Review Article

Review of extralabel use of isoxazolines for treatment of demodicosis in dogs and cats

Xueying Zhou dvm ABSTRACT Alexandra Hohman dvm Amitraz is presently the only FDA-approved treatment for demodicosis in dogs in the United States. Amitraz treatment involves a protracted course Walter H. Hsu dvm, phd of administration and risks of severe adverse effects such as sedation, From the Departments of Veterinary Clinical Sciences bradycardia, and respiratory depression, which are caused by activation of (Zhou) and Biomedical Sciences (Hohman, Hsu), Col- α2-adrenergic receptors. Other treatment options include macrocyclic lac- lege of Veterinary Medicine, Iowa State University, tones and lime sulfur, but these products have varied efficacy and high risks Ames, IA 50011. Dr. Zhou’s present address is the of adverse effects. Several recent studies have indicated that isoxazolines Department of Veterinary Clinical Sciences, College of Veterinary Medicine, China Agricultural University, are capable of reducing Demodex mite counts in canine and feline patients Beijing 100083, People’s Republic of China. Dr. Zhou with demodicosis by ≥ 99% in as little as 1 month with few adverse effects. was a fourth-year veterinary student at the time of This article reviews the status of isoxazolines in regard to labeled uses in the study. dogs and cats in the United States, extralabel clinical use for treatment of demodicosis in these species, and safety of orally administered formulations Address correspondence to Dr. Hsu (whsu@iastate. of these drugs. (J Am Vet Med Assoc 2020;256:1342–1346) edu).

emodex canis is the species of mites most com- this use in the United States include oral formulations Dmonly implicated in canine demodicosis, al- of ivermectin, moxidectin, and milbemycin oxime; an though Demodex cornei and Demodex injai are injectable formulation of doramectin; and lime sulfur occasionally found on dogs and Demodex gatoi is dips, as well as topical and oral formulations of isoxazo- occasionally found on cats.1–3 Demodex spp are trans- lines.7,11 Many of the presently implemented treatment mitted to neonates from the dam as a result of close modalities have varying degrees of efficacy,13 and some contact and are generally considered a normal com- are associated with relatively high risks of adverse ef- ponent of the microbiota of canine skin.1 Demodico- fects such as CNS, cardiovascular, and gastrointestinal sis is recognized as aberrant mite proliferation with disturbances; in addition, some treatments require high secondary pyoderma. It is believed that demodicosis dosing frequencies, making them cost prohibitive.2,10 is secondary to alterations in immunity.4 Demodico- Isoxazolines are a novel class of insecticide and sis is characterized by the time of onset (juvenile vs acaricide with potent inhibitory activity on gluta- adult) and clinical involvement (localized vs gener- mate-gated and γ-aminobutyric acid ligand-gated alized). The full pathogenesis and epidemiology of chloride channels.14 Various isoxazoline compounds aberrant Demodex spp proliferation and associated have been successfully used for the treatment of gen- clinical disease have yet to be delineated. Whereas lo- eralized demodicosis in dogs.15–18 Isoxazolines that calized demodicosis is generally self-limiting, gener- are presently approved by the FDA for use against alized demodicosis can be persistent and difficult to specific flea and tick infestations in dogs or dogs and treat. Because of the impact on quality of life, many cats in the United States include afoxolaner,19 fluralan- severely affected animals were euthanized prior to er,20,21 sarolaner,22 and lotilaner.23 the development of new treatment modalities.2,4 Topically applied amitraz, a formamidine acari- cide and octopamine receptor agonist,5,6 has been the Labeled use of isoxazolines standard of treatment for decades and is the only FDA- Afoxolaner is available in the United States as a approved drug for treatment of generalized demodi- chewable tablet labeled for the treatment and preven- cosis in dogs in the United States.7 Amitraz treatment tion of flea Ctenocephalides( felis) infestations and involves the removal of hair, prolonged contact time, treatment and control of black-legged tick (Ixodes a protracted course of treatment,8 