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Publication of interim decisions proposing to amend, or not amend, the current Poisons Standard, September 2018

Scheduling medicines and poisons

10 September 2018

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1.2 Budesonide

1. Advisory Committee on Medicines Scheduling (ACMS #24)

Delegate's interim decision

The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to budesonide as follows:

Note

New text is shown as green, larger font, with a horizontal line above it.

Deleted text is shown as red, smaller font, with a strikethrough.

Schedule 2 - Amend Entry

BUDESONIDE in aqueous nasal sprays delivering 5064 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.

Proposed implementation date: 1 February 2019

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:
    • Intra-nasal corticosteroids (INC) are a first-line recommended treatment for allergic rhinitis and are associated with minimal risks.
    • The proposed change does not alter the recommended dose maximum daily dose.
    • Intranasal corticosteroids such as budesonide are well-established as recommended agents for effective long-term management of symptoms of allergic rhinitis. There is almost 30 years' experience with budesonide in Australia including 20 years non-prescription experience.
    • Long-term safety profile has been established from clinical trials and extensive post-marketing data with insignificant systemic absorption of budesonide used nasally or from any portion of the dose that is swallowed.
    • Making budesonide available in a larger pack size is unlikely to impact the risk-benefit profile significantly.
    • Making budesonide available in a higher strength dose means less frequent administration by the consumer to achieve the maximum recommended dose. This 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:
    • The purpose for which budesonide is used is for the symptomatic treatment and prophylaxis of allergic rhinitis in adults and children over 12 years. Intra-nasal corticosteroids such as budesonide are a first-line recommended treatment for allergic rhinitis.
  3. the toxicity of a substance:
    • Budesonide has high tolerability and safety with low frequencies of adverse events in clinical trials and post-marketing. There have been no significant adverse events attributable to budesonide nasal sprays since their inclusion in Schedule 2.
    • Local adverse effects related to oropharyngeal and septal exposures are minor and minimised through appropriate inhalation technique.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Availability of a second, higher strength product would allow reduced number of doses to achieve same maximum daily dose. Product labelling can be used to differentiate the two products;
    • A reduction in the number of sprays required to achieve the desired dose increases convenience for the consumer and may assist with compliance.
    • Removing the actuation limit will allow new larger pack sizes and provide a longer duration of treatment;
    • Access to a higher strength product will result in enhanced compliance, symptom control, quality of life, and reduced medicine and healthcare resource costs.
  5. any other matters that the Secretary considers necessary to protect public health:
    • This change to the scheduling of budesonide in the Poisons Standard will align the Schedule 2 entry with other intranasal corticosteroids.

Delegate's considerations

The delegate considered the following in regards to this interim decision:

  • The application to amend the current Poisons Standard with respect to budesonide;
  • The advice received from the Advisory Committee on Medicines Scheduling (ACMS#24);
  • The public submissions received before the first closing date;
  • The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
  • Section 52E of the Therapeutic Goods Act 1989, in particular: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

Scheduling proposal

The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.

Background information for budesonide

Delegate's referral to ACMS

An application was submitted to amend the Poisons Standard with respect to budesonide. The application proposed to amend the Schedule 2 entry of budesonide.

Applicant's scheduling proposal and reasons

The applicant's proposed amendments to the Poisons Standard were:

Note

New text is shown as green, larger font, with a horizontal line above it.

Deleted text is shown as red, smaller font, with a strikethrough.

Schedule 2 - Amend Entry

BUDESONIDE in aqueous nasal sprays delivering 5064 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.

The applicant's reasons for the proposal were:

