Lufenuron: what the FDA reviewed for dog products
5 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Lufenuron, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Cats and kittens, six weeks of age and older; Dogs (Indication: dogs and puppies six weeks of age and older; no Species/Class field); Dogs and cats (Indication: dogs and puppies six weeks of age and older; cats and kittens, six weeks of age and older; no Species/Class field); Dogs, six weeks of age and older.
Products
- Program® Flavor Tabs® (NADA/ANADA 141-035)
Program® Flavor Tabs® NADA 141-035, Supplemental approval, August 01, 1998; sponsor Elanco US Inc.; species: Dogs and cats (Indication: dogs and puppies six weeks of age and older; cats and kittens, six weeks of age and older; no Species/Class field); foi_id 1371; FDA PDF
Indication
Prevention and control of flea populations in dogs and puppies six weeks and older; control of flea populations in cats and kittens six weeks and older (flavored tablet formulation added).
Dose regimen
4.5 mg/lb (10 mg/kg) minimum (dogs), Oral, once a month, Cats: recommended minimum 13.6 mg/lb (30 mg/kg) once a month
For Use in Dogs: PROGRAM Flavor Tabs are given orally, once a month, at the recommended minimum dosage of 4.5 mg/lb (10 mg/kg).
Extraction notes: Formulation supplement only: 'This supplemental provides for adding a flavored tablet formulation with the same indications as the non-flavored tablets.' Effectiveness and safety based on existing lufenuron approvals; flavoring agent palatability referenced to NADA 141-062 and 141-084. No studies, no PK.
Program® Flavor Tabs® NADA 141-035, Supplemental approval, December 31, 1996; sponsor Elanco US Inc.; species: Dogs (Indication: dogs and puppies six weeks of age and older; no Species/Class field); foi_id 1372; FDA PDF
Indication
Prevention and control of flea populations in dogs and puppies six weeks of age and older.
Dose regimen
4.5 mg/lb (10 mg/kg) minimum, Oral, once a month
For Use in Dogs: PROGRAM Flavor Tabs are given orally, once a month, at the recommended minimum dosage of 4.5 mg/lb (10 mg/kg).
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Post-approval adverse drug experience reports added to labeling: vomiting, depression/lethargy, pruritus, urticaria, diarrhea, anorexia, skin congestion | ADVERSE REACTIONS: The following adverse reactions have been reported in dogs after giving Program tablets: vomiting, depression/lethargy, pruritus (itchy, scratchy skin), urticaria (wheals, hives), diarrhea, anorexia (loss of appetite) and skin congestion (red skin). |
Extraction notes: Category II supplement changing Rx to OTC and adding an Adverse Reactions labeling section based on adverse drug experience reports (no incidence figures). Effectiveness not affected; safety referenced to the original approval FOI Summary (November 23, 1994). The summary's dosage text says 'PROGRAM Flavor Tabs' although the product is Program Tablets.
Program® Flavor Tabs® NADA 141-035, Supplemental approval, January 23, 1997; sponsor Elanco US Inc.; species: Cats and kittens, six weeks of age and older; foi_id 568; FDA PDF
Indication
Control of flea populations in cats and kittens six weeks of age and older (new species added to NADA 141-035).
