TABLE 4.

US approved canine drugs that have undergone safety studies in P‐gp deficient dogs and their reported adverse reactions

Drug	Active ingredient	Route	Safety information in P‐gp deficient dogs on the product label	Warnings or precautions related to safety risk in P‐gp deficient dogs on the product label
Advantage Multi™ for Dogs NADA 141–251	Imidacloprid, moxidectin	Topical	Dermal Safety Study in Ivermectin‐Sensitive collies: Advantage Multi™ for Dogs was administered topically at 3 and 5 times the recommended dose every 28 days for 3 treatments to Collies which had been prescreened for avermectin sensitivity. No clinical abnormalities were observed. Oral Safety Study in Ivermectin‐Sensitive Collies: Advantage Multi™ for Dogs was administered orally to 5 pre‐screened ivermectin‐sensitive collies. The collies were asymptomatic after ingesting 10% of the minimum labeled dose. At 40% of the minimum recommended topical dose, 4 of the dogs experienced neurological signs indicative of avermectin toxicity including depression, ataxia, mydriasis, salivation, muscle fasciculation, and coma, and were euthanized	For the first 30 min after application: Ensure that dogs cannot lick the product from application sites on themselves or other treated dogs, and separate treated dogs from one another and from other pets to reduce the risk of accidental ingestion. Ingestion of this product by dogs may cause serious adverse reactions including depression, salivation, dilated pupils, incoordination, panting, and generalized muscle tremors. In avermectin sensitive dogs, the signs may be more severe and may include coma and death. Some dogs are more sensitive to avermectins due to a mutation in the MDR1 gene. Dogs with this mutation may develop signs of severe avermectin toxicity if they ingest this product. The most common breeds associated with this mutation include collies and collie crosses. Although there is no specific antagonist for avermectin toxicity, even severely affected dogs have completely recovered from avermectin toxicity with intensive veterinary supportive care
Bravecto® NADA: 141–532	Fluralaner	Oral	No studies in avermectin‐sensitive collies are described on the product insert. However, a safety study in MDR1 (−/−) collies at 3 times the recommended dose was published. No adverse events were seen in at 3 times the maximum recommended therapeutic dose (Walther et al., 2014)	None
Heartgard® NADA# 140–886	Ivermectin	Oral	Studies with ivermectin indicate that certain dogs of the collie breed are more sensitive to the effects of ivermectin administered at elevated dose levels (more than 16 times the target use level) than dogs of other breeds. At elevated doses, sensitive dogs showed adverse reactions which included mydriasis, depression, ataxia, tremors, drooling, paresis, recumbency, excitability, stupor, coma, and death. Heartgard® demonstrated no signs of toxicity at 10 times the recommended dose (60 mcg/kg) in sensitive collies. Results of these trials support the safety of Heartgard® products in dogs, including collies, when used as recommended	None
Heartgard® Plus NADA# 140–971	Ivermectin, pyrantel pamoate	Oral	Studies with ivermectin indicate that certain dogs of the collie breed are more sensitive to the effects of ivermectin administered at elevated dose levels (more than 16 times the target use level) than dogs of other breeds. At elevated doses, sensitive dogs showed adverse reactions which included mydriasis, depression, ataxia, tremors, drooling, paresis, recumbency, excitability, stupor, coma, and death. Heartgard® demonstrated no signs of toxicity at 10 times the recommended dose (60 mcg/kg) in sensitive collies. Results of these trials and bioequivalency studies, support the safety of Heartgard® products in dogs, including collies, when used as recommended	None
Interceptor® NADA: 140–915	Milbemycin oxime	Oral	A rising‐dose safety study conducted in rough‐coated collies, manifested a clinical reaction consisting of ataxia, pyrexia, and periodic recumbency, in one of fourteen dogs treated with milbemycin oxime at 12.5 mg/kg (25 times the monthly use rate). Prior to receiving the 12.5 mg/kg dose (25 times the monthly use rate) on day 56 of the study, all animals had undergone an exaggerated dosing regimen consisting of 2.5 mg/kg milbemycin oxime (5 times the monthly use rate) on Day 0, followed by 5.0 mg/kg (10 times the monthly use rate) on Day 14, and 10.0 mg/kg (20 times the monthly use rate) on Day 32. No adverse reactions were observed in any of the collies treated with this regimen up through the 10.0 mg/kg (20 times the monthly use rate) dose	None
Interceptor® Plus NADA: 141–338	Milbemycin oxime, praziquantel	Oral	A rising‐dose safety study conducted in rough‐coated Collies resulted in ataxia, pyrexia, and periodic recumbency in one of fourteen dogs administered milbemycin oxime at 12.5 mg/kg (5 times the maximum exposure dose of Interceptor Plus). Prior to receiving the 12.5 mg/kg dose on day 56 of the study, all animals had undergone a dosing regimen consisting of 2.5 mg/kg milbemycin oxime on Day 0, followed by 5.0 mg/kg on Day 14, and 10.0 mg/kg on Day 32. No adverse reactions were observed in any of the collies treated with doses less than 12.5 mg/kg. No studies with avermectin‐sensitive dogs with praziquantel are described on the product label	None
