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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 138-953 Stafac® 500 Type A Medicated Article, Stafac® 50 Type A Medicated Article, Stafac® 20 Type A Medicated Article, Stafac® lO Type A Medicated Article, Bio-Cox®Type A Medicated Article, 3-Nitro®-10, 3-Nitro®-20, 3-Nitro®-50 3-Nitro®-80 Type A Medicated Artic - original approval

November 1, 1988

I. GENERAL INFORMATION:

NADA 138-953
Sponsor: SmithKline Animal Health Products
1600 Paoli Pike
West Chester, PA 19380
Generic Name: Virginiamycin, Salinomycin, Roxarsone
Trade Name: Stafac® 500 Type A Medicated Article, Stafac® 50 Type A Medicated Article, Stafac® 20 Type A Medicated Article, Stafac® lO Type A Medicated Article, Bio-Cox®Type A Medicated Article, 3-Nitro®-10, 3-Nitro®-20, 3-Nitro®-50 3-Nitro®-80 Type A Medicated Artic
Marketing Status: Over the Counter (OTC)

II & III. INDICATIONS FOR USE AND DOSAGE

Feed continuously as sole ration to broiler chickens.

For improved feed efficiency, 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.

Stafac® (virginiamycin) 5g/ton
Bio-Cox® (salinomycin) 40-60g/ton
3-Nitro® (roxarsone) 45.4g/ton

This approval does not provide for a single Type A Medicated Article containing virginiamycin, salinomycin and roxarsone.

Route of Administration: Orally in finished feed.

Limitations: Do not feed to layer chickens. Not approved for use with pellet binders. May be fatal if accidentally fed to horses or adult turkeys. Withdraw 5 days before slaughter; as sole source of organic arsenic; drug overdose or lack of water may result ln leg weakness; feed continuously throughout growing period.

IV. EFFECTIVENESS

In the approved NADA (132-447) for salinomycin and roxarsone, it has been established that salinomycin and roxarsone are safe and effective 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, 48 FR 46023 October 11, 1983.

Virginiamycin is approved (NADA 91-467, 91-513) for increased rate of weight gain and improved feed efficiency, 46 FR 18966; March 27, 1981. In the present NADA, it has been established that the addition of virginiamycin to salinomycin and roxarsone improves feed efficiency. The data also demonstrate that the addition of virginiamycin to salinomycin and roxarsone does not interfere with the coccidiostatic activity of the latter compound. Therefore, the data support the effectiveness of the virginiamycin/salinomycin/roxarsone combination when used as indicated in 2,3. above.

A. Non-interference Studies
Two hundred eighty twelve-day old, Hubbard x Hubbard, broiler chickens were used in two adequate, well-controlled battery studies with approved protocols. The studies were conducted in a uniform environment with adequate air exchange to test for non-interference of virginiamycin with the effectiveness of salinomycin and roxarsone. For each study, combinations of Emeria maxima, E. acervulina , and E. teneIla , or E. mivati, E. brunetti , and E. necatrix were used. This arrangement facilitated identification of lesions.

These studies (Tables I and II) were conducted using the lowest approved level of the coccidiostat; i.e., 40 grams per ton of salinomycin and 45.4 g/ton roxarsone with the highest level of virginiamycin, viz., 20 g/ton. The protocols were designed to show "non-interference" of each component with the others for the virginiamycin/salinomycin/roxarsone combination.

Evaluations were by lesion scores (analysis was performed on preselected birds from each pen), dropping scores, weight gains, and feed conversions.

Investigators:

Shi E. Cheng, D.V.M.
Michael D. Sims
A.H. Robins Company
1211 Sherwood Avenue
Richmond, Virginia 23220

Forty birds were placed on each of seven treatments as indicated below, with ten chicks in each of four battery pens per treatment. An eighth group, consisting of two pens of ten infected, unmedicated chicks each was used to monitor progress of the applied infections in each study.

(Eds. note: The following table consists of 3 columns.)

