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Consultation: Miconazole and fluconazole: proposed advisory statements for medicines

24 May 2018

This consultation closed on 21 June 2018.

Invitation to comment

The TGA sought comments from interested parties on the wording of additional and amended advisory statements for labels of non-prescription medicines containing miconazole for topical oral or vaginal use, as well as for fluconazole for oral use, for inclusion in the Required Advisory Statements for Medicine Labels (RASML) document.

In particular, the additional RASML advisory statement 'Ask your doctor or pharmacist before use if you are taking warfarin, a medicine used to thin the blood, because bleeding or bruising may occur' is proposed in order to ensure that health professionals and patients are warned about the risks of drug interaction with warfarin.

Proposed amended RASML entries for medicines containing miconazole for vaginal use or topical-oral use (the proposed new additional text is indicated by bold/red text)
Column 1 Substance(s) Column 2 Conditions Column 3 Required statement(s)
Miconazole
(Entry 1 of 2)
In preparations for vaginal use
  • Seek medical advice before first course of treatment
  • See a doctor before use if you are pregnant or diabetic
  • Ask your doctor or pharmacist before use if you are taking warfarin, a medicine used to thin the blood, because bleeding or bruising may occur. 
  • See a doctor if no better after [Insert number of days as per approved Product Information] days.
  • See a doctor if problem returns.
Miconazole
(Entry 2 of 2)
In preparations for topical oral use
  • Ask your doctor or pharmacist before use if you are taking warfarin, a medicine used to thin the blood, because bleeding or bruising may occur. 
Proposed amended RASML entries for medicines containing fluconazole for oral administration
Column 1 Substance(s) Column 2 Conditions Column 3 Required statement(s)
Fluconazole In oral medicines for treatment of vaginal candidiasis
  • Seek medical advice before first course of treatment
  • Do not use if pregnant or likely to become pregnant
  • See a doctor before use if you are diabetic
  • Ask your doctor or pharmacist before use if you are taking warfarin, a medicine used to thin the blood, because bleeding or bruising may occur.
  • See a doctor if no better after [Insert number of days as per approved Product Information] days.
  • See a doctor if problem returns.

Timetable

Documents released for consultation on Thursday, 24 May 2018.

Interested parties should respond by close of business Thursday, 21 June 2018.

Feedback will be released following consideration of submissions. (see 'What will happen').

About the consultation

The recent TGA Medicines Safety Update of 20 March 2018 recommended an additional advisory statement for labels of OTC medicines containing miconazole for topical oral or vaginal use.

As the Australian Regulatory Guidelines for OTC Medicines (ARGOM) indicate that this statement is also relevant to fluconazole, the TGA proposes to update the RASML entries for both miconazole and fluconazole.

With this consultation, the TGA is seeking comments on the proposed wording of the new and amended RASML advisory statements.

Through the consultation process, the TGA is requesting comments that will help ensure that the wording of the proposed advisory statements is appropriate and supports the quality use of the medicines; and that the label changes that would be required for these medicines are made in the most convenient, efficient and cost-effective way.

Background

Medicines Scheduling

The Standard for Uniform Scheduling of Medicines and Poisons (SUSMP) sets out the level of control on the availability of medicines in Australia.  The majority of medicines that are included in the SUSMP fall under one of the following classifications: Schedule 2 - Pharmacy Medicine (available from a pharmacy without a prescription); Schedule 3 - Pharmacist Only Medicine (available from a pharmacist without a prescription); or Schedule 4 (Prescription Only Medicine). Medicines that are not included in the SUSMP are referred to as 'unscheduled' medicines (freely available from general retail outlets).

Medicines that are unscheduled or included in Schedules 2 or 3 of the SUSMP are collectively referred to either as 'non-prescription medicines', 'over-the-counter medicines' or 'OTC medicines'.

The SUSMP scheduling of miconazole for human use is currently as follows:

  • Topical preparations for dermal use for treatment of tinea pedis – unscheduled
  • Other topical preparations for dermal or nail use - Pharmacy Medicine (SUSMP Schedule 2)
  • Topical preparations for treatment of oral candidiasis – Pharmacist Only Medicine (SUSMP Schedule 3)
  • Topical preparations for vaginal use – Pharmacist Only Medicine (SUSMP Schedule 3)
  • All other preparations – Prescription Only Medicine (SUSMP Schedule 4).

The SUSMP scheduling of fluconazole is currently as follows:

  • Single-dose oral preparations containing 150 mg or less of fluconazole for treatment of vaginal candidiasis - Pharmacist Only Medicine (SUSMP Schedule 3
  • All other preparations - Prescription Only Medicine (SUSMP Schedule 4)

Advisory statements

Consumers rely on information from their health practitioner, pharmacist and medicine label in order to use medicines safely and effectively. However, the enhanced access and availability of OTC medicines means that consumers may not always receive comprehensive advice from a practitioner or pharmacist.

In the context of self-medication, the medicine label is the primary source of information for the consumer; so the label must contain the directions and advisory statements that are needed for safe and effective use of these medicines.

The TGA Labelling Orders require medicine labels to include 'warning statements' where these apply to the medicines, including any advisory statements specified in the instrument made under subsection 3(5A) of the Therapeutic Goods Act 1989 ('the Act'), as in force from time to time.

