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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-843 Monteban®, Flavomycin®, 3-Nitro® - original approval

Approval Date: December 23, 1997

I. GENERAL INFORMATION:

NADA140-843
Sponsor:Hoechst Roussel Vet
30 Independence Blvd.
P. O. Box 4915
Warren, New Jersey 07059
Generic Name:narasin, bambermycins, roxarsone
Trade Name:Monteban®, Flavomycin®, 3-Nitro®
Marketing Status: 

 

II. INDICATIONS FOR USE:

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

 

III. DOSAGE

A.DOSAGE FORMThis NADA provided for the combined use of these three Type A medicated articles, narasin as per 21 CFR §558.363, bambermycins as per 21 CFR §558.95, and roxarsone as per 21 CFR §558.530. Narasin is supplied as a Type A medicated article in a single concentration of 45 grams of narasin activity per pound. Bambermycins is supplied as a Type A medicated article in concentrations of 4 and 10 grams of bambermycins activity per pound. Roxarsone is supplied as a Type A medicated article in concentrations of 45.4, 90, and 227 grams of roxarsone activity per pound.
B.ROUTE OF ADMINISTRATIONOral, via the feed.
C.RECOMMENDED DOSAGES: 
 NarasinNarasin is added to broiler chicken feed at concentrations from 54 to 72 g/ton for the prevention of coccidiosis caused by Eimeria necatrix, E. tenella, E. acervulina, E. brunetti, E. mivati and E. maxima
 BambermycinsBambermycins is added to broiler chicken feed at concentrations from 1 to 2 g/ton for improved feed efficiency and increased rate of weight gain.
 RoxarsoneRoxarsone is added to broiler feed at concentrations from 22.7 to 45.4 g/ton for increased rate of weight gain, improved feed efficiency, and improved pigmentation.
 NOTESFeed continuously as the sole ration. Withdraw five (5) days before slaughter. For broiler chickens only. Do not feed to laying hens. Do not allow adult turkeys, horses, or other equines access to formulations containing narasin. Ingestion of narasin by these species has been fatal. Use as the sole source of organic arsenic. Poultry should have access to drinking water at all times. Drug overdosage or lack of water intake may result in leg weakness or paralysis.

 

IV. EFFECTIVENESS:

In accordance with the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Animal Drug Availability Act of 1996, if the active ingredients or animal drugs intended for use in combination in animal feed have previously been separately approved for the particular uses and conditions of use for which they are intended for use in combination, FDA will not refuse to approve an NADA for the combination on effectiveness grounds unless the Agency finds that the NADA fails to demonstrate that 1) there is substantial evidence to demonstrate that any active ingredient or animal drug intended only for the same use as another active ingredient or animal drug in the combination makes a contribution to the labeled effectiveness, 2) each of the active ingredients or animal drugs intended for at least one use that is different from all other active ingredients or animal drugs used in the combination provides appropriate concurrent use for the intended target population, or 3) where the combination contains more than one nontopical antibacterial active ingredient or animal drug, there is substantial evidence that each of the nontopical antibacterial active ingredients or animal drugs makes a contribution to the labeled effectiveness (21 USC §512(d)(4)(D)).

Narasin, as provided by Elanco Animal Health, has previously been separately approved for use in feed for broiler chickens for the prevention of coccidiosis caused by Eimerianecatrix, E. tenella, E. acervulina, E. brunetti, E. mivati, and E. maxima (21 CFR §558.363 (c)(1)(i)). Bambermycins, as provided by Hoechst Roussel Vet, has previously been separately approved for use in feed for broiler chickens for increased rate of weight gain and improved feed efficiency (21 CFR §558.95 (d)(1)(i)). Roxarsone, as provided by Alpharma Inc., has previously been separately approved for use in feed for growing chickens for increased rate of weight gain, improved feed efficiency and improved pigmentation (21 CFR §558.530 (d)(1)). Effectiveness for each drug, bambermycins, narasin, and roxarsone, when administered alone in accordance with its approved uses and conditions of use, is demonstrated in Hoechst Roussel Vet’s approved NADA 44-759, and in approved NADAs 118-980 and 7-891, respectively, to which Hoechst Roussel Vet has a right of reference.