Group         Treatment, g/ton                Infection
I               None                                    No
II              None                                   Yes
III             Saiinomycin, 40                        Yes
IV              Virginiamycin, 20                      Yes
V               Salinomycin, Virginiamycin, 40/20      Yes
VI              Virginiamycin/Roxarsone, 20/45.4       Yes
VII             Salinomycin/Virginiamycin/
                    Roxarsone, 40/20/45.4              Yes

Group I served as unmedicated, uninfected controls and Group II as the infected controls.

The treatments were administered in medicated feed starting at day 0, 14 days of age. Two days later each bird was inoculated orally with three species of coccidia as follows:

(Eds. note: The following table consists of 2 columns.)

First study:             No. oocysts per bird 
E. acervulina                       40,000
E. maxima                           30,000
E. tenella                          60,000 
 
Second study:  
 
E. mivati                           40,000
E. brunetti                         60,000
E. necatrix                         90,000

Through 14 days after challenge, the following parameters were recorded:

  1. Lesion scores
  2. Total and coccidiosis-induced mortality
  3. Dropping scores
  4. Bird weights
  5. Feed consumption

The results are presented in Tables I and II.

(Eds. note: The following table consists of 7 columns.)

Table I. Salinomycin vs E. acervulina, E. maxima, E. tenella
                                   Coccidiosis   Dropping   Weight        Feed        Lesion
Treatment             Infection     Mortality     Score     Gain,g     Conversion     Scores
I.   None                    -              0/40           0        5872.5          1.72           0.0
II.  None                    +              8/40          2.4       3484.1          2.36           6.5
III. Salinomycin, 40         +              4/40          1.3       5145.7          1.88           2.2
IV.  Virginiamycin, 20       +             13/40          2.7       3346.8          2.44           6.7
V.   Salinomycin 40/
      Virginiamycin 20       +              4/40          1.6       4920.4          1.89           2.8
VI.  Virginiamycin 20/
      Roxarsone 45.4         +              6/40          1.8       4664.1          2.02           6.3
VII. Salinomycin 40/
      Roxarsone 45.4/
      Virginiamycin 20       +              3/40          1.1       5201.5          1.80           2.6

Comparisons based on Duncan's Multiple Range Test at P < 0.05.

(Eds. note: The following table consists of 7 columns.)

Table II. Salinomycin vs E. mivati, E. necatrix and E. brunettii

                                   Coccidiosis   Dropping   Weight        Feed        Lesion
Treatment             Infection     Mortality     Score     Gain,g     Conversion     Scores
I.   None                    -              0/40           0        4991.0          1.90           0.0
II.  None                    +             10/40          3.0       2300.0          3.96           7.2
III. Salinomycin, 40         +              0/40          0.4       5485.0          1.74           1.2
IV.  Virginiamycin, 20       +             16/40          3.3       2566.0          3.47           7.1
V.   Salinomycin, 40/
      Virginiamycin, 20      +              0/40          0.2       5470.0          1.79           1.O
VI.  Virginiamycin, 20/
      Roxarsone, 45.4        +             13/40          2.9       2451.0          3.28           6.1
VII. Salinomycin, 40/ 
      Roxarsone 45.4/
      Virginiamycin 20       +              0/40          0.4       5704.0          1.72           0.9
Comparisons based on Duncan's Multiple Range Test at P < 0.05.

B. Floor-Pen Studies

Seven adequate and well-controlled floor-pen studies, utilizing approved protocols and 13,104 broiler chickens (equal numbers of males and females) of a variety of commercial strains, were conducted in seven geographic locations in the United States under conditions simulating actual use to determine the effectiveness of virginiamycin in the feed for performance enhancement in the presence of salinomycin and roxarsone.

The same general experimental design was used in all studies. Salinomycin, 60 g/ton, and roxarsone, 45.4 g/ton, was used with virginiamycin at 0 or 15 g/ton in each study. Birds (half male, half female) were selected at random and assigned to pens; pens were assigned to one of the two treatments within blocks as follows:

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

Location        Investigator      Replications      Birds/Pen
Washington       Dr. J. McGinnis             8                 24
Colorado         Dr. C. Quarles              8                 50
Virginia         Dr. S. Cheng               11                 50
Arkansas         Dr. J. Yates               12                160
Missouri         Mr. R. Primo               16                 50
New Jersey       Mr. R. Roth                 4                 66
Georgia          Dr. K. Washburn             9                 86

The studies were designed to simulate varying conditions such as geographic location, differences in climate, changes In weather, differences in management practices, and degree of disease contamination of the premises. The diets were balanced to provide adequate levels of nutrients (protein, energy, minerals, vitamins, and fatty acids). All chickens were maintained from one day of age to market weight.

