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Scheduling delegate's final decisions, June 2017

Scheduling medicines and poisons

29 June 2017

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1.5 Flurbiprofen

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

Advisory Committee on Medicines Scheduling (ACMS #20)

1.5 Flurbiprofen

Referred scheduling proposal

An application was submitted to down-schedule flurbiprofen from Schedule 2 to unscheduled containing 0.25 per cent or less of flurbiprofen or containing 10 mg or less per dose of flurbiprofen when in undivided dosage forms.

Current scheduling status

Flurbiprofen is currently listed in Schedules 4 and 2 as follows:

Schedule 4

FLURBIPROFEN except when included in Schedule 2.

Schedule 2

FLURBIPROFEN in preparations for topical oral use when:

  1. in divided preparations containing 10 mg or less of flurbiprofen per dosage unit; or
  2. in undivided preparations containing 0.25 per cent or less, or 10 mg or less per dose, of flurbiprofen.
Scheduling history

Flurbiprofen was first included in Schedule 4 in November 1993. The committee decided to reschedule flurbiprofen in divided preparations for topical oral use containing 10 mg or less of flurbiprofen per dosage unit from Schedule 4 to Schedule 3 in February 2000. Subsequent rescheduling to Schedule 2 for this type of preparation followed in October 2002. The committee's decision was based on post-marketing safety data demonstrating that the preparation had a very low potential for causing adverse effects and no evidence of abuse or misuse.

In February and June 2010, the NDPSC considered an application to reclassify flurbiprofen to unscheduled in lozenges and liquid preparations for topical oral use. Members generally felt that the case for unscheduled access to topical oral flurbiprofen had not been made. Members agreed that there was only a small risk, but this needed to be balanced against little benefit. The committee agreed that preparations of flurbiprofen for topical oral use (10 mg or less) should remain in Schedule 2. The discussion on whether to include undivided preparations in Schedule 2 (and not unscheduled) included: a lack of experience with the use of undivided preparations in Australia; flurbiprofen had been classified as a Category C pregnancy risk and this was not appropriate for an unscheduled product; while there was only a small risk, there was little demonstrated benefit; the risk of idiosyncratic reactions to flurbiprofen. The committee confirmed the February 2010 decision to broaden the Schedule 2 flurbiprofen entry to include undivided preparations containing 0.25 per cent or less or 10 mg or less per dose of flurbiprofen.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 4 – Proposed Amendment

FLURBIPROFEN except when included or expressly excluded from Schedule 2.

Schedule 2 – Proposed Amendment

FLURBIPROFEN in preparations for topical oral use when:

  1. in divided preparations containing 10 mg or less of flurbiprofen per dosage unit; or
  2. in undivided preparations containing 0.25 per cent or less, or 10 mg or less per dose, of flurbiprofen except:
    1. in preparations containing 0.25 per cent or less of flurbiprofen; or
    2. in preparations containing 10 mg or less per dose of flurbiprofen.

The applicant's reasons for the request are:

  • The proposed rescheduling would allow the sale of throat sprays containing flurbiprofen in retail outlets other than pharmacy.
  • Although there are no 'factors' for an 'unscheduled' classification, XXXX meets or exceeds all of the factors for Schedule 2.
  • The dose of the non-steroidal anti-inflammatory drug (NSAID) in XXXX is low, at around 15% of the maximum recommended oral dose of flurbiprofen. Systemic exposure is further reduced by relatively low absorption from the oral mucosa of around 10% of the equivalent dose when swallowed.
  • NDPSC in February 2010, in relation to a proposal for unscheduled status for flurbiprofen products for topical oral use, "agreed that there was only a small risk, but this needed to be balanced against little benefit".
  • The NDPSC's conclusion on risk has been confirmed by the low number of adverse events reported in TGA's Database of Adverse Event Notifications since 2001 and the low incidence of adverse events in relation to cumulative exposure worldwide since 1976.
  • In terms of benefit, XXXX containing flurbiprofen 8.75 mg per 0.54 mL actuation was registered in September 2015 following evaluation by TGA. The approved indications are: "For relief of pain, swelling and inflammation associated with severe sore throats".
  • Efficacy was further confirmed in a recent study sponsored by the applicant/sponsor (de Looze F 2016) investigating the use of XXXX in adults with sore throat due to upper respiratory tract infection. This study concluded: "Flurbiprofen spray provides rapid and long-lasting relief from sore throat symptoms, and is well-tolerated over three days".
  • The currently marketed XXXX products include the standard label warning statements that are required for all NSAIDS, including the small packs of ibuprofen that are available for sale in supermarkets.
  • Given the low level of risk associated with flurbiprofen for topical oral use, the mitigation of that risk by appropriate labelling, the accepted efficacy of XXXX for the symptomatic treatment of sore throat and the long-standing acceptance of this condition as being suitable for self-treatment by consumers in a non-pharmacy environment, an 'unscheduled' classification is warranted.
Australian regulatory information

Currently, in Australia, flurbiprofen products are available as lozenges for the treatment of sore throats (Schedule 2) and eye drops for the treatment of intraoperative meiosis (Schedule 4).

