Publication of interim decisions amending, or not amending, the current Poisons Standard, June 2018

Scheduling medicines and poisons

7 June 2018

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3.3 Eprinomectin

3. Advisory Committee on Chemicals Scheduling (ACCS #22)

3.3 Eprinomectin

Delegate's interim decision

The delegate's interim decision is to amend the Poisons Standard by creating a new Schedule 6 entry for eprinomectin and amending the Schedule 7 entry to reflect this change as follows:

Schedule 6 - New Entry

EPRINOMECTIN for internal use in preparations containing 5 per cent or less of eprinomectin except when included in Schedule 5.

Schedule 7 - Amend Entry

EPRINOMECTIN except when included in Schedule 5 or 6.

Proposed implementation date: 1 October 2018

The delegate considers the Committee's proposed implementation date of 1 October 2018 as being reasonable and appropriate in the circumstances.

Reasons:

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:

  1. the risks and benefits of the use of a substance:
    • Benefits: control of parasites in animals and the increased availability for use by farmers.
    • Risks: Accidental self-injection may result in injury due to moderate acute oral/dermal toxicity.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Only limited quantities are available for exposure at a single time, thus limiting risk of accidental self-injection.
    • Product will be sold through retailers servicing the rural cattle industry and not directly to the public or through retail outlets normally serving the public.
  3. the toxicity of a substance:
    • High acute oral and dermal toxicity resulting in neurological toxicity. Repeat dose toxicity NOAEL 0.8-5 mg/kg in rats/dogs.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • When packed as a divided dose preparation, exposure is highly controlled. The packaging and labelling are under APVMA control.
    • Topical preparation for use on animals and long-acting injection. APVMA regulated product.
Scheduling proposal

The pre-meeting scheduling proposal for eprinomectin was published on the TGA website on 21 December 2017 at Consultation: Proposed Amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS-ACMS meetings, March 2018.

Background information for eprinomectin
Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Poisons Standard with respect to eprinomectin. The application proposes to amend the Schedule 5 entry for eprinomectin to include 'for internal use' and to increase the cut-off from 0.5% to 5%.

Scheduling application

The proposed amendments to the Poisons Standard are:

Schedule 5 - Amend Entry

EPRINOMECTIN in preparations for internal use containing 0.5 per cent or less of eprinomectin.

The applicant's reasons for the request are:

  • The scheduling delegate may consider that the risk, hazard profile and presentation of the injectable eprinomectin product supports a proposed cut-off to Schedule 5.
  • Injectable avermectin-based products (e.g. ivermectin, doramectin) that do not require veterinarian oversight have entries in Schedule 5.
  • Registration of the injectable product containing 5% eprinomectin in Australia is pending.
Current scheduling status

Eprinomectin is listed in Schedules 5 and 7 of the Poisons Standard as follows:

Schedule 7

EPRINOMECTIN except when included in Schedule 5.

Schedule 5

EPRINOMECTIN in preparations containing 0.5 per cent or less of eprinomectin.

Related substances that are in the Poisons Standard as follows:

Schedule 7

ABAMECTIN except when included in Schedule 5 or 6.

DORAMECTIN except when included in Schedule 5 or 6.

EMAMECTIN except when included in Schedule 5 or 6.

IVERMECTIN except when included in Schedule 4 or 5.

MOXIDECTIN except when included in Schedule 4, 5 or 6.

Schedule 6

ABAMECTIN:

  1. in preparations for pesticidal use containing 4 per cent or less of abamectin except when included in Schedule 5; or
  2. in slow-release plastic matrix ear tags for livestock use containing 1 g or less of abamectin.

DORAMECTIN for external use for the treatment of animals, in preparations containing 2 per cent or less of doramectin.

EMAMECTIN in preparations containing 5 per cent or less of emamectin except when included in Schedule 5.

MILBEMECTIN except when included in Schedule 5.

MOXIDECTIN for external use:

  1. in preparations containing 2.5 per cent or less of moxidectin when packed in single dose tubes for the treatment of cats and dogs; or
  2. in preparations containing 2 per cent or less of moxidectin for the treatment of animals,

except when included in Schedule 5.

Schedule 5

ABAMECTIN

  1. in preparations, for internal use for the treatment of animals, containing 1 per cent or less of abamectin; or
  2. in gel formulations containing 0.05 per cent or less of abamectin in applicators containing 50 mg or less of abamectin.

DORAMECTIN for internal use for the treatment of animals, in preparations containing 2 per cent or less of doramectin.

