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Scheduling delegate's interim decisions and invitation for further comment: ACMS, February 2015

4 February 2015

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Interim decisions on matters referred to an expert advisory committee: ACMS February 2015: (1.1-1.6)

1. Scheduling proposals referred to the November 2014 meeting of the Advisory Committee on Medicines Scheduling (ACMS #13)

1.1 Performance and image enhancing drugs (PIEDS)

Scheduling proposal

To include new entries for Growth Hormone Releasing Hormones and Analogues (GHRHs), Growth Hormone Secretagogues (GHSs), Growth Hormone Releasing Peptides (GHRPs) and Growth Hormone Variants, as well as new individual substance entries for CJC-1295, ipamorelin, GHPR-2, GHPR-6, hexarelin and AOD-9604 in Schedule 4 and Appendix D.

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

Substance summary

This application includes Growth Hormone Releasing Peptides (GHRP), a class of compounds, which stimulate the release of growth hormone. GHRP variants include GHRP-2, GHRP-6, hexarelin, ipamorelin (Thomas et al. 2011) and agents with similar actions including CJC-1295 (Teichman et al. 2006, Acherman et al, 1999, Walker et al. 2006). These agents are considered peptide hormones. GHRPs are thought to act by stimulating the release of endogenous human growth hormone leading to pharmacological effects such as increased bone mineral density, increased lean muscle mass, modest improvements in strength and improved recovery from injuries such as fractures (Smith, 2005).

Scheduling status

The substances are not currently scheduled.

Scheduling history

These substances not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

Two submissions were received, both in relation to AOD-9604. One submission did not comment on the scheduling proposal, but wished to inform the committee that the substance is an ingredient in cosmetic products being sold overseas, has an International Nomenclature Cosmetic Ingredient (INCI) name of 27701 sh-Oligopeptide-74 and is published in the International Cosmetic Ingredient Dictionary and Handbook as well as the International Buyer's Guide.

The other submission commented on the consideration to place AOD-9604 in Appendix D. The submission supported listing in Schedule 4, but raised concerns that listing the substance in Appendix D would limit any future development work, including clinical trials that are currently being conducted on the substance. The submitter notes that there are currently 5 clinical trials notified to the TGA using this substances, with these approved clinical trials going ahead on the basis that the substance is safe for human use. Inclusion in Appendix D may place unnecessary burden on those conducting these clinical trials.

ACMS advice to the delegate

The ACMS recommended that Growth Hormone Releasing Hormones (GHRHs), Growth Hormone Secretagogues (GHSs), Growth Hormone Releasing Peptides (GHRPs) as well as new individual substance entries for CJC-1295, ipamorelin, pralmorelin (Growth Hormone Releasing Peptide-2), Growth Hormone Releasing Peptide-6, hexarelin and AOD-9604 be included in Schedule 4.

The ACMS recommended listing Growth Hormone Releasing Hormones (GHRHs), Growth Hormone Secretagogues (GHSs), Growth Hormone Releasing Peptides (GHRPs) as well as new individual substance entries for CJC-1295, ipamorelin, pralmorelin (Growth Hormone Releasing Peptide-2), Growth Hormone Releasing Peptide-6, hexarelin and AOD-9604 in Appendix D, Item 5. The ACMS recommended an implementation date of 1 June 2015.

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; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • There is limited information on the risks and benefits of the substances as there has been minimal use under appropriate medical supervision. Risks from misuse are considered to be similar to those associated with the misuse of growth hormone.
  • There is increasing evidence that the PIEDs are being advertised to attract a number of user markets including:
    • Strength enhancement/muscle enhancement
    • Anti-ageing
    • Fat loss
    • Injury rehabilitation
    • Libido enhancement
    • Growth hormone deficiency
  • There is the potential for the side effects associated with use of growth hormone when growth hormone secretagogues are used, particularly if the use is not under medical supervision. There are limited data on the safety of intravenous and subcutaneous use of AOD-9604 and on the long-term oral use of AOD 9604 in doses in excess of those used in clinical trials.
  • Many of the substances are injected. This carries additional risks compared with other routes of administration. Injections need to be administered by persons who use appropriate infection control procedures.
  • There is misuse of the substances in sport and by body builders.
  • There is evidence of involvement of organised crime in supply of the substances. The substances are offered for sale via the internet. Many of the substances are promoted as safe alternatives to traditional performance enhancing substances such as the anabolic steroids. Suppliers are making unproven assertions about the efficacy and safety of the substances.
Delegate's considerations

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;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is to include in Schedule 4 and in Appendix D Item 5 Growth Hormone Releasing Hormones (GHRHs), Growth Hormone Secretagogues (GHSs), Growth Hormone Releasing Peptides (GHRPs) as well as new individual substance entries for CJC-1295, ipamorelin, pralmorelin (Growth Hormone Releasing Peptide-2), Growth Hormone Releasing Peptide-6, hexarelin and AOD-9604.

