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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 135-321 Bio-Cox®; BMD®; 3-Nitro® - supplemental approval (May 5, 1997)

Approval Date: May 5, 1997

I. GENERAL INFORMATION:

NADA 135-321
Sponsor: Roche Vitamins & Fine Chemicals
Hoffmann-La Roche, Inc.
45 Eisenhower Drive
Paramus, New Jersey 07652-1429
Generic Name: salinomycin sodium, bacitracin methylene disalicylate, roxarsone
Trade Name: Bio-Cox®; BMD®; 3-Nitro®
Marketing Status: Over the Counter (OTC)
Effect of Supplement: Category II supplemental change providing for an additional use level of roxarsone.

II. INDICATIONS FOR USE:

For prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati, including some field strains of E. tenella which are more susceptible to roxarsone combined with salinomycin than to salinomycin alone, and for increased rate of weight gain in broiler chickens.

III. DOSAGE

A. DOSAGE FORM This supplemental NADA provides for the combined use of these three Type A medicated articles, salinomycin as per 21 CFR [[section]]558.550 (a) (1), bacitracin methylene disalicylate as per 21 CFR [[section]]558.76, and roxarsone as per 21 CFR [[section]]558.530 (a) (2). Salinomycin sodium is supplied as a Type A medicated article in a single concentration of 30 grams salinomycin sodium activity per pound. Bacitracin methylene disalicylate is supplied as a Type A medicated article in concentrations of 30, 50, 60, and 75 grams bacitracin activity per pound. Roxarsone Type A medicated articles are supplied in concentrations of 45.4, 90, and 227 grams of roxarsone activity per pound.
B. ROUTE OF ADMINISTRATION Oral, via the feed.
C. RECOMMENDED DOSAGES:  
  Salinomycin sodium Salinomycin is added to broiler chicken feed at concentrations from 40-60 grams/ton for the prevention of coccidiosis caused by Eimeria acervulina, E. brunetti, E. maxima, E. mivati, E. necatrix, and E. tenella..
  Bacitracin methylene disalicylate Bacitracin methylene disalicylate is added to broiler chicken feed at a concentration of 4-50 grams/ton for increased rate of weight gain.
  Roxarsone Roxarsone is added to broiler chicken feed at a concentration of 34.1 or 45.4 grams/ton for the prevention of coccidiosis caused some field strains of E. tenella that are more susceptible to roxarsone combined with salinomycin than to salinomycin alone. The use of 34.1 or 45.4 g/ton roxarsone is indicated to meet the E. tenella challenge, which varies with environmental and management conditions.

IV. EFFECTIVENESS:

A series of three independent coccidial-challenge tests using cross-bred broiler chickens were conducted to determine the effectiveness of roxarsone (ROX) in the presence of salinomycin (SAL) and bacitracin methylene disalicylate (BMD). Chickens were challenged with different field strains of Eimeria tenella isolated from different geographic areas (Arkansas, Maryland, and North Carolina). The experiments were conducted at Colorado Quality Research, Inc., 400 East Count Road 72, Wellington, CO 80524. The investigator was Donald R. McIntyre, Ph.D.

On day 0 of each test (birds were approximately 13 days of age) sex separated broiler chickens (Ross x Arbor Acre) were randomized and placed in Petersime growing/finishing battery cages. Ten broiler chickens were placed in each pen.

Each experiment consisted of four treatments:

1) Noninfected, nonmedicated

2) Infected, nonmedicated

3) Infected, salinomycin (SAL; 60 g/ton) + bacitracin methylene disalicylate (BMD 50.0 g/ton)

4) Infected, salinomycin (SAL; 60 g/ton) + bacitracin methylene disalicylate (BMD; 50.0 g/ton) + roxarsone (ROX; 34.1 g/ton)

On day 2 of the study, birds were orally inoculated with E. tenella oocysts. There were four replicated pens of each drug treatment per sex. Each drug x sex treatment combination appeared once on each level of the battery. On day 8 of the study birds were euthanized, weighed, and necropsied for intestinal lesion scoring. The lesions were scored according to the method of Johnson and Reid (Experimental Parasitology, 28:30-36, 1970).

