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

Xueying Zhou 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

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Alexandra Hohman 2Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

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Walter H. Hsu 2Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

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Abstract

Amitraz is presently the only FDA-approved treatment for demodicosis in dogs in the United States. Amitraz treatment involves a protracted course of administration and risks of severe adverse effects such as sedation, bradycardia, and respiratory depression, which are caused by activation of α2-adrenergic receptors. Other treatment options include macrocyclic lactones and lime sulfur, but these products have varied efficacy and high risks of adverse effects. Several recent studies have indicated that isoxazolines are capable of reducing Demodex mite counts in canine and feline patients with demodicosis by ≥ 99% in as little as 1 month with few adverse effects. This article reviews the status of isoxazolines in regard to labeled uses in dogs and cats in the United States, extralabel clinical use for treatment of demodicosis in these species, and safety of orally administered formulations of these drugs.

Abstract

Amitraz is presently the only FDA-approved treatment for demodicosis in dogs in the United States. Amitraz treatment involves a protracted course of administration and risks of severe adverse effects such as sedation, bradycardia, and respiratory depression, which are caused by activation of α2-adrenergic receptors. Other treatment options include macrocyclic lactones and lime sulfur, but these products have varied efficacy and high risks of adverse effects. Several recent studies have indicated that isoxazolines are capable of reducing Demodex mite counts in canine and feline patients with demodicosis by ≥ 99% in as little as 1 month with few adverse effects. This article reviews the status of isoxazolines in regard to labeled uses in dogs and cats in the United States, extralabel clinical use for treatment of demodicosis in these species, and safety of orally administered formulations of these drugs.

Demodex canis is the species of mites most commonly implicated in canine demodicosis, although Demodex cornei and Demodex injai are occasionally found on dogs and Demodex gatoi is occasionally found on cats.1–3 Demodex spp are transmitted to neonates from the dam as a result of close contact and are generally considered a normal component of the microbiota of canine skin.1 Demodicosis is recognized as aberrant mite proliferation with secondary pyoderma. It is believed that demodicosis is secondary to alterations in immunity.4 Demodicosis is characterized by the time of onset (juvenile vs adult) and clinical involvement (localized vs generalized). The full pathogenesis and epidemiology of aberrant Demodex spp proliferation and associated clinical disease have yet to be delineated. Whereas localized demodicosis is generally self-limiting, generalized demodicosis can be persistent and difficult to treat. Because of the impact on quality of life, many severely affected animals were euthanized prior to the development of new treatment modalities.2,4

Topically applied amitraz, a formamidine acaricide and octopamine receptor agonist,5,6 has been the standard of treatment for decades and is the only FDA-approved drug for treatment of generalized demodicosis in dogs in the United States.7 Amitraz treatment involves the removal of hair, prolonged contact time, a protracted course of treatment,8 and the risk of severe adverse effects such as bradycardia, sedation, and respiratory depression9 resulting from activation of α2-adrenergic receptors.2 Topical moxidectin formulations are labeled for treatment of generalized demodicosis in dogs in other countries such as Serbia, Albania, France, and Germany, but not in the United States.10–12 Additional treatments that are not presently FDA approved for this use in the United States include oral formulations of ivermectin, moxidectin, and milbemycin oxime; an injectable formulation of doramectin; and lime sulfur dips, as well as topical and oral formulations of isoxazolines.7,11 Many of the presently implemented treatment modalities have varying degrees of efficacy,13 and some are associated with relatively high risks of adverse effects such as CNS, cardiovascular, and gastrointestinal disturbances; in addition, some treatments require high dosing frequencies, making them cost prohibitive.2,10

Isoxazolines are a novel class of insecticide and acaricide with potent inhibitory activity on glutamate-gated and γ-aminobutyric acid ligand-gated chloride channels.14 Various isoxazoline compounds have been successfully used for the treatment of generalized demodicosis in dogs.15–18 Isoxazolines that are presently approved by the FDA for use against specific flea and tick infestations in dogs or dogs and cats in the United States include afoxolaner,19 fluralaner,20,21 sarolaner,22 and lotilaner.23

Labeled use of isoxazolines

Afoxolaner is available in the United States as a chewable tablet labeled for the treatment and prevention of flea (Ctenocephalides felis) infestations and treatment and control of black-legged tick (Ixodes scapularis), American dog tick (Dermacentor variabilis), brown dog tick (Rhipicephalus sanguineus), and lone star tick (Amblyomma americanum) infestations in dogs.19 Afoxolaner tablets are available in 4 sizes and prescribed as a monthly treatment to deliver a minimum dose of 2.5 mg/kg (1.1 mg/lb) up to a maximum recommended dose of approximately 6.2 mg/kg (2.8 mg/lb) in dogs ≥ 8 weeks of age.19