The proposed implementation date is 1 June 2015.

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; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • The long-term safety of PIEDs is not established. The potential adverse effects may include those associated with administration of growth hormones.
  • PIEDs have the potential for downstream health effects such as adverse cardiovascular and hormonal effects.
  • AOD-9604 was initially developed as an anti-obesity drug, but the obesity program was discontinued in 2007 as the clinical trials did not show a meaningful weight loss outcome across the trial population. AOD-9604 is now being investigated in Phase II trials for cartilage repair.
  • The limited safety data on AOD-9604 do not provide evidence that repeated intravenous or subcutaneous injections are safe or that long term use of oral doses in excess of those used in the clinical trials are safe.
  • Scheduling of the substances would help ensure there is appropriate medical supervision of use and may make the substances more difficult to obtain without a lawful purpose.
  • There is evidence of misuse of these substances.
  • It would be appropriate that they are listed in Item 5 of Appendix D similar to anabolic and androgenic steroid hormones etc.
  • There is limited information on the risks and benefits of the substances as there has been minimal use under appropriate medical supervision. Risks from misuse are considered to be similar to those associated with the misuse of growth hormone.
  • There is increasing evidence that the PIEDs are being advertised to attract a number of user markets including:
    • Strength enhancement/muscle enhancement
    • Anti-ageing
    • Fat loss
    • Injury rehabilitation
    • Libido enhancement
    • Growth hormone deficiency
  • There is the potential for the side effects associated with use of growth hormone when growth hormone secretagogues are used, particularly if the use is not under medical supervision. There are limited data on the safety of intravenous and subcutaneous use of AOD-9604 and on the long-term oral use of AOD 9604 in doses in excess of those used in clinical trials.
  • Many of the substances are injected. This carries additional risks compared with other routes of administration. Injections need to be administered by persons who use appropriate infection control procedures.
  • There is misuse of the substances in sport and by body builders.
  • There is evidence of involvement of organised crime in supply of the substances. The substances are offered for sale via the internet. Many of the substances are promoted as safe alternatives to traditional performance enhancing substances such as the anabolic steroids. Suppliers are making unproven assertions about the efficacy and safety of the substances.
Scheduling proposal
Schedule 4 - New entries

AOD-9604 (CAS No. 221231-10-3)

CJC-1295 (CAS No. 863288-34-0)

PRALMORELIN ((GROWTH HORMONE RELEASING PEPTIDE-2) (GHRP-2))

GROWTH HORMONE RELEASING PEPTIDE-6 (GHRP-6)

GROWTH HORMONE RELEASING HORMONES (GHRHs)

GROWTH HORMONE RELEASING PEPTIDES (GHRPs)

GROWTH HORMONE SECRETAGOGUES (GHSs)

HEXARELIN

IPAMORELIN.

Appendix D Item 5 - New entries

AOD-9604 (CAS No. 221231-10-3)

CJC-1295 (CAS No. 863288-34-0)

PRALMORELIN ((GROWTH HORMONE RELEASING PEPTIDE-2) (GHRP-2))

GROWTH HORMONE RELEASING PEPTIDE-6 (GHRP-6)

GROWTH HORMONE RELEASING HORMONES(GHRHs) including those separately specified in Schedule 4.

GROWTH HORMONE RELEASING PEPTIDES (GHRPs) including those separately specified in Schedule 4.

GROWTH HORMONE SECRETAGOGUES (GHSs) including those separately specified in Schedule 4.

HEXARELIN

IPAMORELIN

1.2 Paracetamol/caffeine

Scheduling proposal

To amend Schedule 2 entry to exempt paracetamol when compounded with caffeine, in a powder or granule product containing 1000mg or less of paracetamol and in tablets or capsules containing 500mg or less of paracetamol when paracetamol is the only therapeutic active constituent and when supplied in primary packs of not more than 20 tablets/caplets or 10 sachets of powders/granules.

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

Substance summary

Paracetamol is used worldwide for its analgesic and antipyretic actions and has been available in Australia since 1956. Caffeine is a stimulant and acts as an analgesic adjuvant, whereby it augments the analgesic effects of pain relievers such as paracetamol. The combination of Paracetamol/caffeine (2x500mg/65mg) is indicated for temporary relief of pain and discomfort associated with headaches, tension headaches, osteoarthritis, arthritis, cold and flu symptoms, toothache, dental procedures, muscular aches, sore through and period pain. It also reduces fever.

