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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 139-473 Stafac, Stenorol - original approval

Approval Date: April 22, 1986

I. GENERAL INFORMATION:

NADA 139-473
Sponsor: American Hoechst Corporation
Generic Name: virginiamycin; halofuginone hydrobromide
Trade Name: Stafac, Stenorol ;
Marketing Status: Over the Counter (OTC)

II. INDICATIONS FOR USE

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

III. DOSAGE FORM

Virginiamycin and halofuginone are marketed as separate feed additive premixes. The virginiamycin premix is sold in four concentrations: 10, 20, 50 and 227 grams virginiamycin activity per pound. Halofuginone premix is sold in one concentration: 2.72 g halofuginone activity per pound.

Dosage:

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

Virginiamycin is mixed into finished feeds at concentrations of 5-15 g/ton for increased rate of weight gain plus 3 ppm halofuginone for the prevention of coccidiosis caused by E.tenella, E. necatrix, E. acervulina, E. maxima, E.mivati, and E. brunetti in broiler chickens.
Virginiamycin is mixed into finished feeds at concentration of 5 g/ton for improved feed efficiency and increased rate of weight gain plus halofuginone 3 ppm for the prevention of coccidiosis caused by E. tenella, E.necatrix, E. acervulina, E. maxima, E. mivati, and E. brunetti in broiler chickens.

IV. EFFECTIVENESS

A. Floor Pen Studies - Body Weight & Feed Efficiency:

The New Animal Drug Application on which approval of virginiamycin in combination with halofuginone is based contains adequate and well controlled studies demonstrating the effectiveness of virginiamycin and halofuginone when fed to broilers. Four experiments using a randomized complete block design were conducted utilizing 8,408 broilers which were fed from one (1) day of age to market weight. Pens were randomly assigned to treatments within blocks; 20 to 66 birds of equal sex were selected at random and assigned to each pen; 9 to .18 replicates were used per treatment group. The drug premixes were fed. at the following levels:

Halofuginone - 3 ppm Virginiamycin- 15 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 virginiamycin on average live bird weight is presented in Table I.

An analysis of the combined data shows an overall significant (P<.05) response in average live bird weight due to feeding virginiamycin at 15 g/t. These data adequately demonstrate the contribution of 15 g/ton of virginiamycin for increased rate of weight gain in the presence of halofuginone.

Further analysis of the combined data showed a significant (P<.05) response in feed efficiency due to feeding virginiamycin. Statistical models were tested and these data adequately demonstrate the contribution of 15 grams/ton of virginiamycin for improved feed efficiency in the presence of halofuginone (Table II).

These studies were conducted under the revisd guidelines for broiler combination efficacy studies (Guideline for Drug Combinations for Use in Animals, Center for Veterinary Medicine, October,l983). Therefore, virginiamycin was not titrated but fed at the highest approvwsed use level for virginiamycin alone in broiler chickens, i.e., 15 g/t. Based on the significant (P< .05) reponse in both body weight and feed efficiency for virginiamycin supplementation and the new guidelines, the approved combination use levels must be the same as the use levels approved for virginiamycin alone in broiler chickens. Thus, in combination with halofuginone hydrobromide at 3 ppm the use levels of virginamycin are:

5-15 g/t, for increased rate of weight gain; and 5 g/t for increased rate of weight gain and improved feed efficiency.

The above studies for body weight and feed efficiency claims were conducted by:

Dr. Carey L. Quarles
2629 Redwing Rd.
Creekside Two, Suite 315
Ft. Collins, CO. 80526
Dr. B.L. Damton
University of Florida
Poultry Science Dept.
Gainesville, FL 32611
Dr. Ben C. Dilworth
Poultry Science Dept.
Mississippi State University
Mississippi State, MS. 39762
Mr. Richard Roth
Research Farm Manager
Cedar Knoll Research Farm
Frenchtown, NJ 08825

(Eds. note: Each of the following tables consists of 5 columns)

TABLE I. Body Weight (grams)

