NexGard COMBO: Product Information (Page 3 of 4)

Contact Information:

To report suspected adverse events, for technical assistance or to obtain a copy of the SDS, contact Boehringer Ingelheim Animal Health USA Inc. at 1-888-637-4251 or www.nexgardforpets.com.

For additional information about reporting adverse drug experiences for animal drugs, contact FDA at 1-888-FDA-VETS or online at www.fda.gov/reportanimalae.

The Safety Data Sheet (SDS) provides additional occupational safety information. For customer service or to obtain product information, including the SDS, call 1-888-637-4251.

Clinical Pharmacology:

Mode of Action:

Esafoxolaner is a member of the isoxazoline family, shown to bind at a 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 post-synaptic transfer of chloride ions across cell membranes. Prolonged esafoxolaner-induced hyperexcitation results in uncontrolled activity of the central nervous system and death of insects and acarines. The selective toxicity of esafoxolaner between insects/acarines and mammals may be inferred by the differential sensitivity of the insects/acarines’ GABA receptors versus mammalian GABA receptors.

Eprinomectin is an endectocide in the macrocyclic lactone class that binds to glutamate gated chloride channels that are present in invertebrate nerve and muscle cells and increases the permeability of the cell membrane to chloride ions that triggers hyperpolarization of the nerve or muscle cell in susceptible parasites, resulting in paralysis and death of the parasite.

Praziquantel’s mode of action is not precisely known, but treated tapeworms undergo muscular paralysis accompanied by a rapid influx of calcium ions and the disruption of the tegument.

Pharmacokinetics:

After a single topical administration to healthy male and female cats of a combined topical formulation containing esafoxolaner (12 mg/mL), eprinomectin (4 mg/mL), and praziquantel (83 mg/mL), at dose volumes of 0.06, 0.12, or 0.24 mL/kg, there was a dose proportional increase in the exposure of each ingredient based on maximum plasma concentration (Cmax) and area under the plasma concentration time curve (AUC). After repeated monthly doses of the combined topical formulation at the target dose of 1.44 mg/kg esafoxolaner, 0.48 mg/kg eprinomectin, and 9.98 mg/kg praziquantel, steady state was reached by the fourth dose for esafoxolaner and after the second dose for eprinomectin and praziquantel. Additionally, modest accumulation was observed for esafoxolaner (approximately 3-fold) and praziquantel (approximately 1.5- to 2-fold) between the first and fifth dose, whereas no accumulation was observed for eprinomectin.

Effectiveness:

Heartworm Prevention:

In well-controlled laboratory studies, NexGard® COMBO (esafoxolaner, eprinomectin, and praziquantel topical solution) was 100% effective in preventing the development of heartworms in cats inoculated with infective larvae of Dirofilaria immitis 30 days prior to the first of three consecutive monthly treatments.

Flea Treatment and Prevention:

In a well-controlled laboratory study, NexGard® COMBO killed >92% of fleas within 24 hours. During subsequent weekly infestations, NexGard® COMBO killed ≥95.5% of fleas within 24 hours through Day 31 and killed fleas before they could lay eggs. The effectiveness against adult fleas at 24 hours post-infestation in the treated cats virtually eliminated flea egg production (99.8 – 100% control of flea egg production by 24 hours) throughout the remainder of the month. In a field safety and effectiveness study in the United States, conducted in households with existing flea infestations, the effectiveness of NexGard® COMBO against fleas was 97.8%, 99.6%, and 99.9% when assessed on Days 30, 60, and 90, respectively. Cats with signs of flea allergy dermatitis showed improvement in alopecia, dermatitis/pyodermatitis, pruritus, erythema, papules, and scaling, as a direct result of eliminating fleas.

Tick Treatment and Control:

In well-controlled laboratory studies, NexGard® COMBO demonstrated ≥95.1% effectiveness against Ixodes scapularis 48 hours post-infestation for a month and ≥95.6% effectiveness against Amblyomma americanum 72 hours post-infestation for a month.

Treatment and Control of Roundworms, Hookworms, and Tapeworms:

In 2 well-controlled laboratory studies, NexGard® COMBO provided 98.9% and 100% effectiveness against natural and/or induced roundworm infections with the dose-limiting gastrointestinal nematode species (adult Toxocara cati), respectively.

