Approval Date: September 13, 1988
Freedom of Information Summary
NADA 138-828
I. GENERAL INFORMATION:
NADA 138-828 Sponsor: SmithKline Animal Health Products
Div. of SmithKline Beckman Corporation
1600 Paoli Pike
West Chester, PA 19380Generic Name: Virginiamycin, Salinomycin 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 Marketing Status: Over the Counter (OTC) II. & III. INDICATIONS FOR USE AND DOSAGE
Feed continuously as sole ration to broiler chickens.
A. For increased rate of weight gain, improved feed efficiency and the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti and E. mivati .
Stafac® (virginiamycin) 5g/ton
Bio-Cox® (salinomycin) 40-60g/tonB. For increased rate of weight gain and the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti and E. mivati .
Stafac® (virginiamycin) 5-15g/ton
Bio-Cox® (salinomycin) 40-60g/ton
This approval does not provide for a single Type A Medicated Article containing both virginiamycin and salinomycin.
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.
IV. EFFECTIVENESS
In the approved NADA (128-686) for salinomycin, it has been established that salinomycin is safe and effective for the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti and E. mivati , 48 FR 30616; July 5, 1983.
Virginiamycin has approved NADAs (91-467, 91-513) for increased rate of weight gain and improved feed efficiency, 40 FR 13959; March 27, 1975. In the present NADA, it has been established that the addition of virginiamycin to salinomycin improves weight gain and feed efficiency. The data also demonstrate that the addition of virginiamycin to salinomycin does not interfere with the coccidiostatic activity of the latter compound. Therefore, the data support the effectiveness of the virginiamycin/salinomycin combination when used as indicated in 2,3.A and 2,3.B 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. For each study, combinations of Eimeria maxima, E. acervulina , and E. tenella, 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 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 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
l2ll 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 Salinomycin, 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 YesGroup I served as unmedicated, uninfected controls and Group II as the infected controls.The treatments were administered in medicated feed starting at day O, 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 90,000Through 14 days after challenge, the following parameters were recorded:
- Lesion scores
- Total and coccidiosis-induced mortality
- Dropping scores
- Bird weights
- 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 < .05.(Eds. note: The following table consists of 7 columns.)
Table II. Salinomycin vs E. mivati, E. necatrix and E. brunetti 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 + O/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 < .05.B. Floor-Pen StudiesSix adequate and well-controlled floor-pen studies, utilizing approved protocols and 9,964 broiler chickens (equal numbers of males and females) of a variety of commercial strains, were conducted in six 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.
The same general experimental design was used in all studies. Salinomycin, 60 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 16 24 Colorado Dr. C. Quarles 16 50 Virginia Dr. S. Cheng 11 50 Arkansas Dr. a. Yates 12 160 Missouri Mr. R. Primo 16 50 New Jersey Mr. R. Roth 8 66Studies 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 increase in rate of weight gain and improvement in feed efficiency in the presence of the highest approved level of salinomycin. Parameters of evaluation included body weights, 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 and mortality treatments at each location for final body weight, feed conversion and mortality 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 3 tables consist of 3 columns each.)
AVERAGE BODY WEIGHT (g) AND MORTALITY FOR EACH LOCATION g/ton Virginiamycin 0 15 Location Salinomycin 60 60 Washington 1912 1951 Colorado 1802 1826 Virginia 2071 2105 Arkansas 1590 1628 Missouri 1912 1880 New Jersey 1870 1930 AVERAGE FEED CONVERSION RATIO FOR EACH LOCATION g/ton Virginiamycin 0 15 Location Salinomycin 60 60 Washington 2.147 2.089 Colorado 1.876 1.843 Virginia 2.027 1.957 Arkansas 1.962 1.925 Missouri 2.029 2.010 New Jersey l.924 l.868 MORTALITY (PERCENT) BY LOCATION g/ton Virginiamycin 0 15 Location Salinomycin 60 60 Washington 3.3 2.8 Colorado 3.1 2.0 Virginia 4.7 3.1 Arkansas 4.3 3.4 Missouri 4.0 4.0 New Jersey 4.2 6.5Statistical AnalysisData were combined over the six 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 Body weight (g) Unweighted 1856 1878 Weighted 1854 1880 Feed Conversion Ratio Unweighted 2.003 1.960 Weighted 2.002 1.962Body weight was significantly improved, P < 0.05, by both analyses. Feed conversion was also improved significantly by both analyses, P < O.Ol. There was no effect on mortality.
