sarolaner

Simparica TRIO® is indicated for the prevention of heartworm disease caused by Dirofilaria immitis and for the treatment and control of roundworm (immature adult and adult Toxocara canis and adult Toxascaris leonina) and hookworm (L4, immature adult, and adult Ancylostoma caninum and adult Uncinaria stenocephala) infections. Simparica TRIO® kills adult fleas (Ctenocephalides felis) and is indicated for the treatment and prevention of flea infestations, the prevention of Dipylidium caninum (tapeworm) infections as a direct result of killing Ctenocephalides felis vector fleas on the treated dog, and 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), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (Asian longhorned tick) for one month in dogs and puppies 8 weeks of age and older, and weighing 2.8 pounds or greater. Simparica TR O® is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

Simparica TRIO®

SIMPARICA® kills adult fleas, and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis), and the treatment and control of tick infestations [Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf Coast tick), Dermacentor variabilis (American dog tick), Ixodes scapularis (black-legged tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (Asian longhorned tick)] for one month in dogs 6 months of age or older and weighing 2.8 pounds or greater. SIMPARICA® is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

SIMPARICA®

revolution® PLUS is indicated for the prevention of heartworm disease caused by Dirofilaria immitis, the treatment and control of roundworm (Toxocara cati) and intestinal hookworm (Ancylostoma tubaeforme) infections, and the treatment and control of ear mite (Otodectes cynotis) infestations. revolution® PLUS kills adult fleas (Ctenocephalides felis) and is indicated for the treatment and prevention of flea infestations, the prevention of Dipylidium caninum (tapeworm) infections as a direct result of killing Ctenocephalides felis vector fleas on the treated cat, and the treatment and control of tick infestations with Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf Coast tick), Dermacentor variabilis (American dog tick), and Ixodes scapularis (black-legged tick) for one month in cats and kittens 8 weeks and older, and weighing 2.8 pounds or greater.

revolution® PLUS

SIMPARICA TRIO is indicated for the prevention of heartworm disease caused by Dirofilaria immitis and for the treatment and control of roundworm (immature adult and adult Toxocara canis and adult Toxascaris leonina) and hookworm (L4, immature adult, and adult Ancylostoma caninum and adult Uncinaria stenocephala) infections. SIMPARICA TRIO kills adult fleas (Ctenocephalides felis) and is indicated for the treatment and prevention of flea infestations, the prevention of Dipylidium caninum (tapeworm) infections as a direct result of killing Ctenocephalides felis vector fleas on the treated dog, and 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), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (Asian longhorned tick) for one month in dogs and puppies 8 weeks of age and older, and weighing 2.8 pounds or greater. SIMPARICA TRIO is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

Simparica TRIO®

REVOLUTION PLUS is indicated for the prevention of heartworm disease caused by Dirofilaria immitis, the treatment and control of roundworm (Toxocara cati) and intestinal hookworm (Ancylostoma tubaeforme) infections, and the treatment and control of ear mite (Otodectes cynotis) infestations. REVOLUTION PLUS kills adult fleas (Ctenocephalides felis) and is indicated for the treatment and prevention of flea infestations, the prevention of Dipylidium caninum (tapeworm) infections as a direct result of killing Ctenocephalides felis vector fleas on the treated cat, and the treatment and control of tick infestations with Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf Coast tick), Dermacentor variabilis (American dog tick), and Ixodes scapularis (black-legged tick) for one month in cats and kittens 8 weeks and older, and weighing 2.8 pounds or greater.

revolution® PLUS

SIMPARICA kills adult fleas, and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis), and the treatment and control of tick infestations [Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf Coast tick), Dermacentor variabilis (American dog tick), Ixodes scapularis (black-legged tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (Asian longhorned tick)] for one month in dogs 6 months of age or older and weighing 2.8 pounds or greater. SIMPARICA is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing lxodes scapularis vector ticks.

Simparica®

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.

Simparica TRIO®

Sarolaner is rapidly and well absorbed following oral administration of SIMPARICA. In a study of 12 Beagle dogs the mean maximum plasma concentration (Cmax) was 1100 ng/mL and the mean time to maximum concentration (Tmax) occurred at 3 hours following a single oral dose of 2 mg/kg to fasted animals. The mean oral bioavailability was 86% and 107% in fasted and fed dogs, respectively. The mean oral T1/2 values for fasted and fed animals was 10 and 12 days respectively. Sarolaner is distributed widely; the mean volume of distribution (Vdss) was 2.81 L/kg bodyweight following a 2 mg/kg intravenous dose of sarolaner. 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 repeat administration of SIMPARICA 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 6th dose. Following treatment at 1X, 3X, and 5X the maximum intended clinical dose of 4 mg/kg, sarolaner systemic exposure was dose proportional over the range 1X to 5X.

