I. GENERAL INFORMATION:
| NADA |
140-533 |
| Sponsor:
|
Rousell-Uclaf
163, Avenue Gambetta
Paris, France
Name and Address of Agent
for Roussel-Uclaf:
Hoechst-Roussel Agri-Vet
Co.
Route 202-206 North
Somerville, NJ 08876 |
| Generic
Name: |
Bacitracin
methylene disalicylate
Roxarsone
Halofuginone hydrobromide |
| Trade Name: |
Bacitracin
MD
3-Nitro
Stenorol |
II. INDICATIONS FOR USE
For the prevention of coccidiosis caused by E. tenella, E. acervulina,
E. maxima, E. brunetti, E. necatrix and E. mivati ; For increased
rate of weight gain and for improved feed efficiency in broiler chickens.
III.
DOSAGE
| A. |
DOSAGE FORM |
Bacitracin MD,
roxarsone and halofuginone are marketed as separate feed additive premixes.
The Bacitracin MD premix is sold in three concentrations: 25, 40 and 50
grams Bacitracin MD activity per pound. Roxarsone premix is sold in three
concentrations: 10, 20 and 50% medicated premix. Halofuginone premix is
sold in one concentration: 2.72 grams of halofuginone hydrobromide activity
per pound. |
| B. |
ROUTE OF ADMINISTRATION |
oral via the
feed |
| C. |
RECOMMENDED DOSAGES: |
|
| |
Bacitracin MD
10-50 g/ton |
Bacitracin MD
is mixed into finished broiler feed at concentrations ranging from 10
to 50 g/ton for increased rate of weight gain and improved feed efficiency.
|
| |
Roxarsone 22.7 to 45.4
g/ton
|
Roxarsone is
added to finished broiler feed at a concentration of 22.7 to 45.4 g/ton
for improved feed efficiency. |
| |
Halofuginone hydrobromide
2.72 g/ton
|
Halofuginone
is added to finished broiler feed at a concentration of 2.72 g/ton for
the prevention of coccidiosis caused by E. tenella, E. acervulina,
E. maxima, E. brunetti, E. necatrix and E. mivati . The resultant
feed containing all three drugs is then fed continuously as the sole ration.
Feeds containing roxarsone and halofuginone must be withdrawn from broilers
5 days before slaughter. |
IV. EFFECTIVENESS
A. Floor Pen Studies - Body
Weight & Feed Efficiency:
The New Animal Drug Application
on which approval of bacitracin MD and roxarsone in combination with halofuginone
hydrobromide is based contains adequate and well controlled studies demonstrating
the effectiveness of bacitracin MD, roxarsone and halofuginone when fed to broilers.
Six experiments using a randomized complete block design were conducted utilizing
6,544 broilers which were fed from one day of age to market weight. These experiments
were summarized and evaluated for significant differences in average live bird
weight and feed efficiency.
In these six studies, pens were
randomly assigned to treatments within blocks; 20 to 100 birds of equal sex
were selected at random and assigned to each pen; three to seven replicates
were used per treatment group.
The summary was done using only
the combination of treatments necessary under the revised guidelines for broiler
combination efficacy studies (Guideline for Drug Combinations for use in Animals,
Center for Veterinary Medicine, October 1983). Thus, only the following treatments
from each of the six studies were pooled and subjected to statistical analysis:
Halofuginone hydrobromide 2.72
g/ton
Bacitracin MD 50 g/ton + halofuginone 2.72 g/ton
Roxarsone 45.4 g/ton + halofuginone 2.72 g/ton
Halofuginone 2.72 g/ton + bacitracin MD 50 g/ton + roxarsone 45.4 g/ton
Studies were designed to simulate
varying conditions such as geographical location, differences in climate, changes
in weather, differences in management practices, and degree of disease contamination
of the premises. The chicks were grown on old litter and diets were balanced
to provide adequate levels of all nutrients.
The effect of bacitracin MD and
roxarsone on average live bird weight and feed efficiency is presented in Table
I.
