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Scheduling delegates' interim decisions and invitation for further comment: ACCS/ACMS, November 2017

Scheduling medicines and poisons

5 February 2018

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1.9. Clotrimazole

Referred scheduling proposal

An application was submitted to amend the Schedule 2 and Schedule 4 entries and to delete the Schedule 3 and Appendix H entries for clotrimazole in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

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

Schedule 2 – Amend Entry

CLOTRIMAZOLE for human use in vaginal preparations, dermal preparations and for application to the nails except in preparations for the treatment of tinea pedis.

Schedule 3 – Delete Entry

CLOTRIMAZOLE in preparations for vaginal use.

Schedule 4 – Amend Entry

CLOTRIMAZOLE except:

  1. when included in Schedule 2, 3 or 6; or
  2. in preparations for dermal use for the treatment of tinea pedis.

Appendix F, Part 3 Warning Statements – Amend Entry

CLOTRIMAZOLE in vaginal preparations when included in Schedule 32.

Appendix H –Delete Entry

CLOTRIMAZOLE.

The applicant's reasons for the request are:

  • Topical preparations containing clotrimazole are well-established as appropriate medicines for consumer self-selection, as demonstrated by their broad self-select availability in both pharmacy and non-pharmacy outlets in most markets worldwide.
  • Clotrimazole vaginal preparations have been available in the USA and UK as an unscheduled medicine since 1990 and 2004 respectively, and have progressively been switched to general sale self-select medicines in other major markets.
  • Clotrimazole has been available in Australia as a Schedule 2 medicine for the topical treatment of fungal infections since 1991. It is also an unscheduled medicine for dermal tinea pedis infections since 2005, with no new safety issues being identified.
  • The predicted public health benefits from the proposal are an increase in women's health literacy and a facilitated positive shift in Australian women's intimate health management.
  • Quality use of medicines can be achieved through well-designed labelling. There is a need to update the labelling of clotrimazole vaginal preparations to focus on accurate symptom identification including accurate self-treatment information and directions to consult a health care professional in cases of:
    • recurring episodes;
    • apparent atypical symptoms of vulvovaginal candidiasis;
    • symptoms being indicative of another causative pathogen; or
    • treatment failure.
  • The rescheduling of vaginal clotrimazole to Schedule 2 will improve access and increase flexibility in self-selection of effective treatments for women with uncomplicated vulvovaginal candidiasis. Clotrimazole vaginal preparations have been available internationally in more than 70 countries as self-select medicines for almost 30-years without any evidence of safety issues. Whilst pharmacists are generally well-equipped and skilled at having personal conversations in private spaces, the down-scheduling proposal represents a long-overdue regulatory change resulting in an end to barriers to access and potential delays in treating vulvovaginal candidiasis for many Australian women.
Current scheduling status

Clotrimazole is currently listed in Schedules 2, 3, 4 and 6 and Appendices F and H of the Poisons Standard as follows:

Schedule 2

CLOTRIMAZOLE for human use in dermal preparations and for application to the nails except in preparations for the treatment of tinea pedis.

Schedule 3

CLOTRIMAZOLE in preparations for vaginal use.

Schedule 4

CLOTRIMAZOLE except:

  1. when included in Schedule 2, 3 or 6; or
  2. in preparations for dermal use for the treatment of tinea pedis.

Schedule 6

CLOTRIMAZOLE for the external treatment of animals.

Clotrimazole is also included in Appendix F and Appendix H as follows:

Appendix F, Part 3

CLOTRIMAZOLE in vaginal preparations when included in Schedule 3.

Warning Statements: 54 (Seek medical advice before first course of treatment); 63 (See a doctor if you are pregnant or diabetic); 64 (See a doctor (or) (dentist) if no better after (Insert number of days as per approved Product Information) days); 66 (See a doctor if problem returns).

Appendix H

CLOTRIMAZOLE.

Scheduling history

Clotrimazole was first scheduled in August 1977. Clotrimazole has an extensive scheduling history since 1985. The scheduling history relevant to vaginal preparations have been presented below.

The August 1977, the Drugs and Poisons Schedule Standing committee (DPSSC) included clotrimazole in Schedule 4.

In April 1994, the National Drugs and Poisons Schedule Committee (NDPSC) agreed to down-schedule preparations of clotrimazole for vaginal use to Schedule 3 to give its current entry. Following out-of-session consideration, the committee also agreed to include the current warning statements in Appendix F for clotrimazole when included in Schedule 3.

In November 1996, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. The committee did not support the rescheduling application.

In February 1997, the NDPSC considered the post-meeting comment concerning the November 1996. The committee agreed that the November 1996 decision remained appropriate and that clotrimazole for vaginal use should remain in Schedule 3.