                                         Treatments in the                    
                                      Presence of Halofuginone
                                       _____________________              
                    Pens Per   Birds     Control     Virg.
Study Location     Treatment  Per Pen    0 g/ton   15 g/ton
 
Colorado              10        50        2115       2154
Florida               18        20        2151       2208
Mississippi            9        50        2085       2103
New Jersey            12        66        2164       2301
                               Average    2129       2192

TABLE II. Feed Efficiency

                                         Treatments in the                    
                                      Presence of Halofuginone
                                       _____________________              
                  Pens Per   Birds       Control     Virg.
Study Locati     Treatment  Per Pen      0 g/ton   15 g/ton
 
Colorado             10       50          1.98       1.96
Florida              18       20          2.06       2.03
Mississippi           9       50          2.02       1.97
New Jersey           12       66          2.04       1.96
                               Average    2.03       1.98

B. Noninterference Battery Study

Fourteen day old broiler chickens were used in an adequate, we11-controlled battery study to test for the noninterference of virginiamycin on the anticoccidial efficacy of halofuginone. Recent field strain isolates of E. acervulina, E. maxima, E. tenella, E. brunetti, E. necatrix, and E. mitis were used. This arrangement faclitated identification of lesions. Tables III-V show the treatment used in these battery studies along with the results for body weight, mortality, lesion scores, and dropping scores. The broilers were randomized by weight and assigned to cages with 10 broilers per cage. There were four (4) replicates of each treatment group.

This battery study adequately demonstrates that there is noninterference of virginiamycin on the anticoccidial efficacy of halofuginone. Therefore, this combination is compatible.

The investigator involved in the above battery study was:

Dr. Larry McDougald
Dept. of Poultry Science
University of Georgia
Athens, GA. 30602

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

TABLE III. Weiqht Gain: Average weight gains in grams for the various weigh periods (labeled in days postinoculation) is given in following tables:

Infection 1 - E. acervulina/E. maxima/E. tenella.
Treatment*       Day 0-6    Day -2-6   Day O-14   Day -2-14  Day 6-14.
1. Unmed/uninf     228        282         402        456        174
2. Unmed/inf        13         69          25         78         12
3. Virg + Rox       52        110         148        206         96
4. Hal             214        255         386        426        172
5. Hal+Virg+Rox    233        289         422        477        189
Infection 2 - E. mitis/E. necatrix/E. brunetti.
Treatment*       Day 0-6    Day -2-6   Day O-14   Day -2-14  Day 6-14.
1. Unmed/uninf     231        286         401        455        170
2. Unmed/inf        32         85          66        118         33
3. Virg + Rox       66        100          95        129         29
4. Hal             203        252         372        421        169
5. Hal+Virg+Rox    237        298         418        479        181

* Drug levels in the feed:
Virginiamycin - 20 g/t
Roxarsone - 0.005%
Halofuginone - 3 ppm

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

TABLE IV. Intestinal lesion scores and droppings scores. Summaries of lesion scores and droppings scores are found in the following tables.

Infection 1

                             Intestinal lesion scores                Droppings
Treatment          upper     mid       lower     ceca      total     Scores (tot.)
1. Unmed/uninf     0.13      0.13      --        0.06      0.31        0.50
2. Unmed/inf       4.00      4.00      --        4.00     12.00       12.75
3. Virg+Rox        3.94      3.63      --        3.63     11.19       13.25
4. Hal             0.94      1.19      --        0.19      2.31        1.50
5. Hal+Virg+Rox    0.81      0.88      --        0.13      1.81        0.50

Infection 2

                             Intestinal lesion scores                Droppings
Treatment          upper     mid       lower     ceca      total     Scores (tot.)
1. Unmed/uninf     --        1.31      0.81      --        2.13        0.25
2. Unmed/inf       --        3.82      3.82      --        7.65       14.50
3. Virg+Rox        --        3.71      3.65      --        7.35       11.25
4. Hal             --        1.31      1.00      --        2.31        0.50
5. Hal+Virg+Rox    --        0.88      0.69      --        1.56        0.50

