2.2. Interim decision in relation to sarolaner

Interim decisions on proposed amendments referred to the Advisory Committee on Chemicals Scheduling (ACCS #25, June 2019)

Interim decision in relation to sarolaner

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to amend the current Poisons Standard in relation to sarolaner as follows:

Proposed date of effect of the proposed amendment

1 February 2020

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Scheduling history | Australian regulations | International regulations | Substance summary | Summary of pre-meeting public submissions | Summary of ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to amend the current Poisons Standard with respect to sarolaner was considered. The application proposed to amend the current Schedule 5 entry for sarolaner to include topical veterinary medicines.

The Applicant's proposed amendments to the Poisons Standard were:

The Applicant's main points provided in support of the proposed amendment were as follows:

• The spot-on product line, XXXXXX, containing 60 mg/mL selamectin plus 10 mg/mL sarolaner, has a significantly reduced acute oral toxicity to sarolaner per se which, together with other acute toxicity endpoints for sarolaner, does not meet the Scheduling Policy Framework (SPF)^[24] criteria for Schedule 6.
• Sarolaner is in Schedule 6 of the Poisons Standard due to its moderate oral toxicity (LD₅₀ = 783 mg/kg bw (rats), point estimate).
• Sarolaner oral preparations containing 120 mg or less sarolaner are in Schedule 5 due to the lower content of sarolaner (4 per cent w/w) and reduced oral toxicity of the product.
• Gastro-intestinal absorption of sarolaner in cats and dogs is >85 per cent versus <55 per cent via skin absorption. Skin absorption in humans is likely to be significantly lower (estimated at <15 per cent by APVMA).
• A topical preparation containing 10 mg or less of sarolaner will therefore present a lower hazard from accidental/incidental ingestion than an oral preparation containing 120 mg or less sarolaner.
• Child-resistant packaging will reduce the risks of a child accidentally ingesting the product.
• Risks to veterinarians and adult public users of XXXXXX (containing 60 mg selamectin and 10 mg sarolaner in a 1 mL tube - max pack size) have been assessed by APVMA as negligible.
• Risks to veterinarians and the public (adults and children) from handling cats treated with the maximum recommended dose of sarolaner (2 mg/kg bw) have been similarly assessed by APVMA as negligible.
• XXXXXX meets the health & safety criteria in Section 5A of the Agricultural and Veterinary Chemicals Code Act (1994)^[25]. In addition, APVMA considers that XXXXXX meets APVMA guidelines (Toxicology, part 3, sections 5.6) for safe use as a domestic product.
• The acute oral (and dermal) LD₅₀ of XXXXXX is >2000 mg/kg bw.^[26] This is similar to the LD₅₀ for sarolaner chews for dogs containing 120 mg or less sarolaner (XXXXX) and to other isoxazoline substances (including afoxolaner, fluralaner and lotilaner), with similar toxicity and use profiles, which are all included in Schedule 5 of the Poisons Standard.
• Currently, although XXXXXX for cats containing sarolaner at 10 mg/mL meets the SPF scheduling factors for inclusion in Schedule 5, topical preparations are excluded by virtue of the specificity of the Schedule 5 entry for sarolaner (i.e. for oral preparations in dogs).

Current scheduling status

Sarolaner is currently listed in Schedules 5 and 6 of the Poisons Standard as follows:

Other members of the isoxazoline class, afoxolaner, fluralaner and lotilaner, are in the Poisons Standard as follows:

Scheduling history

On 17 March 2016, the Delegate made a delegate-only decision following consideration of an Applicant's proposal for a new Schedule 5 entry for sarolaner. The Delegate confirmed the interim decision to schedule sarolaner in Schedule 6 with a cut-off to Schedule 5 for the treatment, prevention and control of fleas and ticks in dogs in oral divided preparations each containing 120 mg or less of sarolaner per dosage unit. The reasons for the Schedule 6 entry were due to the acute toxicity profile of the substance, which met the SPF factors for Schedule 6. However, the acute poisoning risk to humans of proposed products containing 120 mg sarolaner was considered to be low, and as a result, the Delegate agreed to a 120 mg cut-off to Schedule 5. This was consistent with the Schedule 5 listing of other ectoparasiticides.

Australian regulations

• Sarolaner is not listed on the TGA Ingredient Database.
• Sarolaner is not used in human medicines. As of 7 May 2019, there are no medicines on the Australian Register of Therapeutic Goods (ARTG)^[27] that contain sarolaner as an active ingredient.
• Sarolaner is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2019^[28].
• As of May 2019, the Database of Adverse Event Notifications (DAEN)^[29] contains no reports of adverse events for products containing sarolaner as an active ingredient.
• On the 13 March 2019, there are seven (7) products containing sarolaner listed on the Public Chemical Registration Information System Search (PUBCRIS)^[30]. Six (6) of these veterinary medicine products are registered as Schedule 5 parasiticides for dogs (as chewable tablets) and one (1) is approved as an active constituent containing sarolaner.
• Sarolaner is an APVMA approved active constituent.

