exempt ibuprofen from scheduling in divided preparations containing 200 mg or less of ibuprofen per dosage unit in packs containing 24 or less dosage units when labelled with a maximum recommended daily dose of 1200 mg of ibuprofen. The NDPSC decided to exempt ibuprofen from scheduling as requested, but with an amended maximum pack size (25 dosage units) and additional restrictions as follows: ibuprofen as the only therapeutically active constituent other than an effervescent agent; and requirements for label warnings (consistent with Appendix F warnings for Schedule 2 ibuprofen). The minutes note that the NDPSC had agreed that the schedule wording should be comparable with that of the current aspirin and paracetamol entries.

In October 2003, following consideration of further public submissions, the NDPSC made some amendments to the label warning statements required for ibuprofen when exempted from scheduling, in particular, by adding warnings not to use the product unless advised by a doctor in children ages 6 years or less, or by people aged 65 years or over.

The NDPSC subsequently made some editorial amendments to the Schedule 2 exemption in June 2004 and February 2005.

In August 2010 the NDPSC considered the scheduling of paracetamol in combination with ibuprofen in June 2010. At that time, divided dose combinations containing up to 200 mg ibuprofen + 500 mg paracetamol were included in Schedule 2 (when labelled with a maximum daily dose of 1200 mg ibuprofen, and in packs of up to 100 dosage units). The NDPSC recommended, and the delegate confirmed, that the scheduling of ibuprofen and paracetamol that was current at that time remained appropriate.

In June 2011 the ACMS considered a proposal from the Advisory Committee on Non-prescription Medicines (ACNM) that the delegate/ACMS consider up-scheduling paracetamol/ibuprofen combinations (containing up to 500 mg paracetamol/200 mg ibuprofen) from Schedule 2 to Schedule 3. The ACNM had also recommended consideration of a maximum pack size for Schedule 3 paracetamol/ibuprofen combinations. The ACNM, in an assessment of an application to register a combination paracetamol/ibuprofen product, had raised concerns that the sponsor had not satisfactorily established the safety of the product, and considered that pharmacist intervention was needed to assist consumers with safe use of the combination.

The ACMS recommended that the combination paracetamol/ibuprofen products that were in Schedule 2 should be rescheduled to Schedule 3, when in packs containing 30 dosage units or less, with larger packs to be included in Schedule 4. The delegate agreed with the ACMS advice.

In February 2013 the ACMS considered proposals to reschedule paracetamol 500 mg when combined with ibuprofen 200 mg from Schedule 3 to Schedule 2 in packs containing 12 dosage units or less, and to also include Schedule 3 paracetamol when combined with ibuprofen in Appendix H. The ACMS recommended that the current scheduling of paracetamol in combination with ibuprofen remained appropriate, and that paracetamol in combination with ibuprofen should not be included in Appendix H. The reasons for opposing rescheduling to Schedule 2 included insufficient data to disprove the safety concerns with the combination, lack of evidence to support rescheduling, lack of long-term evidence of safety of the combination, potential for additive gastrointestinal side effects, potential for inadvertent misuse and no experience with use of paracetamol/ibuprofen combination products in Australia. The ACMS also considered that there were no public health benefits with inclusion of the combination in Appendix H, and that advertising could lead to inappropriate use. The delegate agreed with the ACMS advice.

In June 2012, the ACMS considered a submission to reschedule ibuprofen from Schedule 2 to unscheduled when in divided preparations containing 200 mg or less of ibuprofen in fixed dose combination with 5 mg or less of phenylephrine, in packs containing not more than 25 tablets. ACMS recommended to the delegate that ibuprofen in combination with phenylephrine should be exempt from scheduling, as requested. The delegate decided to also restrict the scheduling exemption to use for the treatment of adults and children aged 12 years of age and over.

In November 2015, the ACMS considered a submission to amend the Schedule 2 entry for paracetamol to include paracetamol when combined with ibuprofen in pack sizes of 12 dosage units or less. The ACMS recommended that paracetamol should be included in Schedule 2 when combined with ibuprofen in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen in divided doses in a pack of not more than 3 day supply. The delegate agreed with the ACMS and made an interim decision based on the ACMS advice. After deferring their final decision to give consideration to a late submission received during the interim decision consultation period, the delegate decided to vary their decision. In view of the dosage levels of paracetamol and ibuprofen the delegate considers it is more appropriate to limit the Schedule 2 part a) entry to 12 dosage units per pack rather than 3 days' supply packs as this would ensure the total paracetamol available in the pack would not be excessive.

In March 2017, the ACMS considered a proposal to amend the Schedule 3 entry for ibuprofen to include a modified release dosage form of 600 mg of ibuprofen per dosage unit in packs of 32 or less dosage units. ACMS recommended that the Schedule 3 entry should be amended as suggested, allowing consumers greater access to a product for pain relief that is longer-lasting than other products currently available. The delegate's final decision was to amend the Schedule 3 entry for ibuprofen to include the modified release dosage form, with an implementation date of 1 October 2017.

Australian regulatory information

The Australian Register of Therapeutic Goods (ARTG) has 229 entries for products containing ibuprofen. They are approved for treatment of infants, children and adults and come in multiple dosage strengths and forms.

Combination products available include ibuprofen with codeine, ibuprofen with paracetamol and ibuprofen with pseudoephedrine. The ARTG also included entries for ibuprofen lysine 324 mg tablets and capsules and ibuprofen sodium dihydrate 256 mg tablets and capsules.

In the last 30 years there have been 1222 reported cases of adverse events related to ibuprofen in the Database of Adverse Events Notification (DAEN) - Medicines: 813 cases with a single suspected medicine and 35 cases where death was a reported outcome.

According to the TGA Ingredient Database, ibuprofen, ibuprofen lysine and ibuprofen sodium dihydrate are available for use as an:

• Active Ingredient in: Biologicals, Export Only, Over the Counter, Prescription Medicines; and
• Excipient Ingredient in: Biologicals, Devices, Prescription Medicines.

International regulations

Canada

Health Canada regulates ibuprofen in strengths of 200 mg, 300 mg and 400 mg as over-the-counter medicines.

New Zealand (NZ)

Medsafe NZ regulates ibuprofen in solid dose forms containing not more than 200 mg in packs of more than 25 and less than 100 tablets as Pharmacy Only.

United States of America (USA)

The USA Food and Drug Administration regulate ibuprofen in varying dose forms as an over-the-counter medicine.

European Union

The European Medicines Authority regulates ibuprofen and dexibuprofen (the dextrorotatory enantiomer of ibuprofen) in varying doses and formulations and these are available on prescription as well as over the counter.