The ARTG has flurbiprofen or its sodium hydrate salt, flurbiprofen sodium dehydrate, as the active ingredient included in 5 registered products associated with two different sponsors. The registered formulations include: 8.5 mg granules; 8.75 mg/0.54 mL throat spray solution pump metered dose aerosol; 0.03% eye drops and 300 microgram/mL eye drops; and 8.75 mg lozenge blister pack.

The current application is referring to 8.75 mg/0.54 mL throat spray solution pump metered dose aerosol.

International regulations

In the USA, flurbiprofen in eye drops and tablets are prescription medicines[20]. It was first entered as a prescription drug in 1985. No information could be found regarding flurbiprofen as an OTC product in the USA.

In Canada, flurbiprofen or its salts was entered on the Prescriptions Drugs List in December 2013 as a product for human use.[21]
In New Zealand, flurbiprofen is a prescription product except in locally acting oromucosal preparations containing 10 milligrams or less per dosage unit, which have been pharmacy-only medicines since 2010.[22]

Flurbiprofen lozenges are also marketed in countries including, New Zealand, Italy, Thailand, Poland, Australia, United Kingdom and Ireland as non-prescription medicines. In addition they are also available in several European countries as prescription medicines.

Substance summary

Flurbiprofen is a non-selective COX inhibitor. It inhibits human recombinant COX-1 and COX-2 with IC50 values of 0.04 and 0.51 µM, respectively[23]. Flurbiprofen is a white crystalline solid, molecular weight 244.3, molecular formula C15H13FO2. Flurbiprofen is a member of the phenylalkanoic acid derivative family of NSAIDs. It is used in ophthalmic solutions, throat lozenges and throat sprays. Other reported uses include orally for arthritis and dental pain. Pharmacokinetic data indicate greater than 99% protein binding, hepatic metabolism (CYP2C9), with an elimination half-life of 4.7 – 5.7 h and renal excretion.

Chemical structure of flurbiprofen

Figure 1.5: Structure of flurbiprofen (anhydrous free acid)

Flurbiprofen is a weak, monoprotic carboxylic acid (pKa 4.2), structurally related to ibuprofen. It has an anti-inflammatory effect when applied directly to the throat (de Looze 2016). Buccal absorption of flurbiprofen is low, with blood levels around 10% of those obtained from the same dose taken orally and swallowed (Gonzales-Younes 1991).

The recommended maximum daily dose of 43.75 mg (5 doses) in the throat spray is less than 15% of the 300 mg maximum recommended daily dose of flurbiprofen for oral ingestion (Martindale November 2016).

Pre-meeting public submissions

One (1) submission was received and this opposed the scheduling proposal. The main points of the submission were:

  • Schedule 2 is appropriate as it gives consumers access to professional advice to enable the determination of the nature and cause of the condition being treated.
  • Unsupervised sales of flurbiprofen would pose unnecessary and preventable risk to consumers, particularly for use in pregnancy, use in children, pre-existing health conditions and interactions with other medications.
  • A sore throat may be an indication of a more serious complication and those from demographics at higher risk of developing such complications may require referral to a doctor.
  • The public submission will be made available on the TGA website.
Summary of ACMS advice to the delegate

The committee advised that the current scheduling of flurbiprofen remains appropriate.

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

The reasons for the advice comprised the following:

  • there has been a fatal hypersensitivity reaction.
  • although other unscheduled substances are also pregnancy Category C, there is limited experience with this product.
  • no public health benefit from availability as unscheduled.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACMS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information
Delegate's interim decision

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

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • There has been a fatal hypersensitivity reaction.
  • Although other unscheduled substances are also pregnancy Category C, there is limited experience with this product.
  • Unsupervised sales of flurbiprofen would pose unnecessary and preventable risk to consumers, particularly for use in pregnancy, use in children, pre-existing health conditions and interactions with other medications.
  • No public health benefit from availability as unscheduled.
Public submissions on the interim decision

Two (2) public submissions were received that opposed the interim decision for flurbiprofen.
The main points were:

  • Both submissions suggested that the rescheduling of flurbiprofen would benefit the general public.
  • There is no evidence of inappropriate use, misuse or abuse.
  • There is only a small risk that a consumer would confuse their condition with a more serious disease/condition.
  • Flurbiprofen only carries a small risk and there is limited systemic absorption from the oral mucosa.
  • One submission suggestions that the risk of fatal hypersensitivity reaction is extremely low.
  • Appropriate warning labels for NSAIDs would reduce the risk of unnecessary and preventable risk to consumers.
Delegate's final decision

The delegate notes the two submissions not supporting the interim decision but supporting the original application. However, in view of the throat spray product having only been approved in Australia since September 2015 and ongoing monitoring of adverse events occurring with continuing requirements for annual Periodic Safety Update Report (PSUR), it is not appropriate at this time.

The delegate's final decision is that the current scheduling of flurbiprofen remains appropriate.


Footnotes

20Drugs@FDA: FDA Approved Drug Products

21Prescription Drug List

22Database of Medicine Classifications

23 J. Barnett, J., et al. Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system. Biochimica et Biophysica Acta 1209 130-139 (1994)

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