International regulations

• The European Chemicals Agency (ECHA) hazard classification for sarolaner is, 'Warning! According to the classification provided by companies to ECHA in CLP notifications this substance is very toxic to aquatic life with long lasting effects and is harmful if swallowed'.
• Sarolaner has been considered by the European Medicines Agency's Committee for Medicinal Products for Veterinary Use (CVMP)^[31], which has recommended the granting of a marketing authorisation for veterinary medicinal product XXXXXX, containing sarolaner at up to 120 mg per chewable tablet. On 21 February 2019, the CVMP recommended the granting of a marketing authorisation for veterinary medicinal product, XXXXXXXX, intended for use in cats (EMEA/V/C/005093, 2019).
• XXXXXX (selamectin & sarolaner) has been approved in the EU (EMEA/V/C/004194, 2016), Japan (2018) and New Zealand (A011536, 2018) and is currently under evaluation in Australia, Brazil, Canada, China and the USA.

Substance summary

Table 1: Chemical information for sarolaner

Property	Sarolaner
Chemical structure
Molecular formula	C23H18C12F4N2O5S
Molecular weight	581.36 g/mol
CAS name	Sarolaner
CAS number	1398609-39-6
IUPAC and/or common and/or other names	Ethanone, 1-[5'-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-5(trifluoromethyl)-4,5-dihydro- 1,2-oxazol-3-yl]-3'H)-spiro[azetidine3,1'-[2]benzofuran]-1-yl]-2-methanesulfonylethan-1-one. PF-6450567

Summary of pre-meeting public submissions

No public submissions were received in response to the proposed amendment.

Summary of ACCS advice/recommendations to the Delegate

The Committee recommended that the Schedule 5 entry for sarolaner be amended as follows:

The Committee also recommended an implementation date of 1 February 2020.

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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice included:

1. risks and benefits of the use of a substance:
   • Benefits:
     • Benefits for companion animals and owners.
   • Risks:
     • Risk controlled by package size and dosage.
2. the purpose for which a substance is to be used and the extent of use:
   • Safe use of ectoparasiticide by pet owners.
3. the toxicity of a substance:
   • Safety margin is sufficient to allow a lower schedule for the type of preparation under consideration i.e. Schedule 5 rather than the parent schedule for sarolaner, which is Schedule 6 due to the acute oral toxicity of the substance itself.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Child resistant unit dose packaging reduces risk of accidental ingestion by a child such that a lower schedule is appropriate (Schedule 5 rather than Schedule 6).
   • The Schedule 5 entry already limits the allowable dose per unit to 120 mg and the current scheduling consideration relates to a product with at most 10 mg per unit dose.
5. the potential for abuse of a substance:
   • Nil.
6. any other matters that the Secretary considers necessary to protect public health:
   • Nil.

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to sarolaner;
• Advisory Committee on Chemicals Scheduling's advice;
• Section 52E of the Therapeutic Goods Act 1989, in particular: (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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• The Australian Health Ministers' Advisory Council's Scheduling Handbook (V 1.0, January 2018).

Reasons for the interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the scheduling factors for Schedule 5.

I have made the decision to amend the current Poisons Standard by amending the Schedule 5 entry for sarolaner and I have set out my reasons below.

I am in agreement with the Applicant's proposal that the removal of the reference to the specific indication (i.e. 'treatment, prevention and control of fleas and ticks') in the Schedule entry is acceptable on the basis that veterinary use is unlikely to have a significant impact on the risk to human toxicity. In making my decision, I have considered that sarolaner is unlikely to be used to treat or prevent conditions other than ectoparasite infestation in animals and that the upper limit on the amount of sarolaner per dosage unit precludes use for very large animals (e.g. non-companion animal).

I consider the critical issue for human toxicity to be the amount of sarolaner which may be accidently ingested or the amount of exposure from contact with topically applied product. I am of the opinion that limiting the maximum quantity per dosage unit and requiring the dosage form to be a 'divided preparation' will mitigate this risk through both formulation and packaging. This will also limit human exposure to a single unit at a time, either through normal use or through accidental ingestion.

I also acknowledge that the Schedule 5 listing will ensure new products are subject to regulatory approval by the APVMA. This will further mitigate public health risks by ensuring that child resistant packaging is used. I am in agreement with the Committee's advice that removal of a reference to the intended route of administration is acceptable, given the assessment considered both oral ingestion and topical application. I am satisfied that the Schedule 5 scheduling factors are met in this instance.

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