  • Budesonide is a potent synthetic glucocorticosteroid with special kinetic properties. In non-clinical pharmacological studies, budesonide demonstrates a wide variety of anti-allergic and anti-inflammatory effects.
  • Current range of Schedule 2 inhaled nasal corticosteroids (INCs) are only available in one strength, which in effect means that delivered dosage and treatment effectiveness are very much dependent on consumers' willingness and compliance to administer the full number of required sprays per day.
  • INCs (including budesonide) are recommended first-line allergic rhinitis (AR) treatment choices in both Australian and international clinical guidelines.
  • While AR is not life-threatening, it is of substantial public health significance. AR is widely considered as the most common chronic respiratory disorder. Reported prevalence varies considerably as it is often underdiagnosed. It affects between 23% and 50% of the population worldwide with progressively increasing prevalence in more-developed countries. In Australia, the current prevalence is in excess of 15% (or 3.7 million of the current population) with a predicted estimate of 27% in 2050.
  • For the individual AR sufferer, symptoms can have a significant impact on the quality of life, often resulting in sleep disturbance, fatigue and an impaired ability to concentrate, learn, and make decisions. In additional to the physical discomfort, AR symptoms have been associated with a reduction in worker productivity, student performance, and higher absenteeism rates from work and school, resulting in 3.5 million lost workdays and 2 million lost schooldays annually in the United States of America (USA). Fifty six per cent of Australian AR sufferers report that their symptoms have a moderate-to-severe impact on their quality of life and 61% report interference with work/school.
  • AR is a condition that has been well established as suitable for both self-diagnosis and self-treatment. Symptoms of AR, including sneezing, runny nose, itchy nose and nasal congestion, are easily identifiable by both allergy sufferers and parents.
  • People who need to continue with the maximum dose of budesonide to maintain symptom control will benefit from the convenience of the proposed Schedule 2 64 µg strength, which requires only 4 sprays per day compared to the current 8 sprays per day.
  • The proposed amendment to the Schedule 2 entry for budesonide is one strategy that is likely to improve AR compliance and treatment outcomes and have a potentially broad positive healthcare impact. No changes have been requested to the current Schedule 2 budesonide entry in regards to the 400 µg daily dosage or the 6-month dosage period limits.
  • In 2006, the National Drugs and Poisons Schedule Committee (NDPSC) agreed that budesonide should have a fully harmonised INC Schedule 2 entry including 5 restriction criteria – formulation, strength, dosage, indication and age. They also agreed to remove the pack size restriction criteria. However, it appears that during implementation of the harmonised Schedule 2 budesonide scheduling entry in February 2007, the pack size restriction criteria was reinstated without a clear rationale.

Current scheduling status

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

Schedule 2

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.

Schedule 4

BUDESONIDE except when included in Schedule 2.

Scheduling history

The scheduling history for budesonide for intra-nasal use is outlined below.

In November 1990, the Drugs and Poisons Schedule Committee (DPSC) included budesonide in Schedule 4 after receiving an application for use in bronchial asthma and AR.

In November 1998, the NDPSC agreed to include budesonide in Schedule 3 in aqueous nasal sprays delivering 50 micrograms per actuation when the maximum recommended daily dose is no greater than 400 micrograms, for the treatment of seasonal and AR. The Schedule 4 entry was also amended to include 'except when included in Schedule 3'.

In February 1999, the NDPSC agreed to amend the Schedule 3 entry for budesonide to 'budesonide in a dose of 50 microgram or less' to allow the supply of lower dose preparations.

In August 1999, the NDPSC agreed to amend the typographical error in Schedule 3 of 'seasonal and allergic rhinitis' to read 'seasonal allergic rhinitis'. The Schedule 3 entry was also amended to include 'and when packed in a primary pack containing 200 actuations or less' and 'in adults and children 12 years and over'.

In August 2000, the NDPSC agreed to amend the Schedule 3 entry for budesonide to include 'for the short-term prophylaxis'. The committee also agreed to include budesonide in Appendix H based on its similarity of other nasal corticosteroids which are permitted to be advertised.

In October 2002, the NDPSC agreed to amend the Schedule 3 entry for budesonide to include perennial allergic rhinitis (PAR) based on post-marketing safety data and no expected safety issues to arise from the short-term use of intranasal budesonide for the prophylaxis or treatment of allergic rhinitis.

In June 2003, the NDPSC agreed reschedule budesonide in aqueous nasal spray to Schedule 2 for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adult and children 12 years and over based on extensive local and overseas experience, AR not requiring medical diagnosis and is easily diagnosed by the consumer and supporting information that budesonide is substantially safe in adults and children 12 years and over.

In October 2005, the NDPSC agreed to consider removing the pack size restriction 'when packed in a primary pack containing 200 actuations or less' from the Schedule 2 entry at the February 2006 meeting to harmonise with New Zealand (NZ).

In February 2006, the NDPSC agreed to amend the Schedule 2 entry for budesonide by removing the limit of actuations, thereby harmonising with NZ.

In February 2007, the NDPSC amended the Schedule 2 entry for budesonide for clarity and consistency by adding 'of age' after '12 years'.

Australian regulations

The Australian Register of Therapeutic Goods (ARTG) has 43 products that contain budesonide. The products marketed include nasal sprays, metered dose inhalers, inhalation ampoules, dry power inhalers, enteric capsules and nebuliser suspension.

Budesonide does not appear in the current Therapeutic Goods (Permissible Indications) Determination No. 2 of 2018 as it is a scheduled substance and is not eligible for use in ARTG listed medicines.

In the last 30 years there have been 521 reported cases of adverse events related to budesonide in the Database of Adverse Events Notification (DAEN) - Medicines: 319 cases with a single suspected medicine and 7 cases where death was the reported outcome.