Because bambermycins is intended only for the same use as roxarsone, the NADA must demonstrate, by substantial evidence, that bambermycins contributes to the labeled effectiveness of the combination. Because narasin and roxarsone each has at least one use that is different from all other animal drugs used in the combination, the NADA must also demonstrate that narasin plus roxarsone provide appropriate concurrent use for the intended target population. The use of narasin plus roxarsone provides appropriate concurrent use because these drugs are intended to treat different conditions (narasin, coccidiosis; roxarsone, pigmentation problems) likely to occur simultaneously with sufficient frequency in broiler chickens. There is no more than one nontopical antibacterial contained in this combination animal drug intended for use in Type C medicated feed. Narasin is not considered to be an antibacterial animal drug for use in broiler chickens for the purposes of 512(d)(4) of the FFDCA, because narasin is approved only for prevention of a protozoal disease in broiler chickens. Roxarsone is not considered to be an antibacterial animal drug for use in broiler chickens for the purposes of 512(d)(4) of the FFDCA, because roxarsone is not approved for use in broiler chickens for the diagnosis, cure, mitigation, treatment or prevention of bacterial disease and is not approved for any other use the Center for Veterinary Medicine deems attributable to its antibacterial properties.

Therefore, for the combination of narasin, bambermycins, and roxarsone, the requirements for effectiveness must be met by demonstrating by substantial evidence that bambermycins in the presence of narasin and roxarsone is effective for increased rate of weight gain and improved feed efficiency in broiler chickens. The data generated, from six floor-pen studies is outlined as follows:

Floor-Pen Nonchallenge Studies:

Effectiveness of bambermycins in the presence of narasin and roxarsone Six floor-pen experiments were conducted under simulated field-use conditions to investigate the growth promoting effects of bambermycins in the presence of narasin and roxarsone. The experiments were conducted at different geographic locations and under varying climatic conditions and animal production practices. The experiments used crossbred broiler chickens. The floor-pen studies were conducted by:

Dr. Larry McDougald
Georgia Poultry Research
P.O. Box 5822
Athens, GA 30604
(Study 2693-5)

Dr. Carey Quarles
Colorado Quality Research
400 E. County Rd. 72
Wellington, CO 80549
(Study 2693-6)

Dr. Carey Quarles
Michigan Quality Research
23392 Hwy. M-60
Mendon, MI 49072
(Study 2693-10)

Mr. Richard Roth
Avian Services
Route 1, Box 85
Frenchtown, NJ 08825
(Study 2693-4)

Mr. Michael Sims
Virginia Scientific Research, Inc.
Suite 327
1790-10 East Market St.
Harrisonburg, VA 22801
(Study 2693-11)

Dr. Thomas W. Sullivan
University of Nebraska-Lincoln
Animal Science Department
Mussehl Hall, East Campus
38th & Fair Streets
Lincoln, NE 68503
(Study 2693-7)

Each study evaluated two treatments, with 5 to 15 replicate pens per treatment. Treatments were:

  1. Narasin (NAR - 72 g/ton) + Roxarsone (ROX - 45.4 g/ton)
  2. Narasin (72 g/ton) + Bambermycins (BAM - 2 g/ton) + Roxarsone (45.4 g/ton)

These six experiments used a randomized complete block design, and utilized 8,820 broiler chickens which were fed from one (1) day of age to market weight. Pens were randomly assigned to treatments within blocks; 50 to 80 birds of equal sex were selected at random and assigned to each pen; 5 to 15 replicates were used per treatment group. The chicks were grown on old litter and diets were balanced to provide adequate levels of all nutrients.

Results from the pooled analysis of the data from the six floor-pen studies are presented in Table 1. The analyses of the pooled data indicate that bambermycins increased the rate of weight gain and improved feed efficiency in broiler chickens in the presence of narasin and roxarsone.

