1.2 Racetams

Part A - Interim decisions on matters referred to an expert advisory committee (November 2018)

1. Advisory Committee on Medicines Scheduling (ACMS #25)

1.2 Racetams

On this page: Delegate's interim decision | Materials considered | Scheduling proposal | Background information for nabiximols

Delegate's interim decision

Materials considered

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

• The proposal to amend the current Poisons Standard with respect to racetams;
• The advice received from the Advisory Committees on Medicines Scheduling (ACMS #25);
• The public submissions received before the first closing date;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• Section 52E of the Therapeutic Goods Act 1989, in particular (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

Scheduling proposal

The pre-meeting scheduling proposal for racetams was published on the TGA website on 31 August 2018 at Consultation: Proposed amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS/ACMS meetings, November 2018.

Background information for racetams

In this section: Delegate's referral to ACCS/ACMS | Delegate's scheduling proposal and reasons | Current scheduling status | Scheduling history | Australian regulatory history | International regulations | Substance summary | Current use pattern in Australia | Pharmacodynamic properties | Pharmacokinetic properties | Pre-meeting public submissions | Joint ACMS-ACCS advice

Delegate's referral to ACCS/ACMS

The proposed amendments to the Poisons Standard are to creating a new Schedule 4 group entry for racetams and new specific Schedule 4 entries for aniracetam, coluracetam, dimiracetam, fasoracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, oxiracetam, phenylpiracetam, pramiracetam, rolziracetam, seletracetam, sunifiram and unifiram.

Delegate's scheduling proposal and reasons

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

The reasons for the proposal are:

• Aniracetam, coluracetam, dimiracetam, fasoracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, oxiracetam, phenylpiracetam, pramiracetam, rolziracetam, seletracetam, sunifiram and unifiram are not specifically scheduled. Although captured as derivatives by the Schedule 4 entries for the racetams, brivaracetam, levetiracetam and piracetam, specifically scheduling these racetams will clarify their scheduling status as Schedule 4 substances.
• Due to their potential use and adverse events, the proposal recommends that these should be prescription only medicines.

Current scheduling status

The racetams brivaracetam, levetiracetam and piracetam are currently in Schedule 4 (Prescription Only Medicine) of the Poison Standard as follows:

Brivaracetam and levetiracetam are also in Appendix K (Drugs required to be labelled with a sedation warning) as follows:

Aniracetam, coluracetam, dimiracetam, fasoracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, oxiracetam, phenylpiracetam, pramiracetam, rolziracetam, seletracetam, sunifiram and unifiram are not specifically scheduled but are all captured as derivatives of the Schedule 4 entries for brivaracetam, levetiracetam and piracetam as above.

Scheduling history

Aniracetam, coluracetam, dimiracetam, fasoracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, oxiracetam, phenylpiracetam, pramiracetam, rolziracetam, seletracetam, sunifiram and unifiram have not been previously considered for scheduling.

Brivaracetam

In November 2016 the Advisory Committee on Medicines Scheduling (ACMS) considered and recommended the creation of new entries for brivaracetam in Schedule 4 and Appendix K of the Poisons Standard. Based on the indication, risks and benefits of brivaracetam (among other considerations), the delegate agreed and published a final decision on the TGA website on 23 March 2017, with a 1 June 2017 implementation date.

Levetiracetam

In May 2001 the National Drugs and Poisons Schedule Committee (NDPSC) considered scheduling the new chemical entity, levetiracetam. Noting the pharmacodynamic characteristics of levetiracetam, the indication, and that the treatment of epilepsy requires ongoing medical supervision and management, the committee decided that Schedule 4 was appropriate for levetiracetam. The committee also agreed that given the very common side effect of somnolence (>10%), an Appendix K entry was appropriate.

Piracetam

In October 2006, the NDPSC decided to harmonise with New Zealand the make piracetam a Schedule 4 substance. It was noted that there were no products containing piracetam on the Australian Register of Therapeutic Goods (ARTG) at that time.

