Ivermectin

Ivermectin is a derivative of avermectin B1, and its use is licensed in dogs for the prevention of dirofilariasis at a dosage of 6 to 12 µg/kg once a month PO. Ivermectin in cats is labeled for prevention of heartworm infection and hookworms when dosed at 24 µg/kg to approximately 70 µg/kg once a month PO. The ivermectin formulation most commonly used in dogs and cats for the extralabel treatment of ectoparasites in veterinary dermatology is available commercially as a 1% nonaqueous injectable solution formulated in 60% propylene glycol and 40% glycerol (Ivomec). This can be diluted with sterile propylene glycol for accurate dosing in kittens and small dogs; however, propylene glycol can be irritating when administered subcutaneously and can cause bradycardia and respiratory and central nervous system depression. For this reason some veterinary dermatologists prefer to use the aqueous 0.8% oral drench approved for use in sheep and goats (Ivomec Liquid), which can be administered undiluted or diluted with sterile water. The oral solution of ivermectin must be given by mouth, whereas the injectable propylene glycol–based formulation can be administered subcutaneously or orally. A 0.5% alcohol-based pour-on ivermectin formulation (Ivomec Pour-On) approved for use in cattle has been used in dogs and cats. Ivermectin is sensitive to ultraviolet light and should be stored in the dark or dispensed in an opaque bag to prolong its shelf life.

Ivermectin has a wide margin of safety in dogs and cats; however, an increased susceptibility to acute toxicity is evident in a subpopulation of collie and collie-type dogs. The oral dose of ivermectin shown to cause adverse effects in noncollie dog breeds is in the range of 2500 to 10,000 µg/kg. In contrast, clinical signs of toxicity develop after the administration of only 100 µg/kg in a subpopulation of susceptible breeds. Clinical signs include mydriasis, depression, ataxia, hypersalivation, bradycardia, hyperthermia, apparent blindness, decreased menace response, muscle tremors, and disorientation, which may progress to weakness, recumbency, unresponsiveness, stupor, and coma. Acute ivermectin toxicity has been reported in other breeds, including Australian shepherds, Shetland sheepdogs, Old English sheepdogs, Doberman pinschers, and their crossbreeds.

Ivermectin sensitivity in collies has been traced to a mutation of the multidrug resistance (MDR1) or ABCB1-1 (the ABCB1-1 Delta genotype). The MDR1 gene encodes a large transmembrane protein forming an integral part of the blood-brain barrier, P-glycoprotein, which plays an important role in the integrity of the blood-brain barrier by limiting drug uptake into the brain. Altered expression or function of P-glycoprotein may allow elevated brain concentrations of ivermectin and thereby potentiate neurotoxicity. Because no functional P-glycoprotein is produced in the homozygous mutated genotype, there is an increased susceptibility to neurotoxicosis from several drugs, including macrocyclic lactones, due to their accumulation in the central nervous system. Dogs that are homozygous for the mutation show the ivermectin-sensitive clinical phenotype. Approximately 35% of collies are homozygous for the ABCB1-1 Delta mutation, with a rate that varies from 24% to 73% based on data from global studies; only 10% to 26% of collies are homozygous for the normal (wild-type) gene. Dogs with heterozygous mutated as well as normal homozygous genotypes normally do not display the severe neurotoxicoses seen in dogs with the homozygous mutated genotype. The same mutation now has been identified with a lower frequency in 10 other dog breeds: Australian shepherd, Shetland sheepdog, longhaired whippet, Old English sheepdog, silken windhound, McNab, English shepherd, Border collie, and white Swiss shepherd as well as two mixed-breed dogs.

Subchronic neurotoxicity occurs in noncollie breeds receiving ivermectin for generalized demodicosis, and in over one third of cases, drug interactions are responsible for these adverse neurologic signs. A number of drugs, including cyclosporin, fluoxetine, ketoconazole, itraconazole, calcium channel antagonists, and other macrocyclic lactones such as selamectin, are capable of P-glycoprotein inhibition and thus can precipitate neurotoxicity in patients receiving ivermectin.

Furthermore, spinosad (Comfortis) may potentiate ivermectin toxicity (mydriasis, hypersalivation, lethargy, ataxia, trembling) when ivermectin is being administered at extralabel dosages. Clinical signs typically occur within 4 to 6 hours of administration of spinosad in conjunction with high-dosage ivermectin. These problems were not noted with concurrent use of spinosad and milbemycin in ivermectin-sensitive collies. The manufacturer has advised that veterinarians delay the administration of spinosad for at least 15 to 30 days after the completion of extralabel dosages of avermectin or milbemycin.