Fluralaner is available in the United States as a chewable tablet for dogs,21 a topical spot-on formulation for dogs,20 and a topical spot-on treatment for cats.20 The products for dogs are labeled for treatment and prevention of flea infestations and for treatment and control of black-legged ticks, American dog ticks, and brown dog ticks for up to 12 weeks and lone star ticks for up to 8 weeks; the product for use in cats is labeled for the treatment and prevention of fleas and for treatment and control of black-legged ticks for up to 12 weeks.20,21 The orally and topically administered products for dogs are available in 5 strengths and are prescribed at a minimum dose of 25 mg/kg (11.4 mg/lb) up to a maximum recommended dose of approximately 56 mg/kg (25.5 mg/lb). The topical treatment for cats is available in 3 strengths prescribed at a minimum dose of 40 mg/kg (18.2 mg/lb) up to a maximum recommended dose of approximately 95 mg/kg (43.2 mg/lb). These products are all labeled for dogs or cats ≥ 6 months of age.20,21

Sarolaner is available in the United States, labeled for the treatment and prevention of flea infestations and the treatment and control of lone star tick, Gulf Coast tick (Amblyomma maculatum), American dog tick, black-legged tick, and brown dog tick infestations in dogs.22 Sarolaner is available as a chewable tablet in 5 strengths for monthly administration at a minimum dose of 2 mg/kg (0.9 mg/lb) up to a maximum recommended dose of approximately 4 mg/kg (1.8 mg/lb), in dogs ≥ 6 months of age.22 Results of an in vitro investigation24 indicate sarolaner is the most potent isoxazoline, with the lowest concentration required to kill 80% of the tested flea population one-tenth that of afoxolaner or fluralaner and the lowest concentration required to kill 100% of the tested soft tick (Ornithodoros turicata) population one-third that of the latter 2 drugs. The effective clinical doses for these isoxazolines reflect the in vitro findings with the lowest dose tested of 1.25 mg/kg (0.57 mg/lb) for sarolaner.24

Lotilaner is available in the United States as a chewable tablet, also in 5 strengths, labeled for treatment of flea infestations and treatment and control of lone star tick, American dog tick, black-legged tick, and brown dog tick infestations in dogs ≥ 8 weeks of age.23 The product is administered monthly at a minimum dose of 20 mg/kg (9.1 mg/lb) up to a maximum recommended dose of approximately 40 mg/kg.23

Extralabel use for treatment of demodicosis in dogs

Fluralaner was introduced to the veterinary product market in 2015. An oral formulation of fluralaner was investigated for efficacy against demodicosis in a study16 of 16 dogs with generalized demodicosis. Eight dogs were randomly allocated to receive a single dose of fluralaner (≥ 25 mg/kg, PO), and the remaining 8 dogs were treated topically with a spot-on imidacloprid-moxidectin solution (positive control) at 4-week intervals for 3 treatments at the labeled dose for indicated use (canine demodicosis) of 10 mg of imidacloprid/kg (4.5 mg/lb) and 2.5 mg of moxidectin/kg (1.1 mg/lb). The number of Demodex mites in skin scrapings was reduced by 99.8%, 100%, and 100% on days 28, 56, and 84, respectively, following administration of fluralaner, and dogs that received the fluralaner treatment had significantly fewer mites than those that received the imidacloprid-moxidectin treatment on days 28, 56, and 84.16 Topically administered fluralaner had similar efficacy to the orally administered product, compared with imidacloprid-moxidectin treatment for canine demodicosis.25

A year later, a study26 on the efficacy of sarolaner against Demodex spp was conducted. Sarolaner was given orally to 8 dogs at 2 mg/kg monthly for 3 treatments in that study, and the results showed that live Demodex mite counts in skin scrapings were reduced by 97.1% within 14 days and by 99.8% within 29 days after the first dose, with no live mites detected thereafter; results for 8 dogs that received a control treatment (imidacloprid-moxidectin) indicated lower efficacy with treatment of higher frequency and longer duration.26

A similar study17 published in 2016 evaluated the efficacy of an oral formulation of afoxolaner for treatment of generalized demodicosis in dogs. Afoxolaner was administered orally at ≥ 2.5 mg/kg (according to labeled monthly use against demodicosis in Europe) on days 0, 14, 28, and 56 to 8 dogs, and another 8 dogs received a control treatment (imidacloprid-moxidectin) at the same intervals. The percentage reduction of mite counts reached 99.2% on day 28 and increased to 99.9% and 100% on days 56 and 84, respectively, for dogs that received afoxolaner, with percentage reductions of 89.8%, 85.2%, and 86.6% on days 28, 56, and 84 for dogs that received the positive control treatment.17