These studies demonstrate that there is no interference of salinomycin 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 guidelines provide for granting a range 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) show a significant (P< 0.05 at least) increase in weight gain and improved feed efficiency (P < 0.01) when compared to salinomycin alone. The range approval, in accordance with the guidelines, is from 15 g/ton to the minimum level approved for virginiamycin in the parent application (5 g/ton). Therefore, the approval levels for this NADA are 5 to 15 g/ton of virginiamycin plus salinomycin, 40-60g/ton, in complete broiler rations.
The investigators involved in the above studies were as follows:
J. McGinnis, Ph.D.
Department of Animal Science
Mashington 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 08825V. ANIMAL SAFETY
The original approved NADAs for virginiamycin (91-467, 91-513) and salinomycin (128-686) 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 virginiamycin (5-15 g/ton) in finished rations can be safely fed to broiler chickens.
Further safety studies were not required because:
A. The drugs have been approved individually.
B. Sufficient data have been provided to establish that these compounds are compatible in combinations fed to broiler chickens.
C. The label claims are not antagonistic.
VI. HUMAN SAFETY
A. Data to Support Human Safety
The safety of each of the approved products, salinomycin (Bio-Cox® ) and virginiamycin (Starac®), has been established by data submitted in each respective original NADA (128-686, salinomycin; 91-467 and 91-513, virginiamycin).
Tolerances established for negligible residues of virginiamycin in the edible tissues of chickens are: O.l parts per million (ppm) for muscle, 0.3 ppm for liver and 0.2 ppm for skin/fat, 21 CFR 556.750.
B. Residue Depletion/Non-Interference Studies
Residue data supporting the approved individual uses of salinomycin and virginiamycin, each having zero withdrawal times, were submitted in their respective original applications (see Part A, above).
Drug residue interference studies were completed using acceptable protocols at SmithKline Animal Health Products facility in Nest 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 l4C-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 Withdrawal Day 0 Liver Muscle Skin/Fat Established Tolerances, ppm 0.3 0.1 0.2 Radioactivity, ppm 0.15 0.01 0.09In the 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 g/ton roxarsone and 15 g/ton virginiamycin for 42 days. On day 42 the medications were withdrawn from the diet and 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.Residues for virginiamycin and salinomycin were below their respective tolerances or, safe concentrations at zero 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 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). The sponsor provided a study showing that virginiamycin did not interfere with the salinomycin analytical method.
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 virginiiamycin (5-15 g/ton) are safe and effective for the claims indicated in Section 2 of the 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 (128-686, salinomycin and 91-467 & 91-513, virginiamycin). 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 agreement with the dosages approved in the individual parent NADAs.
Residue data show that salinomycin is well within the established safe concentratrion 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.
Non interference studies demonstrate that salinomycin prevented an outbreak of coccidiosis, alone and in combination with virginiamycin, when the birds were exposed to the six major species of Eimeria . The data from six well controlled floor pen studies deomonstrate the effectiveness of virginiamycin (15 g/ton) in the presence of salinomycin (60 g/ton). These data satisfy CVM's guidelines on combination drugs, permitting the granting of range approval for salinomycin (40-60 g/ton) for the prevention of coccidiosis caused by the six major species of Eimeria in combination with virginiamycin at 5 g/ton for increased rate of weight gain and improved feed efficiency, or with virginiamycin at a range of 5-15 g/ton for increased rae of weight gain in broiler chickens.
Salinomycin and virginiamycin are sold over the counter (OTC). Therefore, this combination drug has OTC status.
VIII. LABELING (Attached)
1. Bluebird Broiler Type C feed VS-1 product label
2. Bluebird Broiler Type C feed VS-2 product label
Copies of these labels may be obtained by writing to the:
Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.