Substance summary

Table 1.6.1: Chemical information of ibuprofen

Property	Ibuprofen
CAS name	Ibuprofen
CAS number	15687-27-1
IUPAC and/or common and/or other names	2-[4-(2-methylpropyl)phenyl]propanoic acid (IUPAC); Ibuprofen (INN);
Chemical structure
Molecular formula	C13H18O2
Molecular weight	206.3 g/mol

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used as an analgesic, antipyretic, and anti-inflammatory. It decreases synthesis of pain and inflammation, promoting prostaglandins via non-selective inhibition of both cyclo-oxygenase 1 and 2 (COX-1 and COX-2) enzymes.

Ibuprofen is a white or almost white, crystalline powder or colourless crystals. It is practically insoluble in water, freely soluble in acetone, in methanol and in methylene chloride. It dissolves in dilute solutions of alkali hydroxides and carbonates.

Numerous oral non-prescription ibuprofen formulations are available in Australia with various dosage forms, strengths and combinations. These 'immediate release' (IR) non-prescription formulations are indicated for the management of mild to moderate pain and inflammation, including reducing fever, and for the treatment of headache including migraine, period pain, dental pain, musculoskeletal and joint pain and post-operative pain.

Australian therapeutic guidelines recommends that the non-prescription ibuprofen oral dose in people aged more than 12 years of age is 200–400 mg every 4 to 6 hours as needed, with a maximum daily dose of 1200 mg.

Toxic effects are unlikely at doses below 100 mg/kg, but can be severe above 400 mg/kg. Risks noted include increased risk of cardiac arrest, risk of spontaneous abortion, risk of gastrointestinal side effects (including bleeding), as well as renal function changes. Additionally, NSAIDs such as ibuprofen may not be suitable for people with stomach problems such as ulcers or bleeding, people with heart or kidney problems or people with high blood pressure.

Pre-meeting public submissions

Seventeen (17) submissions were received, three (3) in support and fourteen (14) opposed.

Main points in support:

• Rescheduling of codeine is likely to increase the use of ibuprofen.
• Guidance and counselling from a pharmacist should be readily available to avoid medication misuse, and to confirm baseline risk factors, comorbidities and medication use to provide individualised treatment.
• Co-administration of ibuprofen with combination tablets of angiotensin-converting-enzyme inhibitor (ACE inhibitor) or Angiotensin II Receptor Blockers (ARBs) with a diuretic for treating hypertension can increase the potential for renal adverse medication events.
• Co-administration of NSAIDs with antithrombotic drugs could result in a major bleeding event.
• Rescheduling ibuprofen would reduce the incidence of self-selection of ibuprofen to treat pain or muscular inflammation.
• Two comprehensive reviews of NSAIDs conducted by the TGA in recent years acknowledged the cardiovascular, hepatotoxicity and pregnancy risks associated with these medicines. Thus it is appropriate that access to these medicines is restricted further to ensure appropriate review by a pharmacist.
• Ibuprofen has a good safety profile for use at over-the-counter doses and short term therapy.
• NSAIDs are potent substances particularly for individuals with risk factors such as asthma, hypertension, renal impairment or heart failure. The wide availability of NSAIDs both OTC and prescription ultimately pose a risk to consumers who may inadvertently take different NSAIDs concurrently or continue therapy for a longer period than clinically necessary.
• At least 50% of all patients, and at least 60% of patients diagnosed with a musculoskeletal disorder had at least one NSAID-relevant coexisting medical condition as identified in a recent study. The frequency of NSAID-relevant coexisting medical conditions also increased with age.^[37]
• Some consumers are known to increase their OTC dose when analgesia is suboptimal.
• Ibuprofen should be considered in the context of scheduling of similar substances such as naproxen given the similar safety profiles.

Main points opposed:

• A previous proposal to reschedule ibuprofen to restrict sale to pharmacies was considered in 2014/15 and was rejected on the grounds that there was insufficient evidence. There have been no new safety alerts or concerns raised since that time to warrant a further review or a change in the scheduling of ibuprofen.
• The TGA (in 2014 and 2016) and the European Medicines Agency (EMA) (in 2015) have both recently conducted safety reviews of NSAIDs, including ibuprofen; these reviews have stated that there is minimal cardiovascular risk associated with ibuprofen when used at recommended OTC doses and duration
• The reviews did not recommend that any changes to access are warranted and proposed new labelling warning statements to improve consumer awareness of risks associated with use by people who have risk factors or use for prolonged periods of time
• Since the reviews were published there has been no evidence of any significant public health concern that could have altered the risk vs benefit profile of ibuprofen, to warrant a departure from the current scheduling arrangements.
• In many international markets, ibuprofen is available through general retail stores. Ibuprofen scheduling in Australia is in line with all major international countries, including the UK, Canada, the USA and New Zealand.
• Ibuprofen (200 mg in small packs and up to 25 dosage units) has been available through retail stores as an unscheduled medicine since 2003 and as a pharmacy medicine (Schedule 2) for over 2 decades. There is no apparent reason why ibuprofen in small pack sizes should be restricted in a way that sees consumers purchasing from a pharmacy instead of a general retail store.
• Ibuprofen is currently available from pharmacies in larger pack sizes, allowing consumers to obtain advice when required.
• Up-scheduling ibuprofen will not provide any significant additional health care professional supervision, with interaction typically provided by a pharmacy assistant, and will only result in reduced access to general pain relief to consumers.
• Rescheduling would reduce the consumer’s ability to self-select pain medication when pharmacies are closed, especially in rural/remote Australia.
• Restricting the sale of ibuprofen to pharmacies only would deny Australian consumers appropriate and timely access to a safe and effective analgesic, thereby limiting their ability to effectively treat or manage sudden symptoms or minor ailments. As such, this would have a negative impact on public health.
• Ibuprofen has an excellent, well known safety profile and the use of labelling and safety warnings facilitates appropriate use by the consumer.
• Access to ibuprofen is currently similar to that of other products used for short term pain relief such as paracetamol and aspirin.
• Ibuprofen continues to demonstrate a favourable benefit versus risk profile.
• Ibuprofen has a wide therapeutic window and when taken orally, the propensity for toxicity in overdose is low. The consequences of misuse of paracetamol are substantially worse than with ibuprofen. There is a low incidence of adverse events relating to the consumption of ibuprofen given the large number of dosage units that are sold unscheduled in Australia.
• The proposed changes to the scheduling will have a significant impact on consumer choice and convenience, reduce competition and increase cost to consumers.
• Limiting options and accessibility will not deliver any health benefits to the community. It may result in possible public health consequences such as those arising from increased consumption of paracetamol.
• Education of at risk patients and improved product labelling would be more effective measures with a greater impact than reduced convenience and impeded access.
• For consumers, OTC medicine labels provide the single most important source of information. Australian medicines that contain ibuprofen must be labelled in accordance with the Required Advisory Statements for Medicine Labelling (RASML), which contains detailed mandatory warning statements in language that consumers are able to understand and act upon.
• Any increase in regulation should be based on sound evidence that (i) the concerns are based on accurate evidence and (ii) that scheduling changes are the only mechanism for addressing these concerns.
• Small packs of ibuprofen that are currently exempt (i.e. 25 dosage units / approximately 4 days' supply) can be appropriately selected and used by the reasonable consumer with acceptable safety.
• A thorough and transparent public examination of the evidence behind this scheduling proposal is required and any regulatory decisions should be consistent with the principles of best practice regulation.

