Publication of interim decisions amending, or not amending, the current Poisons Standard, June 2018

Scheduling medicines and poisons

7 June 2018

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1.3 Fluticasone

1. Advisory Committee on Medicines Scheduling (ACMS #23)

1.3 Fluticasone

Delegate's interim decision

The delegate's interim decision is to amend the Schedule 2 entry for fluticasone in the Poisons Standard to read as follows:

Schedule 2 - Amend Entry

FLUTICASONE in aqueous nasal sprays delivering 50 micrograms or less of fluticasone per actuation when the maximum recommended daily dose is no greater than 400 micrograms, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.

Proposed implementation date: 1 October 2018

The delegate considers the Committee's proposed implementation date of 1 October 2018 as being reasonable and appropriate in the circumstances.

Reasons:

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:

  1. the risks and benefits of the use of a substance:
    • Benefits:
      • Over 30 years' experience with this agent in Australia including 16 years non-prescription experience.
      • Intranasal corticosteroids such as fluticasone are well-established as recommended agents for effective long-term management of symptoms of allergic rhinitis with favourable long-term use safety profile.
      • Long-term safety profile established from clinical trials and extensive post-marketing data with insignificant systemic absorption of fluticasone from intranasal administration or any portion of dose that is swallowed.
    • Risks:
      • There is no difference in the risks of the substance by allowing more doses per pack.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Symptomatic treatment and prophylaxis of allergic rhinitis in adults and children over 12 years.
    • Australian prevalence of allergic rhinitis ranges from 12-26% (AIHW analysis of ABS National Health Survey, 2014-15).
  3. the toxicity of a substance:
    • High tolerability and safety with low frequencies of adverse events reported in clinical trials and post-marketing.
    • Larger pack size will not affect the toxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Removal of actuation limit would allow the supply of a larger number of doses per occasion of supply to treat a chronic condition, providing up to 6-months of treatment, which will enhance adherence, improve symptom control and quality of life, and reduce medicine and healthcare resource costs.
  5. any other matters that the Secretary considers necessary to protect public health:
    • Minimising barriers to compliance with intranasal corticosteroids is of benefit.
    • Enhanced consumer access and treatment continuity.
Scheduling proposal

The pre-meeting scheduling proposal for fluticasone was published on the TGA website on 21 December 2017 at Consultation: Proposed Amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS-ACMS meetings, March 2018.

Background information for fluticasone
Referred scheduling proposal

An application was submitted to amend the Poisons Standard with respect to fluticasone. The application proposes to amend the Schedule 2 entry for fluticasone to remove the limit of 200 actuations.

Scheduling application

The application proposed the following amendments to the Poisons Standard:

Schedule 2 - Amend Entry

FLUTICASONE in aqueous nasal sprays delivering 50 micrograms or less of fluticasone per actuation when the maximum recommended daily dose is no greater than 400 micrograms and when packed in a primary pack containing 200 actuations or less, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.

The applicant's reasons for the request are:

  • There is substantial evidence to support the removal of the existing limit of 200 actuations for fluticasone.
  • This would positively contribute to the following outcomes:
    • Ensure success and long-term relief from symptoms of allergic rhinitis: multiple spray bottle primary packs up to a six month period would last not only during the acute phase of symptoms (2 weeks), but would also provide additional control on the downgraded dose needed to deliver optimal efficacy and control symptoms of a disease that has been described as a chronic inflammatory condition.
    • Availability of a treatment needed not only during seasons but also for those patients that fall into the group of permanent sufferers and demand prompt and efficacious relief.
    • Reduced costs related to poor control of the disease: Fewer complications/comorbidities, as well as reduced public-health-related issues that consequently reflect important improvement in quality-of-life for patients.
    • Strengthen treatment compliance amongst patients, by ensuring the adequate amount of medication needed is readily available.
    • Demonstrates a favourable safety profile regarding a long-term use up to 6 months.
    • Brings consistency to the Schedule 2 entry for fluticasone so as to be aligned to the similar entry for mometasone.
  • In summary:
    • The benefit:risk profile of the fluticasone is highly favourable.
    • The purpose of the product is for the prevention and treatment of allergic rhinitis. Its clinical benefits in this indication have been established.
    • The global safety experience with fluticasone is extensive and the safety profile is well-defined and not expected to change due to the access changes. There is consistent evidence from clinical trial data and from post-marketing experience that existing non-prescription use results in good tolerability.
    • Extensive post-marketing experience has established that the likelihood of off-label use is extremely low and that abuse or misuse of the fluticasone in this treatment setting is unlikely to be a significant problem.
Current scheduling status

