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Scheduling delegate's final decisions: ACCS, November 2015
Scheduling medicines and poisons
3.1 Afoxolaner and Milbemycin oxime
Part B - Final decisions on matters not referred to an expert advisory committee
3. Agriculture and veterinary chemicals
3.1 Afoxolaner and Milbemycin oxime
The applicant has applied for a reconsideration of the scheduling entry for milbemycin oxime, proposing designated as a Schedule 5 product. The applicant did not provide specific justification or argument to support their request to amend the scheduling listing for milbemycin oxime.
In August 2015 the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for registration of a new veterinary medicine, requested that the delegate consider amending the entry for afoxolaner in Schedule 5. The recommended amendment is as follows:
Afoxolaner for the treatment and prevention of flea infestations, control of ticks, gastrointestinal nematodes and heartworm in dogs in oral divided preparations each containing 150 mg or less of afoxolaner per dosage unit.
The basis for the OCS recommendation is that:
The proposed product containing 18.75 mg/g afoxolaner (and 3.75 mg/g milbemycin oxime) meets the APVMA data guidelines for domestic use products as;
- it is expected to have low acute oral and acute dermal toxicity and is considered to have low skin and eye irritancy and is not sensitising to the skin;
- it is considered that repeated use of the product will pose a low risk to the user; and
- it is considered that the proposed formulation and packaging in conjunction with recommended safety directions will further mitigate any risk to users.
The previous Scheduling consideration with regards to afoxolaner active constituent is also relevant to the current Scheduling consideration. That is that afoxolaner: was listed in Schedule 5 as a delegate only decision in April 2014. The decision to list the active in Schedule 5 was due to its low toxicity profile which was consistent with the SPF for listing in Schedule 5 and because the treatment instruction were sufficiently clear that pet owners should be able to manage the required dosage regimen without a veterinarian's oversight.
There is no evidence of an altered toxicokinetic profile or additional toxicity when afoxolaner is administered in a chewable tablet formulation at a higher rate than currently scheduled (2.5 mg/kg bw equivalent to a maximum 150 mg in the highest dose chewable) or when in a novel combination with milbemycin oxime. Studies in dogs conducted with the formulated product and submitted by the applicant indicate that there is no significant change in toxicokinetic parameters for afoxolaner when administered in combination with milbemycin oxime in a chewable formulation. The applicant provided:
- toxicokinetic studies which showed comparable toxicokinetic parameters for afoxolaner when administered alone and in combination with milbemycin oxime.
- target animal species safety studies indicating no additional toxicity up to 5 X the recommended dose when afoxolaner is administered in combination with milbemycin oxime.
An acute toxicity study with the technical forms of afoxolaner and milbemycin in combination which showed minor clinical signs (decreased defaecation, decreased size of faeces, stained urogenital and anogenital region, red material on nose or forelimb) at a dose of 1273 mg/kg bw (approximating to 1000 mg/kg bw afoxolaner and 200 mg/kg bw milbemycin oxime).In an accidental poisoning scenario, the likely maximum ingested dose by a child (entire 6-pack of the largest chewable size) would be 900 mg of afoxolaner (and 180 mg of milbemycin oxime), equivalent to 81.8 mg/kg bw afoxolaner (and 16.4 mg/kg bw milbemycin oxime) for an 11 kg child. Considering the estimated acute oral LD50 of the product (LD50 is low i.e. >>5000 mg/kg bw), the lack of evidence of increased risk when the active constituents are administered in combination and the type of product packaging proposed is considered child resistant, it is likely that there is an adequate margin in this scenario between the maximally ingested dose and the real acute oral LD50.
The OCS notes that the product meets the APVMA data guidelines for domestic use products as they are expected to have low acute oral and acute dermal toxicity and will be considered to have low skin and eye irritancy and will not be sensitising to the skin. It is also considered that repeated use of the product should pose a low risk to the user. Further, it is considered that the proposed formulation and packaging in conjunction with recommended safety directions will further mitigate the risk to users.
Consideration of the SPF criteria and application of the cascading principles outlined in the SPF indicates that the active constituent afoxolaner when administered for use in a chewable tablet formulation meets the scheduling criteria for Schedule 5 for the treatment and prevention of flea infestations, control of ticks, gastrointestinal nematodes and heartworm in dogs in oral divided preparations each containing 150 mg or less of afoxolaner per dosage unit as:
- it is non-corrosive,
- it has low toxicity,
- it has a low health hazard from repeated use,
- it does not require specialised equipment for safe use,
- there is no evidence of a significantly altered toxicokinetic profile or additional toxicity when afoxolaner is administered in a novel combination with milbemycin oxime;
- the risk mitigation measures proposed for the product (i.e. appropriate labelling to inform the consumer of safety measures to apply during handling or use and child resistant packaging) will assist to protect the user from undue harm; and
- it has a low potential for causing harm.
Toxicity of afoxolaner
Afoxolaner, a member of the isoxazoline family, binds at a binding site to inhibit insect and acarine ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA)14, thereby blocking pre- and post-synaptic transfer of chloride ions across cell membranes. Prolonged afoxolaner-induced hyperexcitation results in uncontrolled activity of the central nervous system and death of insects and acarines. The selective toxicity of afoxolaner between insects and acarines and mammals may be inferred by the differential sensitivity of the insects and acarines' GABA receptors versus mammalian GABA receptors15.
