Afoxolaner

Overview

Afoxolaner (NexGard) is an isoxazoline-class ectoparasiticide approved for oral administration in dogs and puppies 8 weeks of age and older weighing at least 1.8 kg (4 lb). It is formulated as a beef-flavored chewable tablet and is designed for once-monthly dosing.

The drug is labeled for the treatment and prevention of flea infestations and for the treatment and control of multiple tick species in dogs. In addition, afoxolaner is indicated for the prevention of Borrelia burgdorferi infection by killing Ixodes scapularis ticks before disease transmission occurs. Beyond labeled uses, it has been widely utilized extra-label in veterinary practice for the treatment of generalized demodicosis and sarcoptic mange.

Mechanism of Action (MOA): Afoxolaner acts by inhibiting gamma-aminobutyric acid (GABA)-gated chloride channels in the central nervous system of insects and acarines. This inhibition disrupts neuronal signaling, resulting in uncontrolled neuronal activity, paralysis, and death of susceptible parasites. Mammalian GABA receptors are less sensitive to isoxazolines, which accounts for the drug’s selective toxicity. Parasites must attach and feed to ingest afoxolaner, after which rapid onset of action occurs.

Onset of action: Fleas are killed within 4 hours of administration, with 99% effectiveness at 8 hours (i.e. before fleas can lay eggs). Ticks are killed within 48 hours, and as fast as 8–12 hours after infestation for some tick species.

Pharmacokinetics: Rapidly absorbed with oral bioavailability of approximately 75%. Peak plasma concentrations occur between 2 and 6 hours after dosing. Food does not impair absorption. Protein binding is very high (>99%). Elimination is via biliary excretion of free afoxolaner and renal excretion of hepatically biotransformed metabolites. Terminal elimination half-life is approximately 15 days, supporting the once-monthly dosing interval.

Indications

Afoxolaner is primarily indicated for the control of ectoparasite infestations in dogs. It is most effective when administered as a once-monthly oral chewable in accordance with label directions and is appropriate for use in dogs and puppies meeting age and weight requirements.

• Flea treatment and prevention: Flea treatment and prevention: Approved for the monthly treatment and prevention of flea infestations caused by Ctenocephalides felis in dogs.
• Tick treatment and control: Tick treatment and control: Labeled for the treatment and control of American dog tick (Dermacentor variabilis), black-legged tick (Ixodes scapularis), lone star tick (Amblyomma americanum), and brown dog tick (Rhipicephalus sanguineus) infestations.
• Prevention of Lyme disease: Prevention of Lyme disease: Indicated for the prevention of Borrelia burgdorferi infections by killing Ixodes scapularis vector ticks before transmission can occur.
• Generalized demodicosis (extra-label): Generalized demodicosis (extra-label): Used in dogs for the treatment of generalized Demodex mite infestations, with documented clinical efficacy in multiple studies.
• Sarcoptic mange (extra-label): Sarcoptic mange (extra-label): Utilized for the treatment of Sarcoptes scabiei var canis infestations in dogs.
• Other ectoparasite infestations (extra-label): Other ectoparasite infestations (extra-label): Demonstrated efficacy in dogs against ear mites (Otodectes cynotis), cutaneous myiasis, bedbugs, sand flies, and additional tick species under experimental or field conditions.
• Non-canine species (extra-label): Has been used experimentally or clinically in cats, pigs, and birds for specific mite or louse infestations; however, these uses are extra-label and not FDA-approved.
• Cuterebra prevention (extra-label): Routine use of isoxazoline products (afoxolaner, fluralaner, lotilaner, sarolaner) may prevent migration and warble formation by Cuterebra spp. when given as ongoing parasite control.
• Dipylidium caninum prevention (extra-label, indirect): Dipylidium caninum prevention (extra-label, indirect): Effective flea control with afoxolaner interrupts the flea-mediated life cycle of Dipylidium caninum (flea tapeworm) and reduces tapeworm infection risk. The afoxolaner-milbemycin combination product has also been studied for this effect and for the prevention of canine thelaziosis (Thelazia callipaeda) in European field studies.

Dosage (Reference)

Dog

Afoxolaner is administered orally as a beef-flavored chewable tablet. It is approved for use in dogs and puppies 8 weeks of age and older weighing at least 1.8 kg (4 lb). The drug is designed for once-monthly administration and may be given with or without food.

Cat

Afoxolaner is not FDA-approved for use in cats; however, limited experimental and clinical studies have evaluated its extra-label use for certain ectoparasite infestations.

Warnings & Precautions

Afoxolaner is generally well tolerated when administered according to label directions; however, as a member of the isoxazoline class, specific neurologic and patient-related precautions must be considered before use.

• Neurologic effects (isoxazolines): Neurologic effects (isoxazolines): Drugs in the isoxazoline class have been associated with neurologic adverse reactions, including muscle tremors, ataxia, and seizures. These effects have been reported in dogs with and without a prior history of neurologic disease.
• History of seizures: History of seizures: Use with caution in dogs with a known history of seizures or epilepsy. A careful risk-benefit assessment is recommended before prescribing.
• Age and weight restrictions: Labeled for use only in dogs and puppies 8 weeks of age and older and weighing at least 1.8 kg (4 lb).
• Species sensitivity: Species sensitivity: Although experimental use has been reported in cats, pigs, and birds, safety and efficacy are not established outside labeled canine use. Extra-label use requires careful monitoring.
• Reproductive status: Reproductive status: Safe use in breeding, pregnant, or lactating dogs has not been evaluated. Use only when the potential benefit outweighs the potential risk.
• Hypersensitivity reactions: Hypersensitivity reactions: Dermatologic and allergic reactions, including pruritus, erythema, hives, or facial swelling, have been reported rarely.
• Gastrointestinal tolerance: Gastrointestinal tolerance: Vomiting, diarrhea, anorexia, or lethargy may occur, particularly shortly after administration.
• Administration considerations: Administration considerations: The chewable tablet should be administered in a manner that ensures the full dose is consumed. Partial ingestion may reduce efficacy.
• Environmental exposure: Environmental exposure: Afoxolaner kills fleas and ticks only after they attach and feed; it does not repel parasites prior to attachment.

