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

Scheduling medicines and poisons

5 February 2018

Book pagination

1.2. Cardarine

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

CARDARINE (GW501516).

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:

"The use of agents that directly or indirectly affect functions known to influence performance by altering gene expression. For example, peroxisome proliferator activated receptor δ (PPARδ) agonists (e.g. GW501516) and PPAR δ-AMP-activated protein kinase (AMPK) axis agonists (e.g. AICAR) are prohibited".

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:

"Cardarine is another drug that is not authorized in Canada for any use. The sarms.ca website also lists cardarine as GW501516. All clinical development of GW501516 was stopped when toxicities, including various cancers, were discovered following routine, long-term animal studies".

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

Figure 1.2.1: the effects of cardarine on the nuclear receptor PPARδ

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:

Schedule 10 – New Entry

CARDARINE.

Index - New Entry

CARDARINE.
Schedule 10

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:

    Schedule 10 – New Entry

    CARDARINE.

    Index – New Entry

    CARDARINE
    Schedule 10

    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

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
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    7. 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.
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