TABLE 5 Mortality: The deaths from coccidiosis were high in both infection groups. The average mortality/pen and mortality are summarized in the following table:

                        % Mortality from Coccidiosis
Treatment               Infection 1      Infection 2
1. Unmed/uninf               0               0
2. Unmed/inf                92.5            62.5
3. Virg+Rox                 47.5            62.5
4. Hal                       0               0
5. Hal+Virg+Rox              0               0

The original NADA's contain complete information on the animal safety of the two products (NADA's 091-467 and 091-513 - virginiamycin, 130-951 - halofuginone). The above effectiveness (Section 4) studies adequately demonstrated that there were no toxicological or pharmacological effects when the two drugs were combined in the same feed. No reactions were expected or found when the two 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:

The drugs have been approved singly; and 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 study, the drug residue elimination study, and the floor pen efficacy studies, we conclude that the combination of these two drugs is safe to be fed to broiler chickens as indicated by the label. The following summary of a growth study demonstrates normal incidence of disease or other abnormalities when the two drugs growth with no were fed at the approved use levels or higher.

A SAFETY GROWTH STUDY

Investigator:

Drs. P. Fiminger & H. Fisher
Dept. of Nutrition
Cook College/Rutgers University
New Brunswick, NJ 08903

The following table shows that the broilers grew well, had low mortality, and feed efficiency was not adversely affected by any of the treatments. After this data was collected, the broilers were sacrificed and tissues were collected. The results of the tissue assays ,for drug residues are presented in Section 5 (Human Safety).

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

TABLE VI SAFETY STUDY SUMMARY - SEVEN WEEK DATA

                         Broiler  Final Body   Final Feed    Mortality
Treatment    Drug Level  Number   Wt. (lb)     Efficiency    (Percent)
Control        ---         75       3.47         3.17          2.6
Halofuginone   3 ppm
Virginiamycin  20 g/T      75       3.83         3.02          4.0
Roxarsone      0.005%

The data provide evidence for the combination of halofuginone and virginiamycin in the feed broiler chickens and these data are consistent with and fulfill all the requirements for a fixed combination drug for animals as follows:

Each drug component makes a contribution to the claimed effects. The dosages of each drug component are such that the combination is safe and effective. This combination demonstrates significant control of a specific disease conditions 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. The label claims are not antagonistic.

V. HUMAN SAFETY:

The original NADA's for each drug (091-467 and 091-513, virginiamycin: 130-951, halofuginone) demonstrate that these products do not cause a hazard to human health when used according to label directions.

For halofuginone, the liver has been designated the target tissue and a tolerance level for safe concentrations of halofuginone (parent drug marker residue) in liver have been established at 0.1 ppm. The safe concentration for total drug residues (including metabolites) is 0.3 ppm in the liver (CFR 556.308). Tolerances are established for negligible residues of virginiamycin in edible tissues of broilers as follows: 0.5 ppm in kidney, 0.3 ppm in liver, 0.2 ppm in skin and fat, and 0.1 ppm in muscle (21 CFR 556.750). The residue data supporting the approved uses of halofuginone alone and virginiamycin alone: and their withdrawal period of 4 days and zero day, respectively, were submitted in the parent NADAs.

The sponsor submitted the results of 2 residue depletion studies in support of this application. In one of the studies, conducted at Cook College/Rutgers University, New Brunswick, NJ, broilers were fed medicated feeds containing halofuginone (3 ppm), virginiamycin (20 g/ton), and roxarsone (0.005%) from day 1 of age to 49 days of age. Samples of liver were collected for assay for halofuginone from birds sacrificed at O, 2, 3 and 4 days of withdrawal. Halofuginone was determined in liver using the sponsor's HPLC method. The results of the assays are summarized in Table VII. Statistical analysis (99% tolerance limit with 95% confidence) of the data for days 2, 3, and 4 of withdrawal provided a 6-day withdrawal period: zero withdrawal values were not included in the statistical analysis because these data did not fall on the linear, first-order portion of the depletion curve.