An analysis of the combined data
shows an overall significant (P<.05) increase in average live bird weight
and improvement in feed efficiency due to feeding bacitracin MD in the presence
of roxarsone and halofuginone. Further analysis of the combined data shows that
roxarsone significantly (P<.05) improved feed efficiency when combined with
bacitracin MD and halofuginone. Therefore, based on the revised Drug Combination
Guidelines, these data are adequate for the claims shown in Item 2, Indications
For Use. Bacitracin MD, roxarsone and halofuginone have all been approved singly
in three separate NADA's for addition to complete broiler feed at the above
use levels.
The above data satisfy the requirements
for evaluation of an application under the CVM Policy outlined in the guidelines
for combination drugs revised October 1983. The policy provides for the granting
of a range approval for production drugs in combination when the maximum level
tested for the claim(s) is demonstrated to make a significant benefit to the
combination. The range approval according to the revised policy is from 50 g/ton
to a minimum level approved for bacitracin MD in the parent application. A minimum
use level of 10 g/ton was used in establishing the feed stability data for this
combination. Accordingly, 10 g/ton of bacitracin MD is the minimum approvable
level. Therefore, use levels approvable for this application are 10 - 50 g/ton
of bacitracin MD.
The above floor pen studies for
body weight and feed efficiency claims were conducted by:
Dr. Park Waldroup
Dept. of Animal Science
University of Arkansas
Fayetteville, Arkansas 72701
Mr. Randall A. Primo
Ponderosa Research Co.
French Village, Missouri 63036
Dr. John A. Herbert
Dept. of Poultry Sci.
Louisiana State Univ.
Baton Rouge, LA 70803
Dr. Frank J. Siccardi
Avian Consultant
2850 Inwood Lane
Fayetteville, Arkansas 72701
Dr. B.L. Damron
Dept. of Poultry Sci.
University of Florida
Gainesville, FL 32601
(Eds. note: The following table
consists of 7 columns.)
Table 1
Body Weight (pounds)
-------------------Treatments*-------------------
Bacitracin MD
(50 g/t)
Study Pens Per Birds Roxarsone Bacitracin Roxarsone
Location Treatment Per Pen Control 45.4 g/t 50 g/t (45.5 g/t)
Arkansas 7 60 3.90 3.93 3.93 4.05
Missouri 3 72 3.97 3.98 4.05 4.08
Louisiana 4 100 3.68 3.59 3.74 3.68
Missouri 6 50 4.02 4.08 4.19 4.31
Arkansas 4 50 3.46 3.49 3.67 3.73
Florida 5 20 4.36 4.35 4.50 4.51
Average: 3.90 3.90 4.01 4.06
Feed Efficiency
-------------------Treatments*-------------------
Bacitracin MD
(50 g/t)
Study Pens Per Birds Roxarsone Bacitracin Roxarsone
Location Treatment Per Pen Control 45.4 g/t 50 g/t (45.5 g/t)
Arkansas 7 60 2.18 2.18 2.15 2.11
Missouri 3 72 2.27 2.17 2.20 2.10
Louisiana 4 100 2.16 2.02 2.02 2.01
Missouri 6 50 2.32 2.31 2.24 2.17
Arkansas 4 50 2.11 2.07 2.06 2.04
Florida 5 20 2.10 2.08 2.04 2.07
Average: 2.19 2.14 2.12 2.07
* All treatments contained halofuginone at 2.72 g/ton (3.0 ppm).
B. Noninterference Battery Studies
Fourteen and 21 day old broiler chickens were used in three adequate, well controlled
battery studies to test for the noninterference of bacitracin MD and roxarsone
on the anticoccidial efficacy of halofuginone. Recent isolates of coccidia were
used. Combinations of E. acervulina, E. maxima, E. necatrix, E. mivati, E.
tenella and E. brunetti were used. This arrangement facilitated identification
of lesions. Tables 2, 3, and 4 show the treatments used in these battery studies
along with the results for body weight, feed efficiency, dropping scores, lesion
scores, and mortality. The broilers were randomized and assigned to cages with
ten broilers per cage. There were four or five replicates of each treatment group.