Paracetamol/caffeine formulations have a long-established safety and efficacy profile over 25 years of use as an open-sale medicine in major markets around the world. The paracetamol/caffeine combination analgesic was registered as a schedule 2 product in Australia and has been marketed since 2010. Since that time no new significant issues or potential risks have been reported.

Both paracetamol and caffeine are regarded as being well tolerated when used at therapeutic doses and there is a low risk of serious expected or serious unexpected adverse events with these products when taken either alone or in combination. Clinical data demonstrate that paracetamol combined with caffeine significantly out performs paracetamol alone. Paracetamol/caffeine formulations are well established globally. Such formulations are marketed in over 90 countries and have been available unscheduled ranging from 14 years to 25 years. Cumulative post-marketing experience to date with the sponsor's paracetamol/caffeine combination products is estimated to be in excess of 488 million patients and has revealed no adverse safety signals or reasons for concern with the use of this produce in an open sale environment.

Evidence review and acceptance by the NDPSC in 2007, demonstrated that paracetamol/caffeine combination analgesics has a very low risk of nephrotoxicity. Similarly, the combination analgesics pose a very low risk of toxicity in overdosing with only two fatal cases reported in the USA. However, these involved other medications in addition to paracetamol/caffeine with the latter being available in very large pack sizes. Further, there are no known contraindications to the paracetamol/caffeine combination apart from hypersensitivity to the constituents.

Scheduling status

Paracetamol is currently listed in Schedule 2.

Schedule 2

PARACETAMOL for therapeutic use except:

  1. when included in Schedule 4;
  2. in individually wrapped powders or sachets of granules each containing 1000 mg or less of paracetamol as the only therapeutically active constituent (other than phenylephrine and/or guaiphenesin or when combined with effervescent agents) when:
    1. enclosed in a primary pack that contains not more than 12 such powders or sachets of granules;
    2. compliant with the requirements of the Required Advisory Statements for Medicine Labels;
    3. not labelled for the treatment of children 6 years of age or less; and
    4. not labelled for the treatment of children under 12 years of age when combined with phenylephrine and/or guaiphenesin; or
  3. in tablets or capsules each containing 500 mg or less of paracetamol as the only therapeutically active constituent (other than phenylephrine and/or guaiphenesin or when combined with effervescent agents) when:
    1. packed in blister or strip packaging or in a container with a child-resistant closure;
    2. in a primary pack containing not more than 25 tablets or capsules;
    3. compliant with the requirements of the Required Advisory Statements for Medicine Labels;
    4. not labelled for the treatment of children 6 years of age or less; and
    5. not labelled for the treatment of children under 12 years of age when combined with phenylephrine and/or guaiphenesin.
Scheduling history

In Australia, the phenacetin ban was followed, in 1977, by a re-scheduling of all analgesic combinations containing two or more of paracetamol, aspirin, salicylamide or caffeine to Schedule 4 on the recommendation of the National Health and Medicine Research Council.

The scheduling of paracetamol and caffeine when combined in a compound analgesic as the only two active ingredients was amended from Schedule 4 to Schedule 2 by the NDPSC at its 50th Meeting in June 2007. Evidence reviewed by the Committee at that time conclusively demonstrated that the key ingredient in terms of analgesic overuse and nephropathy was phenacetin and not caffeine.7-11 It was agreed that the indications for use, safety profile and potential for misuse met the criteria for a Schedule 2 medicine.

At that time this decision was made, paracetamol/caffeine combinations were available over-the-counter in over 50 other countries and had been exempt from scheduling in a number of major markets that are similar to Australia in terms of population type and regulatory status. Experience with the unscheduled sale of this product was extensive: UK 19 years, Ireland 12 years and New Zealand for 7 years. However, the Committee determined not to consider paracetamol combined with caffeine for exemption from scheduling until market experience has been gained with use as a Schedule 2 product in Australia.

The scheduling of paracetamol and caffeine when combined in a compound analgesic as the only active ingredients was again reviewed by the NDPSC at its 57th Meeting in October 2009 after the Committee had received a request to reconsider the scheduling on the grounds of potential toxicity if used in excess. This issue had been extensively reviewed at the June 2007 meeting and it was decided that Schedule 2 remained appropriate.

Pre-meeting public submissions

Six public submissions were received. Five of the submissions did not support the proposal while the sixth submission did. The former contend that potential risks of inadvertent use of caffeine in those at risk of an adverse event will be increased if selection of an analgesic is made without the assistance or intervention of a healthcare professional. There was also concern that the proposed exemption may result in an increase in liver damage due to excessive consumption of such a product. This was likely to result from people abusing these products as a source of stimulants.

ACMS advice to the delegate

The ACMS recommended that the current scheduling of paracetamol when compounded with caffeine remains appropriate.

