Spinosad: what the FDA reviewed for dog products
2 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Spinosad, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs; Dogs and Cats.
Products
- Comfortis™ (NADA/ANADA 141-277)
Comfortis™ NADA 141-277, Supplemental approval, August 20, 2012; sponsor Elanco US Inc.; species: Dogs and Cats; foi_id 838; FDA PDF
Indication
Supplement adds use in cats (kills fleas; prevention and treatment of flea infestations (C. felis) for one month in cats and kittens 14 weeks and older, 2 lb or greater) and a 90 mg tablet size for dogs 3.3-4.9 lb.
Dose regimen
22.5 mg/lb (50 mg/kg) minimum (cats), oral (chewable tablet), once a month, Cats dosed after feeding (fed state needed for absorption); cat weight bands give 50-100 mg/kg; dogs unchanged at 13.5 mg/lb (30 mg/kg) minimum with new 90 mg tablet for 3.3-4.9 lb
CATS COMFORTIS is given orally, once a month at the minimum dosage of 22.5 mg/lb (50 mg/kg) body weight.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| tmax | 10 (3) hours spinosyn A | Fed/fasted PK study T9CUS090007 in cats: COMFORTIS target 80 mg/kg single oral dose, 4 male + 4 female adult cats per group, mean (SD); values normalized to dose. Row order: Tmax (h), Cmax/dose (ng/mL per mg/kg), AUC0-inf/dose (hr x ng/mL per mg/kg), t1/2 (h); fed group | Fed Group 10 (3) 46 (14) 4489 (1182) 280 (74) |
| cmax | 46 (14) ng/mL per mg/kg spinosyn A (dose-normalized) | Fed/fasted PK study T9CUS090007 in cats: COMFORTIS target 80 mg/kg single oral dose, 4 male + 4 female adult cats per group, mean (SD); values normalized to dose. Row order: Tmax (h), Cmax/dose (ng/mL per mg/kg), AUC0-inf/dose (hr x ng/mL per mg/kg), t1/2 (h); fed group | Fed Group 10 (3) 46 (14) 4489 (1182) 280 (74) |
| auc | 4489 (1182) hr x ng/mL per mg/kg spinosyn A (dose-normalized AUC to infinity) | Fed/fasted PK study T9CUS090007 in cats: COMFORTIS target 80 mg/kg single oral dose, 4 male + 4 female adult cats per group, mean (SD); values normalized to dose. Row order: Tmax (h), Cmax/dose (ng/mL per mg/kg), AUC0-inf/dose (hr x ng/mL per mg/kg), t1/2 (h); fed group | Fed Group 10 (3) 46 (14) 4489 (1182) 280 (74) |
| half-life | 280 (74) hours spinosyn A | Fed/fasted PK study T9CUS090007 in cats: COMFORTIS target 80 mg/kg single oral dose, 4 male + 4 female adult cats per group, mean (SD); values normalized to dose. Row order: Tmax (h), Cmax/dose (ng/mL per mg/kg), AUC0-inf/dose (hr x ng/mL per mg/kg), t1/2 (h); fed group | Fed Group 10 (3) 46 (14) 4489 (1182) 280 (74) |
| cmax | 11 (7) ng/mL per mg/kg spinosyn A (dose-normalized) | Fed/fasted PK study T9CUS090007 in cats: COMFORTIS target 80 mg/kg single oral dose, 4 male + 4 female adult cats per group, mean (SD); values normalized to dose. Row order: Tmax (h), Cmax/dose (ng/mL per mg/kg), AUC0-inf/dose (hr x ng/mL per mg/kg), t1/2 (h); fasted group (fed 2 h post-dose); Tmax 6 (4) h, t1/2 193 (60) h | Fasted Group 6 (4) 11 (7) 781 (406) 193 (60) |