Simparica®

Following topical administration of REVOLUTION PLUS both selamectin and sarolaner are well absorbed with mean absolute bioavailability of 40.5% and 57.9%, respectively, and distribute systemically. In cats, selamectin and sarolaner are low clearance compounds with a long half-life of 12.5 days and 41.5 days following topical administration, respectively. Following IV dose, the total body clearance for selamectin was 10.2 mL/kg/hr and for sarolaner was 3.41 mL/kg/hr. The volume of distribution at steady state was 1.26 L/kg for selamectin and 3.87 L/kg for sarolaner. The primary route of elimination for both drugs is hepatobiliary excretion (approximately 50% of dose excreted in feces). Following repeated monthly doses of REVOLUTION PLUS, there was a less than dose proportional increase in the Cmax and AUC of sarolaner and selamectin. The accumulation of both sarolaner and selamectin was observed with Cmax plateauing after the 6th dose for sarolaner and the 3rd dose for selamectin.

revolution® PLUS

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

Simparica TRIO®

Human warnings: Not for human use. Keep this and all drugs out of the reach of children. Do not come into contact with or allow children to contact the application site until 4 hours post application. In humans, REVOLUTION PLUS may be irritating to skin and eyes. REVOLUTION PLUS and selamectin topical solution contain isopropyl alcohol and the preservative butylated hydroxytoluene (BHT). Reactions such as hives, itching and skin redness have been reported in humans after accidental dermal contact with selamectin topical solution. Individuals with known hypersensitivity to selamectin topical solution should use caution or consult a health care professional before applying this product on a cat. Wash hands after use and wash off any product in contact with the skin immediately with soap and water. If contact with eyes occurs, then flush eyes copiously with water; if wearing contact lenses, rinse the eyes first then remove contact lenses and continue to rinse for 5 – 10 minutes and seek medical attention. In case of ingestion by a human, contact a physician immediately. The safety data sheet (SDS) provides more detailed occupational safety information. For a copy of the SDS or to report a suspected adverse reaction, call Zoetis at 1-888-963-8471. Flammable - Keep away from heat, sparks, open flames or other sources of ignition.

revolution® PLUS

Not for use in humans. Keep this and all drugs out of reach of children. For use in dogs only. Do not use SIMPARICA in cats. SIMPARICA should not be used in dogs less than 6 months of age (see Animal Safety). Keep SIMPARICA in a secure location out of reach of dogs, cats and other animals to prevent accidental ingestion or overdose.

Simparica®

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.

Simparica TRIO®

In a field safety and effectiveness study, REVOLUTION PLUS was administered to cats with fleas. The study included a total of 430 cats (282 treated with REVOLUTION PLUS and 148 treated with imidacloprid + moxidectin once monthly for three treatments). Over the 90-day study period, all observations of potential adverse reactions were recorded. Reactions reported in the REVOLUTION PLUS group included those presented in the following table. Adverse Reactions by Treatment Group Adverse Reaction REVOLUTION PLUS (n = 282) Imidacloprid + moxidectin (n =148) Lethargy 12 (4.3%) 1 (0.7%) Skin lesions* 10 (3.5%) 3 (2.0%) Anorexia 9 (3.2%) 3 (2.0%) Pruritus 7 (2.5%) 3 (2.0%) Conjunctivitis 7 (2.5%) 1 (0.7%) Sneezing 6 (2.1%) 1 (0.7%) Administration site hair changes (alopecia) 5 (1.8%) 0 (0.0%) Administration site lesions (scabbing) 2 (0.7%) 0 (0.0%) *Lesions not associated with application site. In a second field safety and effectiveness study, REVOLUTION PLUS was administered to 124 cats with ear mites. Adverse reactions in cats treated with REVOLUTION PLUS included emesis, dermatitis and eczema, and pruritus. In a third field safety and effectiveness study, REVOLUTION PLUS was administered to 70 cats with hookworms. Adverse reactions in cats treated with REVOLUTION PLUS included diarrhea, anorexia, emesis, and lethargy. Post-Approval Experience (2022) The following adverse events are based on post-approval adverse drug experience reporting forREVOLUTION PLUS. Not all adverse events are reported to FDA/CVM. It is not always possible to reliably estimate the exposure using these data. The following adverse events reported in cats are listed in decreasing order of reporting frequency: Application site reactions (including alopecia, lesions, erythema, and pruritus), lethargy, anorexia, vomiting, generalized pruritus, behavioral disorders (including hiding, hyperactivity, and vocalization), ataxia, muscle tremor, diarrhea, generalized alopecia, and seizure. Contact Information 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 http://www.fda.gov/reportanimalae.