Fluticasone is listed in Schedules 2 and 4 of the Poisons Standard as follows:

Schedule 2

FLUTICASONE in aqueous nasal sprays delivering 50 micrograms or less of fluticasone per actuation when the maximum recommended daily dose is no greater than 400 micrograms and when packed in a primary pack containing 200 actuations or less, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.

Schedule 4

FLUTICASONE except when included in Schedule 2.

Related substances listed in Schedule 2 in the Poisons Standard are as follows:

Schedule 2

BECLOMETASONE in aqueous nasal sprays delivering 50 micrograms or less of beclometasone per actuation when the maximum recommended daily dose is no greater than 400 micrograms and when packed in a primary pack containing 200 actuations or less, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.

BUDESONIDE in aqueous nasal sprays delivering 50 micrograms or less of budesonide per actuation when the maximum recommended daily dose is no greater than 400 micrograms and when packed in a primary pack containing 200 actuations or less, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.

MOMETASONE in aqueous nasal sprays delivering 50 micrograms or less of mometasone per actuation when the maximum recommended daily dose is no greater than 200 micrograms for the prophylaxis or treatment of allergic rhinitis for up to six months in adults and children 12 years of age and over.

TRIAMCINOLONE in aqueous nasal sprays delivering 55 micrograms or less of triamcinolone per actuation when the maximum recommended daily dose is no greater than 220 micrograms, for prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.

Scheduling history

In April 1994, the National Drugs and Poisons Scheduling Committee (NDPSC) considered an application for fluticasone propionate for the prophylactic management of asthma in adults and children. The committee decided to include fluticasone in Schedule 4.

In November 2000, the NDPSC considered an application to reschedule fluticasone aqueous nasal spray from Schedule 4 to Schedule 3 for the prophylaxis or treatment of seasonal allergic rhinitis, with an inclusion in Appendix H - Schedule 3 Poisons Permitted to be Advertised. Due to the proposed fluticasone nasal spray formulation being comparable in safety to other Schedule 3 nasal corticosteroids, the committee decided to down-schedule fluticasone from Schedule 4 to Schedule 3, with a maximum daily dose of no greater than 200 micrograms in a primary pack containing 200 actuations or less, for the short-term prophylaxis or treatment of seasonal allergic rhinitis in adults and children 12 years and over.

In November 2001, the NDPSC considered an application to reschedule fluticasone intranasal spray for perennial allergic rhinitis from Schedule 4 to Schedule 3. The committee agreed to amend the Schedule 3 entry for fluticasone to allow a maximum daily dose of no greater than 400 micrograms, in a primary pack containing 200 actuations or less, for up to 6 months in adults and children 12 years and over.

In October 2003, the NDPSC considered an application to reschedule fluticasone from Schedule 3 to Schedule 2 for the short-term (3-6 month) prophylaxis or treatment of allergic rhinitis in adults and children 12 years and over. The committee agreed to include intranasal fluticasone propionate in Schedule 2 with a maximum daily dose of no greater than 400 micrograms in a primary pack containing 200 actuations or less, and removal of fluticasone from Appendix H. The decision was based on the safety of use, low incidence of adverse effects, availability of pharmacist advice or counselling when required, use for a minor ailment that is easily identified, low potential of misuse and abuse and the low potential to mask a serious disease.