Australian regulatory history

None of the 15 racetams (aniracetam, coluracetam, dimiracetam, fasoracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, oxiracetam, phenylpiracetam, pramiracetam, rolziracetam, seletracetam, sunifiram and unifiram) are permitted for use in listed medicines in Australia according to the Therapeutic Goods (Permissible Ingredients) Determination No.3 of 2018 - external site.

None of the 15 racetams (aniracetam, coluracetam, dimiracetam, fasoracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, oxiracetam, phenylpiracetam, pramiracetam, rolziracetam, seletracetam, sunifiram and unifiram) are approved therapeutic substances in Australia and are not in any therapeutic goods on the Australian Register of Therapeutic Goods.

Substance summary

There is increasing interest in racetam nootropic drugs for the treatment of Central Nervous System (CNS) disorders including epilepsy, neurodegenerative diseases such as dementia and Alzheimer's disease, stroke, ischemia and stress. These agents are also used in efforts to restore memory and brain performance in patients with encephalopathies of various aetiologies, including cranial traumas and inflammation.

Aniracetam

Synonyms: 1-[(4-Methoxybenzoyl)]-2-pyrrolidinone; 1-(4-methoxybenzoyl)pyrrolidin-2-one; Ro 13-5057; Draganon; Sarpul; Ampamet; Memodrin; Referan; 1-p-anisoyl-2-pyrrolidinone

Aniracetam is an ampakine nootropic derived from the racetam class of drugs, and shares a similar chemical structure with piracetam. Aniracetam has possible cognition enhancing effects.

Aniracetam is considered to be substantially more potent (likely due to its lipid solubility) than piracetam. Like piracetam, aniracetam modulates of the acetylcholine system and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Aniracetam possesses a wide range of anxiolytic properties, which may be mediated by an interaction between cholinergic, dopaminergic and serotonergic systems. Aniracetam is reported to preserve cognitive function in people with dementia.

Aniracetam is suspected of being a reproductive toxin, damaging fertility or the unborn child.

Reports indicate that aniracetam is no longer in clinical use.

Coluracetam

Synonyms: N-(2, 3-Dimethyl-5, 6, 7, 8-tetrahydrofuro [2, 3-b] quinolin-4-yl)-2-(2-oxo-1-pyrrolidinyl) acetamide; MKC-231; bci-540

Coluracetam is a nootropic agent of the racetam family. Coluracetam is a chemical analogue of piracetam.

Coluracetam boosts choline conversion to acetylcholine in the brain through the high affinity choline uptake (HACU) process and is reported to be a potential therapeutic drug for schizophrenia.

Dimiracetam

Synonyms: Neurotune; 3,6,7,7a-tetrahydro-1H-pyrrolo[1,2-a]imidazole-2,5-dione; Dihydro-1H-pyrrolo(1,2-a)imidazole-2,5(3H,6H)-dione

Dimiracetam has been shown to have a beneficial effect on peripheral neuropathic pain in rats.

Fasoracetam

Synonyms: (5R)-5-(piperidine-1-carbonyl) pyrrolidin-2-one; NS-105; N-(5-Oxo-D-prolyl) piperidine; Ichem

Fasoracetam is a nootropic and cognitive enhancer.

Fasoracetam stimulates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) formation, which is implicated in a variety of signal transduction processes such as learning and memory. It mitigated deficits in learning and memory induced by baclofen in rats Fasoracetam was originally developed by Nippon Shinyaku in search for the treatment of Alzheimer's disease, and has been in clinical trials for vascular dementia and attention deficit hyperactivity disorder.

Methylphenylpiracetam

Synonyms: 2-(5-Methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide; 2-[(2S, 3R)-2-methyl-5-oxo-3-phenylpyrrolidin-1-yl] acetamide

Methylphenylpiracetam is the methylated form of piracetam and a positive allosteric modulator of the sigma-1 receptor. Methylphenylpiracetam has shown to enhance cognition and efficacy against cholinergic dysfunction in mice. Methylphenylpiracetam is more potent that phenyl piracetam.