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; d) the dosage, formulation, labelling, packaging and presentation of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • Potential risk of harm through excessive unintentional use of caffeine.
  • No strong argument for increasing availability.
  • Concern of the product being used with other caffeine containing products and concern about the toxicity of the combination in intentional overdose.
  • Preference for combination analgesics to only be available where professional advice is available.
  • There was not a supported argument for public health benefit. Risk of consumer confusion without access to advice.
Delegate's considerations

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 factors2;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is the interim decision is that the current scheduling of paracetamol when compounded with caffeine remains appropriate.

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; and d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  • Potential risk of harm through excessive unintentional use of caffeine.
  • No strong argument for increasing availability.
  • Concern of the product being used with other caffeine containing products and concern about the toxicity of the combination in intentional overdose.
  • Preference for combination analgesics to only be available where professional advice is available.
  • There was not a supported argument for public health benefit.
  • Risk of consumer confusion without access to advice.
  • Risk of consumer confusion regarding their caffeine intake from multiple sources, given that many caffeine-containing products (including foods, drinks and dietary supplements, as well as medicinal products) are freely available to consumers.

1.3 Paracetamol/ibuprofen

Scheduling proposal

To amend Appendix H to include a new entry for paracetamol/ibuprofen.

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

Substance summary
Ibuprofen

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used in the management of mild to moderate pain and inflammation in conditions such as dysmenorrhoea, headache including migraine, post-operative pain, dental pain, musculoskeletal and joint disorders such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis including juvenile idiopathic arthritis, peri-articular disorders such as bursitis and tenosynovitis, and soft tissue disorders such as sprains and strains. It is also used to reduce fever.

Paracetamol

Paracetamol is a p-aminophenol derivative that inhibits analgesic and antipyretic effects and weak anti-inflammatory activity. Paracetamol is used for the relief of mild to moderate pain.

Scheduling status

Paracetamol combined with ibuprofen is listed in Schedule 4 and Schedule 3.

Schedule 4

PARACETAMOL:

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

PARACETAMOL when combined with ibuprofen in a primary pack containing 30 dosage units or less.

Scheduling history

In June 2010, the National Drugs and Poisons Schedule Committee (NDPSC) considered the scheduling of paracetamol in combination with ibuprofen. Paracetamol preparations containing 500 mg or less of paracetamol as the only therapeutically active constituent (other than phenylephrine, effervescent agents or guaiphenesin) in packs of 25 or less were exempt from scheduling. However, when these preparations were combined with another therapeutically active ingredient they became Schedule 2. The NDPSC considered that the Schedule 2 entry remained appropriate, but noted the possibility that more robust evidence of additional risk could come to light through any application for product approval with the Therapeutic Goods Administration. The delegate confirmed the NDPSC's decision and the reasons for the decision in August 2010.

The medicines delegate referred the proposal to upschedule paracetamol/ibuprofen from Schedule 2 to Schedule 3 to the Advisory Committee on Medicines Scheduling (ACMS) in early 2011. The proposal was submitted by the Advisory Committee on Non-Prescription Medicines (ACNM) as they were currently assessing a product in which the sponsor did not satisfactorily establish the efficacy and safety of the product and that public health concerns raised during the assessment of the product could be addressed by access to a pharmacist. AFT Pharmaceuticals had submitted a product application with the TGA at the time of this item being considered by the delegate and ACMS.

The ACMS recommended that paracetamol/ibuprofen be rescheduled from Schedule 2 to Schedule 3 and the delegate agreed with this recommendation for the following reasons:

  • There were concerns regarding the number of contraindications and precautions and whether consumers would be able to interpret these appropriately without a requirement for pharmacist advice. There were concerns regarding gastro-intestinal, renal and other adverse effects related to the potential interactions of ibuprofen and paracetamol. Also raised were concerns regarding the potential for paracetamol overdose.
  • a lack of toxicity and clinical safety data for the combination. There was insufficient meaningful post-marketing data to ensure safe use without the need to consult with a pharmacist or GP.

In October 2012 the ACMS provided the medicines delegate with their recommendation to refuse the proposals to down-schedule paracetamol/ibuprofen for pack sizes of 12 units or less and to include paracetamol when combined with ibuprofen in Appendix H. The delegate agreed for the following reasons:

  • Safety concerns with this combination since 2009 and that there had not been enough data provided to disprove these concerns.
  • Lack of evidence to support rescheduling to Schedule 2. The Scheduling Policy Framework scheduling factors for Schedule 2 had not been satisfied, especially in relation to the risk profile of the product.
  • Additive gastro-intestinal side effects.
  • Concern about lack of professional intervention for this combination product to ensure safe and effective use.
  • Concern with the lack of long-term evidence.
  • Therapeutically sub-optimal combination.
  • Potential for inadvertent misuse.
  • No public benefit.
  • No experience with the use of the product in Australia.