The public submissions will be made available on the TGA website.

Summary of ACMS advice to the delegates

The committee recommended that the current Schedule 2 and Schedule 3 entries for ibuprofen remain appropriate.

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:
• Increased incidence of NSAID (ibuprofen) cardiovascular (CV) effects especially (but not exclusively) in people at risk at high doses and longer duration than OTC doses.
• There are no new safety concerns. The evidence of potential CV risk associated with OTC doses of ibuprofen is not substantiated (Bally M et al., BMJ 2017).
• Benefits: 24 hour availability of 24 pack sizes as exempt for acute pain.

the purposes for which a substance is to be used and the extent of use of a substance:

• OTC Indication is for acute pain (1200 mg/day for short term of not more than 4 days).the toxicity of a substance:

the toxicity of a substance:

• Cardiovascular disease and other complications of NSAID use (gastrointestinal, blood pressure, renal impairment); confusion in elderly.
• Covered by RASML statement.

the dosage, formulation, labelling, packaging and presentation of a substance:

• Covered by RASML statement.

the potential for abuse of a substance:

• Ibuprofen is non-addictive.
• Minimal risk of misuse or abuse.

any other matters that the Secretary considers necessary to protect public health

• Ibuprofen (200 mg in small packs and up to 25 dosage units) has been available through retail stores as an unscheduled medicine since 2003 and as a Pharmacy Medicine (Schedule 2) for over 2 decades.
• No evidence provided of excessive use, purchasing or harm through general sale or Schedule 2 availability.

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)

Delegate's interim decision

The delegate's interim decision is that the current Schedule 2 and Schedule 3 entries for ibuprofen remain 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:

1. the risks and benefits of the use of a substance:

• The October 2014 TGA ‘Review of cardiovascular safety of non-steroidal anti-inflammatory drugs’ stated:

Based on the current evidence, there are no major changes required to the availability and warnings on labels for over-the-counter (OTC) diclofenac, ibuprofen and naproxen. These drugs provide effective pain relief when used according to the label at recommended doses for short durations.

• EMA advice in May 2015 following a review was:
No increase in cardiovascular risk is seen with ibuprofen at doses of up to 1,200 mg per day, which is the highest dose generally used for over-the-counter (OTC) preparations taken by mouth in the European Union (EU).
• There are no new safety concerns. The evidence of potential cardiovascular (CV) risk associated with OTC doses of ibuprofen is not substantiated (Bally M et al., BMJ 2017).
• Risks: increased incidence of NSAID (ibuprofen) CV effects are especially (but not exclusively) seen in people at risk, at high doses and at longer duration, rather than OTC doses.
• Benefits
• 24 hour availability of 24 pack sizes as exempt for acute pain.
• Ibuprofen has a good safety profile for use at over-the-counter doses and short term therapy.

the purposes for which a substance is to be used and the extent of use of a substance:

• Indication is for acute pain (1200 mg/day for short term of not more than 4 days).

the toxicity of a substance:

• Although there are cardiovascular disease and other complications of NSAID use (gastrointestinal, blood pressure, renal impairment) and confusion in the elderly these are well covered in the labelling as per the RASML statement.
• Ibuprofen has a wide therapeutic window and when taken orally, the propensity for toxicity in overdose is low.

the dosage, formulation, labelling, packaging and presentation of a substance:

• RASML statement and hence the labelling mitigate any risk.
• Ibuprofen scheduling in Australia is in line with major international countries including the UK, Canada, the USA and New Zealand.
• There is 24 hour availability of exempt pack sizes for acute pain as well as easy accessibility in rural/remote areas.

the potential for abuse of a substance:

• Minimal risk of misuse or abuse.

any other matters that the Secretary considers necessary to protect public health

• No evidence provided of excessive use, purchasing or harm through general sale or Schedule 2 availability.
• Ibuprofen scheduling in Australia is in line with major international countries including the UK, Canada, the USA and New Zealand.

---

Footnotes

37. Bloom L, Blacketer M, Boyle K et al. Aging and the frequency of NSAID-relevant coexisting medical conditions in the primary care setting. Innovation in Aging 2017;1(suppl_1):875.

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

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:

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.

Related substances listed in the Poisons Standard

Schedule 4

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.

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.

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On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

An application was submitted to amend the Schedule 4 entry and create a new Schedule 3 entry for orphenadrine 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:

The applicant's reasons for the request are:

