Scheduling delegate's interim decisions and invitation for further comment: ACMS, May 2014

29 May 2014

This consultation closed on 12 June 2014

Notice under subsections 42ZCZP of the Therapeutic Goods Regulations 1990 (the Regulations)

A delegate of the Secretary to the Department of Health hereby gives notice of delegate's interim decisions for amending the Poisons Standard (commonly referred to as the Standard for the Uniform Scheduling of Medicines and Poisons - SUSMP) under subsections 42ZCZP of the Therapeutic Goods Regulations 1990 (the Regulations). This notice also provides the reasons for each decision and the date of effect of the decision.

This notice provides the interim decisions of delegates, the reasons for those decisions and invites further submissions from the applicant and parties who made a valid submission in response to the original invitations for submissions published on 21 November 2013 and 30 January 2014 at: Invitation for public comment - ACMS meeting, March 2014 and Invitation for public comment - ACCS, ACMS and joint ACCS/ACMS meetings, March 2014, respectively. Edited versions of these submissions are available at Public submissions on scheduling matters.

Further submissions must be relevant to the proposed amendment, must address a matter mentioned in section 52E of the Therapeutic Goods Act 1989 and be received by the closing date 12 June 2014.

Further submissions from parties other than those who made a valid submission in response to the original invitation or the applicant, or those received after the closing date, need not be considered by the delegate.

Please note that all valid submissions received on or before the closing date will be published following removal of confidential information. It is up to the person making the submission to highlight any information which they wish to be considered as confidential. Material claimed to be commercial-in-confidence will be considered against the guidelines for the use and release of confidential information set out in Chapter 6 of the Scheduling Policy Framework (SPF), issued by the National Coordinating Committee on Therapeutic Goods. The SPF is accessible at NCCTG scheduling policy framework.

Persons making submissions are strongly encouraged to lodge submissions in electronic format (word or unsecured PDF preferred) via the email address provided below. Submissions, preferably in electronic format, should be made to:

Medicines and Poisons Scheduling Secretariat (MDP88)
GPO Box 9848
CANBERRA ACT 2601

email: SMP@health.gov.au

Facsimile: 02 6289 2650

The closing date for further submissions was 12 June 2014.

Part A - Final decisions on matters referred to an expert advisory committee

Scheduling proposals referred to the March 2014 meeting of the Advisory Committee on Medicines Scheduling (ACMS#11)

1.1 Diclofenac

Scheduling proposal

The medicines scheduling delegate considered a proposal to amend the current Schedule 2 diclofenac entry to exempt dermal use preparations containing 2 per cent or less of diclofenac from scheduling. This would be more closely harmonised with its New Zealand medicine classification.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance details

Diclofenac, a phenylacetic acid derivative, is a cyclo-oxygenase inhibitor and used as a non-steroid anti-inflammatory drug (NSAID). It is used mainly as the sodium salt for the relief of pain and inflammation in various conditions: musculoskeletal and joint disorders such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.

Diclofenac shows therapeutic efficacy by inhibiting a biochemical reaction path which is necessary for the biosynthesis of the pain inducer, prostaglandin. Diclofenac is an antifebrile, antipyretic and anti-inflammatory substance that is widely applicable in rheumatoid arthritis, osteoarthritis, spastic spondylitis, acute gout and inflammation or gout of lesion after operation. Administration via the transdermal route can by-pass the first pass metabolism. Transdermal delivery of diclofenac is reported to overcome all the problems of conventional dosage forms.

Scheduling status

Diclofenac is included in Schedules 2, 3 and 4, and Appendices F and H of the Standard for Uniform Scheduling of Medicines and Poisons (SUSMP), as follows:

Schedule 2

DICLOFENAC when:

  1. in divided preparations for oral use containing 12.5 mg or less of diclofenac per dosage unit in a pack containing 20 or less dosage units and labelled with a recommended daily dose of 75 mg or less of diclofenac;
  2. in preparations for dermal use containing 4 per cent or less of diclofenac except in preparations for dermal use containing 1 per cent or less of diclofenac or for the treatment of solar keratosis; or
  3. in transdermal preparations for topical use containing 140 mg or less of diclofenac.
Schedule 3

DICLOFENAC in divided preparations for oral use containing 25 mg or less of diclofenac per dosage unit in a pack containing 30 or less dosage units except when included in Schedule 2.