Dose regimen
13.6 mg/lb (30 mg/kg) minimum, Oral (direct dosing or broken into wet food), given with a full meal, once a month, Tablets 90.0 mg (up to 6 lb) and 204.9 mg (7-15 lb); separate cats in multi-cat households during treatment
PROGRAM Cat Tablets are given orally, once a month, at the recommended minimum dosage of 13.6 mg lufenuron per pound (30 mg/kg) of body weight.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| other | mean blood lufenuron concentration 542 ± 372 (Day 1), 294 ± 264 (Day 2), 299 ± 283 (Day 4), 165 ± 172 (Day 29); units not stated | cats; Group 2 (tablets crushed and mixed with food), 30 mg/kg oral, n=6; Groups 3 (pilled tablet pieces) and 4 (suspension in food) also tabulated | Day 1 Day 2 Day 4 Day 29 2 542 ± 372 294 ± 264 299 ± 283 165 ± 172 |
| bioavailability | crushed tablets in food (Group 2) and suspension in food (Group 4) similar and both greater than manually dosed tablet pieces (Group 3), by AUC to Day 29 | cats, 30 mg/kg oral; small n and high inter-subject variability, no statistical conclusion | The area under the curve (AUC) calculations to Day 29 show that the crushed tablets (Group 2) and the suspension mixed with food (Group 4) have similar bioavailabilities which are both greater than the manually dosed tablets (Group 3). |
Effectiveness
Range-finding study in cats (Stillmeadow, TX): experimental C. felis infestations (Days -1, 24, 29, 54); 4 untreated controls and 3 groups of 6 cats treated at 30 mg/kg on Days 0 and 30 as crushed tablet in food, pilled tablet pieces, or suspension in food; flea eggs collected Days 5, 30, 35, 60 and adult emergence counted 36 days later; n = 22 cats (not dogs): 4 untreated controls and 3 treated groups of 6; primary endpoint: Percent efficacy (reduction in adult flea emergence from eggs) vs untreated control; therapeutic equivalence of tablets to suspension by 95% CI; result: Percent efficacy vs control: crushed tablets 95.5-97.7%, pilled tablet pieces 88.0-98.7%, suspension 86.8-97.6% across Days 5-60; tablets therapeutically equivalent to PROGRAM Suspension, so suspension efficacy/safety data (NADA 141-026) referenced
Twenty-two adult domestic mixed breed cats, 11 males and 11 females, ranging in weight from 2.0 to 3.2 kg were used. The 22 animals were divided into 4 groups, 1 untreated control group of 4 animals and 3 treated groups of 6 animals.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| None reported (range-finding and field acceptability studies) | Adverse Reactions: None reported. |
Extraction notes: CAT summary filed under the dog NADA 141-035 (species-flag was 'dog'; recorded as cats). Supplement adding cats; OTC. Field dosage-form acceptability study: 99 client-owned cats, 93/99 (94%) successfully dosed (66 manually, 27 in food). TAS referenced to PROGRAM Suspension NADA 141-026; no new safety study. Blood-concentration units are not given in the summary.
Program® Flavor Tabs® NADA 141-035, Supplemental approval, June 11, 2003; sponsor Elanco US Inc.; species: Dogs and cats (Indication: dogs and puppies six weeks of age and older; cats and kittens, six weeks of age and older; no Species/Class field); foi_id 1370; FDA PDF
Indication
Prevention and control of flea populations in dogs and puppies six weeks and older; control of flea populations in cats and kittens six weeks and older (labeling changed for concurrent use with Capstar and minimum age lowered to 4 weeks).
Dose regimen
4.5 mg/lb (10 mg/kg) minimum (dogs), Oral, once a month, Cats: recommended minimum 13.6 mg/lb (30 mg/kg) once a month
For Use in Dogs: PROGRAM Flavor Tabs are given orally, once a month, at the recommended minimum dosage of 4.5 mg/lb (10 mg/kg).
Extraction notes: Labeling supplement only: 'This supplement provides for labeling changes reflecting the concurrent use with Capstar® (nitenpyram) Tablets (NADA 141-175) and reflecting a decrease in the minimum age from 6 weeks to 4 weeks.' Effectiveness and safety are based on existing lufenuron approvals (NADA 141-035, 141-026); no studies, no PK; no marketing exclusivity.
Program® Flavor Tabs® NADA 141-035, Original approval, November 23, 1994; sponsor Elanco US Inc.; species: Dogs, six weeks of age and older; foi_id 567; FDA PDF
Indication
Prevention and control of flea populations in dogs six weeks of age and older (insect development inhibitor; prevents flea egg development, does not kill adult fleas).
Dose regimen
10 mg/kg (minimum recommended dose level), Oral (swallow tablet), monthly, Tablet sizes 45.0, 90.0, 204.9, 409.8 mg by body weight band; laboratory studies dosed on a full stomach
The ingredients of PROGRAM Tablets are formulated into various sized tablets to be administered orally (swallow) as appropriate for the weight of the dog (see below) at monthly dosing intervals. The tablets supply the minimum recommended dose level of 10 mg lufenuron per kilogram of body weight.
Target-animal safety
dose multiples 1X, 3X, 5X, 2X, 6X, 10X; duration Ten months; dosed three consecutive days per month (1X/3X/5X months 1-3, doubled to 2X/6X/10X months 4-10); dogs entered at 8 weeks of age; animals 4 groups of 12 dogs (six males and six females each).