EMAMECTIN in preparations containing 2 per cent or less of emamectin.

IVERMECTIN for use in animals:

  1. in preparations for the prophylaxis of heartworm in cats and dogs;
  2. in intraruminal implants containing 160 mg or less of ivermectin;
  3. in preparations containing 3.5 per cent or less of ivermectin when packed in child-
  4. resistant packaging or in packaging approved by the relevant registration authority; or
  5. in other preparations containing 2 per cent or less of ivermectin.

MILBEMECTIN in preparations containing 1 per cent or less of milbemectin. MOXIDECTIN:

  1. in preparations for external use for the treatment of animals other than cats and dogs, containing 0.5 per cent or less of moxidectin;
  2. in preparations for external use for the treatment of cats and dogs, containing 2.5 per cent or less of moxidectin packed in single dose tubes with a volume of 1 mL or less; or
  3. for internal use for the treatment of animals:
    1. in divided preparations for dogs, containing 250 micrograms or less of moxidectin per dosage unit in a pack containing six or less dosage units; or
    2. in other preparations containing 2 per cent or less of moxidectin.

SELAMECTIN except in preparations containing 12 per cent or less of selamectin.

Schedule 4

IVERMECTIN

  1. for human use; or
  2. for the treatment of mange in dogs.

Appendix J, Part 2

ABAMECTIN

Condition: 1 (Not to be available except to authorised or licensed persons.)

Scheduling history

In August 1997, the National Drugs and Poisons Scheduling Committee (NDPSC) considered an application to schedule eprinomectin, a new semi-synthetic second generation avermectin. Due to the similarities in structure and metabolism of eprinomectin and emamectin, the toxicological data for emamectin was used to support the scheduling application for eprinomectin. The committee decided to place eprinomectin in Schedule 7 with a cut-off to Schedule 5 at 0.5%, based on the toxicological data and uncertainties around neurotoxicity related hypersensitivity, as observed in a sub-population of CF-1 mice.

Australian regulations

Eprinomectin does not appear to be in any products on the Australian Register of Therapeutic Goods (ARTG).

Eprinomectin does not appear in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018.

Eprinomectin is approved by the APVMA in four (4) pour-on (topical) veterinary parasiticide products in beef and dairy cattle and deer.

International regulations

United States of America

Eprinomectin 5% in an extended release injectable parasiticide for cattle, at 1 mg/kg by subcutaneous injection (approved September 2011; Food and Drug Administration New Animal Drug Application 141-327).

European Union

The European Medicines Agency included eprinomectin in Annex I of Council Regulation (No 2377/90) in 1996 and recommends a dosage regimen is a single dose of 0.5 mg/kg applied topically.

New Zealand

Eprinomectin is permitted as a pour-on solution at 0.5% for cattle and deer.

Substance summary
Table 3.3A: Chemical information for eprinomectin
Property Eprinomectin
CAS name (4”)-4"-acetylamino-4"-deoxyavermectin B1a
CAS numbers 123997-26-2 (eprinomectin B1a is 133305-88-1, eprinomectin B1b is 133305-89-2)
Chemical structure Chemical structure of eprinomectin
Molecular formula C50H75O14
Molecular weight 900.1 g/mol
IUPAC and/or common and/or other names

Mixture of eprinomectins B1a and B1b

(2aE,4E,8E)-(5′S,6S,6′R,7S,11R,13S,15S,17aR,20R,20aR,20bS)-6′-[(S)-sec-butyl]-5′,6,6′,7,10,11,14,15,17a,20,20a,20b-dodecahydro-20,20b-dihydroxy-5′,6,8,19-tetramethyl-17-oxospiro[11,15-methano-2H,13H,17H-furo[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2′-[2H]pyran]-7-yl 4-O-(4-acetamido-2,4,6-trideoxy-3-O-methyl-α-L-lyxo-hexopyranosyl)-2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranoside (major component)

(2aE,4E,8E)-(5′S,6S,6′R,7S,11R,13S,15S,17aR,20R,20aR,20bS)- 5′,6,6′,7,10,11,14,15,17a,20,20a,20b-dodecahydro-20,20b-dihydroxy-6′-isopropyl-5′,6,8,19-tetramethyl-17-oxospiro[11,15-methano-2H,13H,17H-furo[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2′-[2H]pyran]-7-yl 4-O-(4-acetamido-2,4,6-trideoxy-3-O-methyl-α-L-lyxo-hexopyranosyl)-2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranoside (minor component)

Table 3.3B: Acute toxicity end-points for eprinomectin
Toxicity Species Eprinomectin SPF (2018) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 55 (female) Schedule 6-7
Mouse 70 (female)
Acute dermal toxicity LD50 (mg/kg bw) Rat >660 Schedule 6
Rabbit 460
Acute inhalational toxicity LC50 (mg/m3/4h) Rat 5110 -
Skin irritation Rabbit Not irritatinga -
Eye irritation Rabbit Irritant Schedule 6
Skin sensitisation LLNA Guinea pig Negative -

Acute toxicity

The acute toxicity of eprinomectin is moderate. Central nervous system clinical signs were the most notable findings in acute toxicity studies when administered at high doses.