These battery studies adequately
demonstrate that there is no interference of bacitracin MD and roxarsone on
the anticoccidial efficacy of halofuginone. Therefore, this combination is compatible.
The investigators involved in the
above battery studies were:
Dr. Cornell A. Johnson
AEF Research Inc.
5492 Kennedy Drive, Rt. 3
Waunakee, WI 53597
Dr. Carey Quarles
Colorado Quality Research
1401 Duff Drive, Suite 700
Ft. Collins, CO 80524
V. ANIMAL SAFETY
The original NADA's contain complete
information on the animal safety of all three products (NADA's 046-592 - bacitracin
MD, 130-951 - halofuginone, and 7-891 MF19 - roxarsone). The above effectiveness
(Section 4) studies adequately demonstrated that there were no toxicological
or pharmacological effects when the three drugs were combined in the same feed.
No reactions were expected or found when the three drugs were combined indicating
that they are equally safe when fed separately or when combined.
This application is in accord with
Animal Safety Guidelines. Further safety studies were not required because:
a. The drugs have been approved
singly; and
b. Sufficient documentation has
been provided to determine that these compounds are compatible in combination
when used in poultry.
Based on the data in the parent
NADA's, the compatibility battery studies, the drug residue elimination study,
and the floor pen efficacy studies, we conclude that the combination of these
three drugs is safe to be fed to broiler chickens as indicated by the label.
(Eds. note: The following table
consists of 6 columns.)
Table II
Average Weight Gain, Feed Efficiency, Total Dropping Score, Coccidiosis
Mortality and Total Lesion Scores for the Noninterference Battery
Study Number 1.(1)
Feed
Treatment(2) Av. Gain (g) Eff. Tot. Drop Sc.(3) Tot. Les. Sc. Tot. Cocc. Mort.
NM 767 2.16 0.0 0.6 0
NMI 498 2.48 7.75 10.5 11
Halo 711 2.27 1.75 4.0 0
Halo + Bac + Rox 703 2.13 2.0 3.6 0
(1) Broilers were infected with isolates of Eimeria acervulina, E. brunetti, E. maxima,
E. mivati, E. necatrix and E. tenella.
(2) NM=nonmedicated, uninfected
NMI=nonmedicated, infected
Halo=halofuginone at 2.72 g/ton
Bac=bacitracin MD at 50 g/ton
Rox=roxarsone at 45.4 g/ton
(3) Scoring based on a system of 0 to 4, 0=normal, 4=very wet
(Eds. note: The following table
consists of 6 columns.)
Table III
Average Weight Gain, Feed Efficiency, Average Dropping Score, Coccidiosis
Mortality and Average Total Lesion Scores for the Noninterference Battery
Study Number Two.(1)
Feed
Treatment(2) Av. Gain (g) Eff. Avg. Drop Sc.(3) Avg. Les. Sc. Tot. Cocc. Mort.
NM 581 2.05 1.00 0.0 0
NMI 399 3.42 2.75 5.88 12
Halo 569 2.08 1.38 1.38 0
Bac + Rox 467 2.41 2.50 5.50 1
Halo + Bac 571 2.14 1.25 0.75 0
Halo + Bac + Rox 563 2.08 1.06 1.00 0
(1) Broilers were infected with isolates of Eimeria acervulina, E. brunetti, E. maxima,
E. mivati, E. necatrix and E. tenella.
(2) NM=nonmedicated, uninfected
NMI=nonmedicated, infected
Halo=halofuginone at 2.72 g/ton
Bac=bacitracin MD at 50 g/ton
Rox=roxarsone at 45.4 g/ton
(3) 1=normal, 2=moderately wet, 3=very wet
(Eds. note: The following table
consists of 6 columns.)
