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Scheduling delegate's final decisions, October 2017

Scheduling of medicines and poisons

31 October 2017

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5.2 Lotilaner

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to create a new entry for lotilaner in Schedule 5 of the Poisons Standard.

Scheduling application

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

Schedule 5 – New Entry

LOTILANER.

The applicant’s reasons for the request are:

  • Lotilaner presents a low hazard from repeated use and is unlikely to produce irreversible toxicity or other significant toxicity.
  • The risk of accidental ingestion by a child is limited by child-resistant packaging.
  • Other members of the isoxazoline class, afoxolaner and fluralaner, are in Schedule 5 of the Poisons Standard and sarolaner is in Schedule 6, except when included in Schedule 5 (for the treatment, prevention and control of fleas and ticks in dogs in oral divided preparation each containing 120 mg or less of sarolaner per dosage unit).

Current scheduling status and relevant scheduling history

Lotilaner is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available

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

Schedule 5

AFOXOLANER in oral divided preparations each containing 150 mg or less of afoxolaner per dosage unit

    1. for the treatment and prevention of flea infestations and control of ticks in dogs; or
    2. for the treatment and prevention of flea infestations, control of ticks, gastrointestinal nematodes and heartworm in dogs, when combined with milbemycin oxime.

FLURALANER for the treatment and prevention of flea infestations and control of ticks in dogs in oral divided preparations each containing 1400 mg or less of fluralaner per dosage unit.

SAROLANER 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.

Schedule 6

SAROLANER except when included in Schedule 5.

Three other members of the isoxazoline class, afoxolaner, fluralaner and sarolaner, also used for treatment of flea infestations and control of ticks in dogs, were all recently considered for scheduling:

Fluralaner

In August 2014, the Office of Chemical Safety (OCS) [based on an application made to the APVMA to register a new active ingredient and the approval of five different tablets that containing various concentrations of fluralaner] submitted a proposal to create a new Schedule 5 listing for oral divided preparations, each containing 1400 mg or less of fluralaner per dosage unit, for the treatment and prevention of flea infestations and control of ticks in dogs. The delegate noted the following in their October 2014 final decision for fluralaner:

"Fluralaner belongs to a novel class of ectoparasiticides (isoxazoline-substituted benzamide derivatives), two other members of which have been listed in Schedule 5 (isoxaflutole and afoxolaner). The toxicology package indicates that fluralaner also has a sufficiently low acute toxicity profile to be consistent with SPF criteria for listing in Schedule 5. The acute poisoning risk to humans (in particular children) is low, partly associated with the proposed packaging of only four tablets in blister packaging. The delegate considered whether Schedule 4 listing could be more appropriate, providing for oversight of treatment by a veterinarian, noting that this is a condition imposed for registration in the USA, but in the end decided against this, on the basis that the treatment instructions are sufficiently clear that pet owners should be able to manage the required dosage regimen."

This delegate-only decision to create a new Schedule 5 entry for fluralaner in the Poisons Standard for the treatment and prevention of flea infestations and control of ticks in dogs in oral divided preparations each containing 1400 mg or less of fluralaner per dosage unit was implemented on 1 February 2015.

Afoxolaner

In April 2014, the delegate made a delegate-only decision to list afoxolaner in Schedule 5 for oral divided preparations of 1400 mg doses; this decision was based on its low acute toxicity profile. The delegate noted that more significant toxicity would be expected with repeated dosage, due to accumulation of active drug. The acute poisoning risk to humans (in particular children) was deemed low, in part due to the proposed packaging of only six tablets in a blister pack.

Sarolaner

In December 2015, an application was submitted to create a new entry for sarolaner in Schedule 5. The applications was referred to the ACCS. On 1 June 2016, a new Schedule 5 entry was created for sarolaner in oral divided preparations containing 120 mg or less per dose and a Schedule 6 entry with an exception to the Schedule 5 criteria.

Australian regulatory information

Lotilaner is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017. Lotilaner is neither an excipient nor active in any medicines on the ARTG.

Lotilaner is not listed on the Australian Inventory of Chemical Substances (AICS).

International regulations

EU: In April 2017, the European Union Committee for Medicinal Products for Veterinary Use (CVMP) granted marketing authorisation for the use of lotilaner, by prescription only, in chewable tablets intended for treatment of flea and tick infestations in dogs.

Substance summary

Lotilaner belongs to the isoxazoline family, a class of parasiticides that are potent inhibitors of gamma-aminobutyric acid-gated chloride channels (GABACls). Exposure to lotilaner results in a spastic paralysis in parasites leading to starvation and death.

Table 5.2a: Chemical information for lotilaner
Property Lotilaner
Chemical structure chemical structure of vinyl acetate
Molecular formula C20H14CI3F6N3O3S
Molecular weight 569.7 g/mol
CAS name [USAN:INN]: Lotilaner (S-enantiomer)
CAS number 1369852-71-0
IUPAC and/or common and/or other names

(S)-3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-carboxamide (IUPAC);

5-((5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl)-3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-thiophenecarboxamide

Stereochemistry S- and R- enantiomers
Table 5.2b: Acute toxicity end-points for lotilaner
Toxicity Species Lotilaner SPF (2015) Classification [56]
Acute oral toxicity LD50 (mg/kg bw) Rat >2000[57] 2/6 deaths Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000[57] (no deaths) Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) - No data -
Skin irritation Rabbit Non-irritating Appendix B
Eye irritation Rabbit Slight Schedule 5
Skin sensitisation (LLNA ) Mouse Non-sensitiser Appendix B

Acute toxicity

  • Low acute oral toxicity in rats:
    • LD50 >2000 mg/kg bw; 2/6 deaths (females tested only).
  • Low dermal toxicity in rats:
    • LD50 >2000 mg/kg; no deaths or treatment related clinical signs.
  • Acute inhalational toxicity not tested. Acceptable for oral veterinary medicine (non-dusty tablet).
  • Not a skin irritant in rabbits with no dermal findings.
  • Slight eye irritant in rabbits:
    • Effects on conjunctiva and iris fully reversed within 24 h, no corneal opacity.
  • Not a skin sensitiser in mice (LLNA).

