Afoxolaner

Dogs (Dogs and Puppies 8 Weeks of Age and Older)

Kills adult fleas and for the treatment and prevention of flea infestations (Ctenocephalides felis), and the treatment and control of Ixodes scapularis (blacklegged tick), Dermacentor variabilis (American dog tick), Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf Coast tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (longhorned tick) infestations in dogs and puppies 8 weeks of age and older, weighing 4 pounds of body weight or greater, for 1 month; and for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

NexGard®

For the prevention of heartworm disease caused by Dirofilaria immitis and for the treatment and control of adult hookworm (Ancylostoma caninum, Ancylostoma braziliense, and Uncinaria stenocephala) and roundworm (Toxocara canis and Toxascaris leonina) infections. Kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) and the treatment and control of Ixodes scapularis (blacklegged tick), Rhipicephalus sanguineus (brown dog tick), Dermacentor variabilis (American dog tick), Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf Coast tick), and Haemaphysalis longicornis (longhorned tick) infestations for one month in dogs and puppies eight weeks of age and older, weighing four pounds of body weight or greater. For the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

NexGard® PLUS

NexGard® PLUS is indicated for the prevention of heartworm disease caused by Dirofilaria immitis and for the treatment and control of adult hookworm (Ancylostoma caninum, Ancylostoma braziliense, and Uncinaria stenocephala) and roundworm (Toxocara canis and Toxascaris leonina) infections. NexGard® PLUS kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) and the treatment and control of Ixodes scapularis (black-legged tick), Rhipicephalus sanguineus (brown dog tick), Dermacentor variabilis (American dog tick), Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf Coast tick) and Haemaphysalis longicornis (longhorned tick) infestations for one month in dogs and puppies eight weeks of age and older, weighing four pounds of body weight or greater. NexGard® PLUS is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

NexGard® PLUS (afoxolaner, moxidectin, and pyrantel chewable tablets)

NexGard® kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis), and the treatment and control of Ixodes scapularis (black-legged tick), Dermacentor variabilis (American dog tick), Amblyomma americanum (lone star tick), Amblyomma maculatum (Gulf Coast tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (longhorned tick) infestations in dogs and puppies 8 weeks of age and older, weighing 4 pounds of body weight or greater, for one month. NexGard® is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing lxodes scapularis vector ticks.

NexGard® (afoxolaner) Chewables

Mode of Action: NexGard® PLUS (afoxolaner, moxidectin, and pyrantel chewable tablets) contains the three active pharmaceutical ingredients afoxolaner, moxidectin, and pyrantel (as pamoate salt). Afoxolaner is a member of the isoxazoline family, shown to bind at a binding site to inhibit insect and acarine ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA), thereby blocking pre- and postsynaptic transfer of chloride ions across cell membranes. Prolonged afoxolaner-induced hyperexcitation results in uncontrolled activity of the central nervous system and death of insects and acarines. The selective toxicity of afoxolaner between insects and acarines and mammals may be inferred by the differential sensitivity of the insects and acarines’ GABA receptors versus mammalian GABA receptors. Moxidectin is an endectocide in the macrocyclic lactone class. Moxidectin acts by interfering with chloride channel-mediated neurotransmission in susceptible parasites, which results in paralysis and death of the parasite. Pyrantel is a nematocide belonging to the tetrahydropyrimidine class. Pyrantel acts as a depolarizing, neuromuscular-blocking agent in susceptible parasites, causing paralysis and death or expulsion of the parasite. Pharmacokinetics: Following a single oral administration of a near-final formulation of NexGard® PLUS (at mean doses of 3.9 mg/kg afoxolaner, 18.8 mcg/kg moxidectin, and 7.8 mg/kg pyrantel pamoate) in fed and fasted Beagle dogs (10 to 21 months of age), afoxolaner and moxidectin were more rapidly absorbed in the fasted state with a time to maximum concentration (Tmax) of 2 to 3 hours. The afoxolaner mean maximum plasma concentrations (Cmax) in the fed and fasted states were 1610 and 2200 ng/mL (CV=33 and 16%) and the moxidectin mean Cmax values were 11.1 and 15.5 ng/mL (CV=39 and 24%), respectively. The area under the curve (AUC) for afoxolaner and moxidectin were similar between fed and fasted states. Post-dose pyrantel plasma concentrations were quantifiable out to 24 hours. Following six oral administrations of NexGard® PLUS at 1, 3, and 5X the maximum exposure dose of 5 mg/kg, 24 mcg/kg, and 10 mg/kg afoxolaner, moxidectin, and pyrantel pamoate, respectively, every 28 days in 8-week-old Beagle dogs, afoxolaner and moxidectin Tmax ranged from 2 to 6 hours. The observed mean Cmax and AUC at steady state in the 1X dose group were 2230 ng/mL and 19000 days*ng/mL for afoxolaner and 14.8 ng/mL and 55.2 days*ng/mL for moxidectin, respectively. Based on mean Cmin, afoxolaner and moxidectin accumulated by less than 4-fold at steady state. Afoxolaner and moxidectin exposure increased in a dose proportional manner between the 1X and 3X dose groups but was less than dose proportional in the 5X dose group. Pyrantel pamoate is poorly absorbed into systemic circulation. Pyrantel pamoate is intended to remain in the gastrointestinal tract to allow effective concentrations to be delivered to gastrointestinal nematodes.