In August 1998, the NDPSC considered a submission to include miconazole in Appendix H, and decided to allow other antifungals currently included in Schedule 3 to be advertised by including them in Appendix H. These substances were clotrimazole, econazole, miconazole and nystatin.

In February 2006, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. After consideration of the new data presented, the committee agreed that the current scheduling of clotrimazole remained appropriate. The committee noted that maintaining mandatory pharmacist involvement in the sale of clotrimazole was needed to fully address the committee's concerns, particularly the risk of repeated clotrimazole use masking an underlying serious condition.

In February 2007, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. The committee agreed that the current scheduling of clotrimazole for vaginal use remained appropriate. Maintaining mandatory pharmacist involvement in the sale of clotrimazole was needed to fully address the committee's concerns, particularly the risk of repeated clotrimazole use masking an underlying serious condition without referral to a pharmacist or doctor or being used incorrectly on non-fungal vaginal infections or conditions.

Australian regulatory information

Clotrimazole is listed in 85 entries on the Australian Register of Therapeutic Goods (ARTG). The products marketed include creams in varying strengths and quantities (including in combination with hydrocortisone), capsules for oral use and pessaries for internal use.

In the last 30 years there have been 141 adverse event reports in the Database of Adverse Events Notification (DAEN) - Medicines: 95 cases with a single suspected medicine and no cases resulting in death.

According to the TGA Ingredient Database, clotrimazole is available for use as an:

  • Active Ingredient in: Biologicals, Export Only, Over the Counter, Prescription Medicines; and
  • Excipient Ingredient in: Biologicals, Devices, Prescription Medicines.
International regulations
New Zealand

Clotrimazole is listed as a prescription medicine in New Zealand, with the exception of preparations for vaginal (restricted) or external use (Pharmacy Only and General Sale).

United States of America (USA)

The USA Food and Drug Administration regulate preparations of clotrimazole as prescription and over-the-counter medicines, based on formulation type and indication. There are a number of lozenges and creams available on prescription, with creams for internal use available over-the-counter.

Canada

Clotrimazole vaginal preparations are available over-the-counter in Canada.

European Union

Clotrimazole is listed in Annex I in the EU for cutaneous use at 1% w/w.

Substance summary

Clotrimazole is an antimycotic drug with activity against the yeast Candida albicans, and lesser activity against other species of Candida. It was first approved in Australia 50 years ago for topical use, and has continued to be available for treatment of mucocutaneous fungal infections in dermal creams and solutions and vaginal creams and pessaries.

Table 1.9.1: Chemical information of clotrimazole
Property Clotrimazole
CAS name Clotrimazole
CAS number 23593-75-1
IUPAC and/or common and/or other names

1-[(2-chlorophenyl)-diphenylmethyl]imidazole (IUPAC);

Clotrimazole (INN);

Chemical structure
Molecular formula C22H17ClN2
Molecular weight 344.8 g/mol
Pharmacology

Clotrimazole is an imidazole derivative with a broad spectrum antimycotic activity arising from inhibition of ergosterol synthesis. This leads to structural and functional impairment of the cytoplasmic membranes of dermatophytes, yeasts and moulds.

Clotrimazole is an antimycotic drug with excellent activity against Candida albicans, and lesser activity against other species of Candida. Clotrimazole also acts on Trichomonas vaginalis. The minimum inhibitory concentration (MIC) is approximately 10-1000 times greater than for Candida albicans. With MICs intermediate to that of Candida sp. and Trichomonas vaginalis, clotrimazole also have activity on gram-positive (Streptococci sp. / Staphylococci sp.) and gram-negative bacteria (Bacteroides sp. / Gardnerella vaginalis).

Primarily-resistant fungal variants to clotrimazole are very rare, and secondary fungal resistance has only been observed in very isolated cases.

A maximum of 10% of the dose of vaginally applied clotrimazole is said to be absorbed systemically. Various pharmacokinetic studies with XXXXXX pessaries demonstrated maximum clotrimazole plasma concentrations 10 to 72 hours post administration of only 10 µg/mL. Similar maximum plasma concentrations were detected after application of XXXXXX vaginal cream.

Clotrimazole is metabolised extensively in the liver to inactive compounds. The primary route of excretion is likely to be via the faeces, given urinary excretion of dermally-applied XXXXXX cream.

Toxicity

No carcinogenicity or mutagenicity has been observed in animal studies. Administration of XXXXXX vaginal preparations to a small number of women in the 2nd and 3rd trimesters of pregnancy was not associated with obvious untoward effects on the course of the pregnancy or on the foetus. Clotrimazole is classified as a pregnancy Category A medicine. There are no contraindications, other than hypersensitivity, for XXXXXX vaginal preparations. There are no precautions for use that have urgent/serious clinical consequences with common and/or high-risk coexisting diseases, treatments or conditions.

