FOI Summary; NADA 140-584 (original); Bacitracin MD, Stenorol (bacitracin methylene disalicylate, halofuginone hydrobromide); original; March 16, 1988 --Editor's abstract   Freedom of Information Summary NADA 140-584   1. General Information: NADA Number: 140-584 Sponsor: Roussel-Uclaf 163 Avenue Gambetta Paris, France Hoechst-Roussel Agri-Vet Co. Route 202-206 North Somerville, NJ 08876 Generic Name: Bacitracin methylene disalicylate & Halofuginone hydrobromide Tradename: Bacitracin MD Stenorol Marketing Status: OTC   2. Indications for Use: For the prevention of coccidiosis by Eimeria acervulina, E. brunetti, E. maxima, E. mivati, E. necatrix and E. tenella and improved feed efficiency in broiler chickens.   3. Dosage Form, Route of Administration, Recommended Dosage: Dosage Form: Bacitracin MD and halofuginone hydrobromide are marked as separate Type A Medicated Articles. The bacitracin MD Type A Article is sold in four concentrations: 10, 25, 40 and 50 grams of bacitracin activity per pound. Halofuginone hydrobromide Type A Article is sold in one concentration: 2.72 grams of halofuginone hydrobromide activity per pound. Route of Administration: The route of administration of these two drugs is oral via the feed. Recommended Dosage: The recommended dosage is:   Bacitracin MD 10 to 50 g/ton: Bacitracin MD is added to finished broiler feed at concentrations ranging from 10 to 50 g/ton for improved feed efficiency. Halofuginone hydrobromide 2.72 g/ton: Halofuginone hydrobromide is added to finished broiler feed at concentration of 2.72 g/ton for the prevention of coccidiosis caused by Eimeria acervulina, E. brunetti, E. maxima, E. mivati, E. necatrix and E. tenella. The resultant feed containing the two drugs is then fed continuously as the sole ration. Feeds containing halofuginone hydrobromide must be withdrawn from broilers five days before slaughter.   4. Effectiveness: A. Floor pen Studies - Body Weight & Feed efficiency   The efficacy data for each individual drug is located in its parent NADA and the FOI contains a summary of the data. NADA 130-951 halofuginone hydrobromide 50 FR 33718, August 21, 1985; NADA 046-592 Bacitracin MD 46 FR 41041, August 14, 1981. The New Animal Drug Application on which approval of halofuginone hydrobromide in combination with bacitracin MD is based contains adequate and well controlled studies demonstrating the effectiveness of bacitracin MD and halofuginone hydrobromide when fed to broilers. Six experiments using a randomized complete block design were conducted utilizing 3,272 broilers which were fed from one day of age to market weight. These experiments were evaluated for significant differences and summarized below. In these six studies, pens were randomly assigned to treatments within blocks; 20 to 100 birds of equal sex were selected at random and assigned to each pen; three to seven replicates were used per treatment group. The summary was done using only the combination of treatments necessary under the revised guidelines for broiler combination efficacy studies (Guidelines for drug Combinations for Use in Animals, Center for Veterinary Medicine, October 1983. The policy provides for the granting of a range approval for production drugs in combination when the maximum level tested for the claim (s) is demonstrated to make a significant benefit to the combination. Thus, only the following treatments from each of the six studies were pooled and subjected to statistical analysis: a. Halofuginone hydrobromide 2.72 g/ton b. Bacitracin MD 50 g/ton + halofuginone hydrobromide 2.72g/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 bacitracin MD on average live bird weight and feed efficiency is presented in Table 1. Two of the six trials were conducted by Randall A. Primo at the Ponderosa Research Farm and were evaluated as replication of the same trial at one location. The feed to gain data for bacitracin MD at 50 g/ton was significantly different (P<.001) from the control. The weight gain