NexGard® PLUS (afoxolaner, moxidectin, and pyrantel chewable tablets)

There are no known contraindications for the use of NexGard® PLUS.

NexGard® PLUS (afoxolaner, moxidectin, and pyrantel chewable tablets)

Margin of Safety: NexGard® PLUS was administered orally at 1, 3, and 5X the maximum exposure doses at approximately 28-day intervals for six treatments to 8-week-old Beagle puppies. Dogs in the control group were sham-dosed. There were no clinically relevant, treatment-related effects on body weights, food consumption, clinical pathology (hematology, coagulation, serum chemistry, and urinalysis), gross pathology, histopathology, organ weights, or ophthalmic examinations. Mild, self-limiting diarrhea (with and without blood) was possibly related to treatment, as there were more incidences in the NexGard® PLUS groups than the control group throughout the study, including within 48 hours after treatment. Avermectin-Sensitive Collie Safety: NexGard® PLUS was administered orally at 1, 3, and 5X the maximum label dose to MDR1-deficient Collies once on Day 0, with a second administration to the 1X group on Day 28. Dogs in the control group were sham-dosed on Days 0 and 28. No clinical signs of avermectin toxicity were noted in any dog at any time during the study. Vomiting was observed in some dogs in the 3X and 5X groups and resolved without treatment. Diarrhea, with or without blood, was observed in some dogs in all of the NexGard® PLUS groups and resolved without treatment. Heartworm-Positive Safety: NexGard® PLUS was administered orally at 1X and 3X the maximum exposure doses at approximately 28-day intervals for three treatments to Beagle dogs with adult heartworm infections and circulating microfilariae. Dogs in the control group were sham-dosed. Diarrhea was observed in one dog in the 1X group and in three dogs in the 3X group, and vomiting was observed in two dogs in the 3X group. No signs of avermectin toxicity were observed at any time during the study. There were no clinical signs associated with death of the microfilariae observed in any of the dogs. Field Safety: In a well-controlled field study, NexGard® PLUS was used concurrently with other medications such as vaccines, antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), anesthetics, sedatives, analgesics, steroids, anthelmintics, antiemetics, and antipruritics. No adverse reactions were associated with the concurrent use of NexGard® PLUS and other medications.

NexGard® PLUS (afoxolaner, moxidectin, and pyrantel chewable tablets)

Not for use in humans. Keep this and all drugs out of the reach of children. In case of accidental ingestion, contact a physician for treatment advice. Keep NexGard® PLUS in a secure location out of the reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

NexGard® PLUS (afoxolaner, moxidectin, and pyrantel chewable tablets)

Not for use in humans. Keep this and all drugs out of the reach of children. In case of accidental ingestion, contact a physician immediately. Keep NexGard® in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

