FOR ORAL USE IN DOGS ONLY

CAUTION

Federal (USA) law restricts this drug to use by or on the order of a licensed

veterinarian.

DESCRIPTION

SIMPARICA TRIO (sarolaner, moxidectin, and pyrantel chewable tablets)

is a flavored, chewable tablet for administration to dogs 8 weeks of age and

older. Each tablet is formulated to provide minimum dosages of 0.54 mg/lb

(1.2 mg/kg) sarolaner, 0.011 mg/lb (24 µg/kg) moxidectin, and 2.27 mg/lb

(5 mg/kg) pyrantel (as pamoate salt).

Sarolaner is a member of the isoxazoline class of parasiticides and the

chemical name is 1‑(5’‑((5S)‑5‑(3,5‑Dichloro‑4‑fluorophenyl)‑5‑

(trifluoromethyl)‑4,5‑dihydroisoxazol‑3‑yl)‑3’‑H‑spiro(azetidine‑3,1’‑(2)

benzofuran)‑1‑yl)‑2‑(methylsulfonyl)ethanone. SIMPARICA TRIO contains

the S‑enantiomer of sarolaner.

Moxidectin is a semi‑synthetic methoxime derivative of nemadectin which

is a fermentation product of Streptomyces cyaneogriseus subspecies

noncyanogenus. Moxidectin is a pentacyclic 16-membered lactone macrolide.

The chemical name for moxidectin is (6R,23E,25S)-5-O-Demethyl-28-deoxy25-[(1E)-1,3-dimethyl-1-buten-1-yl]-6,28-epoxy-23-(methoxyimino)

milbemycin B.

Pyrantel belongs to a family classified chemically as tetrahydropyrimidines

and the chemical name is (E)-1,4,5,6-Tetrahydro-1-methyl-2-[2-(2-thienyl)

vinyl] pyrimidine 4,4’ methylenebis [3-hydroxy-2-naphthoate](1:1). It is a

yellow, water-insoluble crystalline salt of the tetrahydropyrimidine base and

pamoic acid containing 34.7% base activity.

INDICATIONS

SIMPARICA TRIO prevents heartworm disease caused by Dirofilaria immitis,

kills adult fleas (Ctenocephalides felis) and is indicated for the treatment and

prevention of flea infestations, the treatment and control of tick infestations

with Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf

Coast tick), Dermacentor variabilis (American dog tick), Ixodes scapularis

(black-legged tick), and Rhipicephalus sanguineus (brown dog tick), and the

treatment and control of roundworm (immature adult and adult Toxocara

canis and adult Toxascaris leonina) and adult hookworm (Ancylostoma

caninum and Uncinaria stenocephala) infections for one month in dogs and

puppies 8 weeks of age and older, and weighing 2.8 pounds or greater.

DOSAGE AND ADMINISTRATION

SIMPARICA TRIO is given orally once a month, at the recommended

minimum dose of 0.54 mg/lb (1.2 mg/kg) sarolaner, 0.011 mg/lb (24 µg/kg)

moxidectin, and 2.27 mg/lb (5 mg/kg) pyrantel (as pamoate salt).

Dosage Schedule

Body Weight

(lbs)

Sarolaner per

Tablet

(mg)

Moxidectin

per Tablet

(mg)

Pyrantel

per

Tablet

(mg)

Number

of Tablets

Administered

2.8 to 5.5 3 0.06 12.5 One

5.6 to 11.0 6 0.12 25 One

11.1 to 22.0 12 0.24 50 One

22.1 to 44.0 24 0.48 100 One

44.1 to 88.0 48 0.96 200 One

88.1 to 132.0 72 1.44 300 One

>132.0 Administer the appropriate combination of tablets

SIMPARICA TRIO can be offered to the dog with or without food.

Care should be taken to ensure that the dog consumes the complete dose

and that part of the dose is not lost or refused. If a dose is missed, give

SIMPARICA TRIO immediately and resume monthly dosing.

Heartworm Prevention:

SIMPARICA TRIO should be administered at monthly intervals year‑round

or at least within one month of the animal’s first seasonal exposure to

mosquitoes and continuing until at least 1 month after the dog’s last seasonal

exposure. If a dose is missed, give SIMPARICA TRIO immediately and

resume monthly dosing. When replacing a monthly heartworm preventive

product, SIMPARICA TRIO should be given within one month of the last dose

of the former medication.

Flea Treatment and Prevention:

Treatment with SIMPARICA TRIO may begin at any time of the year.

SIMPARICA TRIO should be administered year‑round at monthly intervals

or started at least one month before fleas become active.

To minimize the likelihood of flea re‑infestation, it is important to treat all

dogs and cats within a household with a flea control product.

Tick Treatment and Control:

Treatment with SIMPARICA TRIO can begin at any time of the year.

SIMPARICA TRIO should be administered year‑round at monthly intervals

or started at least one month before ticks become active.