Table 1. Least squares means for average weight gain and feed efficiency in broiler chickens

Treatment groupsAverage weight gain/bird (kg)1Feed:Gain ratio1
NAR + ROX2.11a1.89a
NAR+ROX+BAM2.15b1.87b

Footnote: 1 Means with different superscripts are significantly different (P<0.05).

 

V. ANIMAL SAFETY:

In accordance with the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Animal Drug Availability Act of 1996, if the active ingredients or animal drugs intended for use in combination have previously been separately approved for the particular uses and conditions of use for which they are intended for use in combination, FDA will not refuse to approve an NADA for the combination on target animal safety grounds unless there is a substantiated scientific issue specific to an active ingredient or animal drug used in the combination or a scientific issue is raised by target animal observations contained in studies submitted to the NADA for the combination and FDA finds that the application fails to establish that such combination active ingredient or animal drug is safe for the target animal.

Narasin, as provided by Elanco Animal Health, has previously been separately approved for use in broiler chicken feed for the prevention of coccidiosis caused by Eimeria necatrix, E. tenella, E. acervulina, E. brunetti, E. mivati, and E. maxima (21 CFR §558.363 (c)(1)(i)). Bambermycins, as provided by Hoechst Roussel Vet, has previously been separately approved for use in broiler chicken feed for increased rate of weight gain and improved feed efficiency (21 CFR §558.95 (d)(1)(i)). Roxarsone, as provided by Alpharma Inc., has previously been separately approved for use in growing chicken feed for increased rate of weight gain, improved feed efficiency and improved pigmentation (21 CFR §558.530 (d)(1)). Target animal safety for each drug, bambermycins, narasin, and roxarsone, when administered alone in accordance with its approved uses and conditions of use, is demonstrated in Hoechst Roussel Vet’s approved NADA 44-759, and in approved NADAs 118-980 and 7-891, respectively, to which Hoechst Roussel Vet has a right of reference. The Agency has found no substantiated scientific issue relating to the target animal safety of narasin, bambermycins, or roxarsone when used in combination under this NADA and no scientific issue has been raised by target animal observations submitted as part of the NADA for this combination. Thus, pursuant to FFDCA, as amended by the Animal Drug Availability Act of 1996, no specific target animal safety study(ies) are required for approval of NADA 140-843. The six floor-pen studies submitted in this application additionally demonstrate that narasin, bambermycins, and roxarsone in combination is safe to be fed to broiler chickens.

 

VI. HUMAN SAFETY:

A. Toxicity Tests:

The original NADAs and FOI Summaries for each drug (NADA 44-759 - bambermycins- 38 FR 1274 - January 11, 1973; NADA 118-980-narasin - 51 FR 29097 - August 14, 1986; NADA 7-891-roxarsone - 46 FR 52331 October 27, 1981) demonstrate that food from animals fed these products is safe for human consumption.

B. Safe concentrations of residues:

Tolerances of arsenic (from roxarsone) in the edible tissues 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. Bambermycins has a no tolerance clearance (40 FR 59726; December 30, 1975). A tolerance for narasin residues in chickens is not needed. 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 and fat. (51 FR 29097; August 14, 1986).

C. Residue depletion noninterference study:

The residue data supporting the approved individual uses of narasin, bambermycins and roxarsone and their respective withdrawal times of 0, 0 and 5 days have been submitted in their respective original applications. The summary of the study conducted for this combination is presented in Table 2 and establishes that each drug in the presence of the other does not exceed its established safe concentration(s) or tolerance(s) and that none of the drugs interferes with the other’s tissue residue assay. The broilers in that study were fed the combination of narasin (91 g/t) and bambermycins (20 g/t) and roxarsone (45.4 g/t) for 49 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 2.

