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Scheduling delegate's final decisions, March 2016

Scheduling medicines and poisons

17 March 2016

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3.1 Sarolaner

Part B - Final decisions on matters not referred to an expert advisory committee

3. Agricultural and Veterinary Chemicals

3.1 Sarolaner

Scheduling proposal

In December 2015 the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for the approval of sarolaner as a new active constituent, and the registration of a product line Sarolaner Palatable Chews for Dogs, containing sarolaner in a chewable tablet formulation, requested that the Delegate consider creating a new entry for sarolaner in Schedule 6 of the SUSMP. An exemption to Schedule 5 for sarolaner when in oral divided preparations each containing 120 mg or less of sarolaner per dosage unit for the treatment, prevention and control of fleas and ticks in dogs has been proposed by OCS.

The applicant proposed a new Schedule 5 entry for sarolaner.

Scheduling application

The Applicant, as part of an application to the APVMA, has requested that the Delegate consider submitted a data package seeking approval of the new active constituent sarolaner, and registration of the new product line Sarolaner Palatable Chews for Dogs containing sarolaner in a chewable tablet formulation. The largest tablet contains a maximum single dose of 120 mg of sarolaner. The product is intended to be administered once per month for the treatment and control of fleas and ticks in dogs.

The applicant has proposed that sarolaner be listed in Schedule 5 of the SUSMP, "consistent with the recent APVMA approvals of afoxolaner and sarolaner...as a substance with a low potential for causing harm, the extent of which can be reduced through the use of appropriate packaging with simple warnings and safety directions on the label."

Sarolaner belongs to the isoxazoline class of parasiticides; similar chemicals previously considered by the Delegate/ACCS include afoxolaner and fluralaner.

Substance summary
Chemical structure of sarolaner

Figure 12. Chemical structure of sarolaner

Acute toxicity

The acute toxicity end-points for this chemical are listed in the below table.

Toxicity Species Sarolaner SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 550 < LD50 < 2000 (point estimate 783) Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rat > 2000 N/A
Acute inhalational toxicity LC50 (mg/m3/4h) N/A N/A N/A
Skin irritation Rabbit Non-irritant N/A
Eye irritation Rabbit Slight irritant Schedule 5
Skin sensitisation (LLNA method) Mouse Non-sensitiser

* Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

No acute toxicity data on the formulated product were submitted. Acute toxicity estimations indicated that the product line Sarolaner Palatable Chews for Dogs is expected to be of low acute oral and dermal toxicity, not skin or eye irritant, and not a skin sensitiser.

Irritation

See acute toxicity table above.

Sensitization

See acute toxicity table above.

Repeat-dose toxicity

Sarolaner was evaluated for repeated dose toxicity in rats and dogs. In rats, both 30- and 90-day studies were conducted to evaluate the potential toxicity of sarolaner. In the 30-day study, key treatment-related effects were elevated adrenal gland weight at 2.233 and 22.33 mg/kg bw/d, elevated ovaries/oviducts weights at 22.33 mg/kg bw/d, with corresponding pathology effects. The adrenal glands at 22.33 mg/kg bw/d were enlarged, an effect that was characterized by enlargement of cells of the zona fasciculata and cytoplasmic vacuolation of the adrenal cortex. In the ovaries, there was apparent hypertrophy of the interstitial cells, which followed a dose response at ≥2.233 mg/kg bw/d and was considered moderately severe at 22.33 mg/kg bw/d. Based on these findings, the NOEL for Sarolaner in the 30-day rat repeated dose toxicity study was 0.223 mg/kg bw/d, based on adverse effects occurring at 2.233 mg/kg bw/d. Similar effects were identified in the 90-day study, with a NOEL for this study established at 0.25 mg/kg bw/d.

In dogs, three studies were conducted with repeated dosing structures, intended to evaluate the margin of safety of administration of Sarolaner to dogs. The first was an exploratory study, conducted over approximately 2 months; this study was non-GLP compliant and did not follow any specific guideline. In addition to the initial exploratory study, a tolerance study was conducted in dogs over approximately 5 weeks. The third was a 9-month dosing study in young beagle dogs; this study was GLP-compliant and followed guidelines specified under VICH GL43. Across the three studies, results suggested that sarolaner is well-tolerated in dogs, up to 20 mg/kg bw. However, in the margin of safety study in young beagle dogs, mild tremors and ataxia were noted at ≥12 mg/kg bw, suggesting that sarolaner administration can elicit a mild neurotoxic effect. This is supported by range-finding information from an oral toleration study in dogs, where tremors, seizures, unsteady gait, stiff/jerky movement, and soft stool were noted at 62.5 mg/kg bw. However, conventional functional observation battery evaluations in the repeat-dose rat toxicity studies did not show functional changes at the doses tested, suggesting that the dog may be more sensitive for neurological effects.

Mutagenicity/genotoxicity

Sarolaner was negative for genotoxic potential in both in vitro (bacterial and mammalian cell) and in vivo (mammalian) testing. It is considered unlikely that sarolaner is genotoxic.

