A. Type A Medicated Article
(premix) blended into complete feed (Type C Feed)
This NADA relies on adequate
well controlled studies showing the anthelmintic efficacy of fenbendazole
in cattle included in the approved NADA 128-620 (Fenbendazole Suspension
10%, 48 FR 42809, September 20, 1983). One study was conducted in cattle
to demonstrate that the premix (Type A Medicated Article) has comparable
efficacy to the 10% suspension formulation when used at the same dose
of 5 mg fenbendazole/kg body weight. Four parasites indicated on the label
were tested. The suspension, premix and pellets are equally efficacious
with respect to those parasites, as indicated by the two confirmatory
studies which provide data to support and confirm the claim of efficacy.
Comparable efficacy was demonstrated
in these pivotal studies:
Study #123-A, Comparison
Study Fenbendazole Suspension 10% versus Premix, Top Dress Pellets made
from Premix and Untreated Controls.
M. Blagburn, Auburn University,
Auburn, Alabama
Forty-four cattle naturally
infected with gastrointestinal nematodes were identified and assigned
to four groups of eleven cattle each. One group remained unmedicated,
one group was given a single dose of fenbendazole suspension at a dose
level of 5 mg/kg and one group each premix or top dress pellets made from
premix at the same dose. Sufficient numbers of parasites were recovered
from the control animals at postmortem to evaluate and compare the effect
of the three formulations on the following species based on biological
and medical expertise:
(Eds. note: The following
table consists of 4 columns.)
--------------% Reduction-------------------
Premix Pellets Suspension
H. contortus 100 100 100
O. ostertagi 100 99.8 99.8
C. punctata 99.9 99.9 99.9
O. radiatum 100 100 100
Study #4-N, Evaluation of
Market Formulations (Premix, and Top Dress Pellets made from Premix) of
Fenbendazole Against Cattle Helminths.
A. Todd, University of Wisconsin,
Madison, WI
Thirty cattle experimentally
infected with gastrointestinal nematodes and lungworms were assigned to
three groups of ten cattle each. One group remained unmedicated, one group
was given as a group treatment a single dose of fenbendazole premix at
a dose level of 5 mg/kg body weight and one group fenbendazole top dress
pellets at the same dose. Sufficient numbers of parasites were recovered
from the control animals at postmortem to evaluate the effect of the two
formulations on the following species based on biological and medical
expertise:
-------% Reduction-------
Premix Pellets
H. contortus 70.9 100
O. ostertagi 99.3 100
C. oncophora 99.3 100
D. viviparus 99.0 100
N. helvetianus 92.5 70.9
Study #4-T, Evaluation of
Market Formulations (Premix and Top Dress Pellets made from Premix) of Fenbendazole
Against Cattle Helminths.
A. Todd,University of Wisconsin,
Madison, WI
This study was designed to
further evaluate the efficacy of fenbendazole premix and pellets on Haemonchus
contortus and Nematodirus helvetianus which were not as much
affected as usual in the previous study (#4-N).
Thirty cattle were experimentally
infected with a mixed inoculum of infective cattle trichostrongylid larvae.
The inoculum contained approximately 47% Haemonchus larvae. Each
animal received also 1,000 Nematodiruslarvae. The cattle were assigned
to 3 groups of 10 animals each. One group remained unmedicated, one group
was given as a group treatment, a single dose of fenbendazole premix at
a dose level of 5 mg/kg body weight and one group fenbendazole pellets
at the same dose. Sufficient numbers of parasites were recovered from
the control animals at postmortem to evaluate the effect of the two formulations
on the following species based on biological and medical expertise:
-------% Reduction-------
Premix Pellets
H. contortus 100 100
O. ostertagi 99.9 99.1
C. oncophora 99.9 99.2
N. helvetianus 100 100
All studies proved that fenbendazole
premix and pellets made from premix have an efficacy comparable to that
of the 10% suspension. The results were analyzed statistically using a nonparametric
procedure. The analysis confirmed the comparable efficacy.
Well documented clinical studies
were conducted in the United States according to a uniform protocol which
was only slightly modified to accomodate local management conditions.
Groups of cattle with a worm infection, as determined by egg counts in
their feces, were selected. Approximately the same number of animals were
treated with 5 mg fenbendazole/kg body weight or left untreated as controls.