According to the TGA Ingredient Database, budesonide is:

  • Available for use as an Active Ingredient in Biologicals, Export Only, Over the Counter, Prescription Medicines;
  • Available for use as an Excipient Ingredient in Biologicals, Devices, Prescription Medicines; and
  • Not available as an Equivalent Ingredient in any application.

International regulations

Canada

In Canada, 64 µg budesonide nasal sprays are regulated as a prescription medicine.

United Kingdom (UK)

In the UK, 64 µg budesonide nasal sprays are regulated as an over-the-counter (OTC) medicine.

NZ

Medsafe NZ regulate budesonide as a Pharmacy Only medicine for the treatment or prophylaxis of allergic rhinitis in adults and children over 12 years of age in aqueous nasal sprays delivering up to 50 micrograms per actuation and when the maximum recommended daily dose is no greater than 400 micrograms (200 micrograms per nostril) in a pack containing 200 actuations or less.

USA

In the USA, 32 µg budesonide nasal sprays are regulated as an over-the-counter (OTC) medicine.

Substance summary

Table 1.2: Chemical information for budesonide
Property Budesonide
CAS name 51333-22-3
IUPAC and/or common and/or other names (11-beta,16-alpha)-16,17-(Butylidenebis(oxy))-11,21-dihydroxypregna-1,4-diene-3,20-dione
Chemical structure chemical structure of budesonide
Molecular formula C25H34O6
Molecular weight 430.5 g/mol

Budesonide is a potent synthetic glucocorticosteroid with special kinetic properties. It has a high affinity for the glucocorticosteroid (aka 'corticosteroid' or simply 'steroid') receptor, and in non-clinical pharmacological studies demonstrates a wide variety of anti-allergic and anti-inflammatory effects.[13] Budesonide inhibits the production and release of a variety of mediators and cytokines from inflammatory cells. Moreover, budesonide inhibits the immediate and late phase allergic reactions, bronchial hyperreactivity and cellular infiltration after provocation.

INCs currently marketed in Australia to treat AR are broadly characterised according to their absorption characteristics, with first-generation including beclomethasone, triamcinolone and budesonide considered hydrophilic molecules, and second-generation molecules mometasone, ciclesonide and fluticasone considered lipophilic.[14],[15] While higher lipophilicity is one pharmacological characteristic that may lead to varied local and systemic absorption, safety and efficacy of INCs is influenced by mucosal solubility (higher hydrophilicity reduces mucociliary clearance) and nasal metabolic pathways inhaler device delivery efficiency.[16],[17] Budesonide's unique reversible fatty acids esterification pathway is believed to contribute to its long duration of action within the airways/lung.[18]

High hepatic metabolism of any swallowed INC dose also contributes to minimise systemic exposure. Budesonide undergoes extensive biotransformation (approximately 90%) on first-passage through the liver to metabolites of 100-fold lower activity than the parent compound.[19],[20]

Pre-meeting public submissions

Four (4) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. All four (4) submissions were in support of the proposed amendments.

The main points provided in support of the amendment were:

  • Budesonide has been available in Australia since 1990 and as an aqueous nasal spray since 2001 for the prophylaxis and treatment of both seasonal and perennial AR. The scheduling proposal will align schedule entries for budesonide with other INCs.
  • INCs are recommended for first-line therapy if symptoms are persistent and/or moderate to severe, and are more effective than oral antihistamines for AR.
  • Treatment of AR may need to be continued for lengthy periods of time, and in some cases for many years. The inclusion of a maximum number of actuations may be unnecessary and be related to the expiry date of the particular formulation after opening.
  • The primary goals of treatment of allergic rhinitis are to reduce symptoms, and to improve quality of life and daily functioning. INC sprays have high efficacy in controlling symptoms of AR and a good safety profile, with minimal risk of systemic side effects due to their low bioavailability. Further, INC sprays containing budesonide are well tolerated. There have not been any significant adverse events attributable to budesonide nasal sprays since their inclusion in Schedule 2.
  • Two strengths of the nasal spray are currently available; 32 µg per actuation (Schedule 2) and 64 µg per actuation (Schedule 4). When used as recommended, the two product strengths provide the same total daily dose of budesonide. However, the 64 µg product offers a more comfortable and convenient application. It is to be expected that the less frequent application will lead to better adherence and clinical outcomes. Product labelling can be used to effectively differentiate between the two products.
  • The proposal has the potential to improve adherence. Two hundred (200) actuations corresponds to about 3.5 weeks' usage of the 32 µg product and about 7 weeks' usage of the 64 µg product. Effective long-term management of AR typically involves longer periods of continuous use.
  • Both the 32 µg per actuation product and the 64 µg per actuation product meet the scheduling factors for Schedule 2.
  • Budesonide has been the subject of numerous clinical studies and its safety and efficacy are well characterised. If there is no clinical justification for the inclusion of 'containing 200 actuations or less' in the budesonide entry then it should be removed. The proposal to remove the actuation limit is also consistent with the Schedule 2 entry for mometasone and with the recent proposal to remove the actuation limit from the Schedule 2 entry for fluticasone.