Inclusion of paracetamol in combination with ibuprofen in Appendix H did not have any public health benefit resulting from any promotional activities that could be quantified and that advertising of the product could potentially lead to inappropriate medication use.

Pre-meeting public submissions

Four public submissions were received.

Two submissions supported the proposal as advertising was considered to bring important benefits in terms of better information for consumers on the availability of a combination product with rapid and effective pain relief and reduced doses of analgesic. Responsible advertising will alert consumers that combination products are available from pharmacies with advice from the pharmacist. One submission opposed the proposal as it was believed that there would be no benefit to the consumer by amending Appendix H to include a new entry for paracetamol/ibuprofen.

One submission requested the involvement of the pharmacy profession in the development of any advertisement or promotional material should the proposal be approved.

The final submission, though not opposed to the proposal, considered that some risks needed to be taken into consideration and mitigated where possible prior to listing on Appendix H being approved.

ACMS advice to the delegate

The ACMS recommended that the current scheduling of paracetamol when combined with ibuprofen remains appropriate.

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; and f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • Public health risk from advertising is that it would be seen as first line therapy

The argument raised for Appendix H was to transfer demand from codeine combination analgesics to non-codeine combination analgesics - there was inadequate evidence to substantiate this claim.

Delegate's considerations

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;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that the current scheduling of paracetamol when combined with ibuprofen remains appropriate. 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; and f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • There are concerns regarding safety of paracetamol-ibuprofen combinations, particularly with respect to gastrointestinal bleeding (in comparison with ibuprofen alone) and perhaps renal adverse effects. Some pre-submissions indicated that paracetamol-ibuprofen combinations should not be not first line therapy for pain relief.
  • The argument raised for Appendix H was to transfer demand from codeine combination analgesics to non-codeine combination analgesics - there was inadequate evidence to substantiate this claim.
  • Pharmacists can recommend a paracetamol-ibuprofen combination product to consumers who request a Schedule 3 codeine-combination analgesic for pain relief. It is considered that more effective promotion of paracetamol-ibuprofen combination analgesic products to pharmacists would be more beneficial than advertising to consumers.

1.4 Paracetamol/phenylephrine

Scheduling proposal
  • To include the following in Schedule 3:
    • 500 mg of paracetamol when combined with more than 2.5 mg phenylephrine per tablet or capsule or caplet
    • Individually wrapped powders or sachets of granules containing paracetamol 1000 mg and more than 5 mg phenylephrine per dose
  • To include in the following in Schedule 2:
    • 500 mg of paracetamol when combined with 2.5 mg phenylephrine or less per tablet or capsule or caplet in packs containing more than 20 tablets or capsules or caplets per pack
    • Individually wrapped powders or sachets of granules containing paracetamol 1000 mg and 5 mg phenylephrine or less per dose in packs containing more than 10 such powders or sachets
  • To exempt from scheduling the following:
    • 500 mg of paracetamol when combined with 2.5 mg phenylephrine or less per tablet or capsule or caplet in packs containing 20 or less tablets or capsules or caplets per pack
    • Individually wrapped powders or sachets of granules containing paracetamol 1000 mg and 5 mg phenylephrine or less per dose in packs containing 10 or less such powders or sachets.

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

Substance summary
Paracetamol

Paracetamol is distinct from non-steroidal anti-inflammatory drugs (NSAIDs). It is a para-acetylaminophenol with both analgesic and antipyretic properties. Originally synthesized in the 1880s and first released for use on prescription in 1955 in the USA and on 1956 in UK. It has been available in most countries, without prescription, for many years. Recent data suggests it acts via a central mechanism, whereby it is deacetylated to 4-aminophenyl and then conjugated with arachidonic acid to form N-arachidonoylphenylamine which is an exogenous cannabinoid (Hogestatt ED et al. 2005).

Paracetamol has long been considered very safe, without the risks of gastric injury associated with aspirin and NSAIDs. But there are distinct risks of liver injury, usually following overdose situations. In response many international regulatory authorities have taken steps to reduce the pack sizes of paracetamol, and to restrict release in some environments to pharmacies. In the USA, FDA has required prescription acetaminophen, when it is usually combined with an opioid, to reduce the dose per dose unit to 325 mg, but without reducing the maximal daily dose. No change of dosing in the USA has yet come for OTC acetaminophen. Use of paracetamol should be kept to a minimum in patients with underlying liver and renal disease. It can reduce the effects of lithium, ACE inhibitors, beta blockers and methotrexate. However, it remains one of the safest and most effective analgesic drugs, particularly in the elderly where the risks of gastric bleeding with NSAIDs are more common, and carries minimal side effects.

