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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-845 Flavomycin, Monteban - original approval

Approval Date: February 7, 1989

I. GENERAL INFORMATION:

NADA 140-845
Sponsor: Hoechst-Roussel Agri-Vet Company
Route 202-206 North
Somerville, N.J. 08876
Generic Name: bambermycins, narasin
Trade Name: Flavomycin, Monteban
Marketing Status:  

 

II. INDICATIONS FOR USE

For the prevention of coccidiosis in broiler chickens caused by Eimeria tenella, E. necatrix, E. mivati, E. acervulina, E. maxima , and E. brunetti,for increased rate of weight gain and for improved feed efficiency in broiler chickens.

 

III. DOSAGE FORM, ROUTE OF ADMINISTRATION, RECOMMENDED DOSAGE:

Bambermycins and narasin are marketed as separate Type A medicated articles. The bambermycins Type A medicated article is sold in two concentrations: 2 and 10 grams bambermycins activity per pound. Narasin Type A medicated article is sold in five concentrations: 36, 45, 54, 72 and 90 grams of narasin activity per pound.

Dosage: The route of administration of these two drugs is oral via the feed. The recommended dosage is as follows:

  • Bambermycins: 1 to 2 g/ton
    Bambermycins is added to finished broiler feed at a concentration of 1 to 2 g/t for increased rate of weight gain and improved feed efficiency.
  • Narasin: 54 to 72 g/ton
    Narasin is added to finished broiler feed at a concentration of 54 to 72 g/t for the prevention of coccidiosis caused by Eimeria tenella, E. acervulina, E. maxima, E. brunette, E. necatrix, and E. mivati.

The resultant feed containing both drugs is then fed continuously as the sole ration.

 

IV. EFFECTIVENESS

A. Floor Pen Studies - Body Weight Gain and Feed Efficiency

The efficacy data for each individual drug are located in its parent NADA and the FOI contains a summary of the data. (NADA 44-759 - bambermycins - 38 FR 1274 - January 11, 1973; NADA 118-980 - narasin - 51 FR 29097 - August 14, 1986).

The New Animal Drug Application on which approval of bambermycins in combination with narasin is based contains adequate and well-controlled studies demonstrating the effectiveness of bambermycins and narasin when fed to broilers. Five experiments using a randomized complete block design were conducted utilizing 5,420 broilers which were fed from one (1) day of age to market weight. These experiments are summarized and evaluated below for significant differences in rate of weight gain and feed efficiency.

In these five studies, pens were randomly assigned to treatments within blocks; 50 to 80 birds of equal sex were selected at random and assigned to each pen; five to 12 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). The Guideline provides for the granting of a range approval for production drugs in the combination when the maximum level tested for the claim(s) is demonstrated to make a significant benefit to the combination. Thus, the following treatments from each of the five studies were pooled and subjected to statistical analysis:

Narasin - 72 g/ton

Narasin - 72 g/ton + bambermycins 2 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 bambermycins on rate of weight gain and feed efficiency is presented in Table 1.

An analysis of the combined data shows an overall significant (P<.05) increase in rate of weight gain and a significant (P<.05) improvement in feed efficiency due to feeding bambermycins in the presence of narasin. Therefore, under the Guideline, these data are adequate for the claims shown on Page 1, Item 2, under Indications for Use.

The floor pen studies for the weight gain and feed efficiency claims were conducted by:

Mr. Richard Roth, President
Avian Services
Route 1 Box 85
Frenchtown, N.J. 08825

Dr. Carey Quarles
Colorado Quality Research
1401 Duff Drive, Suite 700
Ft. Collins, CO 80524

Dr. Larry McDougald
Georgia Poultry Research
P.O. Box 5822
Athens, GA 30604

Dr. Thomas W. Sullivan
Univ. of Nebraska-Lincoln
Animal Science Dept.
Mussehl Hall, East Campus
38th & Fair Streets
Lincoln, NE 68503

(Eds. note: The following table consists of 5 columns.)

Table 1 Body Weight (grams)

                                   --------Treatments*--------    
                                                 Bambermycins
Study       Pens Per     Birds     Narasin     (2 g/t) Narasin
Location    Treatment    Per Pen   (72 g/t)      (72 g/ton)
Colorado         5             50         2060             2109
New Jersey       8             80         2024             2044
Georgia         12             60         2044             2097
Colorado        10             50         1930             1955
Nebraska        10             60         2394             2410 
Replicate Weighted Average:               2096             2129

(Eds. note: The following table consists of 5 columns.)