• Orphenadrine is a skeletal muscle relaxant. Its citrate salt is used to relieve pain due to muscle spasm. Paracetamol is an analgesic. The combination of a skeletal muscle relaxant and an analgesic is useful in conditions where pain is associated with muscle spasm. The individual substances relieve the two defining symptoms of the targeted indication (pain and muscle spasm) and contribute to the clinical effect via different modes of action.
• Orphenadrine containing tablets have been available in Australia as a Schedule 4 medicine for over 40 years, and have a known efficacy and safety profile.
• The combination of orphenadrine 35 mg and paracetamol 450 mg provides effective relief of pain associated with muscle spasm including painful muscular conditions, musculoskeletal spasm, sports muscle injuries, lower back ache and muscle contraction headaches. It is useful in helping to break the pain-spasm-pain cycle resulting from minor trauma or injury.
• Painful musculoskeletal conditions are readily recognisable by the consumer. They are generally self-limiting and suitable for short-term treatment under the supervision of a pharmacist.
• Orphenadrine is an alternative treatment that provides a specific treatment for muscle spasms without the risks associated with low-dose non-steroidal anti-inflammatory drugs (NSAIDs) and codeine.
• Post codeine up-scheduling, there will be fewer preparations available for pharmacist's to recommend for painful musculoskeletal conditions.
• Treatment of muscle spasm with a combination of orphenadrine and paracetamol helps avoid undue immobilisation and consequential loss of work/other activities of daily living.
• Adverse effects associated with the combination are mainly due to the anticholinergic activity of orphenadrine and are more likely to occur at doses higher than proposed for the Schedule 3 entry. The safety of the combination is comparable to that of other anticholinergic medicines. Orphenadrine can potentially cause adverse effects such as dry mouth, palpitations, confusion and dizziness in elderly people. These effects are reversible and are usually mild and self-limiting at the recommended dosage. They can be managed by reducing the dose.
• The risk-benefit profile for the fixed dose regimen is positively supported with clinical trial evidence of up to 10 weeks treatment and includes comparison with the single actives.
• There are over 45 years of global post-marketing surveillance with orphenadrine. Its safety profile is comparable to that of other over-the-counter (OTC) medicines with anticholinergic activity. The safety profile of paracetamol is well known and does not appear to be affected by orphenadrine.
• There is a low level of relative risk associated with the rescheduling of orphenadrine when used in combination with paracetamol. Many products with anticholinergic activity are already available as Schedule 2 medicines for use in adults (e.g. hyoscine or diphenhydramine) and are often used with paracetamol-containing products. Pharmacists are familiar with counselling and educating consumers on the use of such medicines. Additionally, paracetamol is available as a general sales medicine in packs of 20 tablets, with larger packs up to 100 tablets available in pharmacies. Thus, pharmacists are already counselling patients on the use of anticholinergics and analgesics as separate medications. The counselling appropriate for a paracetamol and orphenadrine combination is consistent with that applied for the separate medicines.
• Strategies to minimise associated risks with a paracetamol and orphenadrine combination are:
• Pack size restriction;
• Inclusion of warning and precautionary statements in the product information (PI), consumer medicines information (CMI) and on the carton; and
• Mandatory intervention by a pharmacist at point of sale to help minimise the potential for adverse effects and misuse.
• The proposed medicine label for the proposed product will comply with the new TGO92 medicine labelling orders set by the TGA, which will show all active ingredients prominently on the label thereby helping to minimise inadvertent misuse.
• The proposed product (same formulation as the Australian product) has been available in several countries, although not always concurrently. In South Africa, the proposed product has been an OTC medicine since 1978.
• The proposed product is a rational combination analgesic product fulfilling the unmet clinical need for an accessible OTC preparation supervised by the pharmacist that:
• Specifically addresses both pain and muscle spasm;
• Is without the risks associated with NSAIDs and codeine; and
• Contains a total daily therapeutic dosage of 2.7 g paracetamol, well under the maximum 4 g recommended daily dosage considered safe by regulatory authorities worldwide and in published literature.
• The 4 day supply pack of the proposed product limits the amount of paracetamol intake. Pharmacists in their mandatory interventionist role as provider of Schedule 3 medicines will counsel individuals against co-administering other paracetamol containing products while taking the proposed product. This precaution will also appear on the label.
• The proposed Schedule 3 pack provides a maximum of 4 days treatment for painful musculoskeletal conditions associated with muscle spasm.
• Orphenadrine has nearly 40 years'; experience in Australia and over 40 years' experience internationally.
• Safety record supported by longstanding Periodic Safety Update Reports (PSURs) and Database of Adverse Event Notifications (DAEN) data.
• Dedicated educational support programme for pharmacists by the sponsor and the Pharmaceutical Society of Australia including the best practice clinical protocol for pharmacists.

Current scheduling status

Orphenadrine is currently listed in Schedule 4 of the Poisons Standard as follows:

Paracetamol is currently listed in Schedules 2, 3 and 4 of the Poisons Standard as follows:

1. when combined with ibuprofen in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen in divided doses in a primary pack containing no more than 12 dosage units per pack; or
2. in tablets or capsules enclosed in a primary pack containing not more than 100 tablets or capsules; or
3. in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules intended only as a bulk medicine pack and labelled 'For dispensing only' and 'This pack is not to be supplied to a patient'; or
4. in individually wrapped powders or sachets of granules enclosed in a primary pack containing not more than 50 wrapped powders or sachets of granules; or
5. in individually wrapped powders or sachets of granules enclosed in a primary pack containing more than 50 wrapped powders or sachets of granules intended only as a bulk medicine pack and labelled 'For dispensing only' and 'This pack is not to be supplied to a patient'; or
6. in other preparations except:
1. when included in Schedule 3 or 4; or
2. in individually wrapped powders or sachets of granules each containing 1000 mg or less of paracetamol as the only therapeutically active constituent (other than caffeine, phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
1. enclosed in a primary pack that contains not more than 10 such powders or sachets of granules,
2. compliant with the requirements of the Required Advisory Statements for Medicine Labels,
3. not labelled for the treatment of children 6 years of age or less, and
4. not labelled for the treatment of children under 12 years of age when combined with caffeine, phenylephrine and/or guaifenesin; or
3. in tablets or capsules each containing 500 mg or less of paracetamol as the only therapeutically active constituent (other than caffeine, phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
1. packed in blister or strip packaging or in a container with a child-resistant closure,
2. in a primary pack containing not more than 20 tablets or capsules,
3. compliant with the requirements of the Required Advisory Statements for Medicine Labels,
4. not labelled for the treatment of children 6 years of age or less, and
5. not labelled for the treatment of children under 12 years of age when combined with caffeine, phenylephrine and/or guaifenesin.

1. when combined with aspirin or salicylamide or any derivative of these substances except when separately specified in these Schedules;
2. when combined with ibuprofen in a primary pack containing more than 30 dosage units;
3. in slow release tablets or capsules containing more than 665 mg paracetamol;
4. in non-slow release tablets or capsules containing more than 500 mg paracetamol;
5. in individually wrapped powders or sachets of granules each containing more than 1000 mg paracetamol;
6. in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules except in schedule 2;
7. in individually wrapped powders or sachets of granules enclosed in a primary pack containing more than 50 wrapped powders or sachets of granules except when included in Schedule 2;
8. for injection.

It is also included under the entry paracetamol in Appendix F with the following statements:

• 97 (Adults: Keep to the recommended dose. Don't take this medicine for longer than a few days at a time unless advised to by a doctor); and/or
• 98 (Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor); and
• 99 (If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26; New Zealand 0800 764 766) or go to a hospital straight away even if you feel well because of the risk of delayed, serious liver damage); and
• 100 (Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist).

Scheduling history

In February 1987, orphenadrine was first scheduled. Based on a jurisdiction list of sedating drugs, orphenadrine was included in Appendix K by the Drugs and Poisons Scheduling Committee (DPSC).

In November 1987, the DPSC noted that orphenadrine was included in the list of substances requiring a child-resistant closure in TGO 20. The committee agreed this was appropriate, and that it should not be replicated in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP).

In June 2011, the ACMS considered a proposal to reschedule orphenadrine in dosage units containing less than 35 mg from Schedule 4 to Schedule 3 when combined with paracetamol in a pack size of 24 dosage units or less. The application was referred to an external evaluator, who recommended that the application be rejected.

In September 2011, the delegate concluded that the recommendations of the ACMS were clear and appropriately supported. The delegate agreed with the recommendations that the scheduling of orphenadrine and paracetamol in Schedule 4 of the Poisons Standard remained appropriate.