| auc | 781 (406) hr x ng/mL per mg/kg spinosyn A (dose-normalized AUC to infinity) | Fed/fasted PK study T9CUS090007 in cats: COMFORTIS target 80 mg/kg single oral dose, 4 male + 4 female adult cats per group, mean (SD); values normalized to dose. Row order: Tmax (h), Cmax/dose (ng/mL per mg/kg), AUC0-inf/dose (hr x ng/mL per mg/kg), t1/2 (h); fasted group | Fasted Group 6 (4) 11 (7) 781 (406) 193 (60) |
| auc | 1045 (321) hr x ng/mL per mg/kg spinosyn D (dose-normalized AUC to infinity) | Fed/fasted PK study T9CUS090007 in cats: COMFORTIS target 80 mg/kg single oral dose, 4 male + 4 female adult cats per group, mean (SD); values normalized to dose. Row order: Tmax (h), Cmax/dose (ng/mL per mg/kg), AUC0-inf/dose (hr x ng/mL per mg/kg), t1/2 (h); fed group, Table 2 (spinosyn D): Cmax/dose 12 (4), t1/2 310 (113) h | Fed Group 10 (3) 12 (4) 1045 (321) 310 (113) |
| other | exposure at 3X and 5X more than dose proportional vs 1X | Cat margin-of-safety study 025821, plasma spinosyn A and D sampled through six monthly intervals | The plasma concentrations demonstrated that exposures in cats in the 3X and 5X treatment groups were more than dose proportional to exposures in cats in the 1X treatment group. |
Target-animal safety
dose multiples 1X, 3X, 5X; duration Six monthly dosing intervals 28 days apart, starting at 14 weeks of age (168-day study); 3X and 5X doses divided over sequential days; animals 32 domestic cats (8 per group).
Evaluate the safety of COMFORTIS when administered orally to 14-week old kittens at 1X, 3X, and 5X the upper half (75-100 mg/kg) of the therapeutic dose band for six monthly dosing intervals 28 days apart. b. Study Animals: 32 domestic cats (8 cats per treatment group)
| Finding | Quote |
|---|---|
| No deaths; vomiting most common, more frequent in treated groups but not dose-related | Vomiting was observed across all groups, but was seen with greater frequency in cats in the groups administered COMFORTIS; it did not increase with increasing doses. |
| Decreased food consumption in 5X females | Food consumption was decreased in the 5X female cats. |
| Minor ALT, AST and cholesterol elevations without clinical signs | Minor elevations were seen in the alanine aminotransferase (ALT), aspartate aminotransferase (AST), and cholesterol values in the clinical chemistry but were not associated with any clinical signs. |
| Phospholipidosis-consistent hepatocellular hypertrophy/vacuolation and lung/adrenal vacuolation at 3X and 5X (one 1X cat with vacuolated lung macrophages); higher liver weights | Hepatocellular hypertrophy and vacuolation of the liver, and vacuolation of the lung and adrenal gland were noted in cats in the 3X and 5X groups. |
| Conclusion: well tolerated at 1X-5X of the upper half of the dose band for six monthly intervals | The oral administration of COMFORTIS at 1X, 3X, and 5X the upper half of the therapeutic dose band once monthly for six dosing intervals in cats was well tolerated in this study. |
Effectiveness