revolution® PLUS

SIMPARICA was administered in a well-controlled US field study, which included a total of 479 dogs (315 dogs treated with SIMPARICA and 164 dogs treated with active control once monthly for three treatments). Over the 90-day study period, all observations of potential adverse reactions were recorded. Table 1. Dogs with adverse reactions Adverse reaction sarolaner sarolaner active control active control N % (n = 315) N # (n =164) Vomiting 3 0.95% 9 5.50% Diarrhea 2 0.63% 2 1.20% Lethargy 1 0.32% 2 1.20% Inappetence 0 0% 3 1.80% Additionally, one female dog aged 8.6 years exhibited lethargy, ataxia while posturing to eliminate, elevated third eyelids, and inappetence one day after receiving SIMPARICA concurrently with a heartworm preventative (ivermectin/pyrantel pamoate). The signs resolved one day later. After the day 14 visit, the owner elected to withdraw the dog from the study. Abnormal neurologic signs such as tremors, decreased conscious proprioception, ataxia, decreased or absent menace, and/or seizures were reported in dogs receiving SIMPARICA (see Animal Safety). Post Approval Experience (2019): The following adverse events are based on post-approval adverse drug experience reporting for SIMPARICA. Not all adverse events are reported to FDA CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data. The following adverse events reported for dogs are listed in decreasing order of reporting frequency: Vomiting, tremors, lethargy, seizure, diarrhea (with and without blood), anorexia, ataxia, pruritus, hypersalivation and hyperactivity.

Simparica®

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. In one well-controlled laboratory study, one dog had a seizure 16 days after administration of SIMPARICA TRIO.

Simparica TRIO®

SimparicaTRIO® 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).

Oral

Simparica TRIO®

0.91 mg/lb (2 mg/kg body weight), one per month.

Oral

SIMPARICA®

The recommended minimum dosage is 2.7 mg selamectin per pound (6.0 mg/kg) of body weight in combination with 0.45 mg sarolaner per pound (1.0 mg/kg) of body weight administered monthly.

Topical

revolution® PLUS

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. Tapeworm 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. SIMPARICA TRIO will only prevent D. caninum infections by killing the fleas on the treated dog. Dogs may also become infected with D. caninum by ingesting fleas from untreated animals, it is therefore recommended that all pets in a household are treated for fleas. 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 hookworm (L4, immature adult, and adult Ancylostoma caninum and adult Uncinaria stenocephala) infections, SIMPARICA TRIO should be administered once as a single dose. Monthly use of SIMPARICA TRIO will control any subsequent infections.

ORAL

Simparica TRIO®

SIMPARICA is given orally once a month at the recommended minimum dosage of 0.91 mg/lb (2 mg/kg). Dosage Schedule: Body Weight SAROLANER per Tablet (mg) Number of Tablets Administered 2.8 to 5.5 lbs 5 One 5.6 to 11 lbs 10 One 11.1 to 22 lbs 20 One 22.1 to 44 lbs 40 One 44.1 to 88 lbs 80 One 88.1 to 132 lbs 120 One >132.1 lbs Administer the appropriate combination of tablets SIMPARICA can be offered by hand, in the food, or administered like other tablet medications. Care should be taken that the dog consumes the complete dose, and treated animals should be observed for a few minutes to ensure that part of the dose is not lost or refused. If a dose is missed, administer SIMPARICA and resume a monthly dosing schedule. SIMPARICA should be administered at monthly intervals. Flea Treatment and Prevention: Treatment with SIMPARICA may begin at any time of the year. In areas where fleas are common year-round, monthly treatment with SIMPARICA can continue the entire year without interruption. To minimize the likelihood of flea re-infestation, it is important to treat all dogs and cats within a household with an approved flea control product. Tick Treatment and Control: Treatment with SIMPARICA can begin at any time of the year (see Effectiveness).

ORAL

Simparica®