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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3.2 Moxidectin

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

3.2 Moxidectin

Delegate's interim decision

The delegate's interim decision is to amend the Schedules 6 and 4 entries for moxidectin in the Poisons Standard as follows:

Schedule 6 - Amend Entry

MOXIDECTIN:

  1. in preparations for external use 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 for external use containing 2 per cent or less of moxidectin for the treatment of animals; or
  3. in preparations for internal use containing 10 per cent or less of moxidectin for the treatment of sheep or cattle,

except when included in Schedule 5.

Schedule 4 - Amend Entry

MOXIDECTIN in preparations for injection containing 10 per cent or less of moxidectin 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:
    • Benefit: Increased access for use in sheep and cattle.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Moxidectin is an antiparasitic drug which is intended for the treatment of endo- and ectoparasites in dogs, cats, cattle and sheep.
  3. the toxicity of a substance:
    • There is a lack of data supporting the request for an increase from 2 to 10 per cent in Schedule 5.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • The availability of the injectable substance at the requested concentration has the potential for harm that has not been addressed if Schedule 5.
Scheduling proposal

The pre-meeting scheduling proposal for moxidectin 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 moxidectin
Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Poisons Standard with respect to moxidectin. The application proposes to amend the Schedule 4 entry for moxidectin by specifying the injection of 10% or less preparations for dogs and to amend the Schedule 5 entry for moxidectin by adding 10% or less injection preparations for sheep and cattle.

Scheduling application

The proposed amendments to the Poisons Standard are:

Schedule 5 - Amend Entry

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; or
  4. in preparations for injection for the treatment of sheep and cattle, containing 10 per cent or less of moxidectin.

Schedule 4 - Amend Entry

MOXIDECTIN in preparations for injection containing 10 per cent or less of moxidectin except when included in Schedule 5 for the treatment of dogs containing 10 per cent or less of moxidectin.

The applicant's reasons for the proposal are:

  • Injectable preparations of moxidectin fall into Schedules 4 and 5. The Schedule 4 entry captures injections containing 10 per cent or less of moxidectin, except when included in Schedule 5. The Schedule 5 entry does not specifically make any reference to preparations for injection. However, in reviewing the scheduling history for moxidectin, it appears that Schedule 5 captures injections under the general description of 'for internal use for the treatment of animals ...in other preparations containing 2 per cent or less of moxidectin'. The Schedule 5 entry description is therefore not obvious for preparations for injection.
  • The history of the scheduling of moxidectin (see Scheduling history) in preparations for injection indicates that the intent was to include the dog injection product in Schedule 4. This is due to the need for veterinary involvement and its presentation as a high concentration injectable that has a long-term effect achieved through a sustained release mechanism. The farm animal injection products remain in Schedule 5. The 2% cut-off in Schedule 5 was based on the concentration of moxidectin in the products that were considered when the entry was created. Due to the low potential for user exposure to moxidectin when using a ready-to-use injectable product for farm animals and farm animal injection products not being sustained release formulations like the dog injection product, the Schedule 5 cut-off for farm animal injection products can be increased from 2% to 10% to accommodate currently registered products.
Current scheduling status

Moxidectin is listed in Schedules 7, 6, 5 and 4 of the Poisons Standard as follows:

Schedule 7

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

Schedule 6

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

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.

Schedule 4

MOXIDECTIN in preparations for injection containing 10 per cent or less of moxidectin except when included in Schedule 5.

Scheduling history

In 1993, the Drugs and Poisons Schedule Committee (DPSC) agreed to include moxidectin in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP). Due to the teratogenic effects of moxidectin and its similar chemical profile to abamectin, the committee decided to list moxidectin in Schedule 4 at 0.15% for use in dogs, Schedule 6 with a cut off of 1% or less for animal treatment and Schedule 7 with exceptions to the listings in Schedule 6 (for preparations <1% in animals) along with Appendix E and F listings.

In 1994 and 1995, the National Drugs and Poisons Schedule Committee (NDPSC) considered the rescheduling of 'moxidectin for use in dogs' from Schedule 4 to Schedule 6. The NDPSC also considered a proposal to amend the Schedule 6 entry to capture a 2% oral horse worming preparation. As part of these rescheduling considerations, the Schedule 4 entry was deleted, the Schedule 5 entry was created and the Schedule 6 entry was amended. The Schedule 6 entry now only captures products containing ≤2% moxidectin for the external treatment of animals, while the Schedule 5 entry captures products for internal use (divided preparations for dogs, containing 140 µg or less of moxidectin per dosage unit in a pack containing 6 or less dosage units, and in other preparations containing 2% or less of moxidectin).

In May 1997, the NDPSC amended the Schedule 5 entry for internal use/divided preparations for dogs by increasing the concentration cut off to ≤250 μg moxidectin to capture a larger sized tablet for dogs.

In November 1999, the NDPSC considered an application to create a new Schedule 4 listing for an injectable formation containing ≤10% of moxidectin. The committee agreed that veterinary control of the 10% injection for dogs would be appropriate, based on moxidectin (as a high concentration injectable) having a long-term effect through a slow-release mechanism.

A review of the filaricides over several meetings from November 2000 through May 2001 confirmed the Schedule 5 entry for moxidectin in relation to the prophylaxis of heartworm in companion animals.

In 2002, the NDPSC considered a rescheduling application of moxidectin for spot-on products for companion animals. The committee amended the Schedule 6 entry to capture topical spot-on products for cats and dogs containing ≤2.5% moxidectin when packed in single dose tubes, based on the acute toxicity and potential for acute neurotoxicity.