ACMS advice

The committee recommended that the Schedule 2 entry be amended as follows:

Note

New text is shown as green, larger font, with a horizontal line above it.

Schedule 2 - Amend Entry

BUDESONIDE in aqueous nasal sprays delivering 64 micrograms or less of budesonide 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.

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

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. risks and benefits of the use of a substance:
    • Intra-nasal corticosteroids are a first-line recommended treatment for allergic rhinitis and are associated with minimal risks.
    • The proposed change does not alter the recommended dose maximum daily dose.
    • Almost 30 years' experience with this agent in Australia including 20 years non-prescription experience. Intranasal corticosteroids such as budesonide are well-established as recommended agents for effective long-term management of symptoms of allergic rhinitis. Long-term safety profile established from clinical trials and extensive post-marketing data with insignificant systemic absorption of budesonide nasally 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.
    • Making the agent available in a higher strength dose means less doses that the consumer needs to administer (ie one dose vs two doses) to achieve the maximum recommended dose. This is unlikely to impact the risk:benefit profile significantly.
  2. the purpose for which a substance is to be used and the extent of use:
    • Intra-nasal corticosteroids are a first-line recommended treatment for allergic rhinitis.
    • Symptomatic treatment and prophylaxis of allergic rhinitis in adults and children over 12 years.
  3. the toxicity of a substance:
    • There have not been any significant adverse events attributable to budesonide nasal sprays since their inclusion in Schedule 2.
    • Local adverse effects related oropharyngeal and septal exposure are minor and minimised through appropriate inhalation technique.
    • High tolerability and safety with low frequencies of adverse events in clinical trials and post-marketing.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Reduction in the number of sprays required to achieve the desired dose increases convenience, may assist with compliance. The reduced treatment burden might result in more consistent inhalation technique and potential result in a reduced risk of oropharyngeal and septal drug exposure.
    • Removal of actuation limit would allow new pack size availability providing longer duration of treatment;
    • Availability of a second, higher strength product would allow reduced number of doses to achieve same max daily dose. Product labelling can be used to differentiate the two products;
    • Both factors enhance adherence, symptom control, quality of life, and reduced medicine and healthcare resource costs.
  5. any other matters that the Secretary considers necessary to protect public health:
    • This change will align the Schedule 2 entry with other intranasal corticosteroids.

Footnotes

  1. Edsbacker, S., 1999. Pharmacological factors that influence the choice of inhaled corticosteroids. Drugs, 58(Suppl 4), pp. 7-16.
  2. Sastre, J., Mosges, R., 2012. Local and Systemic Safety of Intranasal corticosteroids, Journal of Investigations into Allergerlogical and Clinical Immunology, 22(1), pp.1-12.
  3. Chong, L., Head, K., Hopkins, C., Philpott, C., Burton, M., Schilder, A. 2016. Different types of intranasal steroids for chronic rhinosinusitis. Cochrane Database of Systematic Reviews 4. [DOI: 10.1002/14651858.CD011993.pub2].
  4. Miller-Larsson, A., Jansson, P., Runström, A., Brattsand, R., 2000. Prolonged airway activity and improved selectivity of budesonide possibly due to esterification. American Journal of Respiratory and Critical Care in Medicine, 162, pp.1455-61.
  5. Lipworth, B., Jackson, C., 2000. Safety of inhaled and intranasal corticosteroids: lessons for the new millennium. Drug Safety, 23(1), pp.11-33.
  6. Tunek, A., Sjodin, K., Hallstrom, G., 1997. Reversible formation of fatty acid esters of budesonide, an antiasthma glucocorticoid, in human lung and liver microsomes. Drugs and Metabolic Disposition, 25, pp. 1311-7.
  7. Johnson & Johnson Pacific Pty Ltd. Rhinocort (budesonide) Product Information, Most recent amendment [at time of this submission]: 2017 August
  8. Jonssön G, Åström A, Andersson P. Budesonide is metabolized by cytochrome P450 3A(CYP3A) enzymes in human liver. Drug Metabolism and Disposition 1995;23:137-42.

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