Worm eggs in fecal samples were counted before and after treatment, the
animals were visually observed for side effects.
Three investigators studied
fenbendazole premix 20% and top dress pellets (0.5%) made from premix
in 3 different states. They treated cattle of various breeds (242 with
premix, 243 with pellets) and compared their observations to those in
242 untreated control animals, investigators, location and numbers of
animals in the trials are tabulated on the following page.
(Eds. note: The following
table consists of 7 columns.)
F.O.I. Summary Clinical Trials
-------------Total Number of Animals--------------
+* +*
Investigator/ Before/After Before/After
Study # Location Treated Treatment Controls Treatment
1684-47-82 Bechtol Premix 100 80/6 100 80/58
Canyon, TX Pellets 101 81/1
1684-14-81 O'Kelley Premix 42 41/0 42 40/37
Terre Haute, IN Pellets 42 41/1
1684-37-81 Horton Premix 100 79/10 100 81/95
Wellington, CO Pellets 100 90/1
*) + = cattle with nematode eggs in their feces.
The clinical studies confirm
the results of the critical studies by eliminating or reducing local egg
counts in virtually all treated cattle.
The recommended treatment
was found to be both safe and practical under field conditions.
B. Vitamin/Mineral mix
(Type C Feed)
For this vitamin/mineral
supplement approval, the critical efficacy study was conducted in the
feed block medium to show the consumption and efficacy of a 3-10 day feeding
of the total dose of 5 mg/kg body weight for fenbendazole.
1. Dose Confirmation.
This cold-press free-choice
protein feedblock was approved as a supplemental filing to NADA 139-189
by letter dated May 9, 1989. The cold-pressed Medicated Feed block study
was conducted by B. Blagburn, Auburn University, Auburn, Alabama (Submitted
in NADA 139-189; Fenbendazole medicated feedblocks).
Thirty calves with natural
infections were divided into three groups of ten each. Group 1 served
as an unmedicated control, group 2 had access to the medicated blocks
for three days, and group 3 had access to the medicated blocks for ten
days. Both medicated groups consumed approximately 5 mg/kg, with the following
results:
(Eds. note: The following
table consists of 3 columns.)
-----------Eggs Per Gram (EPG)-----------
Average (Range) Average (Range)
Group Pretreat - EPG Posttreat - EPG
1 Control 1,207 1,620
(100 to 3,900) (0 to 6,600)
2 Medicated-3 days 1,880 0
(400 to 6,200)
3 Medicated-10 days 1,240 0
(300 to 2,800)
% Reduction of Worms Reported at Necropsy
Medicated Medicated
Parasite 3 days 10 days
H. contortus 100% 100%
O. ostertagi 99 100
C. punctata 100 100
C. oncophora 100 100
Trich. axei 100 100
Oesoph. radiatum 100 100
B. phlebotomum 100 100
2. Clinical Trials:
For this vitamin/mineral
20% protein supplement, the clinical trials were conducted by adding the
fenbendazole premix (Type A Article) to vitamin/mineral Free Choice feeds
(Type C feeds) to confirm and verify dosage consumption and efficacy under
field-use conditions. These studies were conducted as follows:
Two hundred sixty-eight (268)
cattle were used in these three studies. The three treatments were control,
3-day fenbendazole treatment and 6-day fenbendazole treatment. These three
clinical trials were conducted using fenbendazole at 5 mg/kg administered
to cattle in medicated vitamin/mineral mixes. The reduction in numbers
of eggs per gram (EPG) of local material before and after treatment were
evaluated from these trials. The data from the trials were combined and
gave the following averages:
(Eds. note: The following table consists of 3 columns.)
Group EPG % Reduction
Control 126 0 3-day treat 24 81% 6-day treat 13 89% These clinical trials
were conducted by:
Dr. D. Bliss
MidAmerica Agricultural Research Inc.
3705 Sequoia Trail
Verona, WI 53593
Dr. Jorgen Hanson
Virginia Tech
Blacksburg, VA 24061
Dr. Gary Rohwer
Bar Diamond Ranch
Parma, ID 83650
Conclusion/Recommendation
The results from these three
clinical trials (eggs per gram of fecal matter) using medicated vitamin/mineral
mixes were approximately 85% reduction, and the necropsy results (worm
counts) from the medicated block confirmation trial were approximately
99% reduction. These data are acceptable and support the claim that the
medicated vitamin/mineral mixes are efficacious when consumed at the recommended
levels.