data were positive but not significant at the traditional 0.05 level. These data meet the requirements of CVM's efficacy guidelines for drugs in combination, revised October 1983, for range approval for bacitracin MD. The range that may be approved for bacitracin MD is 4 to 50 g/ton. Because the feed stability data for bacitracin MD was established at 10 g/ton the range is limited to 10 to 50 g/ton for improved feed efficiency in broiler chickens in combination with halofuginone hydrobromide at 2.72 g/ton. The floor pen trials that support this combination application were conducted by: Dr. Park Waldroup Dr. Frank J. Siccardi Dept. of Animal Science Avian Consultant Univ. of Arkansas 2850 Inwood Lane Fayetville, AR 72701 Fayetteville, AR 72701 Mr. Randall A. Primo Dr. B.L. Damron Ponderosa Research Farm Dept. of Poultry Science French Village, MO 63036 Univ. of Florida Gainesville, FL 32601 Dr. John A. Hebert Dept. of Poultry Science Louisiana St. Univ. Baton Rouge, LA 70703 Ed. note: The following table has 5 columns. Table 1 Body Weight (pounds) reatments* Pens Per Birds Bacitracin MD Study Location Treatment Per Pen Control (50 g/ton)   Arkansas 7 60 3.90 3.93 Missouri 3 72 3.97 4.05 Louisiana 4 100 3.68 3.74 Missouri 6 50 4.02 4.19 Arkansas 4 50 3.46 3.67 Florida 5 20 4.36 4.50   Average: 3.90 4.01 Feed Efficiency Treatments* Pens Per Birds Bacitracin MD Study Location Treatment Per Pen Control (50 g/ton)   Arkansas 7 60 2.18 2.15 Missouri 3 72 2.27 2.20 Louisiana 4 100 2.16 2.02 Missouri 6 50 2.32 2.24 Arkansas 4 50 2.11 2.06 Florida 5 20 2.10 2.04   Average: 2.19 2.12   *All treatments contained halofuginone hydrobromide at 2.72 g/ton (3.0 ppm). B. Noninterference Battery Studies   Fourteen and 21 day old broiler chickens were used in three adequate, well controlled battery studies to test for the noninterference of bacitracin MD on the anticoccidial efficacy of halofuginone hydrobromide. Recent isolates of coccidia were used. Combinations of E. acervulina, E. maxima, E. necatrix, E. mivati, E. tenella and E. brunetti were used. This arrangement facilitated identification of lesions. The broilers were randomized and assigned to cages with ten broilers per cage. There were four or five replicates of each treatment group. Tables 2, 3 and 4 show the treatments used in these battery studies along with the results for average body weight gain, feed efficiency, dropping scores, lesion scores, and coccidiosis mortality. These battery studies adequately demonstrate that there is no interference of bacitracin MD on the anticoccidial efficacy of halofuginone hydrobromide. Therefore, this combination is compatible. The investigators involved in the above battery studies were: Dr. Cornell A Johnson Dr. Carey Quarles AEF Research Inc. Colorado Quality Research 5492 Kennedy Drive, Rt. 3 1401 Duff Drive, Suite 700 Waunakee, WI 53597 Ft. Collins, CO 80524   5. Animal Safety: The original NADA's contain complete information on the target animal safety of the two products (NADA's 046-592 bacitracin MD 46 FR 41041, August 14, 1981; 130-951 halofuginone hydrobromide 50 FR 33718, August 21, 1985). 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. Further safety studies were not required because: a. The drugs have been approved singly; and b. Sufficient documentation has been provided to determine that these compounds are compatible in combination when used in poultry. Ed. note: The following table has 6 columns. Table 2 Average Weight Gain, Feed Efficiency, Total Dropping Score, Coccidiosis Mortality and Total Lesion Scores for the Noninterference Battery Study Number One(1) Average Feed Total Total Total Treatment(2) Gain (g) Eff. Drop Score(3) Lesion Score Coccidiosis Mortality   NM 767 2.16 0.0 0.6 0 NMI 498 2.48 7.75 10.5 7 Halo. 711 2.27 1.75 4.0 0 Halo + Bac 703 2.13 2.0 3.6 0   (1) Broilers were infected with isolates of Eimeria tenella, E. acervulina, E. maxima, E. brunetti, E. mivati and E. necatrix. (2) NM=nonmedicated, uninfected NMI=nonmedicated, infected Halo=halofuginone at 2.72 g/ton Bac=bacitracin MD at 50 g/ton (3) Scoring based on a system of 0 - 4, 0 = normal, 4 = very wet Table 3 Average Weight Gain, Feed Efficiency, Average Drop Score, Coccidiosis Mortality and Average Total Lesion Scores for the Noninterference Battery Study Number Two.