Data were collected to evaluate virginiamycin for improvement in feed efficiency in the presence of the highest approved levels of salinomycin and roxarsone. Parameters of evaluation included mortality, and feed-to-body-weight ratio.

Birds medicated with the combinations were healthy throughout the respective studies. Mortality was within the normal range for each house, and there was no evidence of any drug toxicity.

The tables below give average arithmetic values for feed conversion and mortality (by percent) at each location for the critical comparison treatments used in the evaluation of these data according to the CVM's October 1983 guidelines for combination drugs (48 FR 51537).

(Eds. note: The following table consists of 3 columns.)

AVERAGE FEED CONVERSION RATIO FOR EACH LOCATION

                                      -----g/ton-----
               Virginiamycin          0          15
               Salinomycin           60          60
Location       Roxarsone             45.4        45.4
Washington                               2.123         2.104
Colorado                                 1.876         1.867
Virginia                                 1.978         1.987
Arkansas                                 1.973         1.957
Missouri                                 2.032         2.004
New Jersey                               1.978         1.935
Georgia                                  1.960         1.962

(Eds. note: The following table consists of 3 columns.)

MORTALITY (PER CENT) BY LOCATION 

                                      -----g/ton-----
               Virginiamycin          0          15
               Salinomycin           60          60
Location       Roxarsone             45.4        45.4
Washington                                1.6          2.3
Colorado                                  2.0          5.4
Virginia                                  5.2          4.6
Arkansas                                  3.4          4.2
Missouri                                  3.5          3.5
New Jersey                                3.5          3.0
Georgia                                   5.0          5.3

Statistical Analysis

Data were combined over the seven locations and analyzed by both weighted and unweighted procedures. Conclusions were the same. The table below contains the combined data.

(Eds. note: The following table consists of 3 columns.)

                              Virginiamycin g/ton          0          15
                              Salinomycin g/ton           60          60
                              Roxarsone g/ton             45.4        45.4
Feed Conversion Ratio
   
   Unweighted                                                    1.992         1.979
   Weighted                                                      1.993         1.979

Feed conversion was improved significantly by both analyses, P = 0.059. There was no effect on mortality.

These studies demonstrate that there is no interference of salinomycin or roxarsone with the effectiveness of virginiamycin. The combinations were compatible.

The above data satisfy the criteria for evaluation of the application under the CVM policy outlined in the guidelines for combination drugs. The guldelines provide for granting approval for the production drug in combination when the maximum level tested for the claim(s) is demonstrated to make a significant contribution to the combination. Data from birds receiving virginiamycin (15 g/ton) in combination with salinomycin (60 g/ton) and roxarsone (45.4 g/ton) show a significant (P= 0.059) improvement in feed efficiency when compared to salinomycin and roxarsone alone. The approval, in accordance with the guidelines, is 5 g/ton. Therefore, the approval levels for this NADA are 5 g/ton of virginiamycin plus 40 to 60 g/ton of salinomycin and 45.4 g/ton roxarsone in complete broiler rations, because 5 g/ton is the only level approved for improved feed efficiency when virginiamycin is used alone.

The investigators involved in the above studies were as follows:

J. McGinnis, Ph.D.
Department of Animal Science
Washington State University
Pullman, Washington 99164

C.L. Quarles, Ph.D.
Colorado Quality Research
Fort Collins, Colorado 80526

S.E. Cheng, D.V.M., Ph.D.
A.H. Robins Company
Richmond, Virginia 23220

J. D. Yates, Ph.D.
Campbell Institute for Research & Technology
Farmington, Arkansas 72730

R.A. Primo
Ponderosa Pork Research Company
French Village, Missouri 63036

R.P. Roth, M.S.
Avian Services, Inc.
Frenchtown, New Jersey 08825

K.N. Washburn, Ph.D.
University of Georgia
Athens, GA 30602

V. ANIMAL SAFETY

The original approved NADAs for virginiamycin (91-467, 91-513), salinomycin (128-686), and roxarsone (7-891) contain adequate data to establish the safety of each drug for broiler chickens.