Repeat-dose toxicity

Some treatment-related effects were observed in repeat-dose studies in rats and dogs, with dosing in rats up to 18 mg/kg bw/d (28-day oral gavage) and in dogs up to 215 mg/kg bw (8 monthly doses). A single target organ was not identified. The lowest repeat-dose NOAEL was identified in a 13-week study in rats, 5 mg/kg bw/d, based on effects on the ovaries (increased weight and microscopic findings) and lungs (microscopic) in males and females, adrenal findings (increased weight and microscopic findings) in males at 20 mg/kg bw/d. A 2-generation reproductive study in rats established a NOAEL of 5 mg/kg bw/d based on weight loss in dams, pup mortality and reduced pregnancy in rats and reduced number of implantation sites, secondary to maternal toxicity. Lotilaner was neither a reproductive nor developmental toxin in rats. Lotilaner was not genotoxic in a standard array of studies.

Genotoxicity

Non-genotoxic based on:

  • In vitro: gene mutations in bacterial cells, chromosome aberrations in mammalian cells (human lymphocytes).
  • In vivo: gene mutations in eukaryotic cells (bone marrow micronucleus test).

Carcinogenicity

No long-term or carcinogenicity studies submitted. Lotilaner was not genotoxic in in vitro and in vivo genotoxicity studies.

Reproduction and developmental toxicity

  • Reproduction was unaffected by treatment. Not a reproductive toxicant in two-generation study in rats.
  • • Evidence of treatment related toxicity at 40 (20)* mg/kg bw/d (reduced body weight gain and food consumption, reduced pregnancy rates, implantation rates, lower mean pup weight, and foetal deaths). [*High dose reduced from 40 to 20 mg/kg bw/d from Day 81 (around the time of implantation) due to marked body weight loss in F0 generation].
  • Development was unaffected by treatment. Not a developmental toxicant in rats.
  • Evidence of treatment-related toxicity at 50 mg/kg bw/d (reduced food consumption and body weight gain) in dams.

Observation in humans

The product is intended to be used by adults and a tablet is not usually removed from the packaging until just prior to pet treatment. In addition, the tablets are packed into blister compartments (1 or 3 tablets/blister). The likelihood of children accessing more than one tablet is further limited. In the worst case scenario, with the accidental oral ingestion scenario where a full high dose tablet (900 mg) were ingested by a 10 kg child, the exposure would be the equivalent of 90 mg/kg bw. For a 70 kg adult, the equivalent exposure is 13 mg/kg bw.

Considering acute studies in laboratory animals, it is evident lotilaner is of low acute toxicity, with acute oral toxicity LD50 >2000 mg/kg bw. In addition, up to 5x the recommended dose (215 mg/kg bw) was well tolerated by dogs. The risks associated with an accidental single oral exposure event to the highest strength tablet, is not considered significant.

Public exposure

The exposure to lotilaner for members of the public or veterinary professionals when treating domestic dogs is expected to be very minimal. A small amount of dermal exposure is expected when handling the tablet to administer to the dog, but inhalational and ocular contact is likely to be negligible. The risk to children accidentally ingesting a tablet is offset by child-proof packaging.

Occupational exposure

XXXX will be manufactured and imported from overseas. Occupational exposure to XXXX is expected to be limited to veterinarians and veterinary support staff dispensing tablets to animals, and dermal exposure patterns are anticipated to be similar to that observed for domestic users, although exposure events may be more frequent in a professional use situation. A quantitative estimate of occupational exposure is not considered necessary due to the minimal exposure to residues expected from handling tablets or via dog faeces/emesis.

Post-application exposure

Post-application exposure to XXXX is unlikely after ingestion of tablets by animals. Any exposure to XXXX is likely through small amounts of the active ingredient on the hands or when handling excreta (potentially including metabolites). However, both scenarios are unlikely to result in exposures at levels which are relevant from a public health standpoint.

Delegate’s considerations

The delegate considered the following regarding this proposal:

Delegate’s final decision

The delegate’s final decision is to create a new Schedule 5 entry for lotilaner as follows:

Schedule 5 – New Entry

LOTILANER.

The reasons for the final decision are:

  • Lotilaner presents a low hazard from repeated use and is unlikely to produce irreversible toxicity or other significant toxicity.
  • The risk of accidental ingestion by a child is limited by child-resistant packaging.
  • Other members of the isoxazoline class, afoxolaner and fluralaner, are in Schedule 5 of the Poisons Standard and sarolaner is in Schedule 6, except when included in Schedule 5 (for the treatment, prevention and control of fleas and ticks in dogs in oral divided preparation each containing 120 mg or less of sarolaner per dosage unit).

The implementation date is 1 February 2018.

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