Feed Efficiency

                                   --------Treatments*--------    
                                                 Bambermycins
Study       Pens Per     Birds     Narasin     (2 g/t) Narasin
Location    Treatment    Per Pen   (72 g/t)      (72 g/ton)
Colorado         5            50         1.96              1.95
New Jersey       8            80         1.97              1.94
Georgia         12            60         2.04              1.97
Colorado        10            50         1.91              1.88
Nebraska        10            60         2.06              2.04 
Replicate Weighted Average:              1.99              1.96

B. Noninterference Battery Studies

Eight day old broiler chickens were used in seven adequate, well-controlled battery studies to test for the noninterference of bambermycins on the anticoccidial efficacy of narasin. Recent isolates of coccidia were used. One of the following isolates was used in six of the experiments with a combination of all six isolates used in the seventh experiment: Eimeria acervulina, E. tenella, E. maxima, E. mivati/mitis, E. brunetti and E. necatrix. This arrangement facilitated identification of lesions. The broilers were randomized and assigned to cages with 4 broilers per cage. There were four (4) replicates of each treatment group in each experiment. Tables II through VIII show the treatments used in this battery study along with the results for average weight gain, feed efficiency, lesion scores, and coccidiosis mortality.

These battery studies adequately demonstrate that there is no interference of bambermycins on the anticoccidial efficacy of narasin. Therefore, this combination is compatible.

The investigators involved in the above battery studies were:

Dr. D.J. Donovan and Dr. K. W. Bafundo
Elanco Products Co.
A Division of Eli Lilly Co.
Indianapolis, Indiana 46285

(Eds. note: The following table consists of 5 columns.)

Table II Experiment No. 1. The Percent Mortality, Weight Gain, Feed/Gain, and Lesion Scores of broiler chickens inoculated with E. acervulina (200,000 oocysts/bird).

Treatment(1)  % Mort(2) Wt.Gain(3)   Feed/Gain(4)  Lesion Scores
NNC                0.0         297.2           1.470            0.0
IC                 0.0         258.6           1.693            3.31
Nar.               0.0         284.1           1.504            0.00
Bam.               0.0         256.9           1.653            3.31
Nar.+ Bam.         0.0         307.8           1.397            0.25

(1) NNC=Noninfected Control
IC=Infected Control
Nar=Narasin at 54 g/t
Bam=Bambermycins at 2 g/t

(2) Due to coccidiosis

(3) Per survivor

(4) Reps without mortality

(Eds. note: The following table consists of 5 columns.)

Table III Experiment No. 2 The Percent Mortality, Weight Gain, Feed/Gain, and Lesion Scores of broiler chickens inoculated with E. tenella (50,000 oocysts/bird).

Treatment(1)  % Mort(2)    Wt. Gain(3)  Feed/Gain(4)  Lesion Scores
NNC                 0.0            291.3           1.498            0.13
IC                  0.0            262.4           1.611            3.02
Nar.                0.0            293.0           1.523            2.00
Bam.               12.5            253.2           1.611            3.42
Nar.+ Bam.          0.0            254.3           1.703            2.31

(1) NNC=Noninfected Control
IC=Infected Control
Nar=Narasin at 54 g/t
Bam=Bambermycins at 2 g/t

(2) Due to coccidiosis

(3) Per survivor

(4) Reps without mortality

(Eds. note: The following table consists of 5 columns.)

Table IV Experiment No. 3 The Percent Mortality, Weight Gain, Feed/Gain, and Lesion Scores  of broiler chickens inoculated with E. maxima (50,000 oocysts/bird).

Treatment(1)  % Mort(2)    Wt. Gain(3)  Feed/Gain(4)  Lesion Scores
NNC                0.0            300.8           1.487            0.0
IC                 0.0            204.7           1.945            3.75
Nar.               0.0            296.3           1.489            0.0
Bam.               0.0            219.6           1.817            3.8
Nar. + Bam.        0.0            299.1           1.488            0.50

(1) NNC=Noninfected Control
IC=Infected Control
Nar=Narasin at 54 g/t
Bam=Bambermycins at 2 g/t

(2) Due to coccidiosis

(3) Per survivor

(4) Reps without mortality

(Eds. note: The following table consists of 5 columns.)

Table V Experiment No. 4 The Percent Mortality, Weight Gain, Feed/Gain, and Lesion Scores  of broiler chickens inoculated with E.mivati/mitis (250,000 oocysts/bird).

Treatment(1)  % Mort(2)    Wt. Gain(3)  Feed/Gain(4)  Lesion Scores  
NNC                0.0            270.4           1.605           0.17
IC                 0.0            214.1           1.930           3.21
Nar.               0.0            270.4           1.610           0.38
Bam.               0.0            207.2           1.907           2.90
Nar. + Bam.        0.0            272.4           1.601           0.19

(1) NNC=Noninfected Control
IC=Infected Control
Nar=Narasin at 54 g/t
Bam=Bambermycins at 2 g/t

(2) Due to coccidiosis

(3) Per survivor

(4) Reps without mortality

(Eds. note: The following table consists of 5 columns.)