Phenylephrine

Phenylephrine is a direct alpha-1 adrenergic agonist, with weak alpha-2 adrenergic agonist activity. It also has very weak beta-adrenergic effects, but at therapeutic doses there are no significant stimulating beta-1 adrenergic effects on the heart, or on the bronchial airways, or on peripheral blood vessels. This contrasts with pseudoephedrine, which has greater beta-adrenergic activity. The effect on the alpha-adrenergic receptors leads to local vasoconstriction and shrinking of mucous membranes. There is no anti-histamine effect. The drug is readily and completely absorbed following oral administration, undergoing extensive first pass metabolism in the intestinal wall and in the liver leading to some variability in individual pharmacokinetics. Nasal decongestion is apparent within 15 to 20 minutes and persists for up to 4 hours (AHFS 2007).

Phenylephrine is readily eliminated by sulphate conjugation in the intestinal wall, and oxidative deamination by monoamine oxidative glucuronidation in the liver. Monoamine oxidase (MAO) inhibitors can enhance the limited potential of phenylephrine for cardiac and pressor effects, by reducing metabolism. As a largely specific alpha adrenergic drug, with very weak beta agonism, there is little direct cardiac effect. However, in higher doses, there can be increases in both systolic and diastolic blood pressure and a reflex bradycardia. As an adrenergic agonist there is the potential to interact with other sympathomimetic drugs. In overdose phenylephrine can cause hypertension, headaches seizures tachycardia, and vomiting. There has been no evidence from carcinogenicity studies in rodents of any enhanced cancer risk over prolonged exposure.

Scheduling status

Paracetamol in combination with phenylephrine is listed in Schedule 2. There is also a separate entry for phenylephrine in Schedule 2 and in Schedule 4.

Schedule 2

PARACETAMOL for therapeutic use except:

  1. when included in Schedule 4;
  2. in individually wrapped powders or sachets of granules each containing 1000 mg or less of paracetamol as the only therapeutically active constituent (other than phenylephrine and/or guaiphenesin or when combined with effervescent agents) when:
    1. enclosed in a primary pack that contains not more than 12 such powders or sachets of granules;
    2. compliant with the requirements of the Required Advisory Statements for Medicine Labels;
    3. not labelled for the treatment of children 6 years of age or less; and
    4. not labelled for the treatment of children under 12 years of age when combined with phenylephrine and/or guaiphenesin; or
  3. in tablets or capsules each containing 500 mg or less of paracetamol as the only therapeutically active constituent (other than phenylephrine and/or guaiphenesin or when combined with effervescent agents) when:
    1. packed in blister or strip packaging or in a container with a child-resistant closure;
    2. in a primary pack containing not more than 25 tablets or capsules;
    3. compliant with the requirements of the Required Advisory Statements for Medicine Labels;
    4. not labelled for the treatment of children 6 years of age or less; and
    5. not labelled for the treatment of children under 12 years of age when combined with phenylephrine and/or guaiphenesin.

PHENYLEPHRINE except:

  1. when included in Schedule 4;
  2. in oral preparations containing 50 mg or less of phenylephrine per recommended daily dose in packs containing 250 mg or less of phenylephrine; or
  3. in topical eye or nasal preparations containing 1 per cent or less of phenylephrine.
Schedule 4

PHENYLEPHRINE

  1. in preparations for injection; or
  2. in preparations for human ophthalmic use containing 5 per cent or more of phenylephrine.
Scheduling history

In October 2005, the NDPSC considered harmonising with NZ on the scheduling of phenylephrine. The NDPSC decided to increase the exemption from scheduling for oral use to include preparations containing 50 mg or less per recommended daily dose.

In June 2007, the NDPSC decided to extend the exemption from the limit on paracetamol combinations being allowed as general sale products to include phenylephrine (as long as it also qualified as exempt from scheduling through the phenylephrine entries). At that time, the NDPSC considered that the safety profile of these substances was such that allowing a fixed combination to be unscheduled was reasonable.

In June 2011 the Advisory Committee on Medicines Scheduling was referred a proposal by the delegate to consider up-scheduling of five (5) then unscheduled substances contained in cold and cough preparations into Schedule 2. One of these substances was phenylephrine and many public submissions received rejected this proposal on the grounds of the paracetamol/phenylephrine exemptions in the Schedule 2 entry. The committee made similar comments and the delegate agreed that the current exempt from scheduling status of phenylephrine was appropriate.

Pre-meeting public submissions

Five public submissions were received. Many of the submissions referred to the article published in the New England Journal of Medicine (NEJM) when giving their reasons for either supporting or rejecting the proposal. Some submissions also noted that a similar proposal is to be considered by an upcoming meeting of the Medicines Classification Committee (MCC) in New Zealand.