Nebracetam

Synonyms: 4-(aminomethyl)-1-benzylpyrrolidin-2-one ; (RS)-4-(Aminomethyl)-1-benzylpyrrolidin-2-one; Web-1881-FU; -Benzyl-4-aminomethyl-pyrrolidin-; Nebracetamum

Nebracetam is a M1 acetylcholine receptor agonist in rats. A small study in humans has shown that nebracetam may have potential in treating Alzheimer's disease. Nebracetam activates the cholinergic system, resulting in Alzheimer symptom improvement.

Nefiracetam

Synonyms: N-(2, 6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl) acetamide; Translon; DM 9384; DMPPA; Motiva; DZL-221; Nefiracetamum;

Nefiracetam is a nootropic drug of the racetam family. Animal studies show that nefiracetam may have anti-dementia properties as well as anti-amnesic effects against a number of memory impairing substances.

Nefiracetam is thought to be an agonist of the GABA-A receptor. Nefiracetam was able to reverse picrotoxin and bicuculline-induced amnesia in mouse models.

Nefiracetam causes renal and testicular toxicity in dogs and rats. There was no evidence of toxicity in humans during clinical trials.

Omberacetam

Synonyms: Noopept; ethyl 2-[[(2S)-1-(2-phenylacetyl) pyrrolidine-2-carbonyl] amino] acetate; N-Phenylacetyl-L-prolylglycine ethyl ester; GVS-111; ethyl phenylacetyl-Pro-Gly; Glycine, 1-(phenylacetyl)-L-prolyl-, ethyl ester

Omberacetam (also commonly known as Noopept) is a nootropic molecule that demonstrates a wide spectrum of cognition improving effects and neuroprotective properties. Omberacetam also shows promise in Alzheimer's disease. Compared to piracetam, omberacetam is more potent, producing a cognition enhancing effect at much lower concentrations.

Oxiracetam

Synonyms: 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide; ISF 2522; 4-Hydroxy-2-oxopyrrolidine-N-acetamide; Hydroxypiracetam; Neuromet; Neuractiv; CT-848; Oxiracetamum

Oxiracetam is a nootropic drug of the racetam family and the hydroxylated analogue of piracetam. These chemicals share a similar structure and both are considered cognitive enhancers. Oxiracetam is also a very mild stimulant. Research suggests that oxiracetam is a more powerful cognitive enhancer than piracetam.

Oxiracetam activates amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptors, but not kainate or NMDA receptors, in neuronal cultures. This action increases the density of receptor binding sites for AMPA and increases neuronal intracellular calcium concentrations.

Reports indicate that oxiracetam is no longer in clinical use. Prior to 1999 there were 22 clinical trials on oxiracetam.

Oxiracetam was developed by SIF, Italy but is no longer available from the supplier. The product insert states that oxiracetam is for "mental syndromes caused by cerebral insufficiency, disturbances in mental performance in the elderly, and no adverse interactions have been noted".

Adverse effects of oxiracetam include psychomotor excitability and sleep disorders.

Phenylpiracetam

Synonyms: Fonturacetam; 2-(2-oxo-4-phenylpyrrolidin-1-yl)acetamide; 4-Phenyl-2-pyrrolidone-1-acetamide; Carphedon; Karfedon; BRN 5030440; J-500892; Phenotropil

Phenylpiracetam, is the phenylated analogue of piracetam, and is also considered a cognitive enhancer. Phenylpiracetam is absorbed rapidly and exhibits high oral bioavailability. Phenylpiracetam is reported to be more potent, and is used for a wider range of indications than piracetam.

Phenylpiracetam is reportedly beneficial to people who develop cognitive deficits and/or depression after encephalopathy and brain injuries. It was reported to increase quality of life in patients with encephalopathy after acute lesions, brain traumas and glioma surgery.

Phenylpiracetam was developed by Medical-Biological Institute of the Russian Academy (manufactured by Valenta Pharmaceuticals in Russia). In 2003, the State Pharmacological Committee of Russia approved phenylpiracetam as a prescription drug for cerebrovascular deficiency, depression, apathy, attention and memory decline, and it is recommended for cosmonauts for increasing physical and mental/cognitive activities in space.

Adverse events associated with phenylpiracetam use include sleep disturbance.

