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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-533 Bacitracin MD, 3-Nitro, Stenorol - original approval

Approval Date: January 11, 1988

I. GENERAL INFORMATION

NADA 140-533
Sponsor:

Roussel-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
Marketing Status:  

 

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 Feeds containing roxarsone and halofuginone must be withdrawn from broilers 5 days before slaughter.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

Table 1 Body Weight (pounds)

      Treatments*
Study
Location
Pens Per
Treatment
Birds
Per Pen
Control Roxarsone
45.4 g/t
Bacitracin
50 g/t
Bacitracin MD
(50 g/t)
Roxarsone
(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*
Study
Location
Pens Per
Treatment
Birds
Per Pen
Control Roxarsone
45.4 g/t
Bacitracin
50 g/t
Bacitracin MD
(50 g/t)
Roxarsone
(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:

  1. The drugs have been approved singly; and
  2. 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.

Table II Average Weight Gain, Feed Efficiency, Total Dropping Score, Coccidiosis Mortality and Total Lesion Scores for the Noninterference Battery Study Number 1.(1)

Treatment(2) Av. Gain (g) Feed 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

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)

Treatment(2) Av. Gain (g) Feed 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

Table IV Average Weight Gain, Feed Efficiency, Average Dropping Score, Coccidiosis Mortality and Average Lesion Scores for the Noninterference Battery Study Number Three. (1)

Treatment(2) Av. Gain (g) Feed 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:

  1. Each drug component makes a contribution to the claimed effects.
  2. The dosages of each drug component are such that the combination is safe and effective.
  3. 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.
  4. 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.

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