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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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3.1. Fluralaner

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the current entry for fluralaner in Schedule 5 to broaden the use to include products for external use on cats and dogs 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 5 – Amend Entry
  • FLURALANER for the treatment and prevention of flea infestations and control of ticks in dogs in oral as a topical or oral veterinary parasiticide for dogs or cats in divided preparations each containing 1400 mg or less of fluralaner per dosage unit.

The applicant's reasons for the request are:

  • Fluralaner 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 and appropriate warnings to keep the product out of reach of children.
  • Two members of the isoxazoline class, afoxolaner and fluralaner, are in Schedule 5; 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

Fluralaner is currently listed in Schedules 5 as follows:

  • Schedule 5
  • 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.

Related ectoparasiticides 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.
  • 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.
    Scheduling history

    In August 2014, the Office of Chemical Safety (OCS) [based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to register a new active ingredient and the approval of five different tablets 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 the 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"

    In October 2014, the delegate made a 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. This was implemented on 1 February 2015.

    Two other ectoparasiticides afoxolaner and sarolaner, also used for treatment of flea infestations and control of ticks in dogs, were all recently considered for scheduling:

    • In April 2014, the delegate made a 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.
    • In March 2016, the delegate made a decision to create a new Schedule 6 entry for sarolaner with a cut-off for oral divided preparations containing 120 mg or less per dose in Schedule 5. The reasons for the Schedule 6 entry were due to the toxicology profile being more consistent with Schedule 6. However, as the acute poisoning risk is low, the delegate agreed to a Schedule 5 entry, and this is consistent with other ectoparasiticides.
    Australian regulatory information

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

    Fluralaner is the active constituent of approved veterinary medicines (oral chews for dogs for the treatment and prevention of flea infestations and control of ticks). Five (5) products are currently registered by the APVMA.

    International regulations

    Fluralaner (as a chewable tablet) was approved for use in the EU and US in 2014, with the spot-on being approved in both jurisdictions in 2016. It is available as a spot-on by prescription for use on dogs and cats for the treatment of fleas and ticks for up to 12 weeks. It is available as a 280 mg/mL solution; the largest pipette contains 1400 mg.

    • In December 2013, the Committee for Medicinal Products for Veterinary Use (CVMP) of the European Medicines Agency recommended the granting of a marketing authorisation for the veterinary medicinal product XXXX chewable tablets for dogs (112.5 mg, 250 mg, 500 mg, 1000 mg, 1400 mg) containing fluralaner.
    • In May 2014, the US Food and Drug Administration (US FDA) approved fluralaner with a condition that the products containing the substance may be dispensed only by or on the lawful order of a licensed veterinarian (Rx marketing status). Adequate directions for lay use cannot be written because professional expertise is required to advise dog owners regarding use in breeding dogs, to monitor for and respond to adverse reactions, and to define the appropriate treatment interval (8 vs. 12 weeks) based on the species of ticks the dog is likely to encounter. Topical solutions are at 280 mg/mL of fluralaner, whereby application is at 25 mg/kg bw, for indications of adult flea or tick treatment.

    Fluralaner is also available as a spot-on and chewable tablet in other countries including Canada and New Zealand.

    Substance summary
    Table 3.1.1: Chemical information for fluralaner
    Property Fluralaner
    CAS number 864732-61-3
    Chemical structure chemical structure of Fluralaner
    Molecular formula C22H17C12F6N3O3
    Molecular weight 556.3 g/mol
    IUPAC and/or common and/or other names 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide (IUPAC)

    Fluralaner is a isoxazoline that has shown potent acaricidal and insecticidal activity through a dual mechanism of binding to neuronal γ-aminobutyric acid (GABA) - and glutamate-gated chloride channels in susceptible invertebrates.

    Fluralaner has high selectivity for arthropods and a very favourable safety profile in vertebrates including dogs.[56] It is a potent inhibitor of parts of the arthropod nervous system by acting antagonistically on ligand-gated chloride channels (GABA receptor and glutamate-receptor). In molecular on-target studies on insect GABA receptors of flea and fly, fluralaner is not affected by dieldrin resistance.

    Table 3.1.2: Acute toxicity end-points for fluralaner
    Toxicity Species Fluralaner SPF (2015) Classification
    Acute oral toxicity LD50 (mg/kg bw) Rat >2000 Schedule 5
    Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 Schedule 5
    Acute inhalational toxicity LC50 (mg/m3/4h) No data - N/A
    Skin irritation Rabbit Nil N/A
    Eye irritation Rabbit Nil N/A
    Skin sensitisation (Maximisation test) Guinea pig Negative N/A
    Acute toxicity

    The delegate previously considered the acute toxicity of fluralaner and no new information is available.

    Repeat-dose toxicity

    The delegate previously considered short-term studies by both the oral and dermal route of exposure in rats, the main signs associated with treatment included minor variations in haematological and blood chemistry parameters, and organ weight changes. Of the organ weight changes, the liver was the most affected with increases in liver weights associated with fatty changes (diffuse and mid-zonal). The route of exposure did not markedly change the effects seen in treated animals, with similar haematological, blood chemistry and organ weight changes in both orally and dermally treated rats. Additional treatment-related findings in the oral toxicity study included thymic atrophy, zymogen depletion in the pancreas and diffuse vacuolation/hypertrophy in the adrenal cortices at high doses. In more recent dermal and oral 28 day and 90 day repeat-dose studies in rats the main signs associated with treatment at high doses again included similar effects on the liver, thymus and adrenals, as well as the lungs (inflammatory lesions).

    Mutagenicity

    The delegate previously considered the mutagenicity of fluralaner and no new information is available. There was no evidence of a mutagenic and/or genotoxic potential in vitro, with and without metabolic activation, or in vivo.