Table VI Experiment No. 5 The Percent Mortality, Weight Gain, Feed/Gain, and Lesion Scores of broiler chickens inoculated with E. brunetti (100,000 oocysts/bird).

Treatment(1)  % Mort(2)    Wt. Gain(3)  Feed/Gain(4)  Lesion Scores
NNC                0.0            290.9           1.643           0.0
IC                 0.0            216.9           1.961           3.81
Nar.               0.0            291.3           1.588           0.88
Bam.               0.0            228.9           1.853           3.88
Nar. + Bam.        0.0            296.1           1.559           0.13

(1) NNC=Noninfected Control
IC=Infected Control
Nar=Narasin at 54 g/t
Bam=Bambermycins at 2 g/t

(2) Due to coccidiosis

(3) Per survivor

(4) Reps without mortality

(Eds. note: The following table consists of 5 columns.)

Table VII Experiment No. 6 The Percent Mortality, Weight Gain, Feed/Gain, and Lesion Scores of broiler chickens inoculated With E. necatrix (100,000 oocysts/bird).

Treatment(1)  % Mort(2)    Wt. Gain(3)    Feed/Gain(4)     Lesion Scores
NNC                0.0            292.6            1.576                0.0
IC                 0.0            238.2            1.731                3.38
Nar.               0.0            290.4            1.589                0.13
Bam.               0.0            233.9            1.748                3.88
Nar. + Bam.        0.0            291.5            1.555                0.00

(1) NNC=Noninfected Control
IC=Infected Control
Nar=Narasin at 54 g/t
Bam=Bambermycins at 2 g/t

(2) Due to coccidiosis

(3) Per survivor

(4) Reps without mortality

(Eds. note: The following table consists of 6 columns.)

Table VIII Experiment No. 7 The Percent Mortality, Weight Gain, Feed/Gain, and Lesion Scores of broiler chickens inoculated with E. mivati/mitis(25,000  oocysts/bird), E. necatrix(10,000 oocysts/bird),E. brunetti (10,000 oocysts/bird), E. tenella(5,000 oocysts/bird), E. acervulina  (40,000 oocysts/bird), and E.maxima(5,000 oocysts/bird).

                                                          Lesion Scores
Treatment(1)  % Mort(2)    Wt. Gain(3)  Feed/Gain(4)    Intestinal  Cecal
NNC                0.0            291.6          1.635            0.00        0.00
IC                 0.0            198.8          1.971            8.25        2.00
Nar.               0.0            281.4          1.553            0.65        0.25
Bam.               0.0            212.6          1.833            8.13        2.83
Nar. + Bam.        0.0            280.2          1.610            0.81        1.19

(1) NNC=Noninfected Control
IC=Infected Control
Nar=Narasin at 54 g/t
Bam=Bambermycins at 2 g/t

(2) Due to coccidiosis

(3) Per survivor

(4) Reps without mortality

 

V. ANIMAL SAFETY:

The data in the original NADA for bambermycins (44-759 approved January 11, 1973; 38 FR 1274) and the data in the original NADA for narasin (118-980 approved August 14, 1986; 51 FR 29097) contain complete information on the safety of the two products to the target animal, (broiler chickens). No reactions were found when the two drugs were combined showing that they are equally safe when fed separately or when combined.

The safety data in the parent NADAs combined with the data from the efficacy floor pen trials and noninterference battery studies for the combination product demonstrate normal growth with no incidence of disease or other abnormalities when the two drugs were fed at the highest approved use level.

Further safety studies were not required because:

  1. The drugs have been approved singly;
  2. Sufficient documentation has been provided to determine that these compounds are compatible in combination when used in poultry feeds.

Safety Growth Study Investigator:

Dr. P. Griminger and Dr. H. Fisher
Dept. of Nutrition
Cook College/Rutgers Univ.
New Brunswick, NJ 08903

(Eds. note: The following table consists of 5 columns.)

Table IX - SAFETY STUDY SUMMARY - Seven Week Data

Treatment      Drug Level    Broiler    Final Body     Final Feed
                             Numbers    Weight lbs.    Efficiency
Control             0             185            4.11            2.24
Narasin +          91 g/t 
bambermycins +     20 g/t         367            4.09            2.27
roxarsone          45.4 g/t

The data provide corroborative evidence of the safety and efficacy of the combination of narasin and bambermycins in the feed of broiler chickens, and these data are consistent with and fulfill all the requirements for the two drugs to be combined in finished feeds for broiler chickens.

  1. Each drug component makes a contribution to the claimed effect.
  2. The dosage of each drug component is such that the combination is safe and effective.
  3. This combination demonstrates significant control of coccidiosis for a large poultry population
  4. The label claims are not antagonistic.