Australian regulatory information

The Australian Register of Therapeutic Goods (ARTG) has two entries for products registered containing both orphenadrine and paracetamol. The products differ in container presentation – blister pack vs. tablet bottle.

In the last 30 years there have been 39 reported cases of adverse events related to orphenadrine, and 3237 related to paracetamol in the Database of Adverse Events Notification (DAEN) - Medicines: 21 cases with the single suspected medicine being orphenadrine, and 1244 cases with paracetamol. Of these, no cases reported death as the outcome associated with orphenadrine, compared to 137 cases reported death as an outcome associated with paracetamol over the same 30 year period.

International regulations

Tablets containing orphenadrine citrate 100 mg (as the only active ingredient) are marketed as OTC in Canada.

Both Medsafe New Zealand and the United States of America’s Food and Drug Authorisation classify orphenadrine citrate as a prescription medicine.

Substance summary

Orphenadrine is a congener of diphenhydramine. It is a tertiary amine antimuscarinic agent with weak antihistaminic and local anaesthetic properties. It also inhibits noradrenaline transport and blocks NMDA receptors and voltage-gated sodium channels.

Orphenadrine is a skeletal muscle relaxant. Its citrate salt is used to relieve pain due to muscle spasm. However, efficacy for this indication is not well established.

Paracetamol is an analgesic. The combination of a skeletal muscle relaxant and an analgesic is useful in conditions where pain is associated with muscle spasm. The individual substances relieve the two defining symptoms of the targeted indication (pain and muscle spasm) and contribute to the clinical effect via different modes of action.

Table 1.8.1: Chemical information of orphenadrine and paracetamol

Property	Orphenadrine	Paracetamol
CAS number	83-98-7	103-90-2
IUPAC and/or common and/or other names	N,N-dimethyl-2-[(2-methylphenyl)-phenylmethoxy]ethanamine (IUPAC); 1S/C18H23NO/c1-15-9-7-8-12-17(15)18(20-14-13-19(2)3)16-10-5-4-6-11-16/h4-12,18H,13-14H2,1-3H3 (InChI); Orphenadrine (INN);	N-(4-hydroxyphenyl)acetamide (IUPAC); 1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) (InChI); Acetaminophen (USP);
Chemical structure
Molecular formula	C18H23NO	C8H9NO2
Molecular weight	269.4 g/mol	151.2 g/mol

Pre-meeting public submissions

Five (5) public submissions were received, four (4) that oppose and one (1) that supports the scheduling proposal for orphenadrine.

Main points in support:

• The rescheduling proposal outlined is for short-term therapy. Although anticholinergic effects of orphenadrine may require some caution, the proposed dosage is low and orphenadrine has an overall well-established safety and efficacy profile.
• The proposed indication for Schedule 3 can be regarded to be recognisable by the patient.
• A pharmacist will be able to consider the patient's circumstance to discuss whether orphenadrine and paracetamol would be the most appropriate analgesic. The submitter also recognises that pharmacist education and relevant practice tools would be required for the implementation of Schedule 3.
• The orphenadrine and paracetamol combination product has been available in Australia for many years. However, pharmacists report it is not widely used. This may be due to low level awareness of prescribers since the product is not listed on the Pharmaceutical Benefits Scheme (PBS). Even if the product was an appropriate therapeutic option, patients may prefer other PBS-listed options.

Main points opposed:

• Orphenadrine is potentially very toxic in overdose.
• Orphenadrine has very limited role in pain management,^[39][40] poor efficacy and patients rapidly develop tolerance to this medicine.
• Orphenadrine has significant abuse potential and Inclusion in schedule 3 would allow greater access to orphenadrine for inappropriate use.
• Clinical toxicology and poison information units have experienced an increase in presentations with orphenadrine ingestion in recent years as the management of chronic pain turns its focus onto alternatives to opioids.
• In the period 6/1/14 to 27/9/17 there have been 45 deliberate self-poisonings, 16 therapeutic errors and 11 accidental exposures involving orphenadrine.
• Anecdotal recount from a pharmacist who has encountered a patient who had overdosed on orphenadrine resulting in ischaemic bowel and the formation of a stoma.
• Within the group of anticholinergic medications it appears to have the greatest risk of death as a result of ventricular dysrhythmias, respiratory depression, seizures and hypoglycaemia. ^[41] Orphenadrine is over represented in deaths when compared to other antimuscarinics or antipsycotics.
• 71.5 deaths per million prescriptions compared to 0-6.1 deaths per million prescriptions for other anticholinergics.^[42]
• Orphenadrine is not a high volume prescription item, and given that those who would benefit from it have conditions which should require medical management, there is no rationale for a proposal to down schedule.

The public submissions will be made available on the TGA website.

Summary of ACMS advice to the delegates

The committee recommended that the current scheduling of orphenadrine remains appropriate.

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: there is significant abuse potential, increased occurrence of abuse episodes, OD-induced deaths, adverse cardiac events, drug-drug interactions, and incompatible pharmacokinetics with other drugs. There is also a lack of efficacy for certain claims for indications.
• Benefit: There is modest evidence of support as a skeletal muscle relaxant.

the purposes for which a substance is to be used and the extent of use of a substance:

• It is not a realistic alternative for those in whom NSAIDs are contraindicated or precautioned (e.g. those over 65) because this same group is also the most sensitive to the anticholinergic adverse effects of orphenadrine.
• Orphenadrine is claimed to be useful for painful conditions where muscle spasm is a component of the pain, such as sprains and strains, sports muscle injuries, whiplash, lower back ache and tension headaches. It is noted that there are no specific data on efficacy for most of these conditions.

the toxicity of a substance:

• There are documented cases of child poisoning with significant toxicity at doses of 6 tablets, and has been associated with fatalities in overdose (e.g. 80 fatalities in Sweden). For overdose, there is evidence that orphenadrine is more toxic than other anticholinergic drugs (Buckley and McManus 1998), and many fatalities have been reported (Jonsson et al., 2004). Orphenadrine has also caused fatalities in children after accidental ingestion.
• Orphenadrine contributes to the anticholinergic burden.

the dosage, formulation, labelling, packaging and presentation of a substance:

• Because of the potential toxicity for children of orphenadrine products, these products need to be presented in child-resistant packing.
• The evaluator noted the applicant’s statement that ingestion of 24 tablets as a single dose would have minimal potential for harm was incorrect, as 10.8 g of paracetamol could lead to serious or fatal hepatotoxicity, even in adults.
• The total content of 840 mg orphenadrine could cause serious problems in children (Van Herrewhege et al., Intensive Care Med 1999; Garza et al., Pediatr Emerg Care 2000).

the potential for abuse of a substance:

• There are some case reports of dependency and abuse (Shariatmadari, BMJ1975; Schifano et al., South Med J 1988; Mugglestone, Lancet 1985), but it does not appear to be a commonly abused substance. With wider use, if there were greater ease of access, this may change.

any other matters that the Secretary considers necessary to protect public health

• The product has not been fully evaluated based on contemporary standards.