The safety of the combination was demonstrated in the drug residue interference studies, in the floor-pen trials, and in the compatibility battery trials described in this document. Birds in the drug residue studies were in good health throughout the studies and did not have any gross pathology at sacrifice. The birds in the floor-pen and battery trials were healthy throughout the experimental periods. Mortality in each study was within an acceptable range for each facility, and there was no evidence of drug-related mortality.

Based on the data in the parent NADAs, in the compatibility battery trials, in the floor-pen trials, and in the drug residue interference studies, CVM concludes that the combination is safe to be fed in complete broiler rations as indicated in the labeling.

The data show that the combination of salinomycin (40-60 g/ton) plus roxarsone (45.4 g/ton) plus virginiamycin (5 g/ton) in finished rations can be safely fed to broiler chickens.

Further safety studies were not required because:

VI. HUMAN SAFETY

A. Data to Support Human Safety

The safety of each of the approved products, salinomycin (Bio-Cox®), roxarsone (3-Nitro®) and virginiamycin (Stafac®), has been established by data submitted tn each original NADA (128-686, sa11nomycin; 7-891, roxarsone; 91-467 and 91-513, virginiamycin).

Tolerances established for negligible residues of virginiamycin in the edible tissues of chickens are: 0.1 parts per million (ppm) for muscle, 0.3 ppm for liver and 0.2 ppm for skin/fat, 21 CFR 556.750. For roxarsone, the tolerances are 0.5 ppm for muscle, 2.0 ppm in edible by-products and 0.5 ppm in eggs, 21 CFR 556.60.

B. Residue Depletion/Non-Interference Studies

Residue data supporting the approved individual uses of salinomycin and virginiamycin, each having zero withdrawal times, and roxarsone with a five-day withdrawal time were submitted in their respective original applications (see Part A, above). Metabolism data on virginiamycin in chickens are included in approved NADAs 91-467 and 91-513. The following studies establish that each drug in the presence of the others does not exceed its established tolerances or safe concentrations at zero withdrawal and that each does not interfere with the tissue residue assay of the others.

Drug residue interference studies were completed using acceptable protocols at SmithKline Animal Health Products' facility in West Chester, Pennsylvania, and by A.H. Robins Company, in Richmond, Virginia. In the Pennsylvania study, 12 male and 12 female birds were assigned to three groups of eight birds each. One group received 45.4 grams of roxarsone per ton of feed plus 80 grams of salinomycin per ton for 21 days, followed by the same drugs plus 20 grams of 14C-virginiamycin per ton for an additional 24 days. A second group received the roxarsone/salinomycin combination for the entire 45-day feeding period. This procedure was sufficient to satisfy equilibration requirements for each drug. A third group received no drug and served as controls. After 45 days medicated feed was withdrawn and replaced by control feed to simulate travel time to a processing plant. Control birds were sacrificed first to avoid possible contamination, followed by the treated birds. Edible tissues were radioassayed. The following table summarizes the results of the assays:

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

VIRGINIAMYCIN RESIDUE DEPLETION - ASSAY RESULTS

                                   Tissue Assay, ppm
Withdrawa1 Day 0              Liver    Muscle   Skin/Fat
Established Tolerances, ppm        0.3        0.1        0.2 
Radioactivity, ppm                 0.15       0.01       0.09

In one A.H. Robins study, 122 birds were divided into two groups, receiving either no medication or a diet containing the combination of 80 g/ton salinomycin, 45.4 g/ton roxarsone, and 20 g/ton virginiamycin for 41 days. On day 41 the medications were withdrawn from the diet of the second group and the birds were sacrificed following drug withdrawal periods of 0 to 5 days. Tissues were collected for roxarsone assay at 0, 1, 3 and 5 days withdrawal.