(1) Average Feed Average Average Total Treatment(2) Gain (g) Eff. Drop Score(3) Lesion Score Coccidiosis Mortality   NM 581 2.05 1.00 0.00 0 NMI 399 3.42 2.75 5.88 12 Halo 569 2.08 1.38 1.38 0 Halo + Bac 571 2.14 1.25 0.75 0   1 Broilers were infected with isolates of Eimeria tenella, E. acervulina, E. maxima, E. brunetti, E. mivati, and E. necatrix. 2 NM=nonmedicated, uninfected NMI=nonmedicated, infected Halo=halofuginone at 2.72 g/ton bac=bacitracin MD at 100 /ton 3 1 = normal, 2 = moderately wet, 3 = very wet Table 4 Average Weight Gain, Feed Efficiency, Average Dropping Score, Coccidiosis Mortality and Average Total Lesion Scores for the Noninterference Battery Study Number Three.(1) Average Feed Average Average Total Treatment(2) Gain (g) Eff. Drop Score(3) Lesion Score Coccidiosis Mortality   NM 696 1.84 1.00 0.00 0 NMI 648 1.96 2.19 3.50 3 Halo. 671 1.88 1.93 0.63 0 Halo + bac 697 1.84 1.68 0.63 1   1 Broilers were infected with isolates of Eimeria mivati, E. necatrix, E. brunetti, E. acervulina, E. maxima, and E. tenella. 2 NM=nonmedicated, uninfected NMI=nonmedicated, infected Halo=halofuginone at 2.72 g.ton bac=bacitracin MD at 100 g/ton 3 1=normal, 2=moderately wet, 3=very wet The summary of the safety data in the parent NADA's combined with the summary of the efficacy floor pen trials and noninterference battery study for the combination product demonstrate normal growth with no incidence of disease or other abnormalities when the three drugs were fed at the highest approved use levels.   A SAFETY GROWTH STUDY Investigator: Dr. Randall A. Primo Ponderosa Research Co. French Village, MO 63036 The following table shows that the broilers grew well and feed efficiency was not adversely affected by any of the treatments. Ed. note: The following table has 5 columns. Table 5 Safety Study Summary Seven Week Data Drug Broiler Final Body Final Feed Treatment Level Number Wt. (lbs) Efficiency   Control ---- 146 4.02 2.32 Halofuginone 2.72 g/t Bacitracin MD 50 g/t 144 4.31 2.17   The data provide the corroborative evidence of the Safety and Efficacy of the combination of halofuginone hydrobromide and bacitracin MD in the feed of broiler chickens and these data are consistent with and fulfill all the requirements for a fixed combination drug for animals as follows: a. Each drug component makes a contribution to the claimed effects. b. The dosages of each drug component are such that the combination is safe and effective. c. This combination demonstrates significant control of a specific disease condition 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. d. The label claims are not antagonistic. Based on the data in the parent NADA's, the compatibility battery studies, the drug residue elimination (summarized in Section 6 Human Safety), and the floor pen studies, we conclude that the combination of these two drugs is safe to be fed to broiler chickens as indicated by the label. 6. Human Safety: The original NADA's and FOI Summaries for each drug (046-592 and 130-951) demonstrate that food from animals fed these products is safe for human consumption. Halofuginone hydrobromide has an established tolerance in broilers of 0.1 ppm for parent halofuginone hydrobromide (marker residue) in liver (the target tissue). A marker residue concentration of 0.1 ppm in liver corresponds to a concentration of total residues of halofuginone hydrobromide of 0.3ppm in the liver. The safe concentrations for total residues of halofuginone hydrobromide in the uncooked edible tissues of broilers are 0.1 ppm in muscle, 0.3 ppm in the liver and 0.2 ppm in skin with adhering fat (50 FR 33718, August 21, 1985). Tolerances for residues of