WHO Acute Hazard classification of pesticides: Not listed

Mechanism of action of Afoxolaner

• Afoxolaner (the active ingredient of NEXGARD) and other isoxazolines with insecticidal and tickicidal efficacy are non-competitive GABA (gamma-aminobutyric acid) receptor antagonists, much more selective for GABA receptors in insects or ticks, than for those in mammals, including humans. They bind to chloride channels in nerve and muscle cells, which blocks the transmission of neuronal signals. Affected parasites are paralyzed and die.
• This mechanism exists not only in insects but also in mammals and other vertebrates. However the binding affinity of afoxolaner to GABA receptors of invertebrates is much higher than to GABA receptors in vertebrates. For this reason it is significantly less toxic to mammals than to insects and other pests.

Acute Toxicity and Tolerance of Afoxolaner

• LD50 acute, rats, p.o. >1000 mg/kg
• LD50 acute, rats, dermal >2000 mg/kg.
• In rats significant effects on bodyweight and/or food consumption were observed after oral administration at dose levels of 100, 300 and 1,000 mg/kg bw. Adverse effects (abnormal gait and stance, decreased body tone, piloerection) were observed after dermal administration at 2000 mg/kg bw, though these effects were not severe or irreversible.
• In puppies treated at approximately 1x, 3x and 5x the maximum recommended therapeutic dose once monthly for 3 months, followed by a further 3 administrations at two week intervals no mortalities occurred, and no test article related changes were seen in clinical parameters, daily food consumption, body weight, hematology and urinalysis parameters or plasma chemistry values.
• In a repeat-dose toxicity study dogs were treated at 40, 120 and 200 mg afoxolaner/kg bw (i.e. aprox. 8x, 20x, and 35x the max. recommended dose) administered orally three times at eight week time intervals. In dogs receiving doses of 120 and 200 mg/kg bw, vomiting was observed in the 24 hours following treatment. Some dogs also showed diarrhea. Female dogs in the treatment groups had lower food consumption but no weight loss could be observed. Hematology, serum chemistry and physical examination parameters did not show dose dependent changes.
• In dermal toxicity study in cats it appears that afoxolaner may cause adverse liver effects (centrilobular vacuolation, biliary hyperplasia and/or hepatocellular necrosis, only in females) in all dose groups including the lowest dose of 10 mg/kg bw. However, it is recognized that the metabolic system of cats is unique when compared e.g. with rats, dogs and human: cats have a deficient glucuronidation. For this reason the liver effects observed in the dermal study in cats are considered not relevant for user and/or target animal safety on dogs.

Toxic Symptoms, Side Effects, Adverse Drug Reactions (ADRs) caused by Afoxolaner

• The most frequent ADRs to be expected are
  • Vomiting (~4%)
  • Dry skin (~3%)
  • Diarrhea (~3%)
    
  • Lethargy (~1.5%)
  • Eating disorders (anorexia) (~1.2%)
• A potential administration error in dogs is administration to small dogs of tablets approved for larger animals.
• In general dogs tolerate very well afoxolaner at the therapeutic dose range (3 to 6.8 mg/kg) apart from sporadic vomiting and diarrhea reported in a number of studies and more notably at higher dose rates: diarrhoea and vomiting was observed at approximately 5x overdose (25 mg/kg bw) in Collies, and at higher doses (120 and 200 mg/kg bw) in Beagles.
• In September 2018 the FDA of the USA has alerted pet owners and veterinarians about potential neurological adverse events following the use of products containing isoxazolines in dogs. In August 2021 The FDA has extended this alert to cats. Some treated animals have experienced adverse events such as muscle tremors, ataxia (lack of voluntary coordination of muscle movements), and seizures. This regards all products containing isoxazolines. Most treated animals will not show such adverse drug reactions, but some may be affected.

Antidote and Treatment of Afoxolaner Intoxication

• There is no antidote for afoxolaner poisoning.
  
• Treatment consists in preventing further exposure together with supportive and symptomatic measures.
• After accidental ingestion stomach lavage as well as administration of active charcoal administration and laxatives may be advisable.

Pharmacokinetics of Afoxolaner

• Afoxolaner orally administered to dogs was rapidly absorbed into blood. Max. blood levels were reached 2 to 12 hours after administration. Mean half-life in blood ranged from 7.7 to 17.8 days. Bioavailability was estimated to be approx. 74%. Half-life was higher in Collies than in Beagles, but no serious adverse effects were observed after treatment of Collies at 25 mg/kg bw (i.e. ~10x the therapeutic dose).
• Absorbed afoxolaner binds strongly (>99%) to blood proteins but it seems not to cause displacement of other drugs with high protein binding capacities.
• In dogs afoxolaner is slowly broken down into various metabolites, the major ones being a hydroxylate and a glucuronide. Elimination of both the metabolites and the parent compound occurrs mainly via biliary excretion and to a lesser extent through urine.

Environmental Toxicity of Afoxolaner

• Little has been published yet regarding the environmental toxicity of afoxolaner. Its use in dogs as recommended is unlikely to pose a risk for the environment, and for this reason no environmental studies have been carried out for the approval of its use on dogs.
• Based on its mode of action it must be assumed that it is highly toxic to both aquatic and terrestrial arthropods (insects, ticks, spiders, crustaceans, etc.).

Additional information

Click here for a list and overview of all safety summaries of antiparasitic active ingredients in this site.

• Afoxolaner belongs to the chemical class of the isoxazolines.
• Afoxolaner is so far not used in livestock.
• Afoxolaner is so far not used in human medicines.
  
• Afoxolaner is so far not used in crop pesticides.
• Afoxolaner is so far not used in public and domestic hygiene as a biocide.
• Click here for General safety of antiparasitics for domestic animals.
• Click here for General safety of antiparasitics for humans.
• Click here for General safety of antiparasitics for the environment.
• Click here for technical and commercial information on afoxolaner.