and the risk of se- scapularis), American dog tick (Dermacentor varia- vere adverse effects such as bradycardia, sedation, and bilis), brown dog tick (Rhipicephalus sanguineus), 9 respiratory depression resulting from activation of α2- and lone star tick (Amblyomma americanum) infes- adrenergic receptors.2 Topical moxidectin formulations tations in dogs.19 Afoxolaner tablets are available in are labeled for treatment of generalized demodicosis in 4 sizes and prescribed as a monthly treatment to de- dogs in other countries such as Serbia, Albania, France, liver a minimum dose of 2.5 mg/kg (1.1 mg/lb) up to and Germany, but not in the United States.10–12 Addition- a maximum recommended dose of approximately 6.2 al treatments that are not presently FDA approved for mg/kg (2.8 mg/lb) in dogs ≥ 8 weeks of age.19

1342 JAVMA | JUN 15, 2020 | VOL 256 | NO. 12 Fluralaner is available in the United States as a imidacloprid/kg (4.5 mg/lb) and 2.5 mg of moxidec- chewable tablet for dogs,21 a topical spot-on formulation tin/kg (1.1 mg/lb). The number of Demodex mites for dogs,20 and a topical spot-on treatment for cats.20 The in skin scrapings was reduced by 99.8%, 100%, and products for dogs are labeled for treatment and preven- 100% on days 28, 56, and 84, respectively, following tion of flea infestations and for treatment and control administration of fluralaner, and dogs that received of black-legged ticks, American dog ticks, and brown the fluralaner treatment had significantly fewer mites dog ticks for up to 12 weeks and lone star ticks for up than those that received the imidacloprid-moxidectin to 8 weeks; the product for use in cats is labeled for treatment on days 28, 56, and 84.16 Topically admin- the treatment and prevention of fleas and for treatment istered fluralaner had similar efficacy to the orally and control of black-legged ticks for up to 12 weeks.20,21 administered product, compared with imidacloprid- The orally and topically administered products for dogs moxidectin treatment for canine demodicosis.25 are available in 5 strengths and are prescribed at a mini- A year later, a study26 on the efficacy of sarolan- mum dose of 25 mg/kg (11.4 mg/lb) up to a maximum er against Demodex spp was conducted. Sarolaner recommended dose of approximately 56 mg/kg (25.5 was given orally to 8 dogs at 2 mg/kg monthly for 3 mg/lb). The topical treatment for cats is available in 3 treatments in that study, and the results showed that strengths prescribed at a minimum dose of 40 mg/kg live Demodex mite counts in skin scrapings were re- (18.2 mg/lb) up to a maximum recommended dose of duced by 97.1% within 14 days and by 99.8% within approximately 95 mg/kg (43.2 mg/lb). These products 29 days after the first dose, with no live mites de- are all labeled for dogs or cats ≥ 6 months of age.20,21 tected thereafter; results for 8 dogs that received a Sarolaner is available in the United States, labeled control treatment (imidacloprid-moxidectin) indicat- for the treatment and prevention of flea infestations ed lower efficacy with treatment of higher frequency and the treatment and control of lone star tick, Gulf and longer duration.26 Coast tick (Amblyomma maculatum), American dog A similar study17 published in 2016 evaluated the tick, black-legged tick, and brown dog tick infestations efficacy of an oral formulation of afoxolaner for treat- in dogs.22 Sarolaner is available as a chewable tablet in ment of generalized demodicosis in dogs. Afoxolaner 5 strengths for monthly administration at a minimum was administered orally at ≥ 2.5 mg/kg (according to dose of 2 mg/kg (0.9 mg/lb) up to a maximum rec- labeled monthly use against demodicosis in Europe) on ommended dose of approximately 4 mg/kg (1.8 mg/ days 0, 14, 28, and 56 to 8 dogs, and another 8 dogs lb), in dogs ≥ 6 months of age.22 Results of an in vitro received a control treatment (imidacloprid-moxidectin) investigation24 indicate sarolaner is the most potent at the same intervals. The percentage reduction of mite isoxazoline, with the lowest concentration required to counts reached 99.2% on day 28 and increased to 99.9% kill 80% of the tested flea population one-tenth that of and 100% on days 56 and 84, respectively, for dogs that afoxolaner or fluralaner and the lowest concentration received afoxolaner, with percentage reductions of