In 2017, another study15 was published that evaluated the use of lotilaner for treatment of 10 dogs with generalized demodicosis. All dogs received lotilaner orally at ≥ 20 mg/kg on days 0, 28, and 56. The mite counts were reduced by > 99.9% up to day 56, with no live mites detected on day 84, 1 month after the last treatment.15

The described studies15–17,25,26 that found satisfactory efficacies of 4 different isoxazolines against demodicosis in dogs were all performed through 1 contract research company in South Africa. In 2018, a multicenter study18 that investigated efficacy of sarolaner against generalized demodicosis and its safety in dogs from France, Hungary, Portugal, and Italy revealed that mite counts were reduced by 77.2%, 95.0%, 98.5%, 99.0%, 100%, and 100% on days 30, 60, 90, 120, 150, and 180, respectively, following monthly oral administration of sarolaner at doses of 2 to 4 mg/kg in 53 dogs for 6 months. For 28 dogs that received a control treatment (imidacloprid-moxidectin), mite reduction was 82.2% after 6 monthly treatments. These results showed less rapid improvement, compared with the previously described study26 in which 99.8% reduction in live mite counts was observed by day 29 after the first dose of sarolaner.

In addition to the aforementioned studies, field trials and clinical reports from various countries have indicated the successful use of isoxazolines for treatment of demodicosis in dogs. A clinical report27 from Peru described successful treatment of naturally-acquired generalized D canis infestation in 4 dogs with afoxolaner. The drug was administered orally every 4 weeks for 8 weeks at doses ≥ 2.5 mg/kg. Substantial clinical improvement of skin lesions was observed 4 weeks after the initial treatment, and skin scrapings were free of live mites 8 and 12 weeks after treatment was started.27

A 2018 report28 of a field trial in Thailand revealed that 1 to 3 treatments with orally administered fluralaner at 25 to 50 mg/kg (11.4 to 22.7 mg/lb) successfully eliminated generalized demodicosis in 66 of 67 dogs for which adequate follow-up was available. Follow-up in that study28 was performed for 2 to 12 months after parasitological cure (2 skin scrapings with negative results achieved 1 month apart). Dogs with adult-onset demodicosis reached parasitological cure in 2 to 4 months, with the same result achieved for dogs with juvenile-onset demodicosis in 2 to 3 months.28 Fluralaner was also used to successfully treat refractory generalized demodicosis in a 12-year-old female Shih Tzu in Japan that had hyperadrenocorticism and hypothyroidism.29 The dog received a single oral dose of fluralaner (50 mg/kg), and although a transient eruption of cutaneous papules was reported a few days after treatment, no mites were found by examination of skin scrapings 60 days after the treatment.29 In addition, a single dose of the oral fluralaner formulation was reported to result in parasitological cure of D injai demodicosis in a dog from Spain 7 weeks after administration.a Interestingly, although the described reports indicate that isoxazoline administration results in resolution of canine demodicosis, treatment with afoxolaner (≥ 2.5 mg/kg, PO; single dose) or fluralaner (≥ 25 mg/kg, PO; monthly doses for 60 days) did not affect cutaneous Demodex populations of healthy dogs (10/treatment type) over a 90-day study period as assessed by real-time PCR assay for DNA of the parasite.30

Extralabel use for treatment of demodicosis in cats

To the authors' knowledge, no studies have been performed to investigate the efficacy of isoxazolines for the treatment of demodicosis in cats. One clinical report31 described 100% elimination of D gatoi mites in 2 cats 1 month after a single dose of the oral formulation of fluralaner at 26 to 34 mg/kg (11.8 to 15.5 mg/lb), with no mites found on examination of repeated skin scrapings 2 and 3 months after treatment. A single oral dose of fluralaner at 28 mg/kg (12.7 mg/lb) was also associated with successful treatment of a generalized form of demodicosis caused by D cati in 1 cat in Italy, with negative results for skin scrapings 1 month after treatment and resolution of clinical signs ≤ 2 months after treatment.32

Safety of orally administered isoxazoline treatments

Oral fluralaner administration every 2 months at up to 5 times the maximum recommended dose of 56 mg/kg21 (25.5 mg/lb) was assessed in 24 puppies 8 weeks of age with no adverse effects identified, compared with results for a control group of 8 puppies sham-treated with water.33 No adverse effects were noted other than single cases of vomiting and gastroenteritis with inappetence that were not deemed treatment-related.