Schedule 4

DICLOFENAC except:

  1. when included in Schedule 2 or 3; or
  2. in preparations for dermal use unless:
    1. for the treatment of solar keratosis; or
    2. containing more than 4 per cent of diclofenac.
Appendix F
Poisons Warning statements Safety direction
Diclofenac 101, 104
Appendix H

Schedule 3 Poisons Permitted to be Advertised.

Scheduling history

In March 1981, diclofenac was included in Schedule 4.

In February 1997, the National Drugs and Poisons Schedule Committee (NDPSC) rescheduled from Schedule 4 to Schedule 2, dermal preparations (creams) containing 1 per cent or less of diclofenac. This decision was based on the safety profile of a 1 per cent formulation and the then approved indications for use in readily recognised conditions (minor pain relief), which did not include treatment of solar keratosis.

In August 1999, the NDPSC decided that the scheduling of diclofenac in dermal preparations remained appropriate after considering recommendations from the Trans-Tasman Harmonisation Working Party to exempt diclofenac for dermal use.

In November 1999, the NDPSC deferred consideration of the scheduling of diclofenac in dermal preparations.

In February 2000, the NDPSC exempted dermal preparations of diclofenac from scheduling based on additional safety data.

In March 2011, following advice from the December 2010 ACMS meeting, the delegate included dermal preparations containing more than 1 per cent of diclofenac or preparations for the treatment of solar keratosis in Schedule 4.

In February 2012, following advice from the October 2011 ACMS meeting, the delegate rescheduled dermal preparations containing more than 1 per cent up to 4 per cent or less of diclofenac, except when for the treatment of solar keratosis, to Schedule 2. The delegate also confirmed that Schedule 4 remained appropriate for preparations containing more than 4 per cent of diclofenac, that preparations containing 1 per cent or less of diclofenac would remain unscheduled and that preparations for use in solar keratosis would remain Schedule 4.

In February 2013, following advice from the October 2012 ACMS meeting, the delegate included transdermal preparations for topical use containing 140 mg or less of diclofenac in Schedule 2, with an implementation date of 1 May 2013.

In a final decision published in June 2013, the delegate considered a proposal to exempt diclofenac when presented in a transdermal drug delivery system containing 140 mg or less of diclofenac. The decision was that the current scheduling was appropriate, as there was no clinical or marketing experience with this formulation in Australia and that Schedule 2 allows for access to professional advice at the time of purchase.

Public pre-meeting submissions

One submission supported the proposal as topical diclofenac has a favourable safety profile and a 2 per cent product would be a convenient addition to the products already available on the market. The submitter doesn't believe that the increased percentage of diclofenac would have a negative impact on consumer safety and that harmonisation would minimise consumer confusion.

The second submission did not support the scheduling proposal on the grounds that increasing the strength to double what is currently exempt from scheduling would pose a risk to public health. They stated that the safety profile of NSAIDs, of which diclofenac is one, requires the supply of higher strength topical preparations to be managed by the pharmacy sector. Furthermore, warning and direction labels do not address concerns of misuse by consumers with poor health literacy, which can be addressed by access to a pharmacist. The submitter also raised concerns regarding the consideration of rescheduling applications on the basis of harmonisation between countries and feels that scheduling should be determined "on best available evidence reflecting quality use of medicines, with harmonisation very much a secondary consideration".

ACMS advice to the delegate

The ACMS recommended that the current scheduling of diclofenac remains appropriate.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: a) risks and benefits of the use of a substance.

The reasons for the recommendation comprised the following:

  • Formulation has not been available for wider community use.
  • Lack of evidence of safety from the wider use in the community.
  • Different dosing regimen from the current product, therefore access from a pharmacist is appropriate.
Delegate's consideration

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors1; and
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that the current scheduling of diclofenac remains appropriate. The delegate is in agreement with the ACMS as to why the current scheduling of diclofenac remains appropriate and notes that a diclofenac 2 per cent topical solution is a prescription medicine in the United States of America.

The delegate decided that the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989 include: a) the risks and benefits of the use of a substance and d) the dosage, formulation, labelling, packaging and presentation of a substance.