The depletion of residues of arsenic vs the established tolerances is indicated below:

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

                                        TotalResidues(ppm)
Tissue      Tolerance (ppm)   -----------Day of Withdrawal-----------
                              0           1            3           5
Muscle/Skin        0.50       0.15-0.43     0.12-0.35      0.06-0.24     0.13-0.23
Liver/Kidney       2.00       0.58-2.81     0.37-l.45      0.17-0.93     0.18-0.86

In another A.H. Robbins study, birds were divided into two groups, receiving either no medication or a diet containing the combination of 75 g/ton salinomycin, 45.4 g/ton roxarsone and 15 g/ton virginiamycin for 42 days. On day 42, the medications were withdrawn from the diet and the birds were sacrificed following zero withdrawal. Tissues were collected for salinomycin analyses using an established HPLC method. The average concentration of unchanged salinomycin in skin/fat was observed to be < 50 ppb. This value is below the upper limit of 200 ppb established for unchanged salinomycin in skin/fat under NADA 128-686.

Prior to conducting this study, A.H. Robins "spiked" chicken tissues with various combinations of salinomycin and virginiamycin and roxarsone and, in this replicated experiment, demonstrated that virginiamycin and/or roxarsone do not interfere with the assay for salinomycin.

Residues for virginiamycin and salinomycin were below their respective tolerances or safe concentrations at zero withdrawal and for roxarsone at 5 days withdrawal, the established periods for each of the drugs, thereby indicating the absence of interference.

A regulatory analytical methodology for virginiamycin is not required. Practical analytical methods for the determination of tissue residues of salinomycin and roxarsone are available in the Food Additives Analytical Manual on display in FDA's Freedom of Information Room (Room 12A-30, 5600 Fishers Lane, Rockville, MD 20857). Assay noninterference data are not required for arsenic because the ashing procedure used in total arsenic determination destroys the arsenic compounds.

VII. AGENCY CONCLUSIONS:

The data submitted in support of this original NADA satisfy the requirements of Section 512 of the Act and demonstrate that salinomycin (40-60 g/ton) plus roxarsone (45.4 g/ton) plus virginiamycin (5 g/ton) are safe and effective for the claims indicated in Section 2 of this FOI Summary.

This original NADA is classified as a Category II application under CVM's supplemental policy (42 FR 64367; December 23, 1977), which did not require reevaluation of safety and efficacy data in the parent NADAs, (91-467 & 91-513, virginiamycin; and 132-447, salinomycin/roxarsone). The drugs are to be supplied to the feed mill in individual premixes (Type A Medicated Articles) for the manufacture of finished feeds (Type C Medicated Feeds) in agreement with the dosages approved in the individual parent NADAs.

Residue data show that salinomycin is well within the established safe concentration of 200 ppb. The concentration of unchanged salinomycin in skin/fat was observed to be <50 ppb at zero withdrawal. Residue data show that virginiamycin is well below the tolerances (21 CFR 556.750) of 0.3 ppm in liver, 0.2 ppm in skin/fat and 0.1 ppm in muscle tissues at zero withdrawal. The roxarsone residue data show levels of arsenic below the tolerances of 0.5 ppm in uncooked muscle and 2.0 ppm in uncooked edible by-products (21 CFR 556.60).

Non-interference studies demonstrate that salinomycin/roxarsone prevented an outbreak of coccidiosis in the presence of virginiamycin when the birds were exposed to the six major species of Eimeria. The data from seven adequate and well controlled floor pen studies demonstrate the effectiveness of virginiamycin (15 g/ton) in the presence of salinomycin (60 g/ton) plus roxarsone (45.4 g/ton). These data satisfy CVM's guidelines on combination drugs, permitting the granting of range approval for salinomycin (40-60 g/ton) plus roxarsone (45.4 g/ton) for the prevention of coccidiosis caused by Eimeria acerruling, E. brunetti, E. maxima, E. mivati, E. necatrix, and E. tenella, including some field strains of E. tenella that are more susceptible to roxarsone combined with salinomycin than to salinomycin alone, and for virginiamycin at 5 g/ton for improved feed efficiency. The approval of the claim for improved feed efficiency is limited to 5 g/ton for virginiamycin because that is the only level approved in the parent NADA (91-467) and codified in the CFR for that claim.

VIII. LABELING (Attached)

  1. Bluebird Broiler Type C Feed VSR bag label

Copies of this label may be obtained by writing to the:

Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20855

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