Three of the submissions did not support the proposal highlighting the impact the change in scheduling would have on product current on the market, industry, pharmacists and consumers. Two submissions noted that there has not been a history of concern with this combination of substances. One submission, referring to the NEJM article, believed that a lack of information about the study means that it cannot be relied upon as there is not a meaningful assessment of the results.

One submission supported the proposal noting the NEJM article which highlights risks to the consumer.

The fifth submission supported the proposal in principal, however felt that consideration needed to be given to the impact the potential rescheduling would have on pharmacists, industry and consumers.

ACMS advice to the delegate

The ACMS recommended that the current scheduling of paracetamol in conjunction with phenylephrine remains appropriate.

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; and d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  • Application would result in all current OTC paracetamol/ phenylephrine products being up-scheduled to S3. Applicant’s justification for changing current combination products from exempt or S2 to S3 is on theoretical basis only, and no evidence provided of clinical risk. Pharmacokinetic study found that co-administration of paracetamol with phenylephrine increased plasma phenylephrine levels - applicant says this has potential for cardiac safety risk in susceptible patients.

TGA evaluator concluded that the consistent absence of any clinically meaningful effects on blood pressure (BP) or heart rate (HR) in the applicant's bioavailability studies, and the absence of any ADR reports of BP, HR or other cardiovascular problems, indicate that "there is no valid reason for concern and no need to take any regulatory against the combination products currently in the ARTG and available in the Australian market", i.e. no demonstrated safety risk, and no evidence provided of efficacy of paracetamol 1000 mg / phenylephrine HCl 5 mg adult dose.

  • Paracetamol/phenylephrine combination products are used for indications such as relief of cold & flu symptoms, or sinus pain & congestion. There are currently approx. 200 OTC combination products (unscheduled or S2) on the ARTG.

All current OTC paracetamol/phenylephrine combination products provide an adult dose of 1000 mg paracetamol / 10 mg phenylephrine HCl - these products are currently unscheduled or S2.

Delegate's considerations

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 factors4;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that the current scheduling of paracetamol in conjunction with phenylephrine remains appropriate.

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; and d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  • Application would result in all current OTC paracetamol/ phenylephrine products being up-scheduled to S3. Applicant's justification for changing current combination products from exempt or S2 to S3 is on theoretical basis only, and no evidence provided of clinical risk. Pharmacokinetic study found that co-administration of paracetamol with phenylephrine increased plasma phenylephrine levels - applicant says this has potential for cardiac safety risk in susceptible patients.
  • TGA evaluator concluded that the consistent absence of any clinically meaningful effects on blood pressure (BP) or heart rate (HR) in the applicant's bioavailability studies, and the absence of any ADR reports of BP, HR or other cardiovascular problems, indicate that "there is no valid reason for concern and no need to take any regulatory against the combination products currently in the ARTG and available in the Australian market".
  • All current OTC paracetamol/phenylephrine combination products provide an adult dose of 1000 mg paracetamol / 10 mg phenylephrine HCl - these products are currently unscheduled or S2.

1.5 Naproxen Schedule 2

Scheduling proposal

To amend the Schedule 2 naproxen entry to exclude naproxen in a dosage form of 200 mg or less of naproxen per dosage unit in packs of 12 or less dosage units with a maximum recommended daily dose of not more than 600 mg of naproxen, and when not labelled for the treatment of children 12 years of age or less.

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

Substance summary

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, Schedule 3 and in Schedule 2 and listed in Appendix F with warning statements 101 and 104.

Schedule 4

NAPROXEN except when included in Schedule 3 or Schedule 2.

Schedule 3

NAPROXEN in modified release dosage form of 600 mg or less 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 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.
Scheduling history

Naproxen first appeared in the Poisons Standard in June 1982 under Schedule 4, however corresponding minutes cannot be located.

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 to 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 S3 and S4 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 considered the application 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 220mg 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 regarding whether all non-prescription diclofenac should carry the same warning statements as the other NSAIDs, e.g. ibuprofen, aspirin, naproxen and mefenamic acid for consistency. 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.

A modified release dosage form of naproxen was referred to the Advisory Committee on Medicines Scheduling in March 2014, with the medicines delegate seeking their expert opinion. Considering their advice, the evaluation report and public submissions received, the delegate decided that modified release naproxen should be listed in Schedule 3 as the advice of a pharmacist would be warranted in the first stage of a new product being introduced to the market and that the advice of the pharmacist 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.

Pre-meeting public submissions

Five public submissions were received. One supported the proposal with appropriate wording that is consistent with other OTC medicines such as paracetamol and ibuprofen. The others opposed any amendment to the S2 entry for naproxen due to potential risks if the substance is accessible to consumers outside registered pharmacy premises.