The delegate's reasons for the decision are:

  • Formulation has not been available for wider community use.
  • Lack of evidence of safety from the wider use in the community.
  • Different dosing regimen from the current product, therefore access from a pharmacist is appropriate.

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1.2 Naproxen

Scheduling proposal

The medicines scheduling delegate considered a proposal to amend the Schedule 2 entry for naproxen to include a modified release dosage form of 600 mg or less of naproxen per dosage unit in packs of 16 or less dosage units when labelled not for the treatment of children under 12 years of age.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance details

The chemical name of naproxen is (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid. Its molecular formula is C14H14O3 and molecular weight is 230.3 g/mole. It is an odourless, white to off-white crystalline substance which is lipid soluble, practically insoluble in water at low pH and freely soluble in water at high pH.

Naproxen, a propionic acid derivative related to the arylacetic acid class of medicines is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory and antipyretic properties. It is unrelated to salicylates and the corticosteroid hormones. Its indications include treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis; symptomatic treatment of primary dysmenorrhoea, and relief of acute and/or chronic pain states in which there is an inflammatory component and as an analgesic in acute migraine attack.

Both the naproxen base and the salt are rapidly and completely absorbed from the gastrointestinal tract, both circulating as the naproxen anion and the difference between them is that peak plasma levels of naproxen occur earlier following oral administration of naproxen sodium than naproxen. When administered as a sodium salt, naproxen sodium promptly dissolves in the gastric juice upon entering the stomach and immediately precipitates into fine particles of naproxen. The subsequent pharmacokinetics of the two formulations are identical. Steady state concentrations are achieved after four to five doses.

Poisoning with NSAIDs is not uncommon but rarely severe. In mild to moderate poisoning, gastrointestinal effects (e.g. dyspepsia, ulceration, bleeding) are most commonly reported. Renal dysfunction, most often in elderly patients, may occur. Mild central nervous system (CNS) effects include altered cognition, drowsiness, headache, and mood changes, especially in the elderly population. Severe poisoning is rare but can include CNS depression, hallucinations, seizures, renal failure, gastrointestinal bleeding, and metabolic acidosis.

Scheduling status

Naproxen is currently scheduled in Schedule 4 and in Schedule 2 and listed in Appendix F with warning statements 101 and 104.

Schedule 4

NAPROXEN except when included in Schedule 2.

Schedule 2

NAPROXEN in divided preparations containing 250 mg or less of naproxen per dosage unit in packs of 30 or less dosage units.

Appendix F, Part 3
Poisons Warning statements Safety direction
Naproxen

101 Don't use [this product/name of the product]:

  • If you have a stomach ulcer
  • In the last 3 months of pregnancy [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.]
  • If you are allergic to (name of substance) or anti-inflammatory medicines.

 

104 Unless a doctor has told you to, don’t use [this product/name of the product]:

 

  • For more than a few days at a time
  • With other medicines containing (name of substance) or other anti-inflammatory medicines
  • If you have asthma
  • If you are pregnant [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea].
Scheduling history

Naproxen first appeared in the Poisons Standard in June 1982 under Schedule 4. In February 1983, the Poisons Scheduling Committee (PSC) considered an application to reschedule naproxen from Schedule 4 to Schedule 3 when supplied in packs of 12 tablets for the treatment of the symptoms of dysmenorrhea. The committee noted the same decision was made in 1979 for a similar substance and the committee agreed that the toxicity, pharmacology and efficacy of naproxen indicated that it could be listed in Schedule 3.

The Department of Health Services, Tasmania, requested the PSC reconsider the Schedule 3 entry for naproxen in February 1985, after reports of massive internal bleeding occurred after ingesting the substance. The committee asked the secretary to contact the company and request sales information on both Schedule 3 and Schedule 4 products. It was noted in the November 1985 meeting that the company provided statistics to show there was not much evidence of this side effect and decided that the Schedule 3 entry should not be altered.

In November 1987, the committee noted that the Australian Drug Evaluation Committee (ADEC) would not support a Schedule 2 entry for naproxen.

A request for a Schedule 2 entry for naproxen sodium when labelled for the treatment of spasmodic dysmenorrhoea in packs of 12 or less was noted by the Drugs and Poisons Scheduling Committee (DPSC) in August of 1988. It was rejected as the submission had pages missing.

