Lufenuron is an insect development inhibitor which breaks the flea life cycle
at the egg stage. The adult female flea is exposed to the drug when feeding on
a treated cat. The drug, which has no deleterious effect on the adult flea,
acts to inhibit the development of flea eggs. The mode of action is
interference with the synthesis, polymerization and deposition of chitin, the
major supportive component of the flea egg case and cuticle that forms the
exoskeleton of larval stages.
A. Range-Finding Study in Cats to Determine Blood Levels of Lufenuron and
Its Efficacy Against Adult Flea Emergence Using Different Dosage Forms of
PROGRAM.
Purpose: PROGRAM Tablets and PROGRAM Suspension were compared
for flea control and changes in lufenuron blood levels
Investigator: Mark S. Holbert. B.S.
Study Location:
Stillmeadow, Inc.
Sugar Land, Texas
Type of Study: Experimental infestations of the cat flea,
Ctenocephalides felis.
Animals: 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.
Dosage Forms:
Group 2: Lufenuron Tablets, crushed and mixed with
food
Group 3: Lufenuron Tablets, pilled with tablet pieces followed
immediately by food
Group 4: Lufenuron Suspension, mixed with food
Route of Administration: Oral
Dose Tested: 30 mg/kg body weight
Frequency of Treatment: Two treatments, Day 0 and Day 30
Controls: Group 1: Untreated control group
Duration of Study: Cats were experimentally infested with 100 cat fleas
on study Days -1, 24, 29, and 54. The cats in Groups 2 through 4 were treated
with lufenuron on Days 0 and 30. Flea eggs were collected from each cat on Days
5, 30, 35, and 60. The number of adult fleas emerging from these eggs were
counted 36 days after they were collected. Blood was collected at 8, 24, 48, 96
hours and 7, 21, and 29 days after treatment. The 24-, 48-, 96-hour and Day 29
blood samples were analyzed for lufenuron.
Results: Efficacy was calculated by comparing the development of eggs
collected from fleas feeding on each of the 3 lufenuron-treated groups versus
control animals. The following table shows the percent efficacy for each
treatment group for each day eggs were collected.
Percent Efficacy Compared to Control
------------------------------------------
Group Day 5 Day 30 Day 35 Day 60
----- ----- ------ ------ ------
1 N/A N/A N/A N/A
2 97.0 96.4 97.7 95.5
3 90.7 88.0 98.7 92.6
4 86.8 94.1 97.6 88.2
The 95% confidence interval method was used to determine if the two forms of
PROGRAM Tablets (crushed in food or manually dosed as pieces) were
therapeutically equivalent to PROGRAM Suspension. The 95% confidence interval
was calculated on the difference between the percent of eggs with non-emerging
adults using the following pairwise treatment group comparisons:
1) Group 2 versus Group 4,
2) Group 3 versus Group 4
3) Group 1 versus Group 2
4) Group 1 versus Group 3 and
5) Group 1 versus Group 4
Each treated group had a non-emergence rate statistically significantly
different from and better than the control group (comparisons 3, 4 and 5
above). Comparison 2 above (between groups 3 and 4) had a 95% confidence
interval on the difference of (-0.00544, 0.01764) and Comparison 1 above
(between groups 2 and 4) had a 95% confidence interval on the difference of
(0.01056, 0.03104).
The following table shows the mean lufenuron concentrations.
Mean Blood Concentration (± Standard Deviation)
----------------------------------------------------
Group Day 1 Day 2 Day 4 Day 29
-------------------------------------------------------------------
2 542 ± 372 294 ± 264 299 ± 283 165 ± 172
3 344 ± 240 210 ± 152 171 ± 136 96 ± 59
4 435 ± 267 325 ± 285 192 ± 63 135 ± 59
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). However, due to the small number of animals studied and the large degree of
intersubject variability, the test for treatment effects lacks the necessary
power to derive meaningful statistical conclusions. Based on the efficacy
parameter (egg hatch), there is no clinical difference between treatment Groups
2, 3 and 4.
Conclusions: PROGRAM Tablets, when administered to cats by either
direct oral dosing of tablet pieces or crushed in wet food are therapeutically
equivalent to PROGRAM Suspension administered in food.
This study indicates that PROGRAM Cat Tablets are therapeutically equivalent
to PROGRAM Suspension, therefore the efficacy data provided in support of
PROGRAM Suspension can be referenced from NADA 141-026. Refer to the original
Freedom of Information Summary for NADA 141-026 for additional information on
efficacy studies conducted with PROGRAM Suspension.
Adverse Reactions: None reported.
B. PROGRAM (Lufenuron) Swallow Tablets: Evaluation of Dosage Form
Acceptability in Cats Study # CAH-6258-95-0297
Purpose: To evaluate the acceptability of PROGRAM (lufenuron)
Tablets when administered orally to cats
Investigators/Study Locations:
Jodi Black, DVM
Best Friends Veterinary Service
1328 Highway
65
Elkert, CO 81418
Mark Silvers, DVM
Cat Clinic of Greensboro
2138-B Lawndale
Drive
Greensboro, NC 27408
Type of Study: Field dosage form acceptability trial
Animals: 101 client owned cats with 99 completing the study and
included in the analysis of dosage form acceptability. Of these 99 cats, 42
were female and 57 were male. These cats ranged in age from 8 weeks to 12 years
and in weight from 1.25 to 16.8 pounds.
Dosage Form: Oral tablet
Route of Administration: The cat owners were instructed to dose
the cat just prior to feeding by first placing the tablet directly in the
mouth. If dosing by this method was unsuccessful, the tablet was to be broken
into a small portion of wet food and offered to the cat.
Dose Tested: Minimum of 30 mg/kg, according to the dosing scale
Frequency of Treatment: Once
Controls: None
Duration of Study: September 26 through October 10, 1995
Results: Of the 99 cats completing the study, 93 were successfully
dosed for a 94% acceptance rate. Of the 93 cats accepting the tablet, 66
accepted the tablet when placed directly in the mouth and 27 accepted the
tablet when broken into food.
Manually Dosed 66/99 67%
Dosed in Food 27/99 27%
----------------------------
Total Dosed 93/99 94%
Some owners reported on the case report forms that the size of the pill made
dosing difficult, prevented manual administration of the pill, or simply looked
large compared to the size of the cat.
Conclusions: PROGRAM Tablets are an acceptable dosage form for
administration to cats.
Adverse Reactions: None reported.