Intestinal Nematode Treatment and Control:

For the treatment of roundworm (immature adult and adult Toxocara canis

and adult Toxascaris leonina) and adult hookworm (Ancylostoma caninum

and Uncinaria stenocephala) infections, SIMPARICA TRIO should be

administered once as a single dose. Monthly use of SIMPARICA TRIO will

control any subsequent infections.

CONTRAINDICATIONS

There are no known contraindications for the use of SIMPARICA TRIO.

WARNINGS

Not for use in humans. Keep this and all drugs out of reach of children.

Keep SIMPARICA TRIO in a secure location out of reach of dogs, cats and

other animals to prevent accidental ingestion or overdose.

PRECAUTIONS

Sarolaner, one of the ingredients in SIMPARICA TRIO, is a member of the

isoxazoline class. This class has been associated with neurologic adverse

reactions including tremors, ataxia, and seizures. Seizures have been reported

in dogs receiving isoxazoline class drugs, even in dogs without a history of

seizures. Use with caution in dogs with a history of seizures or neurologic

disorders.

Prior to administration of SIMPARICA TRIO, dogs should be tested for

existing heartworm infections. Infected dogs should be treated with an

adulticide to remove adult heartworms. SIMPARICA TRIO is not effective

against adult D. immitis.

The safe use of SIMPARICA TRIO has not been evaluated in breeding,

pregnant, or lactating dogs.

ADVERSE REACTIONS

In a field safety and effectiveness study, SIMPARICA TRIO was administered

to dogs for the prevention of heartworm disease. The study included a total of

410 dogs treated once monthly for 11 treatments (272 treated with

SIMPARICA TRIO and 138 treated with an active control). Over the 330-day

study period, all observations of potential adverse reactions were recorded.

The most frequent reactions reported in the SIMPARICA TRIO group are

presented in the following table.

Table 1. Dogs with Adverse Reactions

Clinical Sign SIMPARICA TRIO

n = 272

Active Control

n = 138

Vomiting 14.3% 10.9%

Diarrhea 13.2% 8.0%

Lethargy 8.5% 6.5%

Anorexia 5.1% 5.8%

Polyuria 3.7% 3.6%

Hyperactivity 2.2% 0.7%

Polydipsia 2.2% 2.9%

In a second field safety and effectiveness study, SIMPARICA TRIO was

administered to 278 dogs with fleas. Adverse reactions in dogs treated with

SIMPARICA TRIO included diarrhea.

In a third field safety and effectiveness study, SIMPARICA TRIO was

administered to 120 dogs with roundworms. Adverse reactions in dogs

treated with SIMPARICA TRIO included diarrhea and vomiting.

For a copy of the Safety Data Sheet or to report adverse reactions, call

Zoetis Inc. at 1-888-963-8471. For additional information about adverse drug

experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or

www.fda.gov/reportanimalae.

CLINICAL PHARMACOLOGY

Following oral administration of SIMPARICA TRIO in Beagle dogs (13 to

15 months of age at the time of initial dosing), sarolaner and moxidectin were

rapidly and well-absorbed. Following a single oral dose of SIMPARICA TRIO

(sarolaner dose of 1.2 mg/kg), the sarolaner mean maximum plasma

concentration (Cmax) was 523 ng/mL with a mean time to maximum

concentration (Tmax) of 3.5 hours and an absolute bioavailability of 88%.

At a moxidectin dose of 0.024 mg/kg, the moxidectin mean Cmax was

13.1 ng/mL with a mean Tmax of 2.4 hours and an absolute bioavailability

of 67%.

Following intravenous (IV) dosing of a combination solution of sarolaner

and moxidectin, the sarolaner volume of distribution (Vss) was 2.4 L/kg and

systemic clearance (CL) was 6.0 mL/kg/hr. For moxidectin the Vss was

7.65 L/kg and CL was 26.6 mL/kg/hr. The terminal half‑lives were similar after

oral and IV dosing for both sarolaner (12 days) and moxidectin (11 days).

The primary route of elimination of both sarolaner and moxidectin is biliary

excretion with minimal metabolism.

Following an oral dose of SIMPARICA TRIO containing 5 mg/kg pyrantel

(as pamoate salt), pyrantel has measurable plasma concentrations, but they

are low and highly variable. Pyrantel pamoate is intended to remain in the

gastrointestinal tract allowing for delivery of effective concentrations to

gastrointestinal nematodes.

MODE OF ACTION

SIMPARICA TRIO contains three active pharmaceutical ingredients,

sarolaner, moxidectin, and pyrantel pamoate.

Sarolaner is an acaricide and insecticide belonging to the isoxazoline

group. Sarolaner inhibits the function of the neurotransmitter gamma

aminobutyric acid (GABA) receptor and glutamate receptor, and works

at the neuromuscular junction in insects. This results in uncontrolled

neuromuscular activity leading to death in insects or acarines.

Moxidectin is an endectocide in the macrocyclic lactone class. Moxidectin

acts by interfering with the chloride channel‑mediated neurotransmission in

the parasite. This results in paralysis and death of the parasite.