The request was resubmitted and discussed at the August 1989 committee meeting. The committee supported the Schedule 2 proposal on the grounds that it did not present an apparent public health hazard.

In November 1989, the committee considered a rescheduling application from Schedule 4 to Schedule 3 for naproxen. During this review, the committee noted strong anecdotal evidence of gastrointestinal bleeding caused by NSAIDs that had not been reported and which was at least partly dose-related. It also noted that there was little evidence to state that naproxen was more effective than aspirin or paracetamol; therefore there was no therapeutic gap to be filled by the substance. The members were not satisfied that the case for Schedule 3 was convincing and lacked evidence. The committee did not support the proposal.

In February 1991, Western Australian Health informed the committee that they would only accept the Schedule 2 entry for naproxen when labelled with an appropriate warning statement. The committee preferred the statement 'Warning - This medication may be dangerous when used in large amounts or for a long time'.

In November 1998, the NDPSC considered a proposal to amend the Schedule 2 entry to include packs of 10 tablets, each containing 220 mg of naproxen for short term pain management. Public submissions supported a Schedule 3 entry to address concerns over inappropriate use. ADEC stated that product information and labels should provide warning statements and indicate short-term use only. The members stated that incidence of gastrointestinal issues associated with naproxen was not greater than with ibuprofen and aspirin. The committee decided that a Schedule 3 entry for the indicated use was more appropriate along with Appendix F warning statement 71. The Schedule 2 entry was amended to allow preparations containing 250 mg or less per dosage unit in packs of 20 or less dosage units.

In November 1999, the committee agreed to reschedule the Schedule 3 entry to Schedule 2 after considering the safety data was similar to that of other NSAIDs already listed in Schedule 2. The NZ member advised that their committee had made a similar decision on the same grounds. The Appendix F warning was to be linked to the Schedule 2 entry.

In February 2000, the committee received comments regarding the perceived inadequacy of labelling for naproxen. The committee decided to await the outcome of a review of product labelling being conducted by the TGA before making decisions regarding changes to labelling.

In August 2001, the committee considered a proposal to exempt naproxen when in 250 mg or less per dosage unit, in packs of 24 or less dosage units, for the short-term analgesic therapy of dysmenorrhoea. While the committee noted a number of key points justifying the proposal, a number of public submissions did not support it on the grounds of maintaining access to professional advice. The evaluation report did not support the proposal due to a lack of evidence regarding safety and the need to be able to access advice and counselling. A Committee member raised concerns on potential misuse of the product, as it may be used routinely for headache rather than dysmenorrhoea. Another concern was that if a product was granted an unscheduled status based on one indication (i.e. for dysmenorrhoea), while the same product remained in S2 for all other indications, and the trade name remained unchanged as proposed, then it would be likely that consumers would use the product routinely for general pain relief. The committee decided that the Schedule 2 entry remained appropriate.

In June 2003, a review of non-prescription analgesics was carried out, mainly in regards to proposed warning statements for inclusion in Appendix F. Outcomes of the review were provided, but the committee felt that further consultation with industry was required. The committee agreed to transitional arrangements in October 2003, supporting the outcome of the review. Warning statements 101 and 104 were to come into effect 1 May 2005.

In October 2004, the committee reviewed the warning statements for NSAIDs. Concerns were raised regarding warning statement 101 not warning against use in patients with a history of stomach ulcers and 104 did not warn against use in elderly patients. The committee discussed the advice sought from the Medicines Evaluation Committee (MEC) and comments received from the Gastroenterological Society. The committee decided it was preferable for the MEC to consider the comments from the Gastroenterological Society and for the MEC to make the necessary labelling changes.

In June 2007, the NDPSC considered a proposal to apply a maximum daily dose restriction to the Schedule 2 entry for Naproxen. This issue arose when it was noted that naproxen didn’t have a maximum daily dose restriction when considering entries for similar substances which did have restrictions. It was felt that this inconsistency needed to be addressed. Public submissions supported the proposal, so that NSAIDs entries could be consistent and provided suggested cut off limits. The Committee discussed this and felt that the regulator would have assessed this data in allowing the current maximum daily doses to be set as part of their registered indications. It was felt that that there was no requirement for the Committee to pursue consistency for consistency's sake and therefore did not support the proposal.