    Genotoxicity

    The delegate previously considered the genotoxicity of fluralaner and no new information is available. Fluralaner was not genotoxic in a standard suite of in vitro and in vivo genotoxicity studies.

    Carcinogenicity

    No carcinogenicity studies have been submitted in support of fluralaner. The use pattern of the spot-on as a quarterly or half-yearly treatment in a non-food-producing use situation, and noting the relatively minor effects seen in short-term studies and the lack of any positive genotoxicity potential, the long-term toxicity potential associated with the proposed use of the active constituent as a veterinary medicine for companion animals (cats and dogs) is likely to be low.

    Reproduction and developmental toxicity

    The delegate previously considered developmental toxicity studies in the rat. Minor effects were seen in treated foetuses, such as a slight decrease in foetal bodyweights, increases in dilated renal pelvis and ureter, and supernumerary ribs. The effects, however, were at dose levels where maternal effects (decreased food consumption and bodyweight gain) were observed, suggesting foetal effects were secondary to maternal toxicity. In a more recent pivotal one-generation oral study in rats, fluralaner had effects on the thymus (reduction in weight and lymphoid atrophy) of foetuses and caused a slight reduction in implantation rates and post-implantation losses at high doses resulting in a slight reduction of living pups at the first litter check. In rabbits, high oral doses of fluralaner had effects on the foetal skeleton (cervical vertebra fusion, and reduced fore- and hind-limb ossification) as well as increases in dilated renal pelvis and ureter.

    Observation in humans

    No information provided.

    Public exposure

    The APVMA will conduct a risk assessment for users of the product as well for bystanders who may have incidental contact with the treated animal or product. The product hazard and exposure risks will be mitigated through label First Aid Instructions and Safety Directions. Any acute exposure is expected to be limited through the product being applied in small dose volumes (up to 5 mL). Also, the product will be supplied packs containing no more than two pipettes each enclosed in a child-resistant sachet (laminated polyester aluminium foil sachet). Acute exposure in the home is expected to be further limited by administration being no less than every three months for an individual animal.

    Pre-meeting public submissions

    No submissions were received.

    Summary of ACCS advice to the delegate

    The committee recommended that the Schedule 5 entry for fluralaner remains appropriate. However, a new Schedule 4 entry should be created for fluralaner, along with an amendment to the index entry as follows:

    Schedule 4 – New Entry

    FLURALANER except when included in Schedule 5.

    Index – Amend Entry

    FLURALANER
    cross-reference: CARBAMOYL BENZAMIDE PHENYL ISOXAZOLINE

    Schedule 4
    Schedule 5

    The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.

    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; 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: there is uncertainty around the human exposure risk and indirect exposure from contact with treated animals.
    • Benefit: fluralaner shows longer-lasting flea and paralysis tick prevention compared to other available products.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • The proposed use in topical spot-on preparations is likely to result in it being perceived by the public to be as safe as other scheduled spot-on flea treatments that are in wide use and have a relatively longer market history in Australia.
  • the toxicity of a substance:
    • The evaluation of the new data since the previous scheduling decision is incomplete.
    • There is no human exposure estimation or risk assessment provided.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • The topical formulation compared to the oral formulation may contribute to unacceptable public exposure and higher MOEs, including from scheduled excipients, and so requires scheduling at a higher level than the current oral formulation.
    • The proposed formulation may present increased risks of accidental exposure compared to the oral formulation.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • Refer to the >previous scheduling decision.
    • There has been reported misuse of existing pet spot-on flea preparations for the treatment of head lice in children in Australia.
    • The recommendation for Schedule 4 is consistent with decisions from international jurisdictions.
    Delegate's considerations

    The delegate considered the following regarding this proposal:

    Delegate's interim decision

    The delegate’s interim decision is to create a new Schedule 4 entry for fluralaner, along with a cross-reference in the index to carbamoyl benzamide phenyl isoxazoline. The proposed Schedule entry is:

    Schedule 4 – New Entry

    FLURALANER except when included in Schedule 5.

    Index – Amend Entry

    FLURALANER
    cross-reference: CARBAMOYL BENZAMIDE PHENYL ISOXAZOLINE

    Schedule 4
    Schedule 5

    The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.

    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; and (f) any other matters that the Secretary considers necessary to protect public health.

    The reasons for the interim decision are the following:

    1. the risks and benefits of the use of a substance:
    • Risks: there is uncertainty around the human exposure risk and indirect exposure from contact with treated animals.
    • Benefit: fluralaner shows longer-lasting flea and paralysis tick prevention compared to other available products.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • The proposed use in topical spot-on preparations is likely to result in it being perceived by the public to be as safe as other scheduled spot-on flea treatments that are in wide use and have a relatively longer market history in Australia.
  • the toxicity of a substance:
    • The evaluation of the new data since the previous scheduling decision is incomplete.
    • There is no human exposure estimation or risk assessment provided.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • The topical formulation compared to the oral formulation may contribute to unacceptable public exposure and higher MOEs, including from scheduled excipients, and so requires scheduling at a higher level than the current oral formulation.
    • The proposed formulation may present increased risks of accidental exposure compared to the oral formulation.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • Refer to the previous scheduling decision.
    • There has been reported misuse of existing pet spot-on flea preparations for the treatment of head lice in children in Australia.
    • The recommendation for Schedule 4 is consistent with decisions from international jurisdictions.

    Footnotes

    1. Fluralaner, a novel isoxazoline, prevents flea (Ctenocephalides felis) reproduction in vitro and in a simulated home environment (link is external). Heike Williams, David R Young, Tariq Qureshi, Hartmut Zoller, and Anja R Heckeroth. Parasit Vectors. 2014; 7: 275. Published online Jun 19, 2014. doi:10.1186/1756-3305-7-275.

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