In February 2006, the NDPSC considered a recommendation that Australia adopt the New Zealand maximum daily dose limit of 200 micrograms of fluticasone in Schedule 2 due to fluticasone being twice as potent as the other nasal corticosteroids. Members agreed to harmonise with the New Zealand scheduling and amended the Schedule 2 entry to a maximum recommended daily dose of no greater than 200 micrograms.

In February 2007, the NDPSC agreed to an editorial amendment to the Schedule 2 entry of fluticasone to add 'of age' after '12 years'. The Schedule 2 entry still reads as a maximum daily dose of no greater than 400 micrograms.

In June 2008, the NDPSC considered an application for the new medicine fluticasone furoate. The committee agreed that fluticasone furoate is captured under the Schedule 4 and Schedule 2 entries for fluticasone.

Australian regulations

Fluticasone does not appear in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018, as it is a scheduled ingredient and is not eligible for use in ARTG listed medicines.

The Australian Register of Therapeutic Goods (ARTG) has 80 products listed that contain fluticasone furoate and fluticasone propionate. The products marketed include nasal drops, nasal sprays, metered dose inhalers and accuhalers.

In the last 30 years there have been 809 reported cases of adverse events related to fluticasone in the Database of Adverse Events Notification (DAEN) - Medicines: 640 cases with a single suspected medicine and 8 cases where death was a reported outcome.

According to the TGA Ingredient Database, fluticasone propionate and fluticasone furoate are available for use as an:

  • Active Ingredient in: Biologicals, Export Only, Over the Counter (fluticasone propionate only), Prescription Medicines; and
  • Excipient Ingredient in: Biologicals, Devices, Prescription Medicines.
International regulations

Canada

Health Canada regulates fluticasone in a nasal spray (50 microgram per spray) as an over-the-counter medicine.

New Zealand

Ingredient Conditions (if any) Classification
Fluticasone except when specified elsewhere in this schedule Prescription
Fluticasone for the treatment or prophylaxis of allergic rhinitis in adults and children over 12 years of age when in aqueous nasal sprays delivering up to 50 micrograms per actuation with a maximum recommended daily dose of 200 micrograms (as a single dose) in a pack containing 200 actuations or less Pharmacy Only

United Kingdom (UK)

The UK regulates fluticasone as a:

  • Prescription only medicine including creams, ointments, nasal drops, nasal sprays, metered dose inhalers, nebules and accuhalers;
  • Pharmacy only medicine including 0.05% nasal spray (fluticasone propionate); and
  • General sales list medicine including 0.05% nasal spray (fluticasone propionate).
Substance summary

Fluticasone propionate is the propionate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with anti-allergic, anti-inflammatory and antipruritic effects.

Fluticasone is an extremely potent vasoconstrictor and anti-inflammatory agent. Its effectiveness in inhaled forms is due to its direct local effect. Approved indications for fluticasone via inhalation include COPD, asthma and allergic rhinitis.

Description: A white to off white crystalline powder.

Solubility: Practically insoluble in water, freely soluble in dimethyl sulfoxide, dimethylformamide and slightly soluble in methanol and 95% ethanol.

Stability: A saturated aqueous solution has a pH of 7.5 to 9.5 and is stable if stored in an airtight container and is protected from light. The stability decreases in acidic conditions, the fluticasone and propionate ion being disassociated from the salt form (fluticasone propionate).

Stability: Stable under normal conditions. Light sensitive in solution/suspension.

Table 1.3A: Chemical information of fluticasone propionate
Property Fluticasone propionate
CAS number 80474-14-2
Chemical structure Chemical structure of Fluticasone propionate
[as fluticasone propionate]
Molecular formula C25H31F3O5S
Molecular weight 500.6 g/mol
IUPAC and/or common and/or other names

S-(fluoromethyl)-6α,9-difluoro-11β, 17-dihydroxy-16α-methyl-3-oxoandrosta-1, 4-diene-17β-carbothioate, 17-propanoate (IUPAC);

Fluticasone propionate (AAN).