US field study T9CUS100002 (8 sites): parallel-arm study in client-owned cats (14 weeks+, 2 lb+) with natural flea infestations, households randomized 2:1 to COMFORTIS 50-100 mg/kg oral monthly x3 (after feeding) vs REVOLUTION selamectin >=6 mg/kg topical monthly x3; primary cat per household as experimental unit; masked flea counts on Days -1, 30 and 90; FAD scoring; non-inferiority criterion >=90% reduction; n = 102 primary cats (68 COMFORTIS, 34 selamectin) for effectiveness; 211 cats for safety; primary endpoint: Percent reduction in geometric mean flea count relative to Study Day -1 (>=90% required); result: COMFORTIS 97.6% reduction at Day 30 and 99.3% at Day 90 (geometric mean 34.9 to 0.2); selamectin 88.8% and 97.7%; FAD improvement 94.2% (weighted) vs 80.0%; corroborated by EU field study T9CDE100004 (263 cats, >90% reductions)
Of the 212 cats enrolled, 211 (139 COMFORTIS and 72 selamectin) received at least one treatment, and were evaluated for safety. Of the 120 primary cats (households) enrolled, 102 primary cats (68 COMFORTIS and 34 selamectin) were evaluated for effectiveness.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Vomiting (cats, Month 1) | 14.4% | 1.4% | Vomiting 14.4 1.4 14.8 1.4 13.6 4.5 |
| Vomiting on day of or day after at least one dose (cats, 3 doses) | 28.1% (39/139) | 2.8% (2/72) | Over the 3-month (3-dose) study, vomiting occurred on the day of or the day after at least one dose in 28.1% (39/139) of the cats treated with COMFORTIS and in 2.8% (2/72) of the cats treated with selamectin. |
| Lethargy (cats, Month 1) | 3.6% | 0.0% | Lethargy 3.6 0.0 0.7 0.0 1.5 1.5 |
| Anorexia (cats, Month 1) | 2.2% | 0.0% | Anorexia 2.2 0.0 0.7 0.0 2.3 1.5 |
| Weight loss (cats, Month 1) | 1.4% | 0.0% | Weight Loss 1.4 0.0 0.0 0.0 3.0 0.0 |
| Diarrhea (cats, Month 1) | 1.4% | 1.4% | Diarrhea 1.4 1.4 0.7 2.9 2.3 1.5 |
Extraction notes: Supplement held under a dog application but all new studies are in cats; dog effectiveness and target animal safety were not required (referenced to the Sept 25, 2007 original). PK, TAS, effectiveness and adverse reactions recorded here are cat data; n_dogs holds cat counts. Adverse reaction table (Table 11) column order: Month 1 COMFORTIS n=139, Month 1 selamectin n=72, Month 2 COMFORTIS n=135, Month 2 selamectin n=69, Month 3 COMFORTIS n=132, Month 3 selamectin n=67; treated/control here are Month 1. Five adult COMFORTIS cats lost >10% body weight (none on selamectin); two cats given extra-label topical otic ivermectin became lethargic. Cat dose determination (T9CUS090006, 8 cats/group, 35-50 mg/kg) supported 50 mg/kg (97.3% at day 30). Cat lab studies: dose confirmation 50-75 mg/kg >=90% through day 37; speed of kill 92.7% at 2 h and 100% at 24 h; simulated home environment 100% at every count.
Comfortis™ NADA 141-277, Original approval, September 25, 2007; sponsor Elanco US Inc.; species: Dogs; foi_id 837; FDA PDF
Indication
Kills fleas; prevention and treatment of flea infestations (Ctenocephalides felis) on dogs for one month.
Dose regimen
13.5 mg/lb (30 mg/kg) minimum, oral (chewable tablet), once a month, Five tablet strengths (140-1620 mg) by weight band giving 30-60 mg/kg; administer with food (fasted dosing reduced the duration of effectiveness)
COMFORTIS chewable tablets are given orally, once a month at the recommended minimum dosage of 13.5 mg/lb (30 mg/kg) body weight as specified in the following table (Table 1):