Effectiveness studies against fourth stage larval Toxocara cati and hookworms (adult and fourth stage larval Ancylostoma tubaeforme ; adult Ancylostoma braziliense) were conducted with an early formulation. The doses of eprinomectin in this early formulation are equivalent to that of the final formulation of NexGard® COMBO.

In well-controlled laboratory studies, NexGard® COMBO provided on average 92.8% effectiveness against natural and/or induced infections with Dipylidium caninum.

Target Animal Safety:

Margin of Safety Study:

NexGard® COMBO was applied topically to healthy kittens (8 to 9 weeks of age) at 1X, 3X, or 5X the maximum exposure dose six times at 28-day intervals; kittens in the control group were dosed with mineral oil. One kitten in the 5X group exhibited recumbency, tremors, hypothermia, ataxia, disorientation, and pupil dilation (responsive to light) 9 hours after the third dose. This kitten received supportive care, including washing the application site, and recovered within 48 hours post-dose. During necropsy, a dark red subcutaneous area (≤5mm diameter) was observed in the treatment site area of three cats in the 5X group, but microscopic examination revealed no histologic abnormalities. No significant changes related to NexGard® COMBO were observed for physical examination, body weight, clinical pathology (hematology, coagulation, and serum chemistry), histopathology, or organ weights.

Study in Heartworm Positive Cats:

Adult cats, 4.7 to 6.6 months of age, were experimentally infected with adult heartworms (D. immitis) by venous transplantation. All cats were negative for heartworm antibody, antigen and microfilariae prior to transplantation. Two weeks after transplantation, immunoserology verified positive antigen and the presence of microfilariae in all enrolled cats. A combination of fipronil, eprinomectin, praziquantel, and (S)-methoprene was applied topically to cats at 1X or 3X the maximum exposure dose once every 28 days for three consecutive treatments; cats in the control group were dosed with mineral oil. One cat in the 1X group exhibited cyanotic mucous membranes and tachypnea for 24 hours following the first treatment. The cat recovered and exhibited no abnormal signs following two subsequent treatments. There was no difference between the treatment groups in the number of adult D. immitis recovered at the end of the study.

Oral Administration Study:

Oral tolerance was evaluated to assess the effects of accidental oral ingestion. Kittens (male and female) ranging in age from 7.4 to 8.9 weeks were orally administered NexGard® COMBO at 1X the maximum exposure dose; kittens in the control group were dosed with saline. Cats were observed for adverse reactions at 1, 2, 3, 4, and 8 hours following administration, then twice a day until Day 14. All 8 cats administered NexGard® COMBO immediately exhibited excessive hypersalivation after oral administration. However, all cats stopped salivating within 1 hour after exposure. No additional health-related observations were seen for the remainder of the study.

How Supplied:

NexGard® COMBO is packaged as a single dose in 0.3 mL (for cats 1.8 – 5.5 lb) and 0.9 mL (for cats 5.6-16.5 lb) applicators.

Each size applicator is available in cartons containing 1, 3 or 6 applications.

Storage Information:

Store at 59° — 86°F (15° — 30°C). Brief periods up to 104°F (40°C) are permitted. Protect from light.

Approved by FDA under NADA # 141-570

Marketed by:

Boehringer Ingelheim Animal Health USA Inc.

Duluth, GA 30096

NEXGARD® is a registered trademark and NEXGARD COMBO is a trademark of Boehringer Ingelheim Animal Health France, used under license.

©2023 Boehringer Ingelheim Animal Health USA Inc. All rights reserved.

184238-003 Rev. 04/2023

Principal Display Panel – 0.3 mL Display Carton

FOR CATS 1.8 – 5.5 LBS 3 Applicators 0.3 mL

NexGard® COMBO

(esafoxolaner, eprinomectin, and praziquantel topical solution)

Apply once a month. Topical solution for cats and kittens 8 weeks of age and older.

Each applicator contains 3.6 mg esafoxolaner, 1.2 mg eprinomectin, and 24.9 mg praziquantel.

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Approved by FDA under NADA # 141-570

Picture of 0.3 mL carton containing 3 applicators.
(click image for full-size original)

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