The dogs were assigned to 4 groups of 12 dogs each, six males and six females. Three groups were dosed at 1X, 3X and 5X the recommended use rate of 10 mg/kg body weight. These dosages were administered on three consecutive days per month for 3 months. For the following seven months, dosages were doubled from 1X to 2X, 3X to 6X and 5X to 10X, respectively.
| Finding | Quote |
|---|---|
| 1X(2X): all criteria comparable to control; 3X(6X) and 5X(10X): comparable except decreased average food consumption (females) | At the 1X (2X) use rate, all criteria evaluated were considered to be comparable to findings in the control group. At the 3X (6X) and 5X (10X) use rates all criteria evaluated were considered to be comparable to findings in the control group with the exception of the average food consumption. |
| No overt toxicity up to 5X (8-week-old puppies, 3 months) and up to 10X (5-month-old puppies, 7 months), three consecutive days per month | There were no overt signs of toxicity when lufenuron was administered to 8 week old puppies at doses up to 5X the intended monthly use rate for three consecutive days per month for 3 months and to 5 month old puppies at doses up to 10X the intended monthly use rate for three consecutive days per month for 7 months. |
| Pivotal Study 5 (6-week-old puppies, up to 5X, 3 days/month x 3 months): increased incidence of dehydration and emesis vs controls, but normal growth and healthy at study end | Six week old puppies treated with lufenuron at up to 5X the use rate on three consecutive days per month for three months showed an increased incidence of dehydration and emesis compared to control puppies (see table below); however, all treated puppies grew at a normal rate and were healthy at the conclusion of the study. |
Effectiveness
Multi-centered well-controlled clinical field trial (21 veterinary clinics) with two regimens: Regimen I (11 clinics) two-group double-blind placebo-controlled in households with low/no flea infestation, monthly lufenuron (min 10 mg/kg) vs placebo for at least six months with monthly in-clinic flea counts; Regimen II (10 clinics) double-blind positive-controlled in dogs with established infestations (lufenuron + adulticide vs placebo + topical adulticide/IGR); n = 411 enrolled (Regimens I and II); 306 accepted for analysis; primary endpoint: Monthly in-clinic flea counts (Savage scores, non-parametric ANOVA) vs placebo; result: Regimen I: significant differences in Savage scores from month 2 onward (p<0.05); month-6 mean flea counts 4.44 (lufenuron, n=85) vs 230.86 (placebo, n=71); lufenuron prevented build-up of flea populations after approximately 60 days of monthly dosing
A total of 411 dogs were enrolled in Regimens I and II of the clinical trials and a total of 306 of the dogs enrolled were accepted for inclusion in the analysis.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| None attributed to lufenuron (field trials; isolated vomiting not treatment-related) | During the course of the trials, no treatment related deaths or adverse reactions were attributed to lufenuron. | ||
| Dehydration (6-week-old puppies, TAS Pivotal Study 5; columns 0X 1X 3X 5X) | 50% (1X), 33% (3X), 67% (5X) | 17% (0X) | CLINICAL SIGN 0X 1X 3X 5X Dehydration 17% 50% 33% 67% Emesis 33% 83% 83% 67% |
| Emesis (6-week-old puppies, TAS Pivotal Study 5; columns 0X 1X 3X 5X) | 83% (1X), 83% (3X), 67% (5X) | 33% (0X) | CLINICAL SIGN 0X 1X 3X 5X Dehydration 17% 50% 33% 67% Emesis 33% 83% 83% 67% |
Extraction notes: 1994 original approval summary (Ciba). Dose established by titration study BPU-D-OH-022 (5, 10, 20 mg/kg; 10 mg/kg gave 98.30% control of egg development on days 28/32; 5 mg/kg 85.46%) plus two 10 mg/kg confirmation studies. Field Regimen I verbatim descriptive statistics: 'Group A/Lufenuron ... 6 85 4.44' and 'Group B/Placebo ... 6 71 230.86'; Regimen I enrolled 107 lufenuron / 106 placebo dogs, 89 / 84 analyzed. Nine TAS studies (10-month oral toxicity extracted as margin-of-safety; also 6-month study with adulticides, 10X and 20X studies, 6-week puppy 90-day study, reproduction studies up to 90X daily, single 45 mg/kg dose). No PK section; blood-level remarks in reproduction studies not extracted. Adverse-reaction percentage rows are from the 6-week puppy safety study table (n=6 per group), not from the field trial.
Reproduce: foi_structured_search(query="Lufenuron") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).