Table IV
Average Weight Gain, Feed Efficiency, Average Dropping Score, Coccidiosis
Mortality and Average Lesion Scores for the Noninterference Battery
Study Number Three. (1)
Feed
Treatment(2) Av. Gain (g) Eff. Avg. Drop Sc.(3) Avg. Les. Sc. Tot. Cocc. Mort.
NM 696 1.84 1.00 0.0 0
NMI 648 1.96 2.19 3.50 3
Halo. 671 1.88 1.93 0.63 0
Bac + Rox 704 1.89 1.81 2.63 0
Halo + Bac 697 1.84 1.68 0.63 1
Halo + Bac + Rox 682 1.81 1.81 0.63 0
(1) Broilers were infected with isolates of Eimeria acervulina, E. brunetti, E. maxima,
E. mivati, E. necatrix and E. tenella.
(2) NM=nonmedicated, uninfected
NMI=nonmedicated, infected
Halo=halofuginone at 2.72 g/ton
Bac=bacitracin MD at 50 g/ton
Rox=roxarsone at 45.4 g/ton
(3) 1=normal, 2=moderately wet, 3=very wet
The following summary of a safety
growth study demonstrates normal growth with no incidence of disease or other
abnormalities when the three drugs were fed at the highest approved use levels.
A SAFETY GROWTH STUDY
Investigator:
Dr. Randall A. Primo
Ponderosa Research Co.
French Village, MS 63036
The following table shows that
the broilers grew well and feed efficiency was not adversely affected by any
of the treatments.
(Eds. note: The following table
consists of 5 columns.)
Table V
SAFETY STUDY SUMMARY - SEVEN WEEK DATA
Broiler Final Body Final Feed
Treatment Drug Level Number Wt. (lb) Efficiency
Control ---- 146 4.02 2.32
Halofuginone 2.72 g/t
Bacitracin MD 50 g/t
Roxarsone 45.4 g/t 144 4.31 2.17
The data provide evidence for the
combination of halofuginone, bacitracin MD and roxarsone in the feed of broiler
chickens and these data are consistent with and fulfill all the requirements for
a fixed combination drug for animals as follows:
a. Each drug component makes a contribution
to the claimed effects.
b. The dosages of each drug component
are such that the combination is safe and effective.
c. This combination demonstrates
significant control of a specific disease condition for a large patient animal
population. Specifically,Eimeria tenella is a major widespread organism
of coccidiosis and the most pathogenic Eimeria species and, as such,
possesses the potential of causing extensive economic losses to broiler producers.
d. The label claims are not antagonistic.
VI. HUMAN FOOD SAFETY:
The original NADA's for each drug
(046-592, 130-951 and 7-891) demonstrate that these products do not cause a
hazard to human health when used according to label directions.
Tolerances of arsenic (from roxarsone)
in the edible tissue of chickens are established at 0.5 ppm in muscle and 2
ppm in edible by products (21 CFR 556.60) with liver as the target tissue. Halofuginone
hydrobromide has an established tolerance in broilers of 0.1 ppm for parent
halofuginone (marker residue) in liver (the target tissue). A marker residue
concentration of 0.1 ppm in liver corresponds to a concentration for total residues
of halofuginone of 0.3 ppm in the liver. The safe concentration for total residues
of halofuginone in the uncooked edible tissues of broilers are 0.1 ppm in muscle,
0.3 ppm in liver and 0.2 ppm in skin with adhering fat (Federal Register, Vol.
50, No. 162, page 33718, August 21, 1985). Tolerances for residues of bacitracin
methylene disalicylate are established at 0.5 ppm, negligible residue, un uncooked
edible tissues of chickens (21CFR556.70) with muscle as the target tissue.
The residue data supporting the
approved individual uses of halofuginone, bacitracin MD and roxarsone and their
respective withdrawal times of four, zero and five days have been submitted
in their respective original applications. The summary of the study presented
in Table 6 establishes that each drug in the presence of the other does not
exceed its established safe concentration or tolerances and they do not interfere
in each other's tissue residue assay. Table 6 summarizes the data obtained from
a study in which broilers were fed the combination of halofuginone (2.72 g/ton),
bacitracin MD (100 g/ton) and roxarsone (45.4 g/ton) for 29 days prior to the
withdrawal period. Edible tissues, including liver and muscle were assayed for
drug residues. The edible tissues were collected on the withdrawal dates indicated
in Table VI.