Pyrantel pamoate is a nematocide belonging to the tetrahydropyrimidine

class. Pyrantel acts as a depolarizing, neuromuscular‑blocking agent in

susceptible parasites, which causes paralysis and death or expulsion of the

organism.

EFFECTIVENESS

Heartworm Prevention

In two well‑controlled laboratory studies, a single oral dose of SIMPARICA

TRIO was 100% effective in preventing the development of adult D. immitis in

dogs inoculated with infective larvae 30 days before treatment.

In a well-controlled US field study consisting of 246 dogs administered

SIMPARICA TRIO and 119 administered an active control, no dogs treated

with SIMPARICA TRIO tested positive for heartworm disease. All dogs treated

with SIMPARICA TRIO were negative for D. immitis antigen and blood

microfilariae at study completion on day 330.

Flea Treatment and Prevention

In a well‑controlled laboratory study, SIMPARICA TRIO began to kill fleas

at 4 hours and demonstrated 100% effectiveness at 8 hours after initial

administration. After weekly re‑infestations, SIMPARICA TRIO reduced the

number of live fleas by ≥97.8% within 12 hours of infestation for 28 days.

In a separate well‑controlled laboratory study, SIMPARICA TRIO

demonstrated 100% effectiveness against adult fleas within 24 hours

following treatment and maintained ≥99.7% effectiveness against weekly

re‑infestations for 35 days.

In a study to explore flea egg production and viability, SIMPARICA TRIO killed

fleas before they could lay eggs for 35 days.

In a well‑controlled 60‑day US field study conducted in dogs with existing flea

infestations of varying severity, the effectiveness of SIMPARICA TRIO against

fleas on Day 30 and 60 visits was 99.0% and 99.7%, respectively, compared

to baseline. 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.

Tick Treatment and Control

In a well‑controlled laboratory study, SIMPARICA TRIO began to kill existing

I. scapularis within 8 hours, SIMPARICA TRIO reduced the number of live

ticks by ≥94.2% within 24 hours of infestation for 28 days.

In well‑controlled laboratory studies, SIMPARICA TRIO demonstrated

≥98.9% effectiveness against an existing infestation of Amblyomma

maculatum, Ixodes scapularis, Rhipicephalus sanguineus, and Dermacentor

variabilis 48 hours post‑administration and maintained ≥90.4% effectiveness

48 hours after re‑infestation for at least 28 days. Against Amblyomma

americanum, SIMPARICA TRIO demonstrated ≥99.4% effectiveness 72 hours

after treatment of existing infestations, and maintained ≥98.4% effectiveness

72 hours after re‑infestation for at least 28 days.

Intestinal Nematode Treatment and Control

Elimination of roundworms (immature adult and adult Toxocara canis and

adult Toxascaris leonina) and adult hookworms (Ancylostoma caninum and

Uncinaria stenocephala) was demonstrated in well‑controlled laboratory

studies.

In a 10-day multi‑center field study, SIMPARICA TRIO was effective against

Toxocara canis and reduced fecal egg counts 99.2%.

ANIMAL SAFETY

Margin of Safety: SIMPARICA TRIO was administered orally to 8‑week‑old

Beagle puppies at doses of 1, 3, and 5X the maximum labeled dose

(2.4 mg/kg sarolaner, 48 µg/kg moxidectin, and 10 mg/kg pyrantel) at

28 day intervals for 7 treatments. Dogs in the control group received

placebo. There were no clinically‑relevant, treatment related effects on

clinical observations, body weights, food consumption, clinical pathology

(hematology, coagulation, serum chemistry, and urinalysis), gross pathology,

histopathology, or organ weights. During the end-of-study ophthalmic

examination, the following change was found: one 1X dog had retinal

dysplasia (OS folds).

Ivermectin-sensitive Collie Safety:

SIMPARICA TRIO was administered orally once at 1, 3 and 5X the maximum

labeled dose to Collies that had been pre‑screened for avermectin sensitivity.

Dogs in the control group received placebo. Clinical signs (ataxia, muscle

fasciculations, mydriasis) associated with avermectin sensitivity were

observed in the 5X group. All dogs were completely recovered by the third

day of the study.

Heartworm-Positive Safety:

SIMPARICA TRIO was administered orally at 1 and 3X the maximum labeled

dose at 28 day intervals for 3 treatments to Beagle dogs with patent adult

heartworm infections and circulating microfilariae. Dogs in the control group

received placebo. Diarrhea occurred more commonly in the treated dogs and

also more often in the 3X group compared with the 1X group. Two dogs

(1 each in 1X and 3X) developed a fever less than 24 hours after the first

dose. The fever may have been a transient reaction to a rapid microfilaria

reduction. Both dogs recovered without treatment.

Field Safety: In three well‑controlled field studies, SIMPARICA TRIO was

used concurrently with other medications such as vaccines, antimicrobials,

anthelmintics, antiprotozoals, steroidal and non‑steroidal anti‑inflammatory

agents, anesthetic agents and analgesics. No adverse reactions were

associated with the concurrent use of SIMPARICA TRIO and other

medications.

STORAGE CONDITIONS

Store at or below 30°C (86°F).