Simparica chewable tablets (120 mg) (Canada)

Mode of Action

Isoxazolines (including sarolaner) are potent inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA) receptor and glutamate receptor function and work at the neuromuscular junction in arthropods. This results in uncontrolled neuromuscular activity leading to rapid death in insects or acarines. Sarolaner has a greater affinity for the GABA receptors in insects compared to mammals.

Pharmacokinetics

Sarolaner is rapidly and well absorbed following oral administration of SIMPARICA chewable tablets. In a study of 12 Beagle dogs, the mean maximum plasma concentration (C_max) was 1100 ng/ml and the mean time to maximum concentration (T_max) occurred at 3 hours following a single oral dose of 2 mg/kg to fasted dogs. The mean oral bioavailability was 86% and 107% in fasted and fed dogs, respectively. The mean oral T1/2 value for fasted and fed dogs was 10 and 12 days respectively.

The mean volume of distribution (Vdss) of sarolaner was 2.81 L/kg bodyweight following a 2 mg/kg intravenous dose, indicating that this drug is widely distributed. Sarolaner is highly bound ~99.9%) to plasma proteins. The metabolism of sarolaner appears to be minimal in the dog. The primary route of sarolaner elimination from dogs is biliary excretion with elimination via the feces. Following repeated administration of SIMPARICA chewable tablets once every 28 days for 10 doses to Beagle dogs at 1X, 3X, and 5X the maximum intended clinical dose of 4 mg/kg, steady-state plasma concentrations were reached after the 6^th dose.

Efficacy:

Tick Control

In well-controlled laboratory studies, SIMPARICA chewable tablets demonstrated ≥99.1% efficacy 48 hours post-dose against existing infestations of five species of ticks (Ixodes scapularis, Amblyomma americanum, Amblyomma maculatum, Dermacentor variabilis, and Rhipicephalus sanguineus). Continuing effectiveness ≥94.5% was maintained against weekly re-infestations of all five species for 35 days.

In a laboratory study against A. maculatum, SIMPARICA chewable tablets provided 80.2% reduction in mean live tick counts within 8 hours after the initial treatment, and 99.0% reduction by 12 hours after the initial treatment.

In two separate, well-controlled laboratory studies, SIMPARICA chewable tablets were effective at preventing Borrelia burgdorferi infections after dogs were infested with room temperature, adult I. scapularis vector ticks 28 days post-treatment.

Flea Control

In a well-controlled laboratory study, SIMPARICA chewable tablets showed a significant reduction in adult flea counts 3 hours after initial administration and achieved 100% efficacy at 8 hours post-administration. SIMPARICA chewable tablets continued to demonstrate ≥89.0% efficacy 8 hours after weekly flea re-infestation for 35 days.

In a separate well-controlled laboratory study, SIMPARICA chewable tablets demonstrated 100% efficacy against adult fleas within 24 hours following treatment and maintained 100% efficacy within 24 hours against weekly re-infestations for 35 days.

In a study to simulate a flea-infested home environment, an infestation was established prior to the start of treatment. Dogs were also re-infested with fleas on Days 7, 37 and 67. SIMPARICA chewable tablets administered monthly for three months demonstrated ≥94.3% reduction in adult fleas within 14 days after the first treatment, and reached 100% efficacy from Day 60 onward. In a study to explore flea egg production and viability, SIMPARICA chewable tablets killed fleas before they could lay eggs and thus prevented 100% of flea egg production in an existing infestation and against weekly re-infestations for 35 days.

In a well-controlled 90-day US field study conducted in households with existing flea infestations of varying severity, the efficacy of SIMPARICA chewable tablets against fleas on Day 30, 60 and 90 visits compared to baseline was 99.5%, 99.9% and 100%, respectively. Dogs with signs of flea allergy dermatitis showed improvement in erythema, papules, scaling, alopecia, dermatitis/pyodermatitis and pruritus as a direct result of eliminating fleas from the animals and their environment.

Ear Mite Treatment

In a well-controlled 60-day laboratory study in 8 dogs, a single treatment with SIMPARICA chewable tablets reduced total Otodectes cynotis mite counts by 98.7% within 30 days after treatment and after two monthly doses of SIMPARICA chewable tablets Otodectes cynotis mite counts were reduced to 99.9% on study Day 60.

In a well-controlled 60-day EU field study, SIMPARICA chewable tablets (163 dogs) or a topical combination of moxidectin and imidacloprid (78 dogs) were administered to dogs with naturally acquired ear mite infestation. Efficacy of SIMPARICA chewable tablets was 90.5% after a single administration. The percent efficacy for SIMPARICA chewable tablets was non inferior to the combination of moxidectin and imidacloprid on study Day 30. If live mites were found on Day 30 a second treatment was administered. Of the 15 dogs treated for a second time with SIMPARICA chewable tablets, efficacy was 93.3% after the second administration.

Animal Safety:

In a margin of safety study, SIMPARICA chewable tablets were administered orally to 8-week-old Beagle puppies at doses of 0, 1X, 3X, and 5X the maximum recommended dose (4 mg/kg) at 28-day intervals for 10 doses (8 dogs per group). Dogs in the control group received placebo tablets. No neurological signs were observed in the 1X group. In the 3X group, one male dog exhibited tremors and ataxia post-dose on Day 0; one female dog exhibited tremors on Days 1, 2, 3, and 5; and one female dog exhibited tremors on Day 1. In the 5X group, one female dog had a seizure on Day 61 (5 days after third dose); one female dog had tremors post-dose on Day 0 and abnormal head coordination after dosing on Day 140; and one female dog exhibited seizures associated with the second and fourth doses and tremors associated with the second and third doses. All dogs recovered without treatment. There were no treatment-related neurological signs observed once the dogs reached the age of 6 months, except for the observation of abnormal head coordination in one dog in the 5X group two hours after dosing on Day 140 (dose 6).

In a separate exploratory pharmacokinetic study, one female dog dosed at 12 mg/kg (3X the maximum recommended dose) exhibited lethargy, anorexia, and multiple neurological signs including ataxia, tremors, disorientation, hypersalivation, diminished proprioception, and absent menace, approximately 2 days after a third monthly dose. The first two doses resulted in plasma concentrations that were consistent with those of the other dogs in the treatment group. Starting at 7 hours after the third dose, there was a rapid 2.5 fold increase in plasma concentrations within 41 hours, resulting in a C_max more than 7-fold higher than the mean C_max at the maximum recommended use dose. No cause for the sudden increase in sarolaner plasma concentrations was identified.

In a laboratory safety study, sarolaner was safely co-administered at doses up to 20 mg/kg (5X the maximum recommended dose) with moxidectin (up to 30 micrograms/kg) and pyrantel pamoate (up to 50 mg/kg) in avermectin-sensitive collie dogs for a single dose. No adverse signs were observed.

In a well-controlled field study, SIMPARICA chewable tablets were used concurrently with other commonly used medications such as vaccines, anthelmintics, heartworm preventatives, antibiotics, and corticosteroids. No adverse reactions were attributed to the concurrent use of SIMPARICA chewable tablets with other medications.

Storage

Store at or below 30°C with excursions permitted up to 40°C.

Presentation:

SIMPARICA chewable tablets are available in six flavoured tablet sizes: 5, 10, 20, 40, 80, and 120 mg. Each tablet size is available in color-coded packages of one, three, or six tablets.

Not all pack sizes may be marketed.

Zoetis^® and Simparica are registered trademarks of Zoetis or its licensors.

Zoetis Canada Inc., Kirkland QC H9H 4M7

10012641-11-4

October 2023

CPN: 1198530.6