NexGard® NDAD: 141–406	Afoxolaner	Oral	No studies in avermectin‐sensitive collies are described on the product label. However, a safety study in MDR1 (−/−) collies evaluated afoxolaner and a combination of afoxolaner and milbemycin oxime (NexGard® Spectra; not currently approved in US). Afoxolaner was evaluated at 3.8 times the maximum recommended dose and the afoxolaner /milbemycin oxime combination was evaluated at 4.7 times the recommended dose. No significant adverse reactions were noted in either group (Drag et al., 2022)	None
ProHeart®6 NADA# 141–189	moxidectin	Injectable	ProHeart®6 administered up to 5 times the recommended dose in ivermectin‐sensitive collies did not cause any adverse reactions	None
ProHeart®12 NADA# 141–519	moxidectin	Injectable	In a laboratory study, 15 ivermectin‐sensitive collie dogs in three treatment groups were administered one dose of saline and one dose of ProHeart®12, 21 days apart. Each dog served as its own control and the order of administration of the saline and ProHeart®12 varied by treatment group. ProHeart®12 was dosed at 0.5 mg/kg body weight (recommended dose, five dogs), 1.5 mg/kg body weight (3 times the recommended dose, five dogs), or 2.5 mg/kg body weight (5 times the recommended dose, five dogs). No clinical signs of moxidectin toxicity were observed during the 42‐day study	None
Revolution® NADA# 141–152	Selamectin	Topical	In a pre‐clinical study selamectin was dosed orally to ivermectin‐sensitive collies. The final market formulation was not used in this study. Oral administration of 2.5, 10, and 15 mg/kg in this dose escalating study did not cause any adverse reactions; however, eight hours after receiving 5 mg/kg orally, one dog became ataxic for several hours, but did not show any other adverse reactions after receiving subsequent doses of 10 and 15 mg/kg orally. In a topical safety study conducted at 1, 3, and 5 times the recommended dose (6 mg/kg) salivation was observed in all treatment groups, including the vehicle control	None
Sentinel® Flavor Tabs NADA: 141–084	Lufenuron, milbemycin oxime	Oral	A rising‐dose safety study conducted in rough‐coated collies manifested a clinical reaction consisting of ataxia, pyrexia and periodic recumbency in one of fourteen dogs treated with milbemycin oxime at 12.5 mg/kg (25 times the recommended minimum dose). Prior to receiving the 12.5 mg/kg dose on day 56 of the study, all animals had undergone an exaggerated dosing regimen consisting of 2.5 mg/kg milbemycin oxime (5 times the recommended minimum dose) on Day 0, followed by 5.0 mg/kg (10 times the recommended minimum dose) on Day 14, and 10.0 mg/kg (20 times the recommended minimum dose) on Day 32. No adverse reactions were observed in any of the collies treated with this regimen up through the 10.0 mg/kg (20 times the recommended minimum dose) dose. No studies with avermectin‐sensitive dogs with lufenuron are described on the product label	None
Sentinel® Spectrum® NADA: 141–333	Milbemycin oxime, lufenuron, praziquantel	Oral	A rising‐dose safety study conducted in rough‐coated collies resulted in ataxia, pyrexia, and periodic recumbency in one of fourteen dogs administered milbemycin oxime at 12.5 mg/kg (5 times the maximum exposure dose of Sentinel® Spectrum® Chews). Prior to receiving the 12.5 mg/kg dose on day 56 of the study, all animals had undergone a dosing regimen consisting of 2.5 mg/kg milbemycin oxime on Day 0, followed by 5.0 mg/kg on Day 14, and 10.0 mg/kg on Day 32. No adverse reactions were observed in any of the collies treated with doses less than 12.5 mg/kg. No studies with avermectin‐sensitive dogs with lufenuron or praziquantel are described on the product label	None
Simparica Trio® NADA: 141–521	Sarolaner, moxidectin, pyrantel	Oral	Simparica Trio® was administered orally once at 1, 3, and 5 times the maximum recommended dose to collies that had been pre‐screened for avermectin sensitivity. Clinical signs (ataxia, muscle fasciculations, mydriasis) associated with avermectin sensitivity were observed in the 5X group. All dogs were completely recovered by the third day of the study	None
Trifexis™ NADA: 141–321	Spinosad, milbemycin oxime	Oral	In an avermectin‐sensitive collie dog study, Trifexis™ was administered orally at 1, 3, and 5 times the upper half of the recommended dose band every 28 days. No signs of avermectin sensitivity were observed after administration of Trifexis™ during the study period to avermectin‐sensitive collie dogs. The adverse reactions observed in the treatment groups were vomiting and diarrhea. Body weights in all treatment groups were comparable with the control group. Hematology and clinical chemistry parameters showed no clinically significant changes from study start to end, and all dogs were considered healthy throughout the study	None

Note: US approved label language found on https://dailymed.nlm.nih.gov/dailymed/index.cfm. Only the original approved products (pioneer approvals) are included. Numerous generic approvals exist for many of the listed products.