Pre-meeting public submissions

Three (3) public submissions were received, two (2) in support and one (1) conditionally supporting the proposal.

The main points provided in support of the amendment were:

  • Fluticasone has been available in Australia for approximately 30 years and the safety and efficacy are well characterised.
  • The use of intranasal corticosteroids is recommended for the effective long-term management of the symptoms of allergic rhinitis. Intranasal corticosteroids have a minimal risk of systemic side effects due to their low bioavailability.
  • 200 actuations is approximately 1.5-3 month's usage of fluticasone depending on usage. The current Schedule 2 entry allows for up to six months' therapy. Effective long-term management of allergic rhinitis typically involves longer periods of continuous use, and by removing the actuation limit, it has the potential to improve adherence.
  • The scheduling proposal will align the Schedule 2 entry for fluticasone with mometasone. It will also be consistent with the scheduling factors for Schedule 2 medicines.

The main points in provided in conditional support of the amendment were:

  • It was noted that other corticosteroids for similar indications such as seasonal allergic and perennial rhinitis (i.e. beclometasone and budesonide) have a 200 actuation limit in their Schedule 2 entries in the Poisons Standard.
  • Intranasal corticosteroid treatment may require lengthy periods of treatment, including for many years. Given this, the inclusion of an actuation treatment may be unnecessary and be related to the expiry date of the particular formulation after opening.
  • If there is no clinical justification for an intranasal corticosteroid entry to have the inclusion of a limit of actuations, then it should be removed. However, if there is clinical justification for an intranasal corticosteroid entry to have the inclusion of a limit of actuations, then it should be included in the entry. As a result, it was recommended that all intranasal corticosteroid Schedule 2 entries be reconsidered.

The public submissions will be made available on the TGA website.

Summary of ACCS advice to the delegate

The committee recommended the Schedule 2 entry for fluticasone be amended in the Poisons Standard as follows:

Schedule 2 - Amend Entry

FLUTICASONE in aqueous nasal sprays delivering 50 micrograms or less of fluticasone per actuation when the maximum recommended daily dose is no greater than 400 micrograms and when packed in a primary pack containing 200 actuations or less, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.

The committee also recommended an implementation date of 1 October 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the extent of use; (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 advice included:

  1. the risks and benefits of the use of a substance:
    • Benefits:
      • Over 30 years' experience with this agent in Australia including 16 years non-prescription experience.
      • Intranasal corticosteroids such as fluticasone are well-established as recommended agents for effective long-term management of symptoms of allergic rhinitis with favourable long-term use safety profile.
      • Long-term safety profile established from clinical trials and extensive post-marketing data with insignificant systemic absorption of fluticasone from intranasal administration or any portion of dose that is swallowed.
    • Making the agent available in a larger pack size is unlikely to impact the risk:benefit profile significantly.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Symptomatic treatment and prophylaxis of allergic rhinitis in adults and children over 12 years.
    • Australian prevalence of allergic rhinitis ranges from 12-26% (AIHW analysis of ABS National Health Survey, 2014-15).
  3. the toxicity of a substance:
    • High tolerability and safety with low frequencies of adverse events reported in clinical trials and post-marketing.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Removal of actuation limit would allow the supply of a larger number of doses per occasion of supply to treat a chronic condition, providing up to 6-months of treatment, which will enhance adherence, improve symptom control and quality of life, and reduce medicine and healthcare resource costs.
  5. the potential for abuse of a substance:
    • Nil.
  6. any other matters that the Secretary considers necessary to protect public health
    • Minimising barriers to compliance with intranasal corticosteroids is of benefit.
    • Enhanced consumer access and treatment continuity.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACMS advice;
  • Public submissions received;
  • Scheduling Policy Framework (SPF 2018); and
  • Section 52E (1) of the Therapeutic Goods Act 1989, in particular: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

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