Investigator for the tissue residue study:

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

Table 2. Residue depletion study assay results (PPM)

DrugTissueWithdrawal (Days)Concentration-ppm
Bambermycins-Liver0ND1 (N=6)
-Muscle0ND (N=6)
-Skin/Fat0ND (N=6)
Roxarsone-Liver01.11 (SD=0.23 N=6)
-Liver10.77 (SD=0.13 N=6)

-Liver

40.38 (SD=0.07 N=6)

-Liver

50.47 (SD=0.24 N=6)
Narasin-Liver00.02 (SD=0.006 N=5)
-Muscle0<0.01 (N=6)
-Skin/Fat00.07 (SD=0.05 N=6)

Footnote: 1 ND = None Detected - bambermycins method sensitivity = 0.0125 ppm

D. Assay noninterference

Along with the residue depletion results presented in Table 2 the sponsor conducted a noninterference study for the bambermycins tissue assay by spiking samples with bambermycins, roxarsone and narasin and conducting assays for bambermycins residues. The results demonstrated no interference by narasin and roxarsone on the assay for bambermycins.

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

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.

E. Withdrawal Time

No drug residues were above the tolerance in any tissues from these broilers. These data support a 5-day withdrawal for the bambermycins/roxarsone/narasin combination.

F. Regulatory Methods:

A microbiological assay method is used to assay tissues for bambermycins residues. The method titled, "Quantitative Agar Well Plate Assay of Bambermycins (Flavomycin®) in Organs and Tissues" is on file at the Center for Veterinary Medicine, Food and Drug Administration (HFV-16), 7500 Standish Place, Rockville, MD 20855.

An HPLC assay method is used to assay tissues for narasin residues. The method is on file at the Center for Veterinary Medicine, Food and Drug Administration (HFV-16) 7500 Standish Place, Rockville, MD 20855.

A spectrophotometric method is used to assay tissues for roxarsone residues. The method is titled "Arsenic (total) Residues in Animal Tissues, Spectrophotometric Method" published in AOAC, 14th Edition 41.009, page 777.

 

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA comply with the requirements of Section 512 of the FFDCA and demonstrate that narasin (54 to 72 g/ton) plus bambermycins (1 to 2 g/ton) plus roxarsone (22.7 to 45.4 g/ton) are safe and effective for the claims indicated in Section II of this FOI summary.

Pursuant to 21 CFR §514.106 (b)(2)(vi), this combination NADA approval is regarded as a Category II supplemental change which did not require a reevaluation of safety and efficacy data in the parent NADAs. The drugs are to be fed in Type C medicated feeds, in accordance with Section II and III of the FOI Summary and the Blue Bird labeling that is attached to this document.

Residue data show that narasin is within the established safe concentrations in edible chicken tissues (0.6 ppm in muscle; 1.8 ppm in liver; 1.2 ppm in skin and fat). Residue data show that roxarsone (as residues of arsenic in edible tissues of chickens) is well below the tolerances of 0.5 ppm arsenic in muscle and 2.0 ppm arsenic in edible chicken tissues. A tolerance for bambermycins in the edible tissues of chickens is not required.

The data from six floor-pen nonchallenge studies demonstrate the effectiveness of bambermycins in the presence of narasin and roxarsone for increased rate of weight gain and improved feed efficiency. In accordance with CVM’s guideline entitled "Guideline for Drug Combinations for Use in Animals" (October 1983), Hoechst Roussel Vet is permitted the range of 1 to 2 g/ton of bambermycins in the Type C medicated feed for the labeled claims as shown in Section II of this FOI summary.

Under section 512(c)(2)(F)(ii) of the FFDCA, this approval for food producing animals qualifies for THREE years of marketing exclusivity beginning on the date of approval because the application contains substantial evidence of the effectiveness of the drugs involved, any studies of animal safety, or, in the case of food producing animals, human food safety studies (other than bioequivalence or residue studies) required for the approval of the application and conducted or sponsored by the applicant.

 

VIII. LABELING (Attached)

Attached labeling: Type C medicated Feed (Blue Bird)

Copies of applicable labels may be obtained by writing to the:

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855