NexGard® (afoxolaner) Chewables

In a well-controlled US field study, which included a total of 333 households and 615 treated dogs (415 administered afoxolaner; 200 administered active control), no serious adverse reactions were observed with NexGard®. Over the 90-day study period, all observations of potential adverse reactions were recorded. The most frequent reactions reported at an incidence of > 1% within any of the three months of observations are presented in the following table. The most frequently reported adverse reaction was vomiting. The occurrence of vomiting was generally self-limiting and of short duration and tended to decrease with subsequent doses in both groups. Five treated dogs experienced anorexia during the study, and two of those dogs experienced anorexia with the first dose but not subsequent doses. Table 1: Dogs With Adverse Reactions. Treatment Group Afoxolaner Oral active control N Number of dogs in the afoxolaner treatment group with the identified abnormality. % (n=415) N Number of dogs in the control group with the identified abnormality. % (n=200) Vomiting (with and without blood) 17 4.1 25 12.5 Dry/Flaky Skin 13 3.1 2 1.0 Diarrhea (with and without blood) 13 3.1 7 3.5 Lethargy 7 1.7 4 2.0 Anorexia 5 1.2 9 4.5 In the US field study, one dog with a history of seizures experienced a seizure on the same day after receiving the first dose and on the same day after receiving the second dose of NexGard®. This dog experienced a third seizure one week after receiving the third dose. The dog remained enrolled and completed the study. Another dog with a history of seizures had a seizure 19 days after the third dose of NexGard®. The dog remained enrolled and completed the study. A third dog with a history of seizures received NexGard® and experienced no seizures throughout the study. In a second US field safety and effectiveness study, NexGard® was administered to 130 dogs with fleas. Adverse reactions included pruritus, diarrhea (with or without blood), vomiting, anorexia, and lethargy.

NexGard® (afoxolaner) Chewables

In a field safety and effectiveness study, NexGard® PLUS was administered to dogs for the prevention of heartworm disease. The study included a total of 272 dogs (134 administered NexGard® PLUS and 138 administered active control) treated once monthly for 11 treatments. Over the 330-day study period, all observations of potential adverse reactions were recorded. The most frequent reactions reported in the NexGard® PLUS group are presented in the following table. Table 1. Dogs With Adverse Reactions Clinical Sign NexGard® PLUS n = 134 Number (Percentage) Active Control n = 138 Number (Percentage) Diarrhea 9 (6.7%) 7 (5.1%) Vomiting 6 (4.5%) 7 (5.1%) Lethargy 3 (2.2%) 5 (3.6%) Itching 3 (2.2%) 3 (2.2%) Dermatitis 2 (1.5%) 1 (0.7%) Anorexia 1 (0.7%) 4 (2.9%) Muscle tremor 1 (0.7%) 1 (0.7%) One dog in the NexGard® PLUS group was reported to exhibit muscle tremors along with nausea and depression for one day after the Day 0 treatment. The dog remained in the study and muscle tremors were not reported after any subsequent treatments.

NexGard® PLUS (afoxolaner, moxidectin, and pyrantel chewable tablets)

The following adverse events are based on post-approval adverse drug experience reporting. 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 for NexGard®: Vomiting, pruritus, lethargy, diarrhea (with and without blood), anorexia, seizure, hyperactivity/restlessness, panting, erythema, ataxia, dermatitis (including rash, papules), allergic reactions (including hives, swelling), and tremors. Contact Information: For a copy of the Safety Data Sheet (SDS) or to report suspected adverse drug events, contact Boehringer Ingelheim Animal Health USA Inc. at 1-888-637-4251 or www.nexgardforpets.com. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or www.fda.gov/reportanimalae.

NexGard® (afoxolaner) Chewables

Dogs (Dogs and Puppies 8 Weeks of Age and Older)

NexGard® is given once a month at the minimum dosage of 1.14 mg/lb (2.5 mg/kg).

Oral

NexGard®

Administer orally once a month at the minimum dose of 1.14 mg/lb (2.5 mg/kg) afoxolaner, 5.45 mcg/lb (12 mcg/kg) moxidectin, and 2.27 mg/lb (5.0 mg/kg) pyrantel (as pamoate salt). For heartworm disease prevention, give once monthly for at least six months after last exposure to mosquitoes.

Oral

NexGard® PLUS

NexGard® PLUS is given orally once a month at the minimum dosage of 1.14 mg/lb (2.5 mg/kg) afoxolaner, 5.45 mcg/lb (12 mcg/kg) moxidectin, and 2.27 mg/lb (5.0 mg/kg) pyrantel (as pamoate salt). For heartworm disease prevention, give once monthly for at least six months after last exposure to mosquitoes (see Effectiveness).

ORAL

NexGard® PLUS (afoxolaner, moxidectin, and pyrantel chewable tablets)

NexGard® is given orally once a month, at the minimum dosage of 1.14 mg/lb (2.5 mg/kg).

ORAL

NexGard® (afoxolaner) Chewables