ACMS advice to the delegate

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

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; d) the dosage, formulation, labelling, packaging and presentation of a substance; and e) the potential for abuse of a substance.

The reasons for the recommendation comprised the following:

  • Risks: GI disorders, allergic reactions, renal toxicities & cardio vascular adverse events are some of the common risks. Potential for inappropriate use & overuse of the product, especially if advice from a pharmacist is not available if the product was to be exempt from scheduling.
  • GI risk with naproxen is greater than with ibuprofen.
  • It has analgesic, anti-inflammatory & anti-pyretic properties. It is used for the relief of a number of common conditions where pain and or inflammation are a component.
  • Poisoning with NSAIDs is known especially in high doses. Common adverse effects include dyspepsia, ulceration, GI bleeding, headaches, confusion & drowsiness. There are no new adverse events associated with this proposed product.
  • The TGA would be responsible for the registered product label. It is to be labelled not for the treatment of children 12 years of age or less. Labelling will be in accordance with mandatory Medicines Advisory Statements Specifications 7, including the Required Advisory Statements for Medicine Labelling (RASML) (101 &104).
  • Low potential for abuse.
Delegate's considerations

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 factors5;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that the current scheduling of naproxen remains appropriate.

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; d) the dosage, formulation, labelling, packaging and presentation of a substance; and e) the potential for abuse of a substance.

The reasons for the recommendation comprised the following:

  • GI disorders, allergic reactions, renal toxicities & cardio vascular adverse events are some of the common risks. Potential for inappropriate & overuse of the product, especially if advice from a pharmacist is not available if the product was to be exempt from scheduling. GI risk with naproxen is greater than with ibuprofen.
  • It has analgesic, anti-inflammatory & anti-pyretic properties. It is used for the relief of a number of common conditions where pain and or inflammation are a component.
  • Poisoning with NSAIDs is known especially in high doses. Common adverse effects include dyspepsia, ulceration, GI bleeding, headaches, confusion & drowsiness. There are no new adverse events associated with this proposed product.
  • The TGA would be responsible for the registered product label. It is to be labelled not for the treatment of children 12 years of age or less. Labelling will be in accordance with mandatory Medicines Advisory Statements Specifications 7, including the Required Advisory Statements for Medicine Labelling (RASML) (101 &104).
  • Low potential for abuse.
  • In view of increased risk versus other NSAIDS which are excluded.

1.6 Naproxen Appendix H

Scheduling proposal

To include naproxen in Appendix H.

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

Substance summary

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.

Scheduling status

Naproxen is currently scheduled in Schedule 4, Schedule 3 and in Schedule 2 and listed in Appendix F with warning statements 101 and 104.

Schedule 4

NAPROXEN except when included in Schedule 3 or Schedule 2.

Schedule 3

NAPROXEN in modified release dosage form of 600 mg or less 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 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, however, corresponding minutes cannot be located.

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 to 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 S3 and S4 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 the application 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 220mg 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 regarding whether all non-prescription diclofenac should carry the same warning statements as the other NSAIDs, e.g. ibuprofen, aspirin, naproxen and mefenamic acid for consistency. 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.

A modified release dosage form of naproxen was referred to the Advisory Committee on Medicines Scheduling in March 2014, with the medicines delegate seeking their expert opinion. Considering their advice, the evaluation report and public submissions received, the delegate decided that modified release naproxen should be listed in Schedule 3 as the advice of a pharmacist would be warranted in the first stage of a new product being introduced to the market and that 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.

Pre-meeting public submissions

Four public submissions were received. Three submissions supported the proposal as it was considered it would better inform the public of products available without prescription. One requested that the pharmacy profession have input into the development of any advertisement or promotional material.

One public submission opposed the proposal as no benefit to the consumer would result from advertising.

ACMS advice to the delegate

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

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.

The reasons for the recommendation comprised the following:

  • The Schedule 3 entry for a sustained released product was recently resolved. There is an inadequate body of evidence to support Appendix H listing.
Delegate's considerations

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 factors6;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that the current scheduling of naproxen remains appropriate.

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.

The reasons for the recommendation comprised the following:

  • Schedule 2 naproxen products can currently be advertised to consumers, and there does not appear to be any additional public health benefit in advertising modified release formulations of naproxen.
  • Concern that advertising of the Schedule 3 product might encourage consumers to ask for the modified release product when use of conventional lower dose product might be more appropriate.
  • Modified release naproxen has only recently been included in Schedule 3. No Schedule 3 naproxen products are currently registered in the Australian Register of Therapeutic Goods (ARTG), and consequently there is no experience with marketing Schedule 3 modified release naproxen products in Australia.

Footnotes

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