It was noted in June 2008 that the scheduling entry for naproxen was essentially harmonised between Australia and New Zealand.

Public pre-meeting submissions

Four public pre-meeting submissions have been received. Two submissions support the scheduling proposal, with one submission providing evidence that the pharmacokinetic profile of the dosage form being considered as a part of this scheduling proposal is similar to products that meet the Schedule 2 naproxen listing. The other submission supported the proposal on the grounds that naproxen has as a well-documented safety profile, is safe for short-term use and has a low risk of inappropriate use. This submission also mentioned that a once daily dose would be considered a useful alternative to current multi dose products for consumers.

The other two submissions did not support the Schedule 2 proposal, instead suggesting that a Schedule 3 entry would be better suited for the proposal. Both highlighted that the proposal being considered more than doubles the amount of naproxen currently available without direct oversight from a health professional and that the use of naproxen can lead to a high risk of adverse gastrointestinal outcomes. The two submitters felt that health professional involvement should be required for a 600 mg of naproxen in a modified release dosage form product to ensure that consumers are well informed about the product. One submission noted that, as a Schedule 2 product, it could be sold in a non-pharmacy environment in a regional area where a pharmacist or health professional is not readily available, increasing the potential risk of adverse events.

ACMS advice to the delegate

The ACMS recommended that a new Schedule 3 entry for naproxen when in a modified release dosage form of 600 mg or less of naproxen per dosage unit in packs of 16 or less dosage units when labelled not for the treatment of children under 12 years of age and amend the current Schedule 4 entry. The committee also recommended to the delegate that the current Appendix F warning for naproxen should apply to this new dosage form.

The ACMS recommended an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: a) risks and benefits of the use of a substance and d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  • With the new dosage formulation there is a need for familiarity for both health practitioners and consumers particularly in view of the risk of use of multiple analgesics concurrently. Advice from the pharmacist is warranted at this stage.
  • The advice of a pharmacist is necessary to ensure patients use the lowest effective dose for the shortest period of time.
Delegate's consideration

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Evaluation report (not publically available);
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors2; and
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that a new Schedule 3 entry for naproxen when in a modified release dosage form of 600 mg or less of naproxen per dosage unit in packs of 16 or less dosage units when labelled not for the treatment of children under 12 years of age and amend the current Schedule 4 entry. The interim decision also is that the current Appendix F warning for naproxen should apply to this new dosage form.

The interim decision is to have an implementation date of 1 October 2014

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: a) risks and benefits of the use of a substance and d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the interim decision include those of the ACMS being:

  • With the new dosage formulation there is a need for familiarity for both health practitioners and consumers particularly in view of the risk of use of multiple analgesics concurrently. Advice from the pharmacist is warranted at this stage.
  • The advice of a pharmacist is necessary to ensure patients use the lowest effective dose for the shortest period of time.

Also the advice of the pharmacists would enhance the quality use of this medicine such that inappropriate use of naproxen ER for more transient pain does not occur, where there are many more appropriate shorter acting alternatives.

Scheduling entry
Schedule 3 - New entry

NAPROXEN in a modified release dosage form of 600 mg or less of naproxen per dosage unit in packs of 16 or less dosage units when labelled not for the treatment of children under 12 years of age.

Schedule 4 - Amendment

NAPROXEN except when included in Schedule 3 or in Schedule 2.

Appendix F, Part 3
Poisons Warning statements Safety direction
Naproxen

101 Don't use [this product/name of the product]:

  • If you have a stomach ulcer
  • In the last 3 months of pregnancy [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.]
  • If you are allergic to (name of substance) or anti-inflammatory medicines.
-

104 Unless a doctor has told you to, don’t use [this product/name of the product]:

  • For more than a few days at a time
  • With other medicines containing (name of substance) or other anti-inflammatory medicines
  • If you have asthma
  • If you are pregnant [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea].
-

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1.3 Perampanel

Scheduling proposal

The medicines scheduling delegate considered a proposal for a new Schedule 8 entry for perampanel and possible inclusion in Appendix D, Item 1.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance details

Perampanel is a first-in-class selective, non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on post-synaptic neurons. It has been proposed for adjunctive treatment of partial-onset seizures.

