Isoxazolines

Isoxazolines kill fleas and are indicated for the treatment and prevention of flea infestations, as well as the treatment and control of various tick infestations.^1-6

Overview

• The isoxazoline drug class was launched in the United States in 2014 with afoxolaner, followed shortly by oral fluralaner, sarolaner, topical fluralaner, and lotilaner.

Mechanism of Action

• Isoxazolines are absorbed systemically; fleas and ticks must bite the animal to be killed. 

  • Isoxazolines work by selective inhibition of GABA- and glutamate-gated chloride channels, leading to hyper-excitation and death of the flea or tick.^7-10 

  • Because GABA channels in mammals have much a lower sensitivity to isoxazolines and mammals lack anion-inhibitory glutamate channels, there is low toxicity potential.⁸

• For fleas, the onset of action for all products is reported to be 2 to 4 hours, with nearly 100% of fleas killed within 8 hours^1-6; for ticks, the onset of action for >90% tick control is 4 to 8 hours, although study protocols often assess tick control at 48 hours after administration.^1-6

Clinical Application

• Several studies have shown that isoxazolines can reduce the risk for tick-borne disease transmission. 

  • Afoxolaner and sarolaner each prevented Borrelia burgdorferi infection (ie, Lyme disease) in controlled laboratory studies.^11,12 

  • In other laboratory studies, afoxolaner, fluralaner, and lotilaner each prevented transmission of Babesia canis.^13-16 

  • Ixodes holocyclus, the Australian paralysis tick, was controlled by afoxolaner, fluralaner, and sarolaner.^17,18 

  • In a comparative laboratory study, transmission of Ehrlichia canis was prevented by permethrin–imidacloprid and prevented in some but not all dogs by either afoxolaner or fluralaner.¹⁹

Administration

• Fluralaner and lotilaner chewables should be administered with food, whereas afoxolaner and sarolaner may be given with or without food.^1-3,6

• Labeled ages, body weights, and dosing intervals vary (see Table).

  • Collies with the multidrug sensitivity gene (MDR1 gene, also known as ABCB1 gene) mutation (ivermectin-sensitive) were treated with up to 10 times the label dose of afoxolaner or 3 times the label dose of fluralaner with no adverse effects noted.^20,21 

• Fluralaner has been shown to be well tolerated with concurrent use of milbemycin–praziquantel and deltamethrin collars in dogs and emodepsid–praziquantel in cats.^22-24

• Extra-label use of isoxazolines for other ectoparasites has been reported. 

  • In one study of generalized demodicosis in 8 adult dogs, a single dose of fluralaner resulted in elimination of Demodex canis mites and resolution of dermatologic signs.²⁵ 

  • Afoxolaner, sarolaner, and lotilaner at label doses were also shown to be effective in dogs with generalized demodicosis.^26-29 

  • In dogs with Sarcoptes scabiei var canis, 2 doses of afoxolaner (on days 0 and 28) or sarolaner (on days 0 and 30) or a single dose of fluralaner eliminated mites and resulted in skin improvement within 4 weeks.^30-33 

  • Dogs with ear mites (Otodectes cynotis) have been successfully treated with afoxolaner, fluralaner, and sarolaner; topical fluralaner is effective in cats with ear mites.^28,34,35

Table 1. Isoxazolines at a glance^1-5

*The administration interval is every 8 weeks for Amblyomma americanum (lone star) ticks.^2,4

Safety & Adverse Effects

• Vomiting, diarrhea, lethargy, and decreased appetite were occasionally observed in safety studies in puppies 8 to 9 weeks old (in both treated and control groups) at 1 time, 3 times, and 5 times the maximum oral label dose and in field studies.^{1-4,6,9,36-38} 

  • Neurologic signs (eg, tremors, seizures) were noted in some puppies treated with sarolaner at 3 to 5 times the label dose.³ 

  • Fluralaner topical solution was similarly studied in dogs and cats; other than cosmetic changes at the application sites, no treatment-related adverse effects were observed.^4,5 

  • In the feline field study, neurologic signs were seen with topical fluralaner in 2 of 224 cats⁵; this drug should be used with caution in cats with a history of neurologic disease.⁵

• Safety in breeding, pregnant, or lactating dogs has not been evaluated for afoxolaner, sarolaner, or lotilaner.^1,3,6 

  • Oral fluralaner was studied at up to 3 times the maximum label dose at 8-week intervals in male and female beagles through breeding, pregnancy, and lactation. 

    • No treatment-related effects were observed in the adult dogs or on reproductive performance. 

    • In litters from 2 of 10 dams, abnormalities (eg, limb deformity, cleft palate) were noted in some puppies on gross examination.²

• In uncontrolled, open-label field studies, all drugs were effective in reducing or resolving signs of flea allergy dermatitis in dogs.^39-43