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 Cat Flavor Tabs 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: Eighteen adult domestic mixed breed cats, 9 males and 9
females, ranging in weight from 2.1 to 6.6 kg were used. The 18 animals were
divided into 3 groups, 1 untreated control group of 6 animals and 2 treated
groups of 6 animals each.
Dosage Forms:
Group 2: Lufenuron Cat Flavor Tabs
Group 3: Lufenuron Suspension, mixed with food
Route of Administration: Oral
Dose Tested: 30 mg/kg body weight
Frequency of Treatment: Once, on Day 0
Controls: Group 1: Untreated control group
Duration of Study: Cats were experimentally infested with 100 cat fleas
on study Days -1, 11, and 24. The cats in groups 2 and 3 were treated with
lufenuron on day 0. Flea eggs were collected from each cat on Days 5, 17, and
30. The number of adult fleas emerging from these eggs were counted 36 days
after they were collected. Blood was collected on Days 1, 2, 4, 16, and 29 for
analysis of lufenuron levels.
Results: Efficacy was calculated by comparing the development of eggs
collected from fleas feeding on each of the 2 lufenuron-treated groups versus
control animals. The following table shows the percent efficacy for each
treatment group for each day eggs were collected.
Group Percent Efficacy Relative to
Control
--------------------------------------------
Day 5 Day 17 Day 30
----- ------ ------
2 99.4 100 99.3
3 84.7 62.2 91.1
The 90% and 95% confidence intervals were calculated on the difference between
the percentage of eggs with non-emerging adults using the following pairwise
comparisons:
Group I versus Group II (control vs flavor tablets),
Group I versus Group III (control vs suspension), and
Group II versus Group III (flavor tablets vs suspension).
The non-emergence rate for the treatment groups were:
Group I Control 0.4781
Group II Flavor Tablets 0.9978
Group III Suspension 0.8911
The 90% and 95% confidence intervals (CI) on the difference between treatment
groups were:
Comparison 90% CI 95% CI
--------------------- ------------ ------------
Group I vs Group II 0.500, 0.539 0.497, 0.543
Group I vs Group III 0.390, 0.436 0.386, 0.440
Group II vs Group III 0.094, 0.119 0.092, 0.121
The confidence bounds indicate that the flavor tablets and the suspension are
not equivalent, and that cats treated the flavor tablets have higher incidence
of flea non-emergence than cats treated with the suspension (i.e., the flavor
tablets are "super" bioequivalent). Although not equivalent, the flavor tabs
were more effective than the suspension in controlling flea emergence. Because
these products were not compared for a determination of bioequivalence under
the provisions of the Generic Animal Drug and Patent Term Restoration Act, but
for a change in formulation with a different method of oral administration of
the same product, this "super" bioequivalence is acceptable.
The following table shows the mean lufenuron concentrations.
Group Mean Lufenuron Concentration (SD) (ppb)
-----------------------------------------------
Day 1 Day 2 Day 4 Day 29
-------- -------- -------- ---------
2 710 366 373 191 289 112 188 75
3* 1320 297 967 307 634 141 392 121
*The data from one cat with levels below the limit of quantification
(50 ppb) were excluded
As shown in the table above, the higher clinical efficacy achieved by the
flavor tabs was not due to higher blood levels of lufenuron. The group dosed
with the suspension had higher mean lufenuron levels at every dosing period.
Therefore, there is no safety concern with the "super" bioequivalence
associated with the flavor tabs compared to the suspension.
Conclusions: PROGRAM Cat Flavor Tabs were more effective than PROGRAM
suspension in controlling flea emergence.
This study indicates that PROGRAM Cat Tablets are "super" equivalent to
PROGRAM Suspension, therefore the efficacy data provided in support of Novartis
Animal Health's PROGRAM Suspension (NADA 141-026) can be used to support this
approval. Refer to the Freedom of Information Summary for NADA 141-026 for
additional information on efficacy studies conducted with PROGRAM
Suspension.
Adverse Reactions: One cat in group 2 showed slight ocular
irritation on day 30 of the study.
B. Flavored PROGRAM (Lufenuron) Tablets: Evaluation Palatability in
Cats
Purpose: To evaluate the palatability of PROGRAM (lufenuron) Cat
Flavor Tablets when administered orally to cats either free choice or by
placing the tablet into the mouth and allowing the cat to chew
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 palatability trial
Animals: 100 client owned cats with 98 completing the study and
included in the analysis of palatability. Of these 98 cats, 51 were female and
47 were male.
Dosage Form: Oral tablet (flavored)
Route of Administration: The cat owners were instructed to dose
the cat just prior to feeding by offering the tablet free choice from the hand,
empty food dish or from the floor. If the cat didn't consume the tablet within
3 minutes the tablet was to be placed directly into the cat's mouth.
Dose Tested: Minimum of 30 mg/kg, according to the dosing scale
Frequency of Treatment: Once
Controls: None
Duration of Study: November 21 through December 9, 1995
Results: Of the 98 cats completing the study, 54 were successfully
dosed for a 55% palatability rate.
Dosed Free Choice 37/98 38%
Dosed in Mouth 17/98 17%
-------------------------------
Total Dosed 54/98 55%
Conclusions: PROGRAM Cat Flavor Tablets are moderately palatable to
cats, with a 55% acceptance rate.
Adverse Reactions: One cat developed lethargy and decreased appetite 1
day post treatment. On Day 3 post treatment, the cat's temperature was elevated
at 105.0°F. The cat responded to treatment with antibiotics.
C. Flavored PROGRAM (Lufenuron) Tablets: Evaluation Dosage Form
Acceptability in Cats
Purpose: To evaluate the dosage form acceptability of PROGRAM
(lufenuron) Cat Flavor Tablets when administered orally to cats either free
choice, manually, or broken and mixed with wet food.
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: 100 client owned cats with 91 completing the study and
included in the analysis of acceptability. Of these 91 cats, 51 were male and
40 were female.
Dosage Form: Oral tablet (flavored)
Route of Administration: The cat owners were instructed to dose
the cat just prior to feeding by offering the tablet free choice from the hand,
empty food dish or from the floor. If the cat didn't consume the tablet within
3 minutes the tablet was to be placed directly into the cat's mouth. If dosing
was still unsuccessful, the tablet was to be broken into a small portion of wet
food.
Dose Tested: Minimum of 30 mg/kg, according to the dosing scale
Frequency of Treatment: Once
Controls: None
Duration of Study: January 18 through February 12, 1996
Results: Of the 91 cats completing the study, 82 were successfully
dosed for a 90% acceptability rate.
Dosed Free Choice 29/91 32%
Dosed in Mouth 34/91 37%
Dosed in Food 19/91 21%
-------------------------------
Total Dosed 82/91 90%
Conclusions: PROGRAM Cat Flavor Tablets are an acceptable dosage form
for administration to cats, with a 90% acceptance rate.
Adverse Reactions: One cat vomited once 1 day post treatment and again
11 days post treatment.