Scheduling status

Perampanel is a new chemical entity and therefore it is not currently scheduled.

Scheduling history

Perampanel is a new chemical entity and therefore scheduling history is not available.

Public pre-meeting submissions

One submission was received, which did not support the scheduling proposal. The submission provided data which does not show a potential risk of abuse and dependency with perampanel. Therefore, the submitter states that the scheduling of the substance should be consistent with other anti-epileptic drugs (AEDs), which are classified as Schedule 4. A Schedule 4 entry for perampanel is consistent with the scheduling status in Europe, Canada and Switzerland. The submission also notes that a recent European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) report of 6 February 2014 concluded "that there is insufficient evidence for an association between Fycompa use and drug abuse, dependency and withdrawal".

ACMS advice to the delegate

The ACMS recommended that perampanel be included in Schedule 4 with an Appendix D, Item 5 entry, as well as an entry in Appendix K.

The ACMS recommended an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee 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 and e) the potential for abuse of a substance.

The reasons for the recommendation comprised the following:

  • Benefits as an adjunctive treatment for seizures outweigh the risks.
  • Medical diagnosis, management and monitoring are required.
  • Close clinical monitoring is required. Toxicity is dose related. Potential for sedation.
  • At therapeutic doses there is a moderate propensity for misuse, abuse or illicit use. Not dissimilar to other substances in Schedule 4.
Delegate's consideration

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors3 ; and
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that perampanel be included in Schedule 4 with an Appendix D, Item 5 entry, as well as an entry in Appendix K.

The interim decision is to have an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: a) risks and benefits of the use of a substance; b) the purpose for which a substance is to be used and the extend of use of a substance; c) the toxicity of a substance and e) the potential for abuse of a substance.

Reasons for the interim decision include those from ACMS being:

  • Benefits as an adjunctive treatment for seizures outweigh the risks.
  • Medical diagnosis, management and monitoring are required.
  • Close clinical monitoring is required. Toxicity is dose related. Potential for sedation.
  • At therapeutic doses there is a moderate propensity for misuse, abuse or illicit use. Not dissimilar to other substances in Schedule 4.

As well as the following reasons:

  • Consistency with other overseas jurisdictions including Europe.
  • Little to no evidence regarding its abuse.
  • An Appendix D Item 5 listing brings a further control beyond Schedule 4.
  • Appendix K listing acknowledges the requirement for a sedation warning.
Scheduling entry
Schedule 4 - New entry

PERAMPANEL

Appendix D - New entry

5. Poisons for which possession without authority is illegal (e.g. possession other than in accordance with a legal prescription). PERAMPANEL for human use.

Appendix K - New entry

Drugs required to be labelled with a sedation warning

PERAMPANEL

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1.4 Sodium oxybate

Scheduling proposal

The medicines scheduling delegate considered a proposal to include sodium oxybate for human therapeutic use in Schedule 8 and in Appendix D, Item 1.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance details

Sodium oxybate (Xyrem) is the sodium salt of gamma hydroxybutyrate (GHB) and is a central nervous system depressant that reduces daytime sleepiness and cataplexy in patients with narcolepsy. The chemical name for sodium oxybate is sodium 4-hydroxybutyrate. The molecular formula is 4H7NaO3, and the molecular weight is 126.09 g/mole.

Sodium oxybate is a white to off-white, crystalline powder that is very soluble in aqueous solutions. Each millilitre of Xyrem contains 0.5 g of sodium oxybate in USP Purified Water, neutralized to pH 7.5 with malic acid.

Scheduling status

Sodium oxybate is not specifically scheduled in the SUSMP. However, it is a derivate of the Schedule 9 entry for 4-hydroxybutanoic acid and its salts. The entry also includes the name GHB.

Scheduling history

In November 1991, Victoria Health wrote to the Drugs and Poisons Scheduling Sub-Committee (DPSSC) requesting that consideration be given to the scheduling of sodium oxybate (gamma hydroxybutyrate) after reports from the USA indicated potential for misuse and serious side effects. The committee felt that more information was required and sought further information from the Drugs of Dependence (DOD) branch, the TGA and State/Territory DPSSC members.