In 2003, the NDPSC considered a rescheduling application for the Schedule 5 listing of moxidectin for pour-on preparations containing ≤0.5% moxidectin for application on cattle or deer. The committee agreed to amend the Schedule 5 and Schedule 6 entries for external use, so that the 0.5% pour-on for cattle was now captured in Schedule 5 (in preparations for external use for the treatment of non-companion animals containing 0.5% or less of moxidectin), due to low toxicity and use pattern limiting exposure to the public, while the ≤2.5% topical spot-on products for cats and dogs remained in Schedule 6.

In 2004, the NDPSC considered the rescheduling of ≤2.5% topical spot-on products for cats and dogs from Schedule 6 to Schedule 5, when in small pipette sizes (≤1 mL). The Schedule 5 entry was amended to include these smaller pipette sizes, while the larger sizes remained in Schedule 6. In addition, the Schedule 5 external use entry for 'non-companion animals' containing 0.5% or less of moxidectin was reworded slightly to refer to 'animals other than cats and dogs' ('preparations for external use for the treatment of animals other than cats and dogs, containing 0.5% or less of moxidectin').

In 2005, the NDPSC agreed to an editorial amendment to the Schedule 6 listing of moxidectin by moving 'except when included in Schedule 5' from the end of Schedule 6, part (a) to the end of the Schedule 6 whole entry. This was to correct an inadvertent outcome of the previous wording, whereby preparations containing ≤0.5% moxidectin for external use in the treatment of animals covered by Schedule 6 part (b) entry were also be captured by the Schedule 5, part (a) entry.

Australian regulations

Moxidectin is an APVMA-approved active constituent. Moxidectin is included as an active constituent in 89 registered veterinary products on the PubCRIS database for the treatment of parasites in/on animals. Formulation types and uses include topical pour-on products for cattle and deer (0.5%), topical spot-on products for dogs and cats (1-2.5%), oral tablets for dogs (30-204 μg/tablet), oral pastes/gels for horses (0.8-2%), oral drenches for sheep (0.1-0.2%), injectables combined with vaccine components for sheep (0.25-0.5%), injectables for cattle and sheep (1-10%), and an injectable for dogs (10%).

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

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

International regulations

European Union (EU)

Moxidectin is approved in the EU Annex I of Council regulation No 237/90. The European Medicines Agency recently conducted an evaluation of the environmental impact of moxidectin-containing veterinary medicines. The Committee for Medicinal Products for Veterinary Use (CVMP) noted the importance of moxidectin use in the treatment of external parasites in cattle, sheep and horses. However, it also concluded that moxidectin fulfils the criteria of a persistent bio-accumulative toxin and poses a risk to the environment. The CVMP recommended risk mitigation measures and warnings to be included in product information including treatment to be only given when necessary.

United States of America, Canada, and New Zealand

Moxidectin is registered for the treatment of animals.

Substance summary
Table 3.2A: Chemical information for moxidectin
Property Moxidectin
CAS name (6R,23E,25S)-5-O-demethyl-28-deoxy-25-[(1E)-1,3-dimethyl-1-butenyl]-6,28-epoxy-23-(methoxyimino)milbemycin B
CAS number 113507-06-5
Chemical structure Chemical structure for moxidectin
Molecular formula C37H53NO8
Molecular weight 639.8 g/mol
IUPAC and/or common and/or other names

(6R,25S)-5-O-Demetyl-28-deoxy-25-[(E)-1,3-dimetyl-1-butenyl]-6,28-epoxy-23-oxomilbemycin B 23-(E)-(O-metyloxime) (WHO);

Milbemycin B, 5-O-demetyl-28-deoxy-25-(1,3-dimetyl-1-butenyl)-6,28-epoxy-23-(metoxyimino)-, [6R,23E,25S(E)]- (USAN)

Acute toxicity

Not relevant - proposal is to clarify an ambiguity in the scheduling entry. No new toxicological information is provided.

Skin and eye irritation

Not relevant - proposal is to clarify an ambiguity in the scheduling entry. No new toxicological information is provided.

Skin sensitisation

Not relevant - proposal is to clarify an ambiguity in the scheduling entry. No new toxicological information is provided.

Repeat-dose toxicity, genotoxicity and carcinogenicity

Not relevant - proposal is to clarify an ambiguity in the scheduling entry. No new toxicological information is provided.

Reproduction and developmental toxicity

Not relevant - proposal is to clarify an ambiguity in the scheduling entry. No new toxicological information is provided.

Observation in humans

Not relevant - proposal is to clarify an ambiguity in the scheduling entry. No new toxicological information is provided.

Public exposure

Not relevant - proposal is to clarify an ambiguity in the scheduling entry. No new toxicological information is provided.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that the Schedules 6 and 4 entries be amended for moxidectin, as follows:

Schedule 6 - Amend Entry

MOXIDECTIN:

  1. in preparations for external use 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 for external use containing 2 per cent or less of moxidectin for the treatment of animals; or
  3. in preparations for internal use containing 10 per cent or less of moxidectin for the treatment of sheep or cattle,

except when included in Schedule 5.

Schedule 4 - Amend Entry

MOXIDECTIN in preparations for injection containing 10 per cent or less of moxidectin 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:
    • Benefit: Increased access for use in sheep and cattle.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Moxidectin is an antiparasitic drug which is intended for the treatment of endo- and ectoparasites in dogs, cats, cattle and sheep.
  3. the toxicity of a substance:
    • There is a lack of data supporting the request for an increase from 2 to 10 per cent in Schedule 5.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • The availability of the injectable substance at the requested concentration has the potential for harm that has not been addressed if Schedule 5.
  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;
  • Public submissions received;
  • 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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