A randomized complete block design was used. Pen location (level) within the battery was a block. The pen was the experimental unit. An analysis of variance was performed on the pen data [average weight gains, cecal lesion scores, feed conversion (adjusted with dead bird weights), average feed consumption, and mortality from coccidiosis] for each field strain of E. tenella.

Results of the three tests are presented in tables 1-3. Effectiveness was determined by comparing lesion scores (pen average) and average weight gain (pen average) between the treatment groups. In each of the three tests, the E. tenella challenge resulted in an infection that significantly depressed average weight gain and increased cecal lesion scores of birds when compared to control birds (noninfected). The results of Tests 1 and 3 demonstrate that the addition of ROX at 34.1 g/ton to BMD at 50 g/ton and SAL at 60 g/ton significantly increased average weight gain and significantly reduced lesion scores in broiler chickens in all contrast comparisons (Tables 1 and 3). The results of Test 2 demonstrate that the addition of ROX at 34.1 g/ton to BMD at 50 g/ton and SAL at 60 g/ton significantly reduced lesion scores but did not improve weight gain of broiler chickens when contrasted to broiler chickens fed feed containing BMD at 50 g/ton and SAL at 60 g/ton (Table 2).

Table 1. Evaluation of roxarsone (34.1 g/ton) in combination with salinomycin plus bacitracin methylene disalicylate in broiler feeds when challenged with a field strain of Eimeria tenella (Test 1).

Preplanned treatment contrasts   Weight gain/bird (g)(1)   Average lesion score(1)
----------------------------------------------------------------------------------
Noninfected, nonmedicated               283(a)                      0(a)           
           vs.
 Infected, nonmedicated                 207(b)                      2.9(b) 
----------------------------------------------------------------------------------                                                                
     SAL+BMD+ROX                        299(a)                      0.2(a)          
         vs.
Infected, nonmedicated                  207(b)                      2.9(b) 
----------------------------------------------------------------------------------
     SAL+BMD+ROX                        299(a)                      0.2(a)           
          vs. 
       SAL+BMD                          272(b)                      1.9(b)
----------------------------------------------------------------------------------

1 Means with different superscripts are significantly different (P<0.05).
Table 2.  Evaluation of roxarsone (34.1 g/ton) in combination with
salinomycin plus bacitracin methylene disalicylate in broiler feeds when
challenged with a field strain of Eimeria tenella (Test 2).
Preplanned treatment contrasts   Weight gain/bird (g)(1)   Average lesion score(1)
----------------------------------------------------------------------------------
Noninfected, nonmedicated               276(a)                      0(a)           
           vs.
 Infected, nonmedicated                 211(b)                      2.7(b) 
----------------------------------------------------------------------------------                                                                
     SAL+BMD+ROX                        254(a)                      0.2(a)          
         vs.
Infected, nonmedicated                  211(b)                      2.7(b) 
----------------------------------------------------------------------------------
     SAL+BMD+ROX                        254(a)                      0.2(a)           
          vs. 
       SAL+BMD                          261(b)                      1.7(b)
----------------------------------------------------------------------------------
1 Means with different superscripts are significantly different (P<0.05).
Table 3.  Evaluation of roxarsone (34.1 g/ton) in combination with
salinomycin plus bacitracin methylene disalicylate in broiler feeds when
challenged with a field strain of Eimeria tenella (Test 3).
Preplanned treatment contrasts   Weight gain/bird (g)(1)   Average lesion score(1)
----------------------------------------------------------------------------------
Noninfected, nonmedicated               283(a)                      0(a)           
           vs.
 Infected, nonmedicated                 132(b)                      3.1(b) 
----------------------------------------------------------------------------------                                                                
     SAL+BMD+ROX                        269(a)                      0.3(a)          
         vs.
Infected, nonmedicated                  132(b)                      3.1(b) 
----------------------------------------------------------------------------------
     SAL+BMD+ROX                        269(a)                      0.3(a)           
          vs. 
       SAL+BMD                          227(b)                      2.0(b)
----------------------------------------------------------------------------------
1 Means with different superscripts are significantly different (P<0.05).