Pramiracetam

Synonyms: N-[2-(Diisopropylamino)ethyl]-2-(2-oxopyrrolidin-1-yl)acetamide; Pramistar; amacetam; Pramiracetamum; Vinpotropil; Neupramir; Q-201610; CNS-1879; Ectapram; CI-879

Pramiracetam is a central nervous system stimulant and nootropic agent belonging to the racetam family of drugs, which shares a similar chemical structure with piracetam. Pramiracetam is considered to be 30 times stronger than piracetam and reportedly improves cognitive deficits associated with traumatic brain injuries.

Pramiracetam increases the rate of sodium-dependent high-affinity choline uptake in rat hippocampal synaptosomes in vitro, and it is proposed that its effect on cognitive functions might occur via acceleration of cholinergic transmission in the septal-hippocampal region.

Prior to 1999 there were four clinical trials on pramiracetam. Pramiracetam was developed by Warner-Lambert, USA. Adverse effects include insomnia, dysphoria, gastralgia and heartburn.

Rolziracetam

Synonyms: 2, 6, 7, 8-tetrahydro-1H-pyrrolizine-3, 5-dione; CI-911; 3, 5-Dioxopyrrolizidine; Rolziracetamum; NSC-122751

Rolziracetam has been shown to improve performance of a delayed-response task in aged Rhesus monkeys. As a result, this drug was proposed as a good candidate for the treatment of cognitive impairment in humans. However, further development has slowed due to its instability in plasma (half-life <25 minutes).

Seletracetam

Synonyms: (2S)-2-[(4S)-4-(2, 2-difluoroethenyl)-2-oxopyrrolidin-1-yl] butanamide; UCB-44212

Seletracetam, like the Schedule 4 substances brivaracetam and levetiracetam, is considered an antiepileptic and anticonvulsive drug. Seletracetam binds to synaptic vesicle 2A (SV2A) protein in brain membranes and fibroblasts with high affinity.

Sunifiram

Synonyms: 1-(4-benzoylpiperazin-1-yl) propan-1-one; 1-Benzoyl-4-propanoylpiperazine; DM-235; CS-2193

Sunifiram (1-benzoyl-4-propionylpiperazine) is a synthetic derivative of piracetam. These chemicals are structurally different; however sunifiram is still considered a piracetam-like nootropic, and is derived from the racetam class of drugs.

Sunifiram is 10,000 times more potent than piracetam, and is used as a cognitive enhancer.

There have been reported cases in the UK of sunifiram being used as a 'smart drug'. Students have also been found to be 'stacking' a variety of nootropic medicines, obtaining them illegally from online suppliers without prescription.

Unifiram

Synonyms: 2-(4-fluorophenyl) sulfonyl-1, 3, 4, 7, 8, 8a-hexahydropyrrolo [1, 2-a] pyrazin-6-one; DM-232;

Like sunifiram, unifiram is also considered a piracetam-like nootropic, derived from the racetam class of drugs. Unifiram is more potent that piracetam and has anti-amnesic and other effects in animal studies.

As of 2015, no formal human studies with unifiram have been conducted. Unifiram is not patented and, despite the lack of human and long-term toxicity studies, it is commonly sold online.

Pre-meeting public submissions

Two public submissions were received before the first closing date in response to an invitation published on 31 August 2018 under regulation 42ZCZK of the Regulations.

Both public submissions supported the scheduling proposal.

The main points provided in support of the amendment were:

• Due to the potential use and adverse events it is appropriate to make these medicines prescription only.
• It will strengthen the way all racetam substances are captured in the Poisons Standard and improve clarity of entries.
• Clarification is sought on the basis for inclusion of substances; for example, etiracetam (CAS number 33996-58-6) is not included on the list.

ACMS advice

The committee recommended that a new Schedule 4 group entry for racetams be established, with new specific Schedule 4 entries for aniracetam, coluracetam, dimiracetam, fasoracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, oxiracetam, phenylpiracetam, pramiracetam, rolziracetam, seletracetam, sunifiram and unifiram, with a new Appendix K entry for seletracetam in the Poisons Standard as follows:

Schedule 4 - New/Entries

RACETAMS

except when separately specified in these Schedules.

ANIRACETAM.