required to kill 100% of the tested soft tick (Ornithod- 89.8%, 85.2%, and 86.6% on days 28, 56, and 84 for dogs oros turicata) population one-third that of the latter that received the positive control treatment.17 2 drugs. The effective clinical doses for these isoxazo- In 2017, another study15 was published that evalu- lines reflect the in vitro findings with the lowest dose ated the use of lotilaner for treatment of 10 dogs with tested of 1.25 mg/kg (0.57 mg/lb) for sarolaner.24 generalized demodicosis. All dogs received lotilaner Lotilaner is available in the United States as a orally at ≥ 20 mg/kg on days 0, 28, and 56. The mite chewable tablet, also in 5 strengths, labeled for treat- counts were reduced by > 99.9% up to day 56, with no ment of flea infestations and treatment and control of live mites detected on day 84, 1 month after the last lone star tick, American dog tick, black-legged tick, treatment.15 and brown dog tick infestations in dogs ≥ 8 weeks of The described studies15–17,25,26 that found satis- age.23 The product is administered monthly at a mini- factory efficacies of 4 different isoxazolines against mum dose of 20 mg/kg (9.1 mg/lb) up to a maximum demodicosis in dogs were all performed through 1 recommended dose of approximately 40 mg/kg.23 contract research company in South Africa. In 2018, a multicenter study18 that investigated efficacy of sa- Extralabel use for treatment rolaner against generalized demodicosis and its safe- ty in dogs from France, Hungary, Portugal, and Italy of demodicosis in dogs revealed that mite counts were reduced by 77.2%, Fluralaner was introduced to the veterinary prod- 95.0%, 98.5%, 99.0%, 100%, and 100% on days 30, 60, uct market in 2015. An oral formulation of fluralaner 90, 120, 150, and 180, respectively, following monthly was investigated for efficacy against demodicosis in oral administration of sarolaner at doses of 2 to 4 mg/ a study16 of 16 dogs with generalized demodicosis. kg in 53 dogs for 6 months. For 28 dogs that received Eight dogs were randomly allocated to receive a sin- a control treatment (imidacloprid-moxidectin), mite gle dose of fluralaner (≥ 25 mg/kg, PO), and the re- reduction was 82.2% after 6 monthly treatments. maining 8 dogs were treated topically with a spot-on These results showed less rapid improvement, com- imidacloprid-moxidectin solution (positive control) at pared with the previously described study26 in which 4-week intervals for 3 treatments at the labeled dose 99.8% reduction in live mite counts was observed by for indicated use (canine demodicosis) of 10 mg of day 29 after the first dose of sarolaner.

JAVMA | JUN 15, 2020 | VOL 256 | NO. 12 1343 In addition to the aforementioned studies, field Safety of orally administered trials and clinical reports from various countries have indicated the successful use of isoxazolines for treat- isoxazoline treatments ment of demodicosis in dogs. A clinical report27 from Oral fluralaner administration every 2 months at Peru described successful treatment of naturally- up to 5 times the maximum recommended dose of acquired generalized D canis infestation in 4 dogs 56 mg/kg21 (25.5 mg/lb) was assessed in 24 puppies 8 with afoxolaner. The drug was administered orally weeks of age with no adverse effects identified, com- every 4 weeks for 8 weeks at doses ≥ 2.5 mg/kg. Sub- pared with results for a control group of 8 puppies stantial clinical improvement of skin lesions was ob- sham-treated with water.33 No adverse effects were served 4 weeks after the initial treatment, and skin noted other than single cases of vomiting and gas- scrapings were free of live mites 8 and 12 weeks after troenteritis with inappetence that were not deemed treatment was started.27 treatment-related. A 2018 report28 of a field trial in Thailand revealed Oral afoxolaner treatment was also assessed in that 1 to 3 treatments with orally administered fluralan- puppies beginning at 8 weeks of age at doses up to 5 er at 25 to 50 mg/kg (11.4 to 22.7 mg/lb) successfully times the maximum exposure dose of 6.3 mg/kg (2.9 eliminated generalized demodicosis in 66 of 67 dogs mg/lb; ie, up to 31.5 mg/kg [14.3 mg/lb]) at 3 monthly for which adequate follow-up was available. Follow- intervals followed by 3 weekly intervals, compared up in that study28 was performed for 2 to 12 months