Miconazole and Fluconazole: Proposed Advisory Statements for Medicines

Consultation: miconazole and fluconazole – JUN proposed advisory statements for medicines 2018

Purpose

The Pharmaceutical Society of Australia (PSA) makes this submission to the Therapeutic Goods Administration (TGA) on the proposed advisory statements for medicines containing miconazole and fluconazole for inclusion in the Required Advisory Statements for Medicine Labels document.

About PSA

PSA is the peak national professional pharmacy organisation representing Australia’s 31,000 pharmacists1 working in all sectors and locations.

PSA’s core functions include:

 providing high quality continuing professional development, education and practice support to pharmacists

 developing and advocating standards and guidelines to inform and enhance pharmacists’ practice

 representing pharmacists’ role as frontline health professionals.

PSA is also a registered training organisation and offers qualifications including certificate and diploma-level courses tailored for pharmacists, pharmacy assistants and interns.

1 Pharmacy Board of Australia. Registrant data. Reporting period: 1 January 2018 – 31 March 2018. At: www.pharmacyboard.gov.au/About/Statistics.aspx

Recommendations

Based on available evidence and information sources, PSA’s recommendations are as follows:

1. PSA suggests the terminology used in the advisory statement relating to the potential for bleeding complications should be revised to more accurately inform consumers about how warfarin works.

2. PSA believes the proposed statements for miconazole in preparations for vaginal use are appropriate (with the additional consideration of Recommendation 1).

3. PSA recommends further strengthening of the advisory statement for miconazole for topical oral use; its use with warfarin should be listed as a contraindication.

4. For fluconazole in oral medicines for the treatment of vaginal candidiasis:

a. PSA believes the proposed addition to the pregnancy-related statement should be clarified with the inclusion of an associated timeframe

b. PSA believes the statement relating to the potential for bleeding complications is appropriate (with the additional consideration of Recommendation 1).

Background

In a recent Medicines Safety Update a reminder2 was provided to health professionals regarding the well-documented potential for interaction between miconazole and warfarin. PSA understands that, while the number of Australian cases is reportedly low, the possibility of life-threatening consequences warranted the advice. Thus amendments are proposed to update advisory statements for miconazole.

Further the consultation information3 indicates that, based on the Australian Regulatory Guidelines for OTC Medicines, updates to advisory statements for fluconazole are also considered appropriate given the common mechanism of action involved in warfarin metabolism through inhibition of the main cytochrome P450 isoenzyme, CYP2C9 (and to a lesser extent with CYP3A4).

2 Therapeutic Goods Administration. Miconazole and potential interaction with warfarin. Medicines Safety Update 2018; Feb-Mar:9(1). At: www.tga.gov.au/sites/default/files/medicines-safety-update-volume-_9-number-1-february-march- 2018.pdf

3 Therapeutic Goods Administration. Consultation: miconazole and fluconazole: proposed advisory statements for medicines. 24 May 2018. At: www.tga.gov.au/consultation/consultation-miconazole-and-fluconazole-proposed-advisory- statements-medicines

Comments on proposed updates

In this consultation, PSA understands the following amendments to existing statements or additional statements are proposed. [Note: Only the statements affected are shown in the table below.]

The purpose of the amendments is to:

 strengthen the warning statements for miconazole and fluconazole to alert patients taking warfarin regarding the potential for bleeding complications

 update the pregnancy-related statement for fluconazole for consistency.

Substance / condition Additions to existing Required statements (shown in red)

Miconazole in  See a doctor before use if you are pregnant or diabetic preparations for vaginal 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.

Miconazole in  Ask your doctor or pharmacist before use if you are taking preparations for topical warfarin, a medicine used to thin the blood, because bleeding or oral use bruising may occur.

Fluconazole in oral  Do not use if pregnant or likely to become pregnant medicines for treatment of vaginal candidiasis  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.