bacitracin methylene disalicylate are established at 0.5 ppm, negligible residue, in uncooked edible tissues of chickens (21 CFR 556.70) with muscle as the target tissue. The residue data supporting the approved individual uses of halofuginone hydrobromide and bacitracin MD and their respective withdrawal times of four and zero days have been submitted in their respective original applications. The summary of the study conducted for this combination is presented in Table 4 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 the study were fed the combination of halofuginone hydrobromide (2.72 g/ton) bacitracin MD 9100 g/ton) and roxarosone (45.4 g/ton) for 29 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 4. Investigator for tissue study:   Dr. Randall A. Primo Ponderosa Research Co. French Village, MO 63036 Ed. note: The following table has 6 columns. Table 4 Residue Depletion Study Assay Results (ppm) Drug Tissue Withdrawal Day(1)   0 1 4 5 Bacitracin Muscle <0.09 - - - Halofuginone Liver 0.84 (±0.22) 0.60 (±0.15) 0.03 (±0.02) 0.018 (±0.01)   (1) Average of six birds, except for halofuginone hydrobromide at withdrawal day four the average is from three birds; standard deviation in parenthesis. Along with the residue depletion results presented in Table 4, the sponsor conducted a noninterference study for the bacitracin MD tissue assay by spiking samples with bacitracin, and halofuginone hydrobromide and conducting assays for bacitracin residues. The results demonstrated no interference by halofuginone hydrobromide on the assay for bacitracin. The sponsor conducted a noninterference study for halofuginone hydrobromide by spiking control tissue samples with halofuginone hydrobromide and bacitracin and then assaying these tissues for halofuginone hydrobromide content. The results demonstrated no interference by bacitracin on the tissue assay for halofuginone hydrobromide. A five day withdrawal period was established for this combination based on a 99% statistical tolerance limit with a 95% confidence. These data support a five day withdrawal for the halofuginone hydrobromide/bacitracin MD combination.   7. Agency Conclusions: The data submitted in support of this NADA satisfy the requirements of Section 512 of the Act and demonstrate that halofuginone hydrobromide (2.72 g/t) plus bacitracin MD (10-50 g/ton) are safe and effective when fed to broiler chickens at the dosage levels for the indications stated in Section 3 of this FOI Summary. Under the Center's supplemental policy (42 FR 64367 December 23, 1977) this original application is regarded as a Category 2 supplemental NADA which did not require a revaluation of safety and efficacy data in the parent NADAs. The drugs are to be fed in Type C Medicated feeds, in accordance with the labeling as approved in the parent NADAs. Residue depletion studies in this application demonstrate that halofuginone hydrobromide depletes to safe concentrations within five days withdrawal to no more than 0.1 ppm in muscle, 0.3 ppm in liver and 0.2 ppm in skin/fat (21 CFR 556.308); bacitracin MD is below the tolerance of 0.5 ppm at zero withdrawal (21 CFR 556.70). Adequate information was submitted to demonstrate noninterference between the assays for each drug. The approval of this application will not significantly increase exposure of humans to residues of the drugs. The data from six well controlled trials demonstrated the effectiveness of bacitracin MD for improved feed efficiency in the presence of halofuginone hydrobromide when mixed in broiler chicken feeds. The data from noninterference battery study demonstrated the effectiveness of halofuginone hydrobromide in preventing coccidiosis in the presence of bacitracin MD. The Guideline permits the granting of range approval for bacitracin MD as shown in Section 3 of this document. A five day withdrawal period is required before the broiler chickens may be slaughtered for human food.   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