Safety in administering oral ivermectin may be improved but not ensured by beginning with a low test dose and increasing the amount administered over several days until the desired dose is reached. In our dermatology clinic we initially administer 100 µg/kg PO and then increase the dose by 100 µg/kg every 48 hours to 200 µg/kg, 300 µg/kg, and so on, in an effort to identify ivermectin-sensitive dogs. Owners are instructed to observe their pets closely during this period and to cease administration if symptoms of lethargy, incoordination, or mydriasis develop. Because of the relatively long half-life of ivermectin, serum concentrations of ivermectin administered daily continue to increase before reaching equilibrium at much higher levels than with weekly therapy. Thus chronic toxicity caused by cumulative therapy may develop with prolonged daily ivermectin treatment. Because of this it is recommended that dogs receiving ivermectin be checked regularly for evidence of clinical signs suggestive of chronic toxicity; in our dermatology clinic we reevaluate dogs every 4 weeks for the first 3 months of treatment and then every 3 months thereafter.

A commercial polymerase chain reaction (PCR)–based method for MDR1 genotyping using canine DNA from mouth cells is available for detecting the mutation in dogs and should be considered if ivermectin must be used in potentially susceptible breeds. Information is available at the Washington State University Veterinary Clinical Pharmacology Laboratory website (www.vetmed.wsu.edu/depts-VCPL/test.aspx). A rapid PCR- based method that can discriminate between homozygous and heterozygous alleles using a small amount of genomic DNA from a blood sample also is available commercially (Geyer et al, 2005).

Acute ivermectin toxicity is rare in adult cats, but kittens are susceptible to the toxic effects of ivermectin, and lethargy, ataxia, coma, and death have been reported after administration of a single 300 µg/kg subcutaneous injection.

Adverse reactions to ivermectin have been encountered with the rapid destruction of the microfilariae of Dirofilaria immitis in dogs. Most reactions are mild, occur within 1 to 4 hours of administration, and manifest as ataxia, vomiting, and dyspnea. However, anaphylactic shock has been observed and is more likely to occur when the microfilaria counts are high. Dogs should be screened for heartworm infection before ivermectin administration, particularly in regions where the disease is endemic.

Selamectin

Selamectin is a derivative of the avermectin endectocide doramectin. It is available as a solution (6% or 12%) in an isopropyl alcohol and dipropylene glycol methyl-ether vehicle (Revolution). It is licensed for topical application at a dose of 6 mg/kg for dogs and cats not younger than 6 weeks of age for the treatment and prevention of infestation or infection with fleas (Ctenocephalides spp.), sarcoptic (Sarcoptes scabiei) and otodectic (Otodectes cynotis) mites, ascarids (Toxocara spp.), and hookworms (Ancylostoma tubaeforme) and for the prevention of heartworm disease (D. immitis). A single dorsal application on the skin at the base of the neck in front of the scapulae is recommended. If the volume of the total dose exceeds 3 ml, the manufacturer recommends that the dose be divided among multiple areas in the dorsal neck region.

Extensive safety studies have shown that selamectin has a wide margin of safety when administered to dogs and cats, including puppies and breeding animals. The drug is safe for topical administration in ivermectin-sensitive breeds and in dogs and cats with dirofilariasis. The likelihood of accidental oral ingestion is reduced by dorsal application at the base of the neck, but inadvertent oral consumption of selamectin causes only mild salivation and intermittent vomiting in cats and no reaction in dogs.

Doramectin

Doramectin (Dectomax) is a relatively new semisynthetic avermectin licensed as an endectocide for subcutaneous administration in cattle, sheep, and swine. It is not licensed for use in dogs and cats, but its extralabel use as an endectocide in these species has been widely reported. It is available commercially as a 1% solution formulated in a 90 : 10 volume : volume sesame oil and ethyl oleate vehicle for subcutaneous injection in the lateral midline of the back as a single dose. It is well tolerated without pain or inflammatory reaction at the injection site. In ruminants and in equine species doramectin shows higher bioavailability and persistent efficacy compared with ivermectin; however, recent studies indicate that this is not the case in the dog. Doramectin reached a significantly lower plasma concentration than ivermectin following oral administration in the dog, whereas no significant differences were observed following subcutaneous administration (Gokbulut et al, 2006). This suggests that different formulations of doramectin for oral and subcutaneous administration may need to be developed for the dog.

There is little reported information on the safety of doramectin in dogs and cats. Some avermectin-sensitive breeds in our dermatology referral practice have demonstrated clinical signs of salivation, mydriasis, vomiting, tremors, ataxia, and depression when doramectin was administered at dosages between 200 and 400 µg/kg by single subcutaneous injection. Similar toxicity was reported in a collie dog following the single subcutaneous administration of 200 µg/kg (Yas-Natan et al, 2003). Caution should be exercised in administering doramectin to potentially avermectin-sensitive breeds. It is recommended that clinicians take precautions similar to those for ivermectin administration (i.e., the dose of doramectin should be increased with each weekly injection, beginning at a test dose of 50 to 100 µg/kg). No toxic reactions have been recorded in cats.