COLURACETAM.

DIMIRACETAM.

FASORACETAM.

METHYLPHENYLPIRACETAM.

NEBRACETAM.

NEFIRACETAM.

OMBERACETAM.

OXIRACETAM.

PHENYLPIRACETAM.

PRAMIRACETAM.

ROLZIRACETAM.

SELETRACETAM.

SUNIFIRAM.

UNIFIRAM.

Appendix K - New entry

SELETRACETAM

Index - New Entries

RACETAMS

Schedule 4

ANIRACETAM
cross reference: RACETAMS

Schedule 4

COLURACETAM
cross reference: RACETAMS

Schedule 4

DIMIRACETAM
cross reference: RACETAMS

Schedule 4

FASORACETAM
cross reference: RACETAMS

Schedule 4

METHYLPHENYLPIRACETAM
cross reference: RACETAMS

Schedule 4

NEBRACETAM
cross reference: RACETAMS

Schedule 4

NEFIRACETAM
cross reference: RACETAMS

Schedule 4

OMBERACETAM
cross reference: RACETAMS

Schedule 4

OXIRACETAM
cross reference: RACETAMS

Schedule 4

PHENYLPIRACETAM
cross reference: RACETAMS

Schedule 4

PRAMIRACETAM
cross reference: RACETAMS

Schedule 4

ROLZIRACETAM
cross reference: RACETAMS

Schedule 4

SELETRACETAM
cross reference RACETAMS

Schedule 4

Appendix K

Schedule 4

SUNIFIRAM
cross reference: RACETAMS

Schedule 4

UNIFIRAM
cross reference: RACETAMS

The committee also recommended an implementation date of 1 June 2019.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

1. the risks and benefits of the use of a substance:
   • The substances are claimed to be memory enhancers but only based on animal studies.
   • The risk is that the substances are being used by healthy individuals, with potential acute and long term harm.
   • Racetams are nootropic agents. There is worldwide interest in nootropics for treatment of CNS disorders including epilepsy, dementia, stroke, ischaemia and stress. They are also used in efforts to restore memory and brain performance in encephalopathies including cranial traumas and inflammation. Those that remain in development and clinical use seem to be well tolerated with low potential for drug interactions.
   • With increasing ageing population and incidence of degenerative disorders (dementias) clinical trials with this group of substances and their derivatives are likely to continue. This clinical use justifies prescription medicine status.
2. the purposes for which a substance is to be used and the extent of use of a substance:
   • Nootropics are used clinically for treatment of CNS disorders including epilepsy, dementia, stroke, ischaemia and stress.
   • They are also used in efforts to restore memory & brain performance in encephalopathies including cranial traumas and inflammation.
   • Other than brivaracetam, levetiracetam and piracetam, none of the racetams are in any products on the ARTG.
3. the toxicity of a substance:
   • Toxicity is poorly studied, but some cause psychomotor agitation, dysphoria, insomnia, heartburn, stomach pain, which are likely to occur with all the 'cognitive enhancers'.
   • Long term effects are not known but potential reproductive, testicular, gastrointestinal and renal toxicity has been seen in animals.
   • Low toxicity in those currently still available in clinical use. Those no longer in clinical use have greater toxicity e.g. aniracetam is suspected of being a reproductive toxicant.
   • Brivaracetam and levetiracetam are listed in Appendix K (sedation warning). This could be considered for seletracetam as it is similar to brivaracetam and levetiracetam and similarly considered an anticonvulsant with somnolence reported as common AE in Phase II trials.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • No products containing the 15 racetams (aniracetam, coluracetam, dimiracetam, fasoracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, oxiracetam, phenylpiracetam, pramiracetam, rolziracetam, seletracetam, sunifiram and unifiram) are approved therapeutic substances in Australia and are not in any therapeutic goods on the Australian Register of Therapeutic Goods.
5. the potential for abuse of a substance:
   • No evidence for dependence or abuse, rather use without evidence of efficacy.
   • Low but some reports of obtaining racetams online as 'smart drugs' for cognition enhancement or supplements for memory performance.
6. any other matters that the Secretary considers necessary to protect public health
   • Nil.