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 2502 (851) ng/mL spinosyn A | Study T9C370103: 30 mg/kg spinosad technical powder in gelatin capsules, single oral dose, 8 adult dogs per group; mean (SD); group 3 (fed dry food) n=4; fed wet food immediately (group 2). Row order: spinosyn A groups 2, 3, 4 then spinosyn D groups 2, 3, 4 | Cmax, ng/mL 2502 (851) 2743 (393) 947 (925) 467 (154) 527 (84) 150 (154) |
| cmax | 947 (925) ng/mL spinosyn A | Study T9C370103: 30 mg/kg spinosad technical powder in gelatin capsules, single oral dose, 8 adult dogs per group; mean (SD); group 3 (fed dry food) n=4; fasted, no food until 4 h post-dose (group 4) | Cmax, ng/mL 2502 (851) 2743 (393) 947 (925) 467 (154) 527 (84) 150 (154) |
| cmax | 467 (154) ng/mL spinosyn D | Study T9C370103: 30 mg/kg spinosad technical powder in gelatin capsules, single oral dose, 8 adult dogs per group; mean (SD); group 3 (fed dry food) n=4; fed wet food immediately (group 2) | Cmax, ng/mL 2502 (851) 2743 (393) 947 (925) 467 (154) 527 (84) 150 (154) |
| tmax | 0.08 day (median; range 0.08-0.33) | Study T9C370103: 30 mg/kg spinosad technical powder in gelatin capsules, single oral dose, 8 adult dogs per group; mean (SD); group 3 (fed dry food) n=4; spinosyn A, fed wet food (group 2) | Tmax, day 0.08a [0.08, 0.33] |
| auc | 4992 (899) day*ng/mL spinosyn A (AUC0-inf) | Study T9C370103: 30 mg/kg spinosad technical powder in gelatin capsules, single oral dose, 8 adult dogs per group; mean (SD); group 3 (fed dry food) n=4; fed wet food (group 2). Row order: spinosyn A groups 2, 3, 4 then spinosyn D groups 2, 3, 4 | AUC0-∞, day*ng/mL 4992 (899) 4986 (1845) 2364 (2241) 889 (111) 873 (267) 662 (323) |
| auc | 2364 (2241) day*ng/mL spinosyn A (AUC0-inf) | Study T9C370103: 30 mg/kg spinosad technical powder in gelatin capsules, single oral dose, 8 adult dogs per group; mean (SD); group 3 (fed dry food) n=4; fasted (group 4) | AUC0-∞, day*ng/mL 4992 (899) 4986 (1845) 2364 (2241) 889 (111) 873 (267) 662 (323) |
| half-life | 10.6 (2.7) days spinosyn A | Study T9C370103: 30 mg/kg spinosad technical powder in gelatin capsules, single oral dose, 8 adult dogs per group; mean (SD); group 3 (fed dry food) n=4; fed wet food (group 2). Row order: spinosyn A groups 2, 3, 4 then spinosyn D groups 2, 3, 4 (spinosyn D fed 11.0 (2.7) days) | Half-Life, days 10.6 (2.7) 6.8 (3.0) 10.6 (2.6) 11.0 (2.7) 6.9 (2.6) 10.6 (3.4) |
| other | milk:reference plasma ratio 2.2-3.5 | Pilot colostrum/milk study T9C750101, 3 pregnant Beagles dosed 90 mg/kg spinosad capsules at gestation day 28 and 1 day before parturition | The spinosad milk: reference plasma ratio ranged from 2.2-3.5. |
Target-animal safety
dose multiples 0X, 1.5X, 4.4X, 7.4X; duration Every 28 days for six consecutive treatment intervals over 168 days, starting at 6 weeks of age (spinosad tablets at 1.5X given on the first 1, 3 or 5 days of each interval to reach 1.5X, 4.4X, 7.4X of the 60 mg/kg maximum dose); animals 4 groups of 12 puppies (6 per sex).
Dogs were allocated to 4 treatment groups of 12 puppies per group (6 per sex).