Skin irritation

Limited information indicates that eprinomectin is not a skin irritant in rabbits.

Eye irritation

There are reports that it may be an irritant to eyes. Other avermectins (e.g. emamectin, moxidectin) are classified as moderate/severe eye irritants.

Sensitization

Eprinomectin is not a skin sensitiser in the guinea pig (GPMT).

Repeat-dose toxicity

Major findings in the repeat dose studies in both rats and dogs were neurological clinical signs and neurological histopathological changes.

In a 14-week dietary toxicity study in rats, the NOAEL was 5 mg/kg/day based on body tremors, decreased weight gain, decreased urine output, increased organ weights (adrenal, liver, uterus and pituitary), decreased ovarian weight, and sciatic nerve degeneration in some animals at 20/30 mg/kg/day.

In a 14-week oral (gavage) toxicity study in dogs, the NOAEL was 0.8 mg/kg/day based on reduced body weight gain and sciatic nerve degeneration at dose levels of 1.6/2.4 mg/kg/day.

In a 53-week oral (gavage) toxicity study in dogs, the NOAEL was 1 mg/kg/day, based on clinical signs e.g. transient mydriasis, and slight neuronal degeneration at higher doses.

The data package for eprinomectin lacked a long-term rodent study. This was discussed at the time of the initial risk assessment of eprinomectin with the Applicant. It was concluded in that initial assessment that due to the structural and metabolic similarities of eprinomectin and emamectin, the toxicological data for emamectin, which includes a chronic toxicity rodent study, as well as carcinogenicity studies, could be used to support the scheduling application for eprinomectin. Moreover, it was noted that both compounds are produced from abamectin by replacement of the 4´-hydroxyl group (with an epi-acetylamino moiety for eprinomectin and an epi-methylamino moiety for emamectin) and that the metabolism of both compounds is limited to deacetylation of the 4´ acetyl group for eprinomectin and deamination at the same position for emamectin.

Given the similarities of eprinomectin and emamectin, it is of relevance to note the toxicological findings for the latter compound. The following data were taken from the European Agency for the Evaluation of Medicinal Products (EMA) Committee for Veterinary Medicinal Products (CVMP) Emamectin Summary Report.

Repeat dose toxicity studies in rats with emamectin included 14-week and 53-week dietary studies. In the 14-week study at doses of 0, 0.25, 1 and 5 mg/kg/day, all males and most females given 5 mg/kg/day showed neuronal vacuolation/degeneration of the brain, spinal cord and sciatic nerve. The NOEL was 1 mg/kg/day. In the 53-week study at doses of 0, 0.1, 1 and 2.5/5 mg/kg/day (high-dose females were given 5 mg/kg/day up to week 18; males were given 2.5 mg/kg/day throughout), neuronal degeneration of the brain and spinal cord was observed in males given 2.5 mg/kg/day and females given 2.5/5 mg/kg/day. The NOEL was 1 mg/kg/day.

Repeat dose toxicity studies in dogs with emamectin included 14-week and 53-week gavage studies. In the 14-week study at doses of 0, 0.25, 0.5 and 1 mg/kg/day (up to the start of week 3, doses were 0, 0.5, 1 and 1.5 mg/kg/day, the NOEL was 0.25 mg/kg/day based on neuronal degeneration (as well as skeletal muscle atrophy) at doses ≥0.5 mg/kg/day. In the 53-week study, at doses of 0, 0.25, 0.5, 0.75 and 1 mg/kg/day, the NOEL was also 0.25 mg/kg/day, with axonal degeneration in the CNS and PNS seen at doses of ≥0.5 mg/kg/day.

Thus, dogs were more sensitive than rats to the neuronal histopathological changes induced by emamectin. As the same appears to be the case with eprinomectin, the lack on a chronic rat toxicity study did not impact on the selection of an NOAEL for the risk assessment.

