WHO Acute Hazard classification of pesticides: Not listed

Mechanism of Action of Lotilaner

• Lotilaner (the active ingredient of CREDELIO) 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 lotilaner 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 Lotilaner

• LD50 acute, rats, p.o. >2000 mg/kg
• LD50 acute, rats, dermal >2000 mg/kg.
• In rats body weight and food decreases were recorded when lotilaner was administered at high doses of up to 60 mg/kg bw/day. Consequent to decreases in food intake and body weight, there were decreases in organ weight and changes in clinical pathology. No main target organ could be defined.
• In a repeat-dose toxicity study Beagle dogs were treated at 1x, 3x, and 5x the max. recommended dose administered orally 1 day every 4 weeks for 8 months. There were no treatment-related (toxicologically relevant) changes in the daily clinical observations, body weights and food consumption data, electrocardiograms, ophthalmoscopy, physical and neurological examinations, clinical chemistry, haematology, coagulation, and urin analysis parameters. There were no test article-related macroscopic findings at terminal necropsy.
• EMEA concludes that the active substance has no significant acute toxic risk, is not embryotoxic or teratogenic, is non-mutagenic and is unlikely to be carcinogenic.
• Credelio chewable tablets for dogs are non-irritant to skin, mildly irritant to the eyes, and do not induce skin sensitization.

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

• In various laboratory and clinical efficacy studies mild gastrointestinal effects (vomiting, loose stool and diarrhoea) were observed in a number of dogs within a short period of time following treatment. However a statistically significant difference between treated and untreated groups was not detected.
• It cannot be excluded that after the launch, once the product is is used in high number of animals of various breeds and conditions more side effects are reported.
• 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 Lotilaner Intoxication

• There is no antidote for lotilaner 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 Lotilaner

• Lotilaner orally administered to dogs was rapidly absorbed but slowly excreted. Max. blood levels were reached 2 hours after administration. The half-life in adult dogs was estimated to be 30.7 days, it was shorted in puppies. Bioavailability is quite high (82%) when administered to fed dogs, but much lower (24%) in fasted dogs. Therefore, lotilaner should be administered at or around the time of feeding.
• Highest tissue levels were recorded in body fat and liver, followed by kidney.
• The major route of elimination is fecal (via biliary excretion). Renal excretion is less than 10% of the dose.
• Unchanged lotilaner is the largely predominant form in blood and tissues and is still the major form in faeces. A number of slightly more hydrophilic metabolites were identified in faeces as well.

Environmental Toxicity of Lotilaner

• Very little is known yet regarding the environmental toxicity of lotilaner. 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.

• Lotilaner belongs to the chemical class of the isoxazolines.
• Lotilaner is so far not used in livestock.
• Lotilaner is so far not used in human medicines.
  
• Lotilaner is so far not used in crop pesticides.
• Lotilaner 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 lotilaner.