1 Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #29 March 2020)
1.4. Interim decision in relation to adapalene
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Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to down-schedule adapalene in topical preparations by amending the current Poisons Standard as follows:
Schedule 4 - Amend Entry
Schedule 3 - New Entry
Appendix H - New Entry
Index - Amend Entry
Proposed date of effect of the proposed amendment
1 June 2021
Reasons for the interim decision (including findings on material questions of fact)
In making this interim decision, the Delegate considered the following material:
- The application to amend the current Poisons Standard with respect to adapalene;
- Advisory Committee on Medicines Scheduling's advice;
- The public submissions received in response to the pre-meeting consultation;
- Section 52E of the Therapeutic Goods Act 1989, in particular (a) the 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 of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance;
- Scheduling handbook: Guidance for amending the Poisons Standard; and
- Scheduling Policy Framework (SPF 2018).
Summary of ACMS advice/recommendations to the Delegate
The Committee recommended the down-scheduling of adapalene to Schedule 3 in the Poisons Standard as follows:
Schedule 4 - Amend Entry
Schedule 3 - New Entry
Appendix H - New Entry
Index - Amend Entry
The Committee recommended that the TGA amend the Required Advisory Statements for Medicine Labels (RASML) statement to align with the Consumer Medicines Information Leaflet.
The Committee also recommended an implementation date of 1 June 2021.
The reasons for the advice included:
- the risks and benefits of the use of a substance
- Adapalene is associated with localised skin reactions.
- Main risk is associated with use in pregnancy and breastfeeding as adapalene is potential teratogenicity.
- Skin irritation and photosensitivity are common adverse events especially in the first weeks of treatment;
- No photocarcinogenicity studies have been conducted, however there are concerns based on animal laboratory studies of other retinoids that exposure to UV sunlight may be associated with increased risk; and
- Effective topical treatment for acne vulgaris.
- the purposes for which a substance is to be used and the extent of use of a substance
- Mild acne.
- Used for acne vulgaris - treatment of comedo, popular and pustular acne on the face, chest or back.
- Extent of use - very widely used especially in adolescents; long history of use (more than 20 years - first registered November 1995).
- the toxicity of a substance
- Low systemic toxicity when used topically.
- Retinoids as a class are known to be teratogenic, although no teratogenic effects were seen in animals when administered orally at up to 120x the maximum daily human topical dose.
- Cutaneous use up to 150 x maximum daily human topical dose showed no teratogenic effects therefore indicating a margin of safety.
- the dosage, formulation, labelling, packaging and presentation of a substance
- Concentration cut-off of 0.1% will prompt medical referral to patients unresponsive to single ingredient or low strength combination adapalene products.
- Proposed labelling was not provided by applicant however warning statements regarding pregnancy, breastfeeding, skin irritation, use of sunscreen and expectations of therapy are appropriate.
- the potential for abuse of a substance
- Adapalene may be used off-label for cosmetic (anti-aging) purposes, however the Schedule 3 classification will be restricted to human therapeutic use thereby prohibiting the over-the-counter supply by pharmacists for this purpose.
- any other matters that the Secretary considers necessary to protect public health
Reasons for interim decision
I have made an interim decision to down-schedule adapalene to Schedule 3 of the Poison Standard with restrictions on the preparation and indication. The reasons for my decision are set out below.
Adapalene is a topical retinoid indicated for comedo, papular or pustular acne of the face, chest and back. It is a potent modulator of cellular differentiation, keratinisation and inflammatory processes, all of which are features in the pathology of acne vulgaris. I made a decision to restrict the indication to acne vulgaris to capture the current approved indication.
Based on my reading of the available data, the most significant area of concern is teratogenicity associated with adapalene use during pregnancy. Adapalene is classified as a Category D medicine, which means it is in a class of medicines, which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. I have taken into account that the evidence demonstrates that cutaneous use up to 150 times the maximum daily human topical dose showed no teratogenic effects indicating there is a margin of safety. I recognise that there may be individual factors such as damaged skin barrier or excessive use that could contribute to increased systemic exposure. I am satisfied that pharmacists are suitably qualified to be able to assess and counsel patients to ensure the quality use of adapalene under a Schedule 3 classification. I am additionally reassured that product labelling, implemented through other legislation, is a mitigating factor to protect against the risks to pregnancy. On the balance of evidence, I am satisfied that adapalene, when supplied in a topical preparation is associated with very low systemic exposure and is substantially safe with pharmacist intervention to ensure its quality use.
My decision to include an age restriction in the Schedule 3 entry for adapalene was made on the basis that the safety and efficacy of adapalene use in children below 12 years has not been established.
I agree with the proposed 0.1% concentration cut-off as proposed by applicant. I consider 0.1% to be a relatively low cut off in the context of products currently available on the market. Consumer consultation with a pharmacist is necessary to reinforce and/or expand on aspects of the safe use of adapalene at the proposed concentration. I am satisfied that, with pharmacist intervention, supply single ingredient preparations, and the low strength combination preparation can be supplied without medical practitioner intervention.
I have made a decision not to support the applicant's proposal to include cosmetic use in the Schedule 3 entry because the safety and efficacy of adapalene for cosmetic use has not been demonstrated. I have had particular regard for the public submission from the College of Dermatologists who were firmly opposed to the inclusion of cosmetic use. I understand that pharmacists are not trained to consult on cosmetic medicine. I am concerned that the off-label supply of adapalene by a pharmacist for cosmetics purposes may result in poor management and an increase in adverse events. I find that the inclusion of cosmetic use in the Schedule 3 entry to be problematic as it is more likely to exacerbate off-label use for cosmetic purposes rather than for medicinal treatment of acne. It may imply that the product can be used for photo-aging, blemishes or other off label uses.
I have deliberated on the appropriateness of adapalene for advertising given its teratogenic properties. Having considered the matters set out in the Guidelines for advertisements for medicines containing Schedule 3 substances I am satisfied that the risks of teratogenicity are low in topical preparations and that any risk can be controlled through pharmacist counselling and product labelling. It is my opinion that the risks associated with teratogenicity will not be exacerbated by advertising.
I have made a decision not to include adapalene in Appendix M. I am satisfied that adapalene meets the Scheduling Factors under a Schedule 3 classification and that additional controls through inclusion in Appendix M are not necessary.
I have not made a decision on the RASML statements, as they are not relevant to the matters, which I must consider under section 52E of the Therapeutic Goods Act 1989. Accordingly, I have not given any weight to the ACMS advice insofar as it relates to the RASML statements and they were not material to my decision.
I agree with the Committee's finding that the relevant provisions of section 52E of the Therapeutic Goods Act 1989 are (a) the 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 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.
I have decided the appropriate implementation date is 1 June 2021 to allow a transition time for labelling changes to be made.