Current use pattern in Australia

Medications available in Australia are now limited to formulations for topical treatment and prevention of mucocutaneous fungal infections. Dermal creams and solutions are commonly used for fungal skin infections including tinea pedis, nappy rash, candididal balanoposthitis and facial, flexural or scrotal seborrheic dermatitis. Vaginal clotrimazole creams and pessaries are used to treat vulvovaginal candidiasis which is primarily caused by Candida albicans. Atypical Candida sp. is isolated in only 5% of women with vulvovaginal candidiasis (VVC).

Pre-meeting public submissions

Five (5) public submissions were received, one (1) that supported and four (4) that opposed the scheduling proposal.

Main points in support:
  • Clotrimazole is effective and has a well-established safety profile.
    • Clotrimazole is an antimycotic drug with proven efficacy against Candida albicans, and lesser activity against other species of Candida.
    • VVC is a prevalent women's health issue, with 70-75% of women experiencing at least one episode (and with 82% of women with VVC being repeat sufferers). VVC is also a source of embarrassment, with this embarrassment being reported as a contributing factor leading to delays in seeking treatment. However, the symptoms of VVC are easily recognised and can be simply treated with clotrimazole.
  • Identification and treatment of VVC, without mandatory recourse to a pharmacist, is something that consumers can reasonably be expected to manage.
    • Clotrimazole was first approved in Australia 50 years ago for topical use and continues to be available for the treatment of mucocutaneous fungal infections, in dermal creams, solutions, vaginal creams and pessaries.
    • Clotrimazole has been available in Australia as a Schedule 2 medicine for the topical treatment of fungal infections since 1991, and as an unscheduled medicine for dermal tinea pedis infections since 2005.
    • The long history of Schedule 3 availability means that women will be familiar with the product and not all women will require pharmacist counselling at the point of purchase.
  • Clotrimazole in vaginal preparations meets the scheduling factors for Schedule 2 medicines as set out in the Scheduling Policy Framework (SPF):
    • Women who have been previously diagnosed with VVC will be capable of recognising their VVC symptoms without pharmacist verification.
    • Clotrimazole has a well-established safety profile, low systemic absorption when used vaginally and there are no reports of Candida spp. resistance.
    • There is no evidence of dependence, misuse or abuse.
    • Clotrimazole has a well-established safety profile and a very low ADR rate.
    • While the risk of masking a serious disease is low, there is a risk of delaying the diagnosis of a non-Candidal infection by a few days. It is very unlikely, however, that a short delay in diagnosis will have any material impact on the clinical prognosis of any likely alternative conditions. This risk will not be appreciably altered by a change from Schedule 3 to Schedule 2 availability and can be easily managed through label content.
  • Amending the scheduling as proposed would bring Australian's access to clotrimazole into line with other comparable markets.
    • Clotrimazole is available over-the-counter (without mandatory pharmacist intervention) in more than 70 other countries (and is available as a general sale item – GSL - in the US and the UK).
Main points opposed:
  • Patients presenting with vaginal disorders should consult a pharmacist to ensure that the diagnosis and treatment is appropriate and/or necessary. This will ensure the best option for optimal patient health outcomes.
  • Pharmacists are able to refer patients to doctors when appropriate. For example when patients are diabetic, under 16, over 60 years of age, pregnant, taking immunosuppressants, or when other vaginal conditions may be suspected.
  • Pharmacist's advice can assist in considering the patient's symptoms, treatment history, current medications and other health conditions.
  • Consultation with a pharmacist is also important to rule out common differential diagnoses such as bacterial vaginosis, candida vaginitis and trichomoniasis which have different first-line treatment options. The use of antifungal products in non-fungal vaginal infections is ineffective, may worsen the condition, and can delay diagnosis and commencement of appropriate therapy.
  • While vaginal candidiasis may be self-diagnosed in some cases, studies have shown that caution is required due to concerns around the accuracy of self-diagnosis.[43] [44] Tenni et al., 44 cited figures and findings from other research reports as follows:
    • Of women who presented with a self-diagnosed initial episode of candidiasis, only 59% actually had the condition.
    • Only 34% who self-diagnosed vaginal candidiasis were correct.
    • Women who had previously had an episode of clinically diagnosed vaginal candidiasis were no more accurate in their diagnosis than women without previous episodes.
  • Pharmacists can advise on the management of repeated episodes or vaginal candidiasis and provide recommendations on ways to minimise the risk of vaginal infections in the future.
    • Studies indicate that the relapse rate for these types of infections is high, possibly due to poor diagnosis.[45]
  • The risk of inaccurate self-diagnosis and subsequent delay in treatment for more serious underlying conditions warrants the continued mandatory oversight of a pharmacist. A pharmacist can also discuss more suitable treatment options where required.
  • A 2002 study[46]showed only a third of women who self-diagnosed vaginal candidiasis were accurate and that prior clinician-based diagnosis and reading the label do not improve women’s ability to properly diagnose vulvovaginal candidiasis.
  • Inclusion in Schedule 2 would allow greater access and therefore an increased likelihood of errors with oral treatments for vaginal thrush. These errors may result in possible gastrointestinal symptoms from ingestions of the pessary, but more importantly result in delays in effective treatment for the patient, leading to increased discomfort from and duration of symptoms.
  • Poisons information centres continue to receive calls from members of the public who have inadvertently ingested the vaginal pessary. Current packaging is not sufficiently clear and the word "pessary" is not widely understood in the community to ensure patients are using these products correctly.
    • Current risks could be minimised by improved packaging and labelling to clarify method of administration and training of pharmacists to clarify administration method with the patients at the time of purchase.
  • The economic cost of these errors is seen in cost of additional treatment for the patient, increased sick leave and greater use of health resources in the form of GP visits, hospital presentation and calls to poison information centers.
  • While some woman may feel uncomfortable discussing such conditions with a pharmacist or have privacy concerns, this is not a sufficient reason to down-schedule clortimazole in vaginal preparations, particularly given the risks. The majority of pharmacies have private consultation areas and pharmacies are encouraged to offer these areas to consumers where appropriate. Consumers can also request to have these conversations discreetly in a more private area.
    • June 2017 Pharmacy Board of Australia registrant data[47] indicates that the majority of registered pharmacists are female. In most cases, this should enable consumers to speak with a female pharmacist if they are more comfortable discussing this condition with a pharmacist of the same gender.