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)

Delegate's interim decision

The delegate’s interim decision is that the current scheduling of orphenadrine 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:

1. the risks and benefits of the use of a substance:

• Risks: there is significant abuse potential, increased occurrence of abuse episodes, OD-induced deaths, adverse cardiac events, drug-drug interactions, and incompatible pharmacokinetics with other drugs. There is also a lack of efficacy for certain claims for indications.
• Benefit: There is modest evidence of support as a skeletal muscle relaxant.

the purposes for which a substance is to be used and the extent of use of a substance:

• It is not a realistic alternative for those in whom NSAIDs are contraindicated or precautioned (e.g. those over 65) because this same group is also the most sensitive to the anticholinergic adverse effects of orphenadrine.
• Orphenadrine is claimed to be useful for painful conditions where muscle spasm is a component of the pain, such as sprains and strains, sports muscle injuries, whiplash, lower back ache and tension headaches. It is noted that there are no specific data on efficacy for most of these conditions.

the toxicity of a substance:

• There are documented cases of child poisoning with significant toxicity at doses of 6 tablets, and has been associated with fatalities in overdose (e.g. 80 fatalities in Sweden). For overdose, there is evidence that orphenadrine is more toxic than other anticholinergic drugs (Buckley and McManus 1998), and many fatalities have been reported (Jonsson et al., 2004). Orphenadrine has also caused fatalities in children after accidental ingestion.
• Orphenadrine contributes to the anticholinergic burden.

the dosage, formulation, labelling, packaging and presentation of a substance:

• Because of the potential toxicity for children of orphenadrine products, these products need to be presented in child-resistant packing.
• The evaluator noted the applicant’s statement that ingestion of 24 tablets as a single dose would have minimal potential for harm was incorrect, as 10.8 g of paracetamol could lead to serious or fatal hepatotoxicity, even in adults.
• The total content of 840 mg orphenadrine could cause serious problems in children (Van Herrewhege et al., Intensive Care Med 1999; Garza et al., Pediatr Emerg Care 2000).

the potential for abuse of a substance:

• There are some case reports of dependency and abuse (Shariatmadari, BMJ1975; Schifano et al., South Med J 1988; Mugglestone, Lancet 1985), but it does not appear to be a commonly abused substance. With wider use, if there were greater ease of access, this may change.

any other matters that the Secretary considers necessary to protect public health

• The product has not been fully evaluated based on contemporary standards.

---

Footnotes

39. Chou R, Peterson K, Helfand M. (2004). Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. Aug;28(2):140-75
40. Richards BL, Whittle SL, Buchbinder R. (2012). Muscle relaxants for pain management in rheumatoid arthritis. Cochrane Database Syst Rev. Jan 18;1:CD008922
41. Dawson AH. Antimuscarinic drugs in Dart RC (ed). Medical Toxicology 3rd Ed.
42. Buckley and McManus (1998) ‘Fatal toxicity of drugs used in the treatment of psychotic illnesses’, Br J Psychiatry, 172, 461

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

An application was submitted to amend the Schedule 2 and Schedule 4 entries and to delete the Schedule 3 and Appendix H entries for clotrimazole 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:

The applicant's reasons for the request are:

• Topical preparations containing clotrimazole are well-established as appropriate medicines for consumer self-selection, as demonstrated by their broad self-select availability in both pharmacy and non-pharmacy outlets in most markets worldwide.
• Clotrimazole vaginal preparations have been available in the USA and UK as an unscheduled medicine since 1990 and 2004 respectively, and have progressively been switched to general sale self-select medicines in other major markets.
• Clotrimazole has been available in Australia as a Schedule 2 medicine for the topical treatment of fungal infections since 1991. It is also an unscheduled medicine for dermal tinea pedis infections since 2005, with no new safety issues being identified.
• The predicted public health benefits from the proposal are an increase in women's health literacy and a facilitated positive shift in Australian women's intimate health management.
• Quality use of medicines can be achieved through well-designed labelling. There is a need to update the labelling of clotrimazole vaginal preparations to focus on accurate symptom identification including accurate self-treatment information and directions to consult a health care professional in cases of:
• recurring episodes;
• apparent atypical symptoms of vulvovaginal candidiasis;
• symptoms being indicative of another causative pathogen; or
• treatment failure.
• The rescheduling of vaginal clotrimazole to Schedule 2 will improve access and increase flexibility in self-selection of effective treatments for women with uncomplicated vulvovaginal candidiasis. Clotrimazole vaginal preparations have been available internationally in more than 70 countries as self-select medicines for almost 30-years without any evidence of safety issues. Whilst pharmacists are generally well-equipped and skilled at having personal conversations in private spaces, the down-scheduling proposal represents a long-overdue regulatory change resulting in an end to barriers to access and potential delays in treating vulvovaginal candidiasis for many Australian women.

Current scheduling status

Clotrimazole is currently listed in Schedules 2, 3, 4 and 6 and Appendices F and H of the Poisons Standard as follows:

Clotrimazole is also included in Appendix F and Appendix H as follows:

Scheduling history

Clotrimazole was first scheduled in August 1977. Clotrimazole has an extensive scheduling history since 1985. The scheduling history relevant to vaginal preparations have been presented below.

The August 1977, the Drugs and Poisons Schedule Standing committee (DPSSC) included clotrimazole in Schedule 4.

In April 1994, the National Drugs and Poisons Schedule Committee (NDPSC) agreed to down-schedule preparations of clotrimazole for vaginal use to Schedule 3 to give its current entry. Following out-of-session consideration, the committee also agreed to include the current warning statements in Appendix F for clotrimazole when included in Schedule 3.

In November 1996, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. The committee did not support the rescheduling application.

In February 1997, the NDPSC considered the post-meeting comment concerning the November 1996. The committee agreed that the November 1996 decision remained appropriate and that clotrimazole for vaginal use should remain in Schedule 3.

In August 1998, the NDPSC considered a submission to include miconazole in Appendix H, and decided to allow other antifungals currently included in Schedule 3 to be advertised by including them in Appendix H. These substances were clotrimazole, econazole, miconazole and nystatin.

In February 2006, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. After consideration of the new data presented, the committee agreed that the current scheduling of clotrimazole remained appropriate. The committee noted that maintaining mandatory pharmacist involvement in the sale of clotrimazole was needed to fully address the committee's concerns, particularly the risk of repeated clotrimazole use masking an underlying serious condition.