In a second study,-conducted by Hazleton Laboratories, Inc., Madison, Wisconsin, eight birds (4 males and 4 females) 3 days of age were fed a diet containing halofuginone (3 ppm) and roxarsone (0.005%) for a total period of 51 days. After 26 days of feeding with roxarsone and halofuginone, 14C-virginiamycin (20 g/ton) was added to the diet for the remainder of the treatment period. The birds were sacrificed at 6 hours of withdrawal and samples of muscle, liver, skin, abdominal fat, and kidney were collected from each bird. Tissue samples were assayed for radioactivity by combustion and scintillation counting. The results of this study are shown in Table VII. The data show that residues of virginiamycin are well below their respective tolerances at zero withdrawal. The above residue depletion data support the assignment of a 6-day withdrawal period for the combination of halofuginone and virginiamycin. A noninterference study for halofuginone was conducted by spiking control tissue samples with 0.1 ppm of halofuginone plus 0.2 ppm virginiamycin and then assaying for halofuginone content. The results demonstrated no interference of virginiamycin on the tissue assay for halofuginone. A demonstration of the non-interference of halofuginone on the determination of virginiamycin was not necessary because virginiamycin was approved without a regulatory assay.

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

TABLE VII RESIDUE DEPLETION STUDY ASSAY RESULTS (PPM)

           
                                                     Tissue(1)
   Drug              Withdrawal Day    Kidney     Liver     Skin/Fat     Muscle
   
14C-Virginiamycin(2)      0            --(3)   0.06(0.01)    <0.16       <0.049
Halfuginone(4)            0            --      1.07(0.35)     --          --
                          2            --      0.15(0.15)     --          --
                          3            --      0.09(0.05)     --          --
                          4            --      0.04(0.03)     --          --

(1) Average of 6 to 8 birds. Standard Deviation in parentheses.
(2) Limit of detection O.O49 ppm for liver and muscle, and (0.16 ppm for skin/fat. Results are from broilers which were fed 14C-Virginiamycin equivalent 20 g/t roxarsone at 0.005% and halofuginone at 3 ppm in the feed.
(3) Not assayed.
(4) Analytical method validated to 0.05 ppm.

VI. AGENCY CONCLUSIONS:

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and demonstrate that halofuginone (3 ppm) plus virginiamycin (5-15 g/ton) are safe and effective for the claims indicated in Section 3 of this FOI Summary. The summary has demonstrated through residue depletion studies that residues of halofuginone deplete below a tolerance of 0.1 ppm in liver (target tissue) of parent halofuginone. A concentration of 0.1 ppm marker residue in liver corresponds to 0.3 ppm total residues of halofuginone in liver, and 0.2 ppm in skin/fat. Withdraw 6 days before slaughter to assure a safe concentration in edible tissues. A regulatory analytical method of assay for halofuginone is in FDA's Food Additive Manual that is on public display. A regulatory method of assay is not required for virginiamycin in chicken tissues. Under the Center's supplemental policy (42 FR 64367) this original NADA is regarded as a Catagory II application which did not require reevaluation of safety and efficacy data in the parent NADAs. The drugs are to be fed in medicated feeds under the same indications and dosages as approved in the parent NADA's.

Non-interference studies demonstrate that halofuginone plus virginiamycin prevented an outbreak of coccidiosis when exposed to the six major species of Eimeria that cause the disease. The data from four well-controlled floor-pen studies demonstrated the effectiveness of virginiamycin to increase rate of weight gain and improve feed efficiency in the presence of halofuginone. The CVM policy outlined in the combination drug efficacy guidelines revised October 1983 permits the granting of a range approval for virginiamycin of 5 to 15 g/ton for increased rate of weight gain and 5 g/ton for increased rate of weight gain and improved feed efficiency in combination with 3 ppm halofuginone for the prevention of coccidiosis caused by the six major species of Eimeria.

VIII. LABELING

(Attached)

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.