Based on the data in the parent NADAs, the noninterference battery studies and the floor pen efficacy studies, the combination of these two drugs is safe to be fed to broiler chickens as indicated by the label.

 

VI. HUMAN SAFETY:

A. Toxicity Tests:

The data in the original NADA for bambermycins (44-759 approved January 11, 1973; 38 FR 1274) and the data in the original NADA for narasin (118-980 approved August 14, 1986; 51 FR 29097) demonstrate that food for human from animals fed these products is safe for consumption.

B. Safe Concentrations of Residues:

The safe concentrations for total narasin residues in uncooked edible chicken tissues are: 0.6 ppm in muscle; 1.8 ppm in liver; 1.2 ppm in skin/fat, (51 FR 29097, August 14, 1986).

A tolerance for bambermycins is not required, (40 FR 59726; December 30, 1975).

C. Residue Depletion Noninterference Study:

The residue data supporting the approved individual uses of narasin and bambermycins have been submitted in their respective original applications. These data also, show that a withdrawal period is not required. A summary of the study conducted for this combination is presented in Table X and establishes that bambermycins in the presence of narasin is not detected (method sensitivity = 0.0125) and that narasin in the presence of bambermycins is well below its established safe concentration. Neither of the drugs interferes with the other's tissue residue method of assay. The broilers in that study were fed the combination of narasin (91 g/t) and bambermycins (20 g/t) for 49 days prior to the birds being sacrificed to obtain tissues for drug assay. Edible tissues, including liver and muscle were assayed for drug residues. The edible tissues were collected on the withdrawal dates indicated in Table X.

Investigator for the tissue residue study:

Dr. P. Griminger and Dr. H. Fisher
Dept. of Nutrition
Cook College/Rutgers Univ.
New Brunswick, NJ 08903

(Eds. note: The following table consists of 4 columns.)

Table X Residue Depletion Study Assay Results (ppm)

Drug        Tissue  Withdrawal(days)    Concentration(ppm)
Bambermycins    liver        0                  ND* (N=5)
                muscle       0                  ND  (N=6)
                skin/fat     0                  ND  (N=6)
 
Narasin         liver        0               0.02(SD=0.006 N=5)
                muscle       0               <0.01 (N=6)
                skin/fat     0               0.07(SD=0.05 N=6)

*ND = None Detected - bambermycins method sensitivity = 0.0125 ppm

D. Assay Noninterference

Along with the residue depletion results presented in Table X, the sponsor conducted a noninterference study for the bambermycins tissue assay by spiking control tissue samples with bambermycins and narasin and conducting assays for bambermycins residues. The results demonstrated no interference by narasin on the assay for bambermycins.

The sponsor conducted a noninterference study for narasin by spiking control tissue samples with narasin and bambermycins and then assaying these tissues for narasin residues. The results demonstrated no interference by bambermycins on the tissue assay for narasin.

No bambermycins residues were detected (method sensitivity = 0.0125 ppm) and no narasin residues were detected above the safe concentration (51 FR 29097; 8/14/86) in any tissues from birds used in this residue depletion study.

E. Regulatory Methods:

A microbiological assay method is used to assay tissues for bambermycins residues. The method titled "Quantitative Agar Well Plate Assay of Bambermycins (Flavomycins) in Organs and Tissues" is on file with the Food and Drug Administration (HFV-16) 5600 Fishers Lane, Rockville, MD 20857.

An HPLC assay method is used to assay tissues for narasin residues. The method is on file with the Food and Drug Administration (HFV-16) 5600 Fishers Lane, Rockville, MD 20857.

 

VII. AGENCY CONCLUSIONS:

The data submitted in support of this original NADA satisfy the requirements of Section 512 of the Act and demonstrate that narasin (54 to 72 g/ton) in combination with bambermycins (1 to 2 g/ton) is safe and effective for the claims indicated in Section 2 of this FOI Summary.

Under the agency's supplemental policy (42 FR 64367; December 23, 1977), this original NADA is regarded as a Category II application which did not require reevaluation of the safety and efficacy data in the parent NADAs (44-759 for bambermycins and 118-980 for narasin). The drugs are to be supplied to the feed mill in individual premixes (Type A medicated articles) for combining in finished feeds (Type C medicated feeds) in accord with the dosages approved in the individual parent NADAs.

The residue data supporting the individual uses of narasin and bambermycins have been submitted in their respective original applications. The residue level of narasin is well below its established safe concentration following a zero withdrawal period. Tissue residue of bambermycins is not detected (method sensitivity = 0.0125 ppm) at zero withdrawal of bambermycins from the feed. A tolerance for bambermycins is not required. The residue depletion noninterference studies for the combination demonstrated that neither drug in the two way combination interfered with the assay of the other drug.

 

VIII . LABELS

  1. BLUE BIRD BROILER FEED MEDICATED (TYPE "C" MEDICATED FEED) 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