The Required Advisory Statements for Medicine Labels (RASML)

The RASML is registered on the Federal Register of Legislative Instruments under subsection 3(5A) of the Act, as the Medicines Advisory Statements Specification ('the Specification'). The RASML sets out the advisory statements that are required to be included on the labels of specified medicines.

The current version of the Specification is the Medicines Advisory Statements Specification 2017 (MASS 2017). The MASS 2017 incorporates two versions of the RASML (currently RASML No. 3 and RASML No. 4) as schedules 1 and 2, respectively, to allow for a transition period for adoption of new advisory statements onto medicine labels. RASML No. 3 is the current version. RASML No. 4 will come into effect on 1 January 2019

The advisory statements required by the RASML are designed to inform consumers about specific risks related to the use of medicines that have been identified during development and evaluation of new medicines, or subsequent pharmacovigilance activities, testing, adverse event reports or from other scientific or clinical information.

The RASML permits the wording of the actual statements that are included on medicine labels to differ from the wording set out in the RASML, as long as the intent is the same.

The RASML currently only requires warning statements for miconazole when formulated in topical preparations for vaginal use. These statements are as follows:

  • See a doctor if you are pregnant or diabetic.
  • Seek medical advice before first course of treatment.
  • See a doctor if no better after [Insert number of days as per approved Product Information] days.
  • See a doctor if problem returns.

The RASML currently requires the following five warning statements for fluconazole in oral medicines (fluconazole is only scheduled OTC in oral preparations for vaginal candidiasis - see under ‘Medicines Scheduling’ above):

  • Do not use if pregnant
  • See a doctor before use if you are diabetic
  • Seek medical advice before first course of treatment
  • See a doctor if no better after [Insert number of days as per approved Product Information] days.
  • See a doctor if problem returns.

Australian Regulatory Guidelines for OTC Medicines (ARGOM) – current requirements for labels for antifungal medicines

The guidance regarding Antifungal Agents in ARGOM Appendix 5 states that miconazole and fluconazole have been shown to increase international normalised ratio (INR) levels in patients taking warfarin, via inhibition of CYP2C9; and that the labels or package inserts of topical oral miconazole, topical vaginal miconazole and oral fluconazole products should therefore include a statement to the following effect:

'Ask your doctor or pharmacist before use if you are taking warfarin or other anticoagulants, because bleeding or bruising may occur',

The preparations for topical oral use and topical vaginal use are affected by this issue because systemic absorption of miconazole will occur via the oral or vaginal mucosa, as well as via unavoidable swallowing of the topical-oral products.

Proposed additional RASML statement for miconazole preparations for topical-oral and topical vaginal use, and for fluconazole for oral use

In the recent TGA Medicines Safety Update (MSU), Volume 9, No. 1, February –March 2018 the TGA published an article that proposed to strengthen warnings about the interaction between warfarin and miconazole. Inhibition of CYP2C9 by miconazole can result in reduced warfarin clearance – leading to supra-therapeutic INR values and to subsequent bleeding complications that can have fatal outcomes.

As foreshadowed in the MSU article, the TGA now proposes that the RASML be updated to include a mandatory warning statement for miconazole preparations for topical-oral and topical vaginal use, and for fluconazole for oral use, as follows:

Ask your doctor or pharmacist before use if you are taking warfarin, a medicine used to thin the blood, because bleeding or bruising may occur.

Additional changes

For fluconazole for oral use, the TGA also proposes to take this opportunity to update the statement 'Do not use if pregnant' to 'Do not use if pregnant or likely to become pregnant' for consistency with the requirements of Therapeutic Goods Order No 92 Standard for labels of non-prescription medicines (as fluconazole is included in category 'D' of the TGA 'Prescribing medicines in pregnancy database').

Since miconazole is in pregnancy Category A, and the relevant preparations are topical, there is no need to amend the current requirements in regards to persons 'likely to become pregnant'. However, for miconazole for topical vaginal use, the TGA proposes to take this opportunity to amend the current statement 'See a doctor if you are pregnant or diabetic' to 'See a doctor before use if you are pregnant or diabetic', for consistency with the wording of the current statement 'See a doctor before use if you are diabetic' that is required for fluconazole.

Submissions

Submissions may address the proposed advisory statements and other identified issues. In addition, submissions might include:

  • Whether or not you support the wording of the advisory statement. If you do not support the wording of the statement you may make suggestions for an alternative acceptable to you.
  • An assessment of how the proposed change will impact on you. That is, what do you see as the likely benefits or costs to you (these may be financial or non-financial). If possible, please attempt to quantify these costs and benefits.

Enquiries

Enquiries should be directed via email to

What will happen

All submissions will be placed on this website unless marked confidential or indicated otherwise in the submission form (see Privacy information).

Submissions will be reviewed by the TGA and feedback on submissions will be provided through this website.

It is proposed that the advisory statements will be included in the next update to the RASML (‘RASML 5’), with an anticipated date of publication on the FRLI in January 2019, and an anticipated date of effect 18 months later (i.e. July 2020) to allow affected sponsors time to update their labels. However, the TGA will expect that all new medicines registered by the TGA from the date of publication of the outcomes of this current consultation will include all the requirements.

Privacy information

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