Genotoxicity

Eprinomectin was tested for genotoxicity in an adequate range of in vitro and in vivo assays and based on these studies eprinomectin was not considered to be genotoxic. This finding has also been shown from other avermectins.

Carcinogenicity

Carcinogenicity studies have not been conducted on eprinomectin. The avermectins are closely related structurally and appear to share a common mechanism of action and mechanism of mammalian toxicity. None of the avermectins has been found to be genotoxic and none possess a structural relationship to known carcinogens. Carcinogenicity studies on abamectin, emamectin and moxidectin (avermectins structurally related to eprinomectin) did not reveal any carcinogenic potential. The negative carcinogenicity findings for emamectin were considered as supporting evidence for the likely lack of carcinogenic hazard of eprinomectin in previous assessments by the APVMA.

Given the above evidence/arguments, it is concluded that a carcinogenic risk for eprinomectin is unlikely.

Reproduction and developmental toxicity

In a two-generation reproductive toxicity study in rats given eprinomectin in the diet, the NOAEL for maternal toxicity and reproductive toxicity was 1.5 mg/kg bw/d, based on reduced body weight gain, reduced food consumption and reduced fecundity at 4.5 mg/kg/day. The NOAEL for offspring toxicity was 0.8 mg/kg/day based on tremors and reduced body weight in pups at higher doses.

In a developmental toxicity study in rats given eprinomectin via gavage, the NOAEL for maternal toxicity was 1 mg/kg/day based on increased maternal body weight at the doses of 3 mg/kg/day and higher. The NOAEL for embryofetal toxicity was 12 mg/kg/day, the highest dose tested.

In two developmental toxicity studies in rabbits given eprinomectin via gavage, the NOAEL for maternal toxicity was 0.5 and 2 mg/kg/day based on reduced pupillary reflexes or mydriasis at higher doses. The NOAEL for embryofetal toxicity was 2 mg/kg/day (highest dose tested) in one study and 8 mg/kg/day (highest dose tested) in the second study. Overall, Eprinomectin showed no evidence of embryofetal toxicity or teratogenicity in rat and rabbit developmental toxicity studies.

Observation in humans

Eprinomectin is not used as a human medicine. The related drug, ivermectin, is used clinically in humans for treating various diseases/infestations e.g. onchocerciasis (river blindness), lymphatic filariasis, strongyloidiasis, head lice and scabies.

Public exposure

Eprinomectin-containing products for use on food-producing animals are registered for use in Australia by the APVMA. Very limited public exposure to eprinomectin would be expected, as current uses are limited to use on farms.

Pre-meeting public submissions

One (1) public submission was received, which opposed the proposal.

The main points provided in opposition of the amendment were:

  • The addition of 'for internal use' to the Schedule 5 entry would result in currently registered external use eprinomectin-based veterinary products being excluded from Schedule 5, resulting in them being captured by the Schedule 7 entry.
  • The proposed scheduling change that will exclude external use products may be unintentional. However, if it is not, a rationale for the exclusion of external use products is requested.

The public submission will be made available on the TGA website.

Summary of ACCS advice to the delegate

The committee recommended that a new Schedule 6 entry for eprinomectin be created and the Schedule 7 entry amended to reflect this change, as follows:

Schedule 6 - New Entry

EPRINOMECTIN for internal use in preparations containing 5 per cent or less of eprinomectin except when included in Schedule 5.

Schedule 7 - Amend Entry

EPRINOMECTIN except when included in Schedule 5 or 6.

The committee also recommended an implementation date of 1 October 2018.

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 were:

  1. the risks and benefits of the use of a substance:
    • Benefits: control of parasites in animals and the increased availability for use by farmers.
    • Risks: Accidental self-injection may result in injury due to moderate acute oral/dermal toxicity.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Only limited quantities are available for exposure at a single time, thus limiting risk of accidental self-injection.
    • Product will be sold through retailers servicing the rural cattle industry and not directly to the public or through retail outlets normally serving the public.
  3. the toxicity of a substance:
    • High acute oral and dermal toxicity resulting in neurological toxicity. Repeat dose toxicity NOAEL 0.8-5 mg/kg in rats/dogs.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • When packed as a divided dose preparation, exposure is highly controlled. The packaging and labelling are under APVMA control.
    • Topical preparation for use on animals and long-acting injection. APVMA regulated product.
  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

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS advice;
  • Scheduling Policy Framework (SPF 2018); and
  • Section 52E(1) of the Therapeutic Goods Act 1989 in particular: (a) the risks and benefits of the use of a substance; (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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

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