Drug Interactions

No clinically significant drug interactions have been reported with afoxolaner when administered at labeled dosages. The drug has demonstrated a wide margin of safety when used concurrently with many commonly prescribed veterinary medications.

• Vaccines:Vaccines: Afoxolaner has been safely administered alongside routine vaccinations without evidence of reduced efficacy or increased adverse effects.
• Anthelmintics:Anthelmintics: Concurrent use with intestinal and heartworm anthelmintics has not been associated with adverse interactions.
• Antibiotics: Antibiotics: No interactions have been reported with systemic or topical antibacterial agents.
• Glucocorticoids and other steroids: Glucocorticoids and other steroids: Afoxolaner has been used safely with corticosteroids without clinically relevant interactions.
• NSAIDs: NSAIDs: No adverse pharmacologic interactions have been identified when used concurrently with nonsteroidal anti-inflammatory drugs.
• Anesthetic agents: Anesthetic agents: Field studies have not demonstrated clinically relevant interactions when afoxolaner is used in patients receiving anesthetic or sedative drugs.
• Antihistamines: Antihistamines: Concurrent administration has not been associated with increased adverse effects or altered efficacy.

Although no interactions are currently documented, caution is advised when administering afoxolaner concurrently with other medications that may lower the seizure threshold, particularly in dogs with a history of neurologic disease.

Side Effects & Overdose

Side Effects

Afoxolaner is generally well tolerated when administered at the labeled dosage. Most reported adverse effects are mild, self-limiting, and occur shortly after administration. Neurologic adverse effects have been reported rarely and may occur in dogs with or without a prior history of neurologic disease.

• Gastrointestinal effects: Vomiting is the most commonly reported adverse effect (4.1% in a 415-dog preapproval field study). Other reported GI effects: diarrhea 3.1%, anorexia 1.2%.
• Dermatologic reactions: Dry flaky skin in 3.1% of dogs (415-dog preapproval study). Erythema, dermatitis, and hypersensitivity (hives, facial swelling) have also been reported.
• Lethargy: Reported in 1.7% of dogs in the 415-dog preapproval field study; usually transient.
• Neurologic effects: Neurologic effects: Muscle tremors, ataxia, hyperactivity, panting, and seizures have been reported. These effects are consistent with FDA class warnings for isoxazoline drugs and may occur in dogs with or without a prior seizure history.
• Hypersensitivity reactions: Hypersensitivity reactions: Rare reactions such as hives, facial swelling, or generalized pruritus have been reported.

Overdose

Information regarding acute overdose in dogs is limited, but available safety studies indicate a wide margin of safety for afoxolaner.

• Experimental overdose studies: Dogs receiving 5× the maximum labeled dose for 3 treatments every 28 days followed by 3 treatments every 14 days (6 total) did not show clinically relevant treatment-related abnormalities on physical examination, body weight, food consumption, clinical pathology, or histopathology.
• Observed signs: Observed signs: Vomiting was noted during overdose studies but occurred at a similar frequency in treated and control groups.
• Rodent data: Rodent data: Oral doses up to 1000 mg/kg in rats and 2000 mg/kg in mice were not lethal.
• Management: Management: Treatment of overdose is supportive and symptomatic. Monitor neurologic status, hydration, and gastrointestinal signs. There is no specific antidote.

For patients that have experienced or are suspected of having ingested a significant overdose, consultation with a 24-hour veterinary poison consultation center is recommended.

Key Notes

Practical clinical considerations that support appropriate use of afoxolaner in veterinary patients, focusing on points not emphasized elsewhere in this monograph:

• Systemic activity required: Systemic activity required: Afoxolaner must be ingested by fleas or ticks during feeding to exert its effect; it does not provide a repellent (anti-attachment) action.
• Consistent monthly dosing: Consistent monthly dosing: Maintaining strict monthly administration is critical to ensure continuous parasite control and to minimize gaps in protection.
• Weight-based accuracy: Weight-based accuracy: Dogs near tablet weight cutoffs should be weighed regularly to ensure they receive the appropriate tablet size and minimum effective dose.
• Extra-label applications:Extra-label applications: While not FDA-approved for mange or mites, clinical evidence supports its effectiveness for several ectoparasitic infestations when used under veterinary supervision.
• No environmental control: No environmental control: Because afoxolaner acts systemically, environmental flea control measures may still be necessary in heavily contaminated environments.
• Rapid flea kill benefit: Fast onset of flea kill helps reduce flea egg production and limits environmental contamination over time.
• Species limitations: Although studied experimentally in other species, only dogs meet FDA-approved labeling criteria in the United States.
• Client education: Emphasize that visible parasites may still be seen briefly after treatment until feeding occurs and the parasites are killed.