Carcinogenicity

No information was provided.

Reproduction and developmental toxicity

No multi-generation reproductive toxicity studies were available for evaluation.

Sarolaner was tested for developmental toxicity in both rats and rabbits. Sarolaner did not cause developmental malformations in either species under the test conditions. The results indicated that sarolaner is unlikely to cause developmental toxicity in the absence of maternal toxicity.

Observation in humans

No information was provided.

Public exposure

The OCS, as part of their evaluation, has considered the potential public exposure and risks associated with use of the product Sarolaner Palatable Chews for Dogs.

Exposure to sarolaner during dosing is unlikely to result in a toxicologically significant exposure. The presentation of Sarolaner Palatable Chews for Dogs (containing up to 120 mg sarolaner/chew), with mostly non-toxic excipients will limit exposure to sarolaner. While dermal exposure to sarolaner could be increased if tablets were crushed or broken to be mixed with food rather than placed whole into food or administered directly, such contact is not expected to notably increase the exposure and risks associated with dermal contact with sarolaner in the palatable chew.

Adults may be exposed to small amounts of sarolaner following dosing of dogs, via contact with wet or partly macerated chews, or from contact with vomitus or urine/faeces. Contact with excreta is unlikely to result in toxicologically significant exposure. Any dermal, oral or ocular exposure via excreta is likely to be infrequent and sporadic, and could be considered as a limited acute exposure event.

In accidental exposure scenarios involving children, as a worst case scenario, it was presumed that a child (infant and toddler) gains access to a 6 pack containing the largest tablet size containing 120 mg sarolaner per tablet. In this event, the resulting accidental exposure would be 65.45 mg/kg bw for an infant weighing 11 kg and 48 mg/kg bw for a toddler weighing 15 kg. Compared with the lower limit of the acute oral toxicity LD50 range for the active constituent sarolaner of 550 mg/kg bw (a dose associated with clinical signs of toxicity), these doses provide a margin of safety of 8 for infants and 11 for toddlers. In the event of exposure to a single tablet of the highest available dose, the comparable exposures would be 10.9 mg/kg bw for an infant weighing 11 kg and 8 mg/kg bw for a toddler weighing 15 kg. Compared to the lower limit of the acute oral toxicity range for the active constituent, the margin of safety would be 50 for infants and 68 for toddlers.

In both cases, the margin of safety would normally be considered insufficient to protect against effects from accidental ingestion. Furthermore, the OCS notes that the available toxicity information in the tolerance study in young beagle dogs reported mild tremors and ataxia as treatment-related effects after a single dose of 12 mg/kg bw, suggesting the possibility that there are acute toxicity risks associated with an accidental exposure event.

However, the OCS notes that the proposed product will be packaged in foil blister packs which are considered to be child resistant. Additionally, to provide adequate warning regarding the potential risks associated with product use, the OCS recommends the following precautionary statements:

  • "Ingestion of sarolaner can be harmful for children upon accidental ingestion. To avoid accidental ingestion administer the chewable to the dog immediately after removal from the package."
  • "Keep out of reach of children"

In addition, the safety directions "do not swallow" and "wash hands after use" are recommended.

International regulations

Sarolaner has been considered by the European Medicines Agency's Committee for Medicinal Products for Veterinary Use (CVMP), see Attachment B, which has recommended the granting of a marketing authorisation for veterinary medicinal product Simparica, containing sarolaner at up to 120 mg per chewable tablet.

Scheduling status

Sarolaner is not specifically scheduled.

Scheduling history

Sarolaner has not been previously considered for scheduling; therefore, scheduling history is not available.

Delegate's interim decision
Schedule 5 - New Entry

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 - New Entry

SAROLANER except when included in Schedule 5.

The delegate considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance; and (d) the dosage, formulation, packaging and presentation of the substance.

The reasons for the interim decision comprised the following:

  • Sarolaner belongs to a novel class of ectoparasiticides (isoxazoline-substituted benzamide derivatives), three other members of which have been listed in Schedule 5 (isoxaflutole, afoxolaner and fluralaner). The toxicology package indicates that, unlike the other three substances, the acute toxicity profile of sarolaner (550 < LD50 < 2000) is more consistent with SPF criteria for listing in Schedule 6.
  • However, the delegate accepts OCS advice that the acute poisoning risk to humans (in particular children) for the proposed product is low, partly associated with the proposed packaging. Accordingly, the delegate accepts the OCS recommendation that a Schedule 6 exception be created so that the proposed product is listed in Schedule 5.
  • The delegate considered whether S4 listing could be more appropriate, providing for oversight of treatment by a veterinarian, but determined that, consistent with the Schedule 5 listing of the related ectoparasiticides, the treatment instructions are sufficiently clear that pet owners should be able to manage the required dosage regimen.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • OCS evaluation report;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors23;
  • Other relevant information.
Submissions on the interim decision

The applicant had no objections to the Delegate's interim decision.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Schedule 5 - New Entry

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 - New Entry

SAROLANER except when included in Schedule 5.

Implementation date: 1 June 2016.


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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