| Finding | Quote |
|---|---|
| Two early euthanasias (control and 1.5X females; diabetes mellitus and malabsorption) unrelated to treatment; all other dogs survived | A female in the control group and a female in the 1.5X group were euthanized early due to poor condition. |
| Vomiting most common, mainly within one hour of dosing, decreasing with age/repeat dosing | Vomiting was the most common observation. The incidence of vomiting one hour following spinosad treatment decreased over time, with substantial reduction after the second day of treatment. |
| Reduced growth rate (lower mean body weights) in spinosad groups from the third dosing interval | From the third dosing interval onward, at least two of the three spinosad groups had significantly lower mean body weights than the control group (Table 16). |
| ALT rising trend at 7.4X (within normal range) | ALT for the 7.4X spinosad group was statistically significantly increased from control at puppy day (PD) 140 (20 wks of age), PD168 (24 wks of age), and at PD196 (28 wks of age). |
| Lymphoid tissue vacuolation (phospholipidosis) at 4.4X and 7.4X, not at 1.5X | Vacuolation of lymphoid tissue was a treatment effect, affecting some dogs in the 4.4X group and all dogs in the 7.4X group. |
| Conclusion: clinically well tolerated up to 7.4X | The administration of spinosad at doses up to 7.4X was clinically well tolerated in the puppies |
Effectiveness
Field study T9C180104: multi-center (16 sites, US and Canada), parallel-arm, randomized, treatment-masked study of COMFORTIS ~30-60 mg/kg oral monthly x3 vs REVOLUTION (selamectin) active control in client-owned dogs with natural flea infestations; household as experimental unit; flea counts at 2, 4, 8 and 12 weeks; FAD signs and palatability assessed; n = 91 spinosad and 38 selamectin dogs (effectiveness); 330 and 140 (safety); primary endpoint: Percent reduction in geometric mean flea count on the primary dog vs pre-treatment (visit 1); result: Spinosad: 98.8% reduction at 2 weeks (15 +/- 5 days) and 99.8% after three months (98.0% and 99.6% at visits 3 and 4); selamectin 92.4% and 99.1% (not statistically compared); FAD signs improved in 86-100% of spinosad dogs; 77% free-choice acceptance
Animals: 330 spinosad-treated dogs and 140 selamectin-treated dogs completed the study and were evaluated for safety. The effectiveness analysis was performed on 91 spinosad-treated dogs and 38 selamectin-treated dogs.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Vomiting (Month 1) | 12.7% | 12.2% | Vomiting 12.7 12.2 7.8 3.2 5.8 4.8 |
| Decreased appetite (Month 1) | 9.1% | 5.0% | Decreased Appetite 9.1 5.0 2.8 1.6 1.9 0.8 |
| Lethargy (Month 1) | 7.6% | 5.0% | Lethargy 7.6 5.0 3.5 4.0 1.2 0.8 |
| Diarrhea (Month 1) | 6.7% | 5.0% | Diarrhea 6.7 5.0 4.3 0.8 1.2 0.0 |
| Cough (Month 1) | 3.9% | 5.0% | Cough 3.9 5.0 0.4 2.4 0.0 0.0 |
| Polydipsia (Month 1) | 2.4% | 1.4% | Polydipsia 2.4 1.4 0.7 0.0 0.4 0.0 |
Extraction notes: Adverse reaction rows are from field study Table 10 (percent of dogs; column order: Month 1 COMFORTIS N=330, Month 1 selamectin N=139, Month 2 COMFORTIS N=282, Month 2 selamectin N=124, Month 3 COMFORTIS N=260, Month 3 selamectin N=125); treated/control here are Month 1 values. Two dogs with pre-existing seizure conditions dosed above the 30-60 mg/kg label range had seizures within a week of dosing; 1.5% of spinosad dogs lost >15% body weight (0% selamectin) and spinosad puppies gained less weight. PK table (Table 5) columns: spinosyn A groups 2 (fed wet), 3 (fed dry, n=4), 4 (fasted) then spinosyn D groups 2, 3, 4; fasted dosing roughly halved exposure and shortened flea effectiveness (61.4% at day 37). Margin-of-safety study T9C420226 enrolled 48 Beagle puppies ('Forty-eight' written in words; n_animals quoted from the allocation sentence). Other TAS: 10 consecutive daily doses of 810 mg (up to 16.7X) in 12 Beagles caused vomiting, ALT elevation (up to 2.5X), weight loss, glycogen depletion and lymphoid phospholipidosis; one-generation reproduction study (33 dams, 1.3X/4.4X) had one 4.4X abortion, two early pregnancy losses and more puppy morbidity; milk pilot study (3 dams, 90 mg/kg) showed spinosyns partition into milk with high puppy mortality in the largest litter. Effectiveness lab studies: dose determination selected 30 mg/kg; two dose-confirmation studies 96.4-100% through day 30; speed of kill 53.7% at 30 min and 100% by 4 h; simulated home environment 96.0-100% over 125 days.
Reproduce: foi_structured_search(query="Spinosad") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).