The results from the clinical
trials with medicated vitamin/mineral mixes for cattle and the trial with
the medicated feed block, all providing fenbendazole for free choice consumption
at 5 mg/kg body weight for periods of three to six days are acceptable
to support the same efficacy claims as approved for the Type A Medicated
Article (NADA 137-600) and the medicated feed block (NADA 139-189).
a. Safe Concentration of
Residues
The safe concentration for
total fenbendazole residues in the uncooked edible tissues of cattle were
established, based upon toxicology studies submitted under NADA 128-620
as 5 ppm in muscle, 10 ppm in liver, 15 ppm in kidney and 20 ppm in fat.
b. Metabolism Studies
Under NADA 128-620 metabolism
studies in cattle were conducted to select a marker substance and target
tissue for fenbendazole. Cattle liver is the target tissue with parent
fenbendazole being the marker substance. The tolerance (Rm) is 0.8 ppm
parent fenbendazole for cattle receiving a single oral dose of 10 mg fenbendazole/kg
BW, i.e. when total fenbendazole residues are 10 ppm in liver, there is
0.8 ppm parent fenbendazole as determined by the regulatory method. Acceptable
comparative metabolism studies were described under NADA 128-620.
c. Regulatory Method
Under NADA 128-620, the method
was developed for the determination of parent fenbendazole at the tolerance
of 0.8 ppm concentration and above in cattle liver.
d. Withdrawal Time
This supplemental NADA provides
for no change in the oral dose of 5 mg fenbendazole/kg BW. The supplemental
NADA provides for a change in a 3-day medicated feed program to a 3 to
6-day medicated feed program. The levels of drug and metabolites in tissues
at zero-hour withdrawal time are inversely related to the duration of
time for administration of the 5 mg/kg BW. The smaller daily dosage is
continuously metabolized, excreted, and eliminated by the target animal
species. We have assigned the longest withdrawal time for fenbendazole,
13 days after the last day of the 3 to 6-day medicated feed program.
e. Safety to Handler
Under NADA 128-620, studies
were conducted which demonstrated that the drug would have no ill effects
on persons handling it if the drug is used according to label recommendations.
The data submitted in this
supplemental NADA satisfy the requirements of section 512 of the Act and
demonstrate that 4% and 20% fenbendazole premix (Type A Medicated Article)
for cattle when used under its proposed conditions of use, is safe and
effective for its labeled conditions. The premix will be used to manufacture
vitamin/mineral supplements (Type C feed) to be fed free choice to cattle
in a 3 to 6 day feeding for removal and control of parasites.
The data submitted consisted
of a Dose Confirmation trial using the feed blocks medium which demonstrated
that a 3-day or a 10-day feeding of a total dose of 5 mg/kg body weight
of fenbendazole is effective in reduction of worms reported at necropsy
of approximately 100%.
Clinical trials were conducted
using various medicated free choice vitamin/mineral mixes in 3-day and
6-day treatment. Fenbendazole was administered in the feeds at a total
dose of 5 mg/kg body weight with a resultant reduction in EPG (eggs per
gram) of fecal material of approximately 85%. This is adequate to demonstrate
the safety and effectiveness of the treatments for cattle.
This was a Category II supplemental
application that required no reevaluation of human food safety data. The
change in duration with no increase in the dose of 5 mg fenbendazole/kg
BW decreases the concentration at zero hour withdrawal time without a
change in the qualitative composition of the residues being unlikely.
Additional residue depletion data were not required for approval of this
supplemental NADA as it poses no increased human risk from exposure to
residues of fenbendazole. This Type C free choice vitamin-mineral mix
will be labeled with a 13 day withdrawal time, the longest withdrawal
time for a fenbendazole medicated feed use. Currently, fenbendazole premix,
feedblocks, paste and suspension are marketed for use in cattle.
Fenbendazole has previously
been approved over the counter for control of the same parasites at the
same dosage level. The agency is not aware of any information suggesting
that the over the counter status of the drug should be changed. The changes
made in this supplemental application (different duration of dosing and
administration through a vitamin/mineral mix) are of the kind that can
be followed by the lay person.
