Isoxazolines in Dogs and Cats: Neurological Safety Considerations

Isoxazolines—including afoxolaner, esafoxolaner, fluralaner, lotilaner, sarolaner, and tigolaner—are widely used for the treatment and prevention of flea, tick, and mite infestations. They are administered orally in dogs and topically in cats and dogs. These compounds act as potent inhibitors of gamma-aminobutyric acid (GABA)-gated chloride channels, and to a lesser degree, glutamate-gated chloride channels in the nervous system of invertebrates. By preventing chloride influx at pre- and postsynaptic sites, they cause hyperexcitation, paralysis, and death of the parasite¹. 

While isoxazolines are claimed to be insect-specific, reports of neurological adverse effects in dogs and cats have raised questions regarding their absolute safety². 

Toxicovigilance and Case Reports 

• Poison centers such as the Veterinary Poisons Information Service (VPIS) and the Dutch Poisons Information Center (DPIC) track adverse effects from veterinary drugs, including isoxazolines². 
• Case data reveal neurological signs occurring after: 
• Therapeutic doses 
• Overdose 

• Accidental ingestion 

Examples from case reports: 

• A 7-month-old Kooikerhondje developed generalized ataxia, myoclonic jerks, tremor, muscle twitching, and oral dysphagia 24 hours after oral fluralaner (28 mg/kg). Signs resolved spontaneously after 10 hours³ 

• A 2-year-old child ingested two chewable sarolaner tablets (13.3 mg/kg), developing ataxia, tremors, confusion, and hallucinations within 2 hours, managed with sedation; minimal ataxia remained after 10 hours¹. 

Incidence of Neurological Adverse Effects¹ 

• Summary of product characteristics (SPCs) lists neurological effects as “very rare” (~0.01%). 

• FDA reports (up to July 2018) indicate ~10% of adverse effect reports involve neurological signs, with ~9% resulting in death or euthanasia. 

• Breakdown from FDA reports (dogs, 2013–2017): 
• Muscular/balance issues: 5.5% 
• Neurological/cognitive: 2.1% 
• Behavioural issues: 28.6% 
• Shaking/tremors/ataxia: 6.9% 
• Seizures: 5.3% 
• Death: 2.5% 
• EMA reports show higher mortality in European cases: 22.7% deaths in adverse event reports². 
• Surveys of veterinarians and owners (2018) indicated serious events in 1070 of 2751 responses, including: 
• Shaking/trembling/ataxia: 43.2% 
• Convulsions: 13.7% 
• Death: 13.7%² 

Pharmacokinetic Considerations 

Isoxazolines are⁴: 

• Highly lipophilic, with Tmax of 2–24 hours orally and 6–25 days topically. 

• Strongly plasma protein-bound (≤99.9%) and distributed to adipose tissue (Vd ~3–6 L/kg). 

• Slowly cleared (0.3% of daily hepatic blood flow in dogs), which may delay or prolong adverse effects. 

Neurological effects may include ataxia, tremors, seizures, and muscle tremors, appearing from 1–6 hours in dogs and 1–4 hours in cats^2,5,6. Recovery typically occurs within 24 hours but may extend to over a week, with some cases taking up to 15 days^1,2. Severity does not correlate with dosage or duration of effects. 

• Anticonvulsants are not always required; seizures may be self-limiting^5,6. 

• Intravenous lipid emulsion therapy is generally not effective due to long elimination half-life (e.g., fluralaner: 15 weeks)¹. 

• Re-exposure may trigger repeat neurological events in susceptible animals¹. 

Recommendations for Practicing Veterinarians 

• Monitor animals closely during and after administration of isoxazolines, especially in the first 24 hour^2,5,6. 

• Report all suspected adverse events to the appropriate regulatory authority, noting: 
• Timing of onset 
• Duration of signs 
• Dose administered 

• Educate owners on potential neurological signs and recovery expectations. 

• Consider previous reactions before re-administration of the same isoxazoline. 

Conclusion 

Isoxazolines are highly effective for controlling ectoparasites in dogs and cats but can cause neurological adverse effects, including tremors, ataxia, seizures, and in rare cases, death. Effects may occur even at therapeutic doses, with variable onset and recovery. Vigilant monitoring, timely reporting, and careful consideration of patient history are essential for safe use. Poison center data and adverse event reporting help identify at-risk animals and improve understanding of these widely used products. 

References  

1. Bates N, Dijkman MA, Edwards JN. Neurological adverse effects of isoxazoline exposure in cats and dogs. Veterinary Record. 2024;e4149. https://doi.org/10.1002/vetr.4149 

2. Palmieri V, Dodds WJ, Morgan J, Carney E, Fritsche HA, Jeffrey J, Bullock R, Kimball JP. Survey of canine use and safety of isoxazoline parasiticides. Veterinary medicine and science. 2020 Nov;6(4):933-45. https://onlinelibrary.wiley.com/doi/pdf/10.1002/vms3.285  

3. Gaens D, Rummel C, Schmidt M, Hamann M, Geyer J. Suspected neurological toxicity after oral application of fluralaner (Bravecto®) in a Kooikerhondje dog. BMC veterinary research. 2019 Dec;15(1):283. https://link.springer.com/article/10.1186/s12917-019-2016-4?fbclid=IwAR3u_yu4v27rtuklUzftMsLbfo6twh4XUiSywNalgngYK-qjw2QIYzra4EM  

4. Zhou X, Hohman AE, Hsu WH. Current review of isoxazoline ectoparasiticides used in veterinary medicine. Journal of Veterinary Pharmacology and Therapeutics. 2022 Jan;45(1):1-5. https://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjvp.12959  

5. FDA. Freedom of information summary: original new animal drug application. NADA 141-452, Simparica (sarolaner chewable tablet dogs). 2016. Available from: https://animaldrugsatfda.fda. gov/adafda/app/search/public/document/downloadFoi/940. Accessed 10 Jan 2024. 
6. Wismer T, Means C. Toxicology of newer insecticides in small animals. Veterinary Clinics: Small Animal Practice. 2012 Mar 1;42(2):335-47. https://www.researchgate.net/profile/Tina-Wismer/publication/288968255_Novel_insecticides/links/619e7bcda0d7893aa31b1908/Novel-insecticides.pdf