Terminology

As warfarin technically does not “thin the blood”, PSA suggests it would be more appropriate and informative to adopt terminology used for consumers, for example, by the Heart Foundation4 or NPS MedicineWise.5

4 National Heart Foundation of Australia. Medicines. Anticoagulant medicines. At: https://www.heartfoundation.org.au/your-heart/living-with-heart-disease/medicines

5 NPS MedicineWise. Warfarin and how to take it. At: https://www.nps.org.au/medical-info/consumer- info/warfarin?c=what-is-warfarin-c3dc24f2

For example, the statement proposed in this consultation:

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. could be reworded to:

Ask your doctor or pharmacist before use if you are taking warfarin, a medicine which helps to prevent blood clots forming and treats existing clots, because bleeding or bruising may occur.

Drug interaction with warfarin

The potential for miconazole and fluconazole to increase international normalised ratio (INR) levels in patients on warfarin therapy is known and documented in clinical references.

Miconazole for vaginal use

Although systemic absorption is usually very low in intravaginal use, miconazole has been reported to provoke an interaction (with warfarin). Appropriate monitoring is therefore needed in potentially at-risk women taking coumarins.6

Miconazole for topical oral use

The Product Information7 (PI) for miconazole (Daktarin) oral gel states the following:

Miconazole is systemically absorbed after administration as the oral gel. Administration of 60 mg dose of DAKTARIN® Oral Gel results in peak plasma concentrations of 31-49 ng/mL, occurring approximately two hours post-dose.

The PI also states that miconazole oral gel is contraindicated in combination with warfarin.

Advice provided in another reference source is that anticoagulant effects of warfarin can be greatly increased when miconazole is given as an oral gel, and bleeding can occur; therefore use should be avoided in patients taking any oral anticoagulant.6

Based on these sources of evidence and information, PSA believes the proposed warning statement for miconazole for topical oral use is not adequate. We strongly suggest strengthening the advice that its use when a person is already taking warfarin is contraindicated.

6 Preston CL ed. Stockley’s drug interactions (online). London: Royal Pharmaceutical Society; 2018.

7 Daktarin oral gel product information. At: www.medicines.org.au/files/pcpdakog.pdf

Fluconazole oral medicine for vaginal candidiasis

Fluconazole has a half-life of approximately 30 hours.8 The PI9 for fluconazole notes the interaction with warfarin and recommends careful monitoring of prothrombin time in patients taking both medicines and possibly dose adjustment of warfarin.

A possible increase in anticoagulant effect of warfarin and risk of bleeding can result from the use of single oral dose fluconazole. The associated recommendation is to monitor INR levels and reduce warfarin dose as needed.10 Similar advice is provided elsewhere on the use of single dose fluconazole although data is reportedly based on a small study.6

PSA’s guidance document for pharmacists on the provision of fluconazole as a Pharmacist Only Medicine11 currently recommends careful monitoring of INR levels for patients on warfarin therapy.

Use in pregnancy

Fluconazole is classified as pregnancy category D. As a Pharmacist Only Medicine it is used as a single dose therapy product. While the single dose regimen appears safe, PSA recommends11 that other treatment options are considered for symptomatic women who are pregnant.

With regards to the proposed addition of “likely to become pregnant” to the advisory statement for fluconazole, PSA believes there is scope to further clarify the intended meaning. Inclusion of a timeframe in relation to the administration of the single dose would help to minimise confusion.

Submitted by:

Pharmaceutical Society of Australia PO Box 42 Deakin West ACT 2600 Tel: 02 6283 4777 www.psa.org.au

Contacts:

Ms Deb Bowden, Acting Chief Executive Officer Dr Kay Sorimachi, Director Policy and Regulatory Affairs 15 June 2018

8 Sansom LN ed. Australian pharmaceutical formulary and handbook. 24th edn. Canberra: Pharmaceutical Society of Australia; 2018.

9 Fluzole product information. At: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2016- PI-02533-1

10 Australian medicines handbook. Adelaide: AMH Pty Ltd; 2018.

11 Pharmaceutical Society of Australia. Guidance for provision of a Pharmacist Only medicine: Fluconazole. 2017.