with nontreated control puppies.34 No impact on gen- after parasitological cure (2 skin scrapings with nega- eral health or growth was associated with the treat- tive results achieved 1 month apart). Dogs with adult- ment. Assessment measures in addition to growth onset demodicosis reached parasitological cure in 2 included physical examination variables, clinicopatho- to 4 months, with the same result achieved for dogs logic variables, and histopathologic findings. with juvenile-onset demodicosis in 2 to 3 months.28 McTier et al24 performed safety investigations of Fluralaner was also used to successfully treat refrac- orally administered sarolaner in small sample groups tory generalized demodicosis in a 12-year-old female of 24 adult Beagles and 32 Beagle puppies beginning Shih Tzu in Japan that had hyperadrenocorticism and at 8 weeks of age. Evaluations in mice were performed hypothyroidism.29 The dog received a single oral dose with up to 30 mg of sarolaner/kg (13.6 mg/lb), PO, of fluralaner (50 mg/kg), and although a transient with no clinical signs indicative of adverse effects, as eruption of cutaneous papules was reported a few a safety screening test.24 Adult dogs (6/group) were days after treatment, no mites were found by examina- treated with a placebo or 1 of 3 sarolaner doses up to tion of skin scrapings 60 days after the treatment.29 In 10 mg/kg (4.5 mg/lb; 5 times the recommended dose addition, a single dose of the oral fluralaner formula- of 2 mg/kg) 3 times at 28-day intervals, and puppies tion was reported to result in parasitological cure of (8/group) received a placebo or 1 of 3 doses up to D injai demodicosis in a dog from Spain 7 weeks after 20 mg/kg twice at a 28-day interval. Evaluation vari- administration.a Interestingly, although the described ables similar to those used for the aforementioned reports indicate that isoxazoline administration results fluralaner study33 were used for safety assessments. in resolution of canine demodicosis, treatment with No adverse effects or clinically relevant changes were afoxolaner (≥ 2.5 mg/kg, PO; single dose) or fluralaner observed as a result of the sarolaner treatments.24 (≥ 25 mg/kg, PO; monthly doses for 60 days) did not af- In a field study35 that involved 112 cats in Europe fect cutaneous Demodex populations of healthy dogs that received lotilaner orally at ≥ 6 mg/kg (2.7 mg/ (10/treatment type) over a 90-day study period as as- lb) for treatment of ticks on day 0 and approximately sessed by real-time PCR assay for DNA of the parasite.30 28 and 56 days later, compared with 57 cats that re- ceived topical (spot-on) fipronil treatment at the same Extralabel use for treatment times, no vomiting or diarrhea was observed in any cats and no adverse effects attributable to the treat- of demodicosis in cats ments were reported. To the authors’ knowledge, no studies have been In an investigation of potential reproductive ef- performed to investigate the efficacy of isoxazolines fects cited in the FDA Freedom of Information Sum- for the treatment of demodicosis in cats. One clinical mary for the approved fluralaner product,21 the safety report31 described 100% elimination of D gatoi mites of orally administered fluralaner was assessed in 20 in 2 cats 1 month after a single dose of the oral for- breeding dogs (10/sex) at 3 times the maximum ex- mulation of fluralaner at 26 to 34 mg/kg (11.8 to 15.5 pected dose of 56 mg/kg, compared with 20 untreated mg/lb), with no mites found on examination of re- dogs (10/sex). Treated animals were administered flu- peated skin scrapings 2 and 3 months after treatment. ralaner at 168 mg/kg (76.4 mg/lb) orally 3 or 4 times at A single oral dose of fluralaner at 28 mg/kg (12.7 mg/ 8-week intervals prior to breeding; females continued lb) was also associated with successful treatment of to be treated at 8-week intervals until puppies were a generalized form of demodicosis caused by D cati weaned. Treatment had no significant effects on repro- in 1 cat in Italy, with negative results for skin scrap- ductive performance or semen quality.21 ings 1 month after treatment and resolution of clini- To the authors’ knowledge, fluralaner is the only cal signs ≤ 2 months after treatment.32 isoxazoline that has been evaluated in dogs with

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