Collectively, these data demonstrate that ROX (34.1 g/ton) in the presence of SAL (60 g/ton) and BMD (50 g/ton) was effective for reducing lesion scores and relieving weight gain depression. These data support the effectiveness of ROX in the presence of SAL and BMD for the prevention of coccidiosis in broiler chickens caused by some field strains of E. tenella that are more susceptible to ROX combined with SAL than SAL alone.

These data together with those previously approved in this NADA establish the effectiveness of ROX at 34.1 or 45.4 g/ton of feed in this combination for some field strains of E. tenella that are more susceptible to ROX combined with SAL than SAL alone. As growing conditions and exposure to E. tenella vary, 34.1 or 45.4 g/ton ROX are indicated for the above claim. Drug levels should be based on production conditions.

V. ANIMAL SAFETY:

The original approved NADAs for Bio-Cox® (salinomycin, NADA 128-686), 3-Nitro®, (roxarsone, NADA 7-891), and BMD® (bacitracin methylene disalicylate, NADA 46-592) contained adequate data to establish the safety of each drug for broiler chickens.

The safety of the combination of the three drugs was established in the original approval of this NADA. This combination has been used safely and effectively by the poultry industry for more than a decade. The effectiveness studies described in Section IV demonstrate that no ill effects occurred when the drugs were combined.

VI. HUMAN SAFETY:

Safety for the approved products -- salinomycin (Bio-Cox®), bacitracin methylene disalicylate (BMD®), and roxarsone (3-Nitro®) -- has been established by data submitted in their respective original NADAs, NADA 128-686 and NADA 46-592, and NADA 7-891.

The original approval of this NADA established the safety of the combination of the three products. This supplement approves the use of a lower level of one of the products in the combination so the safety data in the original approval are adequate.

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and demonstrate that salinomycin (40-60 g/ton) plus bacitracin methylene disalicylate (4 to 50 g/ton) plus roxarsone (34.1 g/ton) are safe and effective for the claims indicated in Section II of this FOI summary.

Pursuant to 21 CFR [[section]]514.106 (b)(2), this combination NADA approval is regarded as a Category II supplemental change which did not require a reevaluation of safety and effectiveness 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.

The battery challenge studies demonstrated that roxarsone in the presence of salinomycin and bacitracin methylene disalicylate prevented coccidiosis caused by E. tenella. In accordance with CVM's guideline entitled "Guideline for Drug Combinations for Use in Animals" (October 1983), Hoffmann-LaRoche is permitted the ranges of 40-60 g/ton of salinomycin and 4-50 g/ton of bacitracin methylene disalicylate in combination with 34.1 or 45.4g/ton roxarsone in the Type C medicated feed for the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati, including some field strains of E. tenella which are more susceptible to roxarsone combined with salinomycin than to salinomycin alone, and for increased rate of weight gain in broiler chickens, as shown in Section II of this FOI summary. The approval on which this supplement is based allows for 45.4 g/ton roxarsone in the combination for the aforementioned claims. This supplemental approval only provides for an additional use level of roxarsone (34.1 g/ton). The use of 34.1 or 45.4 g/ton roxarsone is indicated to meet the E. tenella challenge, which varies with environmental and management conditions.

Under section 512(c)(2)(F)(iii) of the FFDCA, this approval for food producing animals qualifies for THREE years of marketing exclusivity beginning on the date of approval because the supplemental application contains substantial evidence of the effectiveness of the drug 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. The three years of marketing exclusivity applies only to the new combination providing for a 34.1 g/ton level of roxarsone for which the supplemental application was approved.

VIII. LABELING (Attached)

Type C medicated Feed (Blue Bird)

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

Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857

Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.