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Scheduling delegate's final decisions: ACMS, March 2015

ACMS meeting - 18 November 2014

18 March 2015

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Part A - Final decisions on matters referred to an expert advisory committee: 1.1-1.4

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

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.

Substance summary

Growth Hormone Releasing Peptides (GHRP) are 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 were not currently scheduled.

Scheduling history

These substances had not been previously considered for scheduling therefore scheduling history was 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 substance , 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 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 interim decision

The interim decision was 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 was 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of 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.
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.
Public submissions on the interim decision

One submission was received, which did not support the inclusion of AOD-9604 in Appendix D as it would create a burden for legitimate clinical development of the substance in those states and territories which adopt Appendix D and therefore be ineffective in those that do not adopt Appendix D.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The implementation date of this decision will be 1 June 2015.

Schedule entry
Schedule 4 - New entry

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 entry

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.

Substance summary

The following information regarding the substance was provided by the applicant:

"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 product in an open sale environment.

Evidence review and acceptance by the NDPSC in 2007, demonstrated that paracetamol/caffeine combination analgesics have 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 cases 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 10 such powders or sachets of granules;
    2. compliant with the requirements of the Required Advisory Statements for Medicine Labels;
    3. not labelled for the treatment of children 6 years of age or less;
    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 20 tablets or capsules;
    3. compliant with the requirements of the Required Advisory Statements for Medicine Labels;
    4. not labelled for the treatment of children 6 years of age or less;
    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. It was agreed that the indications for use, safety profile and potential for misuse met the criteria for a Schedule 2 medicine.

At the time that 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 had 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; and f) any other matters that the Secretary considers necessary to protect 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 interim decision

The delegate's interim decision was 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 delegate 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.
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.
Public submissions on the interim decision

One submission was received, which did not support the delegate's interim decision, as available data support that the fixed dose paracetamol/caffeine combination product provides clinically meaningful efficacy over paracetamol alone; has an excellent safety profile; a very low risk of nephrotoxicity, toxicity in overdose, misuse, abuse or illicit use; and a highly favourable risk/benefit profile.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

1.3 Paracetamol/ibuprofen

Scheduling proposal

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

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 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 delegate 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.
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.
Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

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.
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 currently 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 interim decision

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.
  • 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.
Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Footnotes

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