Figure 1: Structure of afoxolaner.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||LD50 > 1,000 (no deaths)|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||LD50 >2000 mg/kg bw|
|Acute inhalational toxicity LC50 (mg/m3/4h)||n/a||No study submitted|
|Skin sensitisation LLNA||Mice||Non-sensitiser|
|Target/critical effect||Reduced food consumption and body weight loss/reduced body weight gain (rats and rabbits)|
Lowest relevant oral NOEL
|10 (90-d oral, rat): based on reduced food consumption and body weight gain, numerous secondary effects on haematology, serum chemistry, urine specific gravity and volume at 50 mg/kg bw/d|
Lowest relevant dermal NOEL
|10 (56-day, rat; limited regulatory value)|
Lowest relevant inhalation NOEC
|No inhalational study submitted|
|Target/critical effect||No long-term studies submitted|
|Carcinogenicity||No studies provided, though afoxolaner, was not genotoxic in in vitro and in vivo genotoxicity studies|
Reproduction target/critical effect
Reproductive parameters unaffected by treatment. Not a reproductive toxicant in one-generation study.
Evidence of treatment-related toxicity at 20 mg/kg bw/d (reduced body weight gain and food consumption, reduced mean number of implantation sites and pups born live and litter size). Foetal death (during lactation period) and lower foetal weights.
Lowest relevant reproductive NOEL
Parental NOEL: 5 (rats), Reproductive NOEL: 5 (rats)
Offspring NOEL: 5 (rats)
|Developmental toxicity||Development unaffected by treatment. Not a developmental toxicant in rats and rabbits|
|Developmental target/critical effect||Evidence of treatment-related toxicity at 10 mg/kg bw/d (reduced food consumption and body weight gain) in dams|
Lowest relevant developmental NOEL
Maternal NOEL: 3 (rats)
Foetal NOEL: 10 (rats)
Toxicity of the product
No acute studies were submitted on the formulated product. Information available indicates the product, containing 18.75 mg/g afoxolaner and 3.75 mg/g milbemycin oxime is formulated with excipients of generally low toxicity. The expected acute toxicity was extrapolated from data on the excipients.
|Toxicity end point||Product|
|Skin irritation||Slight irritant**|
|Eye irritation||Slight irritant**|
|Skin sensitisation||Not sensitising|
* based on the toxicological profile of all ingredients in the product
** expected to be low exposure by this route, due to nature of formulation (chewable tablet) and use pattern
Observation in humans
No information was provided.
The product will be administered primarily by pet owners.
Potential users should be warned that accidental ingestion of afoxolaner can be harmful. Furthermore, while repeated dosing is unlikely to occur accidentally or inadvertently, there is no PPE that can be used to prevent such repeat exposure. The inclusion of the statement "Do not swallow" in the recommended safety directions is considered to appropriately reflect the risks associated with cumulative exposure in this case. Noting the formulation type and the intended domestic use of the product, the inclusion of the safety directions "Do not open inner pouch until ready for use" and "Wash hands after use" are also considered appropriate.
No information was provided.
Afoxolaner is listed in Schedule 5 of the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) for the treatment and prevention of flea infestations and control of ticks in dogs in oral divided preparations each containing 140 mg or less of afoxolaner per dosage unit.
In April 2014, the delegate made a delegate-only decision to list afoxolaner in Schedule 5.
This decision was based on its low acute toxicity profile which was consistent with the SPF for listing in Schedule 5.
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) is low, in part due to the proposed packaging of only six tablets in a blister pack.
The delegate also considered whether a Schedule 4 listing for afoxolaner could be more appropriate, providing for oversight of treatment by a veterinarian. The delegate indicated that because the treatment instructions are sufficiently clear that pet owners should be able to manage the required dosage regimen without a veterinarian's oversight.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- Public submissions received;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors16;
- Other relevant information.
Delegate's final decision
Schedule 5 - Amend Entries
AFOXOLANER in oral divided preparations each containing 150 mg or less of afoxolaner per dosage unit
- for the treatment and prevention of flea infestations and control of ticks in dogs; or
- for the treatment and prevention of flea infestations, control of ticks, gastrointestinal nematodes and heartworm in dogs, when combined with milbemycin oxime.
- for the prophylaxis of heartworm in dogs and cats; or
- for the treatment and prevention of flea infestations, control of ticks, gastrointestinal nematodes and heartworm in dogs, when combined with afoxolaner, in oral divided preparations each containing 150 mg or less of afoxolaner per dosage unit
While this is a re-scheduling application, and the SPF suggests that such applications be referred to an Advisory Committee, in effect the amendment sought is simply to extend the range of indications for a product where the two active ingredients are already included in Schedule 5 for the indications sought.
The delegate decided that the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 include (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The implementation date is 1 February 2016.
- 4-Azolylphenyl isoxazoline insecticides acting at the GABA gated chloride channel. Lahm et al March 2013.
- Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)