WHO Acute Hazard classification of pesticides: Not listed

Mechanism of action of Fluralaner

• Fluralaner (the active ingredient of BRAVECTO) 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 fluralaner 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 Fluralaner

• LD50 acute, rats, p.o. >2000 mg/kg
• LD50 acute, rats, dermal >2000 mg/kg.
• In rats the main target organ in the repeated dose toxicity studies was the liver. Increased organ weight, hepatocellular fatty change and effects in related blood parameters were observed mainly in the highest dose groups, thus at large overdoses relative to recommended/proposed use in the dogs. At the dose of 400 mg/kg bw/day effects on thymus and adrenal weight and microscopic changes in lung and thymus were observed. Comparable effects were reported after dermal administration at very high doses.
• In Beagle puppies treated at 1x, 3x and 5x the maximum recommended dose (= 25 to ~60 mg/kg bw) three times with a 56 day interval, fluralaner was well tolerated. There was no evidence of product-related effects in food consumption, body weight, clinical parameters or physical examination variables, or clinical pathology findings.
• In a pivotal reproductive study Beagle dogs were treated up to 3X the recommended dose 3 times at 8 weeks intervals starting 12 weeks (males) and 4 weeks (females) before expected mating. Treatment continued until the females had whelped (males) or the puppies were weaned (females). No adverse reactions were observed in adult dogs and no detrimental effect on reproductive functions, number of puppies and puppy survival was detected.
• Safety data collected during field studies with the tablets for dogs in Europe and the USA showed that the product was in general well tolerated. In the European field study mild and transient diarrhea, vomiting, lack of appetite and drooling were recorded in 1.6% of dogs during the first days after treatment.
• Laying hens treated orally at up to 15X the recommended dose of 0.5 mg/kg tolerated the treatment very well and showed no signs of intoxication or whatever side effects.

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

• The most frequent ADRs to be expected (based on field studies) are:
  • Vomiting (~7% in dogs with the tablets, ~6.3% with the spot-on; in cats ~7.6% with the spot-on)
  • Decreased appetite (~6.7% in dogs with the tablets, ~1.4% with the spot-on; in cats ~3.6% with the spot-on)
  • Pruritus (itching) (in cats ~5.4% with the spot-on)
  • Alopecia (hair fall) (~4.1% in dogs with the spot-on; in cats 4.9% with the spot-on)
  • Diarrhea (~5% in dogs with the tablets, ~2.7% with the spot-on; in cats ~4.9% with the spot-on)
  • Lethargy (~5.5% in dogs with the tablets, ~2.7% with the spot-on; in cats ~3.1% with the spot-on)
  • Excessive thirst (polydipsia) (~2% in dogs with the tablets)
  • Scabs/ulcerated lesions (in cats 2.2% with the spot-on)
  • Excessive gas in stomach or intestine (flatulence) (~1% in dogs with the tablets)
• A potential administration error is administration to small dogs or cats of tablets or spot-ons approved for larger animals.
• In general dogs tolerate very well fluralaner at the therapeutic dose range (25 to ~57 mg/kg) apart from the ADRs previously indicated.
• 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 Fluralaner Intoxication

• There is no antidote for fluralaner 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 Fluralaner

• Fluralaner orally administered to dogs was rapidly absorbed into blood. Max. blood levels were reached 24 hours after administration. Mean half-life in blood was 12 to 15 days. Bioavailability was higher when fluralaner was administered to fed animals.
• After topical administration max concentrations are achieved between 7 and 21 days following topical administration and the elimination half-life ranges between 11 and 13 days.
• After absorption, fluralaner was well distributed to tissues. Highest concentrations were found in fat, followed by liver, kidney and muscle. Fluralaner was also quantifiable in hair and skin. Clearance from tissues was very low.
• Absorbed fluralaner binds strongly (~100%) to blood proteins but it seems not to cause displacement of other drugs with high protein binding capacities.
• Excretion occurs mainly in the form of unchanged parent molecule, primarily in the feces (~90% of the dose). Less than 0.01% of the dose was found in urine, indicating that renal excretion plays a marginal role.

Environmental Toxicity of Fluralaner

• Little to nothing has been published yet regarding the environmental toxicity of fluralaner.>
• Fluralaner is very persistent in the soil both under aerobic and anaerobic conditions. In aquatic sediments fluralaner breaks down under anaerobic conditions, but is very persistent under aerobic conditions.
• 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 fluralaner 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.

• Fluralaner belongs to the chemical class of the isoxazolines.
• Fluralaner is so far not used in livestock, excepting chicken.
• Fluralaner is so far not used in human medicines.
  
• Fluralaner is so far not used in crop pesticides.
• Fluralaner 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 fluralaner.