In February 2007, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. The committee agreed that the current scheduling of clotrimazole for vaginal use remained appropriate. Maintaining mandatory pharmacist involvement in the sale of clotrimazole was needed to fully address the committee's concerns, particularly the risk of repeated clotrimazole use masking an underlying serious condition without referral to a pharmacist or doctor or being used incorrectly on non-fungal vaginal infections or conditions.

Australian regulatory information

Clotrimazole is listed in 85 entries on the Australian Register of Therapeutic Goods (ARTG). The products marketed include creams in varying strengths and quantities (including in combination with hydrocortisone), capsules for oral use and pessaries for internal use.

In the last 30 years there have been 141 adverse event reports in the Database of Adverse Events Notification (DAEN) - Medicines: 95 cases with a single suspected medicine and no cases resulting in death.

According to the TGA Ingredient Database, clotrimazole is available for use as an:

• Active Ingredient in: Biologicals, Export Only, Over the Counter, Prescription Medicines; and
• Excipient Ingredient in: Biologicals, Devices, Prescription Medicines.

International regulations

New Zealand

Clotrimazole is listed as a prescription medicine in New Zealand, with the exception of preparations for vaginal (restricted) or external use (Pharmacy Only and General Sale).

United States of America (USA)

The USA Food and Drug Administration regulate preparations of clotrimazole as prescription and over-the-counter medicines, based on formulation type and indication. There are a number of lozenges and creams available on prescription, with creams for internal use available over-the-counter.

Canada

Clotrimazole vaginal preparations are available over-the-counter in Canada.

European Union

Clotrimazole is listed in Annex I in the EU for cutaneous use at 1% w/w.

Substance summary

Clotrimazole is an antimycotic drug with activity against the yeast Candida albicans, and lesser activity against other species of Candida. It was first approved in Australia 50 years ago for topical use, and has continued to be available for treatment of mucocutaneous fungal infections in dermal creams and solutions and vaginal creams and pessaries.

Table 1.9.1: Chemical information of clotrimazole

Property	Clotrimazole
CAS name	Clotrimazole
CAS number	23593-75-1
IUPAC and/or common and/or other names	1-[(2-chlorophenyl)-diphenylmethyl]imidazole (IUPAC); Clotrimazole (INN);
Chemical structure
Molecular formula	C22H17ClN2
Molecular weight	344.8 g/mol

Pharmacology

Clotrimazole is an imidazole derivative with a broad spectrum antimycotic activity arising from inhibition of ergosterol synthesis. This leads to structural and functional impairment of the cytoplasmic membranes of dermatophytes, yeasts and moulds.

Clotrimazole is an antimycotic drug with excellent activity against Candida albicans, and lesser activity against other species of Candida. Clotrimazole also acts on Trichomonas vaginalis. The minimum inhibitory concentration (MIC) is approximately 10-1000 times greater than for Candida albicans. With MICs intermediate to that of Candida sp. and Trichomonas vaginalis, clotrimazole also have activity on gram-positive (Streptococci sp. / Staphylococci sp.) and gram-negative bacteria (Bacteroides sp. / Gardnerella vaginalis).

Primarily-resistant fungal variants to clotrimazole are very rare, and secondary fungal resistance has only been observed in very isolated cases.

A maximum of 10% of the dose of vaginally applied clotrimazole is said to be absorbed systemically. Various pharmacokinetic studies with XXXXXX pessaries demonstrated maximum clotrimazole plasma concentrations 10 to 72 hours post administration of only 10 µg/mL. Similar maximum plasma concentrations were detected after application of XXXXXX vaginal cream.

Clotrimazole is metabolised extensively in the liver to inactive compounds. The primary route of excretion is likely to be via the faeces, given urinary excretion of dermally-applied XXXXXX cream.

Toxicity

No carcinogenicity or mutagenicity has been observed in animal studies. Administration of XXXXXX vaginal preparations to a small number of women in the 2nd and 3rd trimesters of pregnancy was not associated with obvious untoward effects on the course of the pregnancy or on the foetus. Clotrimazole is classified as a pregnancy Category A medicine. There are no contraindications, other than hypersensitivity, for XXXXXX vaginal preparations. There are no precautions for use that have urgent/serious clinical consequences with common and/or high-risk coexisting diseases, treatments or conditions.

Current use pattern in Australia

Medications available in Australia are now limited to formulations for topical treatment and prevention of mucocutaneous fungal infections. Dermal creams and solutions are commonly used for fungal skin infections including tinea pedis, nappy rash, candididal balanoposthitis and facial, flexural or scrotal seborrheic dermatitis. Vaginal clotrimazole creams and pessaries are used to treat vulvovaginal candidiasis which is primarily caused by Candida albicans. Atypical Candida sp. is isolated in only 5% of women with vulvovaginal candidiasis (VVC).

Pre-meeting public submissions

Five (5) public submissions were received, one (1) that supported and four (4) that opposed the scheduling proposal.

Main points in support:

• Clotrimazole is effective and has a well-established safety profile.
• Clotrimazole is an antimycotic drug with proven efficacy against Candida albicans, and lesser activity against other species of Candida.
• VVC is a prevalent women's health issue, with 70-75% of women experiencing at least one episode (and with 82% of women with VVC being repeat sufferers). VVC is also a source of embarrassment, with this embarrassment being reported as a contributing factor leading to delays in seeking treatment. However, the symptoms of VVC are easily recognised and can be simply treated with clotrimazole.
• Identification and treatment of VVC, without mandatory recourse to a pharmacist, is something that consumers can reasonably be expected to manage.
• Clotrimazole was first approved in Australia 50 years ago for topical use and continues to be available for the treatment of mucocutaneous fungal infections, in dermal creams, solutions, vaginal creams and pessaries.
• Clotrimazole has been available in Australia as a Schedule 2 medicine for the topical treatment of fungal infections since 1991, and as an unscheduled medicine for dermal tinea pedis infections since 2005.
• The long history of Schedule 3 availability means that women will be familiar with the product and not all women will require pharmacist counselling at the point of purchase.
• Clotrimazole in vaginal preparations meets the scheduling factors for Schedule 2 medicines as set out in the Scheduling Policy Framework (SPF):
• Women who have been previously diagnosed with VVC will be capable of recognising their VVC symptoms without pharmacist verification.
• Clotrimazole has a well-established safety profile, low systemic absorption when used vaginally and there are no reports of Candida spp. resistance.
• There is no evidence of dependence, misuse or abuse.
• Clotrimazole has a well-established safety profile and a very low ADR rate.
• While the risk of masking a serious disease is low, there is a risk of delaying the diagnosis of a non-Candidal infection by a few days. It is very unlikely, however, that a short delay in diagnosis will have any material impact on the clinical prognosis of any likely alternative conditions. This risk will not be appreciably altered by a change from Schedule 3 to Schedule 2 availability and can be easily managed through label content.
• Amending the scheduling as proposed would bring Australian's access to clotrimazole into line with other comparable markets.
• Clotrimazole is available over-the-counter (without mandatory pharmacist intervention) in more than 70 other countries (and is available as a general sale item – GSL - in the US and the UK).