Oral afoxolaner treatment was also assessed in puppies beginning at 8 weeks of age at doses up to 5 times the maximum exposure dose of 6.3 mg/kg (2.9 mg/lb; ie, up to 31.5 mg/kg [14.3 mg/lb]) at 3 monthly intervals followed by 3 weekly intervals, compared with nontreated control puppies.34 No impact on general health or growth was associated with the treatment. Assessment measures in addition to growth included physical examination variables, clinicopathologic variables, and histopathologic findings.

McTier et al24 performed safety investigations of orally administered sarolaner in small sample groups of 24 adult Beagles and 32 Beagle puppies beginning at 8 weeks of age. Evaluations in mice were performed with up to 30 mg of sarolaner/kg (13.6 mg/lb), PO, with no clinical signs indicative of adverse effects, as a safety screening test.24 Adult dogs (6/group) were treated with a placebo or 1 of 3 sarolaner doses up to 10 mg/kg (4.5 mg/lb; 5 times the recommended dose of 2 mg/kg) 3 times at 28-day intervals, and puppies (8/group) received a placebo or 1 of 3 doses up to 20 mg/kg twice at a 28-day interval. Evaluation variables similar to those used for the aforementioned fluralaner study33 were used for safety assessments. No adverse effects or clinically relevant changes were observed as a result of the sarolaner treatments.24

In a field study35 that involved 112 cats in Europe that received lotilaner orally at ≥ 6 mg/kg (2.7 mg/lb) for treatment of ticks on day 0 and approximately 28 and 56 days later, compared with 57 cats that received topical (spot-on) fipronil treatment at the same times, no vomiting or diarrhea was observed in any cats and no adverse effects attributable to the treatments were reported.

In an investigation of potential reproductive effects cited in the FDA Freedom of Information Summary for the approved fluralaner product,21 the safety of orally administered fluralaner was assessed in 20 breeding dogs (10/sex) at 3 times the maximum expected dose of 56 mg/kg, compared with 20 untreated dogs (10/sex). Treated animals were administered fluralaner at 168 mg/kg (76.4 mg/lb) orally 3 or 4 times at 8-week intervals prior to breeding; females continued to be treated at 8-week intervals until puppies were weaned. Treatment had no significant effects on reproductive performance or semen quality.21

To the authors' knowledge, fluralaner is the only isoxazoline that has been evaluated in dogs with the MDR1 deletion mutation. These dogs have been found to lack expression of functional P-glycoprotein, making them susceptible to neurotoxic effects of macrocyclic lactones.36 In a study performed by Walther et al,37 a small sample of 16 purpose-bred Collies homozygous for the MDR1 mutation were treated with a 1-time oral dose of 168 mg of fluralaner/kg (3 times the maximum expected clinical dose; 8 dogs) or with a sham treatment (water; 8 dogs) and evaluated for 28 days. Only minor clinical findings that were not associated with the treatment (eg, evidence of estrus) were observed in fluralaner-treated dogs over the course of the study. These findings suggested that fluralaner is well tolerated in dogs with the MDR1 mutation. As a potent blocking agent of γ-aminobutyric acid–gated chloride channels in invertebrates, isoxazolines have the potential to cause neurological excitation in vertebrates. According to an Animal Drug Safety Communication released by the FDA, adverse neurologic reactions such as muscle tremors, ataxia, and seizures in some animals have been reported consistently across the isoxazoline class of products.38 A European Medicines Agency report39 also described investigations in which neurologic signs were observed in some dogs at sarolaner doses higher than the recommended dose of 2 to 4 mg/kg, PO. Furthermore, a recent clinical report40 described transient neurologic abnormalities in a young dog after administration of fluralaner at the recommended dose of 25 mg/kg, PO.39,40 The FDA carefully reviewed studies and other data prior to approval of the products and has stated that the isoxazoline class products are safe and effective for the majority of animals.38

Conclusions

The availability of isoxazolines has provided veterinarians and pet owners with a new option to treat demodicosis in dogs and cats in a convenient and affordable manner. Although isoxazolines are not presently labeled for treatment of demodicosis in the United States, the results of numerous studies, clinical reports, and field trials indicate that these drugs can be successfully used to treat this challenging condition with few adverse effects.

Footnotes

a.

Benito MM, Sastre N, Ravera I. A case of demodicosis (Demodex injai) treated with a novel isoxazoline (abstract presentation). 11th South Eur Vet Conf, Barcelona, Spain, November 2017.

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