At the May 1992 meeting, the committee noted that gamma-hydroxybutyrate (sodium oxybate) was being used in conjunction with illicit amphetamines and being used as a substitute for anabolic steroids by the fitness/bodybuilding industry. It was also reported that GHB was being sold as 'Fantasy' in night clubs at $80 for 5 grams. As the substance had no approved therapeutic use or safety assessment, the committee felt that scheduling was not appropriate and suggested the DOD branch make the substance a prohibited import.

GHB was on the agenda again in November 1994, where the committee recommended the matter be referred to the Ministerial Committee on Drug Strategy, after it was noted that it was a substance of concern to the Australian Bureau of Criminal Intelligence because of substance related deaths in the USA.

According to the November 1996 meeting minutes, the committee approved an out of session Schedule 9 proposal for sodium oxybate, which was the new entry of 4-hydroxybutanoic acid. Concerns were raised that the entry may inadvertently capture derivatives that were not of concern. The committee decided to amend the entry so that salts of 4-hydroxybutanoic acid that could be subject to abuse were clearly captured by the entry.

In June 2002, when the committee considered gamma-butyrolactone (GBL) as a possible derivate of the GHB entry, the 4-hydroxybutanoic acid entry was reviewed. The outcome was that the current scheduling of 4-hydroxybutanoic acid is consistent with the committee's intent to exclude other derivatives of 4-hydroxybutanoic acid, except its salts, from the requirements of scheduling, as they are appropriately controlled through other State and Territory mechanisms. Therefore, GBL remained unscheduled.

While the scheduling of 4-hydroxybutanoic acid and it’s salts was not reviewed in June of 2003, information was provided regarding the entry formed part of a consideration to schedule 1,4-butanediol and related analogues and metabolic precursors - mainly in relation to what substances are precursors/analogues to GHB and how they were currently being controlled.

Public pre-meeting submissions

Eleven pre-meeting submissions were received from the public. All were in favour of the decision to include sodium oxybate in Schedule 8, citing the potential health benefits it could bring to sufferers of narcolepsy and cataplexy. A majority of the submitters feel that the benefit of the substance outweighs the risks that sodium oxybate potentially poses. A number of the submissions outline side-effects and issues associated with current medication used to treat individuals who have been diagnosed with narcolepsy and cataplexy.

ACMS advice to the delegate

The ACMS recommended that sodium oxybate for human therapeutic use be included in Schedule 8 and in Appendix D, Item 1.

The ACMS recommended an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: a) risks and benefits of the use of a substance.

The reasons for the recommendation comprised the following:

  • Recognition of the therapeutic use warrants listing in Schedule 8 to enable prescription with appropriate supervision.
Delegate's consideration

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Evaluation report (not publically available);
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors4; and
  • Other relevant information.
Delegate's interim decision

The interim decision is that sodium oxybate for human therapeutic use be included in Schedule 8 and in Appendix D, Item 1, with the Schedule 9 GHB entry amended accordingly.

The interim decision is to have an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate: a) risks and benefits of the use of a substance; b) the purpose for which a substance is to be used and the extent of use of a substance and e) the potential for abuse of a substance.

The reasons include:

  • Sodium oxybate is currently available in the United States of America and in the European Union solely for the treatment of narcolepsy, sleep fragmentation and catalepsy.
  • The product Xyrem is safe and efficacious at the therapeutic dose of 9 grams and when dispensed at its therapeutic dose, abuse of the substance is low.
  • United Nations Convention on Psychotropic Substances made a decision to transfer GHB from Schedule IV to Schedule II of the 1971 Convention.
  • Recognition of the therapeutic use warrants listing of Schedule 8 to enable prescription with appropriate supervision.
  • Inclusion in Appendix D Item 1 provides further controls above those required for Schedule 8 medicines alone.
Scheduling entry
Schedule 8 - New entry

SODIUM OXYBATE for human therapeutic use.

Schedule 9 - Amendment

4-HYDROYXBUTANOIC ACID and its salts except for sodium oxybate when in Schedule 8. *(GAMMA HYDROXYBUTYRATE (GHB)).

Appendix D - New entry

1. Poisons available only from or on the prescription or order of an authorised medical practitioner.

SODIUM OXYBATE for human use.

Footnotes

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