Main points opposed:

• Patients presenting with vaginal disorders should consult a pharmacist to ensure that the diagnosis and treatment is appropriate and/or necessary. This will ensure the best option for optimal patient health outcomes.
• Pharmacists are able to refer patients to doctors when appropriate. For example when patients are diabetic, under 16, over 60 years of age, pregnant, taking immunosuppressants, or when other vaginal conditions may be suspected.
• Pharmacist's advice can assist in considering the patient's symptoms, treatment history, current medications and other health conditions.
• Consultation with a pharmacist is also important to rule out common differential diagnoses such as bacterial vaginosis, candida vaginitis and trichomoniasis which have different first-line treatment options. The use of antifungal products in non-fungal vaginal infections is ineffective, may worsen the condition, and can delay diagnosis and commencement of appropriate therapy.
• While vaginal candidiasis may be self-diagnosed in some cases, studies have shown that caution is required due to concerns around the accuracy of self-diagnosis.^{[43] [44]} Tenni et al., ⁴⁴ cited figures and findings from other research reports as follows:
• Of women who presented with a self-diagnosed initial episode of candidiasis, only 59% actually had the condition.
• Only 34% who self-diagnosed vaginal candidiasis were correct.
• Women who had previously had an episode of clinically diagnosed vaginal candidiasis were no more accurate in their diagnosis than women without previous episodes.
• Pharmacists can advise on the management of repeated episodes or vaginal candidiasis and provide recommendations on ways to minimise the risk of vaginal infections in the future.
• Studies indicate that the relapse rate for these types of infections is high, possibly due to poor diagnosis.^[45]
• The risk of inaccurate self-diagnosis and subsequent delay in treatment for more serious underlying conditions warrants the continued mandatory oversight of a pharmacist. A pharmacist can also discuss more suitable treatment options where required.
• A 2002 study^[46]showed only a third of women who self-diagnosed vaginal candidiasis were accurate and that prior clinician-based diagnosis and reading the label do not improve women’s ability to properly diagnose vulvovaginal candidiasis.
• Inclusion in Schedule 2 would allow greater access and therefore an increased likelihood of errors with oral treatments for vaginal thrush. These errors may result in possible gastrointestinal symptoms from ingestions of the pessary, but more importantly result in delays in effective treatment for the patient, leading to increased discomfort from and duration of symptoms.
• Poisons information centres continue to receive calls from members of the public who have inadvertently ingested the vaginal pessary. Current packaging is not sufficiently clear and the word "pessary" is not widely understood in the community to ensure patients are using these products correctly.
• Current risks could be minimised by improved packaging and labelling to clarify method of administration and training of pharmacists to clarify administration method with the patients at the time of purchase.
• The economic cost of these errors is seen in cost of additional treatment for the patient, increased sick leave and greater use of health resources in the form of GP visits, hospital presentation and calls to poison information centers.
• While some woman may feel uncomfortable discussing such conditions with a pharmacist or have privacy concerns, this is not a sufficient reason to down-schedule clortimazole in vaginal preparations, particularly given the risks. The majority of pharmacies have private consultation areas and pharmacies are encouraged to offer these areas to consumers where appropriate. Consumers can also request to have these conversations discreetly in a more private area.
• June 2017 Pharmacy Board of Australia registrant data^[47] indicates that the majority of registered pharmacists are female. In most cases, this should enable consumers to speak with a female pharmacist if they are more comfortable discussing this condition with a pharmacist of the same gender.

The public submissions will be made available on the TGA website.

Summary of ACMS advice to the delegates

The committee recommended that the scheduling of clotrimazole remains appropriate.

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: the major risk is from inaccurate self-diagnosis, or delayed treatment if the product is used to treat other vaginal infections not caused by Candidia albicans.
• Benefits: clotrimazole is a safe and effective treatment for vulvovaginal candidiasis caused by Candidia albicans.
2. the purposes for which a substance is to be used and the extent of use of a substance:
• Clotrimazole in vaginal preparations are used to treat uncomplicated vulvovaginal candidiasis caused by Candidia albicans.
• It is a first-line treatment for vulvovaginal candidiasis in current Australian guidelines along with intravaginal nystatin cream, intravaginal miconazole and oral fluconazole.
3. the toxicity of a substance:
• Low potential toxicity.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
• Warning statements are already required for clotrimazole vaginal preparations. More detailed information on when a health professional should be consulted and the likely symptoms of conditions that will not respond to clotrimazole are proposed. However, there is evidence that women do not read the package information and that reading the label does not improve the accuracy of self-diagnosis.
• The packaging of vaginal pessaries has been associated with an increase in oral ingestion of the pessaries. This proposal does not address this poisoning risk.
5. the potential for abuse of a substance:
• Low potential for abuse.
6. any other matters that the Secretary considers necessary to protect public health
• Clotrimazole vaginal preparations are currently included in Appendix H. The company is free to make the educational campaign that they propose.

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)

Delegate's interim decision

The delegate's interim decision is that the current scheduling of clotrimazole 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:

1. the risks and benefits of the use of a substance:
• Risks: the major risk is from inaccurate self-diagnosis, or delayed treatment if the product is used to treat other vaginal infections not caused by Candidia albicans.
• Benefits: clotrimazole is a safe and effective treatment for vulvovaginal candidiasis caused by Candidia albicans.
2. the purposes for which a substance is to be used and the extent of use of a substance:
• Clotrimazole in vaginal preparations are used to treat uncomplicated vulvovaginal candidiasis caused by Candidia albicans.
• It is a first-line treatment for vulvovaginal candidiasis in current Australian guidelines along with intravaginal nystatin cream, intravaginal miconazole and oral fluconazole.
3. the toxicity of a substance:
• Low potential toxicity.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
• Warning statements are already required for clotrimazole vaginal preparations. More detailed information on when a health professional should be consulted and the likely symptoms of conditions that will not respond to clotrimazole are proposed. However, there is evidence that women do not read the package information and that reading the label does not improve the accuracy of self-diagnosis.
• The packaging of vaginal pessaries has been associated with an increase in oral ingestion of the pessaries. This proposal does not address this poisoning risk.
5. the potential for abuse of a substance:
• Low potential for abuse.
6. any other matters that the Secretary considers necessary to protect public health
• Clotrimazole vaginal preparations are currently included in Appendix H. The company is free to make the educational campaign that they propose.