Investigator for tissue residue
study:
Dr. Randall A. Primo
Ponderosa Research Co.
French Village, Missouri 63036
Along with the residue depletion
results in Table VI, a noninterference study for the bacitracin MD tissue assay
was conducted by spiking samples with bacitracin, halofuginone and roxarsone
and conducting assay for bacitracin residues. The results demonstrated no interference
by halofuginone and roxarsone on the assay for bacitracin.
(Eds. note: The following table
consists of 6 columns.)
Table VI
Residue Depletion Study Assay Results (ppm)
------------Withdrawal Day (1)------------
Drug Tissue 0 1 4 5
Bacitracin MD Muscle <0.09 - - -
Halofuginone Liver 0.84(±.22) 0.60(±.15) 0.03(±.02) 0.018(±.01)
Roxarsone Liver 0.87(±.09) 1.46(±.25) 0.32(±.16) 0.13(±.11)
(1) Average of six birds, except for halofuginone at withdrawal day
four the average is from three (3) birds; standard deviation in parenthesis.
A noninterference study for halofuginone
was conducted by spiking control tissue samples with halofuginone, bacitracin
and roxarsone and then assaying these tissues for halofuginone content. The
results demonstrated no interference by bacitracin and roxarsone on the tissue
assay for halofuginone. A noninterference study for roxarsone is not required
because the assay method for roxarsone is done by ashing the tissue prior
to determination of roxarsone residues.
A 5-day withdrawal period was established
for this combination based on a 99% statistical tolerance limit with 95% confidence.
These data support a 5-day withdrawal for the halofuginone/roxarsone/bacitracin
MD combination.
VII.
AGENCY CONCLUSIONS:
The data submitted in support of
this NADA comply with the requirements of Section 512 of the Act and demonstrate
that halofuginone (2.72 g/ton) plus bacitracin MD (10 to 50 g/ton) plus roxarsone
22.7 to 45.4 g/ton) are safe and effective to be fed to broiler chickens at
the dosage level indicated.
Under the Center's supplemental
policy (42 FR 64367) this original application is regarded as a Category II
supplemental NADA which did not require a revaluation of safety and efficacy
data in the parent NADAs. The drugs are to be fed in Type C medicated feeds
in agreement with the labeling as approved in the parent NADAs.
Residue depletion studies summarized
in this application demonstrate that halofuginone depletes to safe concentration
within five days withdrawal to no more than 0.1 ppm in muscle, 0.3 ppm in liver
and 0.2 ppm in skin/fat, (CFR 556.70); bacitracin MD is below the tolerance
of 0.5 ppm at zero withdrawal, (CFR 556.70); and arsenic from roxarsone has
a tolerance of 0.5 ppm in muscle, 2.0 ppm in liver and kidney with a 5-day withdrawal,
(CFR 556.60). Adequate information was submitted to demonstrate noninterference
between the assays for each drug. The approval of this application will not
significantly increase exposure of humans to residues of the drugs.
The data from six well controlled
trials demonstrate the effectiveness of bacitracin MD and roxarsone for increased
rate of weight gain and improved feed efficiency in the presence of halofuginone
when mixed in broiler chicken feeds. The data from noninterference battery studies
demonstrated the effectiveness of halofuginone in preventing coccidiosis in
the presence of bacitracin MD and roxarsone. The CVM policy outlined in the
combination drug efficacy guidelines revised October, 1983 permits the granting
of range approval for bacitracin and roxarsone as shown in Section 2 of this
document. A five (5) day withdrawal period is required before the broiler chickens
are to be slaughtered for human food.
VIII. LABELING (Attached)
1. BLUE BIRD BROILER FEED MEDICATED
package label
Copies of these labels may be obtained
by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855
