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Isoxazolines

Isoxazolines

Craig Datz, DVM, MS, DABVP (Canine & Feline), DACVN, University of Missouri

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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 hours1-6; 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 & DOSING

  • 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 Isoxazolines at a Glance).
    • 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

ISOXAZOLINES AT A GLANCE1-5

Drug Species Product Minimum Age Minimum Body Weight Dosing Interval
Afoxolaner Dog Chew 8 weeks 4 lb (1.8 kg) 1 month
Fluralaner Dog Chew 6 months 4.4 lb (2 kg) 12 weeks*
Sarolaner Dog Chew 6 months 2.8 lb (1.3 kg) 1 month
Lotilaner Dog Chew 8 weeks 4.4 lb (2 kg) 1 month
Fluralaner Dog Topical solution 6 months 4.4 lb (2 kg) 12 weeks*
Fluralaner Cat Topical solution 6 months 2.6 lb (1.2 kg) 12 weeks*

 

*The dosing 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

References

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