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

Summary of ACMS advice to the delegates

The committee recommended that the scheduling of clotrimazole 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:

  1. the risks and benefits of the use of a substance:
    • Risks: the major risk is from inaccurate self-diagnosis, or delayed treatment if the product is used to treat other vaginal infections not caused by Candidia albicans.
    • Benefits: clotrimazole is a safe and effective treatment for vulvovaginal candidiasis caused by Candidia albicans.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Clotrimazole in vaginal preparations are used to treat uncomplicated vulvovaginal candidiasis caused by Candidia albicans.
    • It is a first-line treatment for vulvovaginal candidiasis in current Australian guidelines along with intravaginal nystatin cream, intravaginal miconazole and oral fluconazole.
  3. the toxicity of a substance:
    • Low potential toxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Warning statements are already required for clotrimazole vaginal preparations. More detailed information on when a health professional should be consulted and the likely symptoms of conditions that will not respond to clotrimazole are proposed. However, there is evidence that women do not read the package information and that reading the label does not improve the accuracy of self-diagnosis.
    • The packaging of vaginal pessaries has been associated with an increase in oral ingestion of the pessaries. This proposal does not address this poisoning risk.
  5. the potential for abuse of a substance:
    • Low potential for abuse.
  6. any other matters that the Secretary considers necessary to protect public health
    • Clotrimazole vaginal preparations are currently included in Appendix H. The company is free to make the educational campaign that they propose.
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)
Delegate's interim decision

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

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the 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 recommendation comprised the following:

  1. the risks and benefits of the use of a substance:
    • Risks: the major risk is from inaccurate self-diagnosis, or delayed treatment if the product is used to treat other vaginal infections not caused by Candidia albicans.
    • Benefits: clotrimazole is a safe and effective treatment for vulvovaginal candidiasis caused by Candidia albicans.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Clotrimazole in vaginal preparations are used to treat uncomplicated vulvovaginal candidiasis caused by Candidia albicans.
    • It is a first-line treatment for vulvovaginal candidiasis in current Australian guidelines along with intravaginal nystatin cream, intravaginal miconazole and oral fluconazole.
  3. the toxicity of a substance:
    • Low potential toxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Warning statements are already required for clotrimazole vaginal preparations. More detailed information on when a health professional should be consulted and the likely symptoms of conditions that will not respond to clotrimazole are proposed. However, there is evidence that women do not read the package information and that reading the label does not improve the accuracy of self-diagnosis.
    • The packaging of vaginal pessaries has been associated with an increase in oral ingestion of the pessaries. This proposal does not address this poisoning risk.
  5. the potential for abuse of a substance:
    • Low potential for abuse.
  6. any other matters that the Secretary considers necessary to protect public health
    • Clotrimazole vaginal preparations are currently included in Appendix H. The company is free to make the educational campaign that they propose.

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