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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-919 Stenorol®, BMD® - original approval

Approval Date: Jan 29, 1993

I. GENERAL INFORMATION:

NADA 140-919
Sponsor: Hoechst-Roussel Agri-Vet Company
Route 202/206
P.O. Box 2500
Somerville, N.J. 08876-1258
Generic Name: halofuginone hydrobromide; bacitracin methylene disalicylate
Trade Name: Stenorol®, BMD®
Marketing Status:  

 

II. INDICATIONS FOR USE:

For the prevention of coccidiosis caused by Eimeria adenoeides, E. meleagrimitis, and E. gallopavonis; and for increased rate of weight gain in growing turkeys.

 

III. DOSAGE

A. DOSAGE FORM This NADA provided for the combined use of these two Type A medicated articles, bacitracin methylene disalicylate as per 21 CFR § 558.76 and halofuginone hydrobromide as per 21 CFR § 558.265 into Type C medicated feed. Halofuginone hydrobromide is supplied as a Type A medicated article in a single concentration of 2.72 grams halofuginone hydrobromide activity per pound. Bacitracin methylene disalicylate Type A medicated articles are supplied in concentrations of 30, 50, and 60 grams bacitracin activity per pound.
B. ROUTE OF ADMINISTRATION Orally, via the feed.
C. RECOMMENDED DOSAGES:  
  Halofuginone hydrobromide Halofuginone Hydrobromide is added to turkey feed at a concentration of 1.36 to 2.72 g/ton for the prevention of coccidiosis caused by Eimeria adenoeides, E. meleagrimitis, and E. gallopavonis.
  Bacitracin methylene disalicylate Bacitracin methylene disalicylate is added to turkey feed at a concentration of 10 to 50 g/ton for increased rate of weight gain.
    Feed containing the two drugs is fed continuously as the sole ration. Feed containing this combination must be withdrawn from turkeys 7 days before slaughter.

 

IV. EFFECTIVENESS:

A. Coccidial-Challenge Study No. 2116-01-20-94

A series of four independent coccidial-challenge experiments using Large White (Experiments 1, 3, and 4 Nicholas strain; Experiment 2 BUTA strain), turkey poults were conducted to determine the anticoccidial effectiveness of halofuginone hydrobromide in the presence of bacitracin methylene disalicylate. Turkeys were challenged with recent (less than three years old) field isolates of Eimeria adenoeides, E. gallopavonis, and E. meleagrimitis as individual infections, and as a mixed infection of all three species. The experiments were conducted at Colorado Quality Research, 1401 Duff Dr.; Suite 700, Ft. Collins, CO 80524. The investigator for the study was Carey Quarles, Ph.D.

For each challenge experiment, day-old, sexed poults were obtained from a commercial turkey hatchery and housed in starting battery cages (separate batteries for each sex). Poults were individually identified and vaccinated for Newcastle Disease by the investigator. Poults were provided water and a uniform, nonmedicated, 28% crude protein, turkey starter diet ad libitum until the experiments were initiated.

Each experiment consisted of five treatments:

  1. Noninfected, nonmedicated control (NINM)
  2. Infected, nonmedicated control (INM)
  3. Infected, halofuginone hydrobromide (HAL; 1.36 g/ton)
  4. Infected, bacitracin methylene disalicylate (BMD; 50 g/ton)
  5. Infected, halofuginone hydrobromide (1.36 g/ton) + bacitracin methylene disalicylate (50 g/ton)

The NINM treatment group served as detached environmental controls in a randomized complete block design. Blocks were comprised of 12 contiguous cages. NINM treatment-sex subclasses were assigned randomly to cages on either end of the block. Infected, treatment-sex subclasses were randomly assigned to the interior eight cages of the block and separated from the NINM controls by an empty cage.

On study-day zero (12 days-of-age), 400 healthy poults were assigned to growing /finishing battery cages, within a block, by body weight within sex. A total of ten male or ten female poults were housed per cage. Experimental batteries were located in an environmentally controlled facility. Poults were maintained under continuous lighting provided by vertically mounted fluorescent lights.

Experimental diets were prepared from a uniform, 28 % crude protein, turkey starter ration. Experimental diets and water were offered ad libitum from study-day zero through study-day eight. Nutritional composition and drug concentration of the experimental diets were verified by appropriate chemical analyses. On study-day 2, NINM birds received 1 ml of distilled water via the crop. All infected treatment groups were inoculated, via the crop, with a 1 ml suspension of Eimeria oocysts in distilled water. Selection of the oocyst dose was based on the results of contemporary virulence titration studies with each field isolate. An oocyst dose was selected to produce a 20-40% reduction in body weight in INM poults when compared to NINM poults. At 6 days post-inoculation (study-day 8) birds were weighed and the experiment terminated. The investigator and personnel involved in the recording of observations and animal care were blinded to the identity of infected treatment groups.

Response variables of interest were mortality and body weight. Percent coccidiosis-related mortality(1) and average daily gain(2) were statistically evaluated using mixed model methodology. Cochran-Mantel-Haenszel tests were used to analyze coccidiosis-related mortality.

(1) Percent coccidiosis-related mortality = (number of birds dying from coccidiosis in a pen / number of birds started in a pen) x 100

(2) Average daily gain = ([the sum of [body weight of birds at the end of the study or at the time of death from coccidiosis - body weight of birds at study initiation]]/number of birds]/days on test)

The statistical analyses for average daily gain and coccidiosis-related mortality were conducted in two stages. In stage one, only the comparison between NINM and INM controls was made. In stage two, the data for NINM controls were excluded from the analyses. Preplanned comparisons between treatments were conducted to evaluate the effectiveness of halofuginone hydrobromide in preventing coccidiosis (prevention of weight gain depression) in the presence of bacitracin methylene disalicylate. The results of statistical analyses showed that:

  1. For each of the four coccidial challenges, the average daily gain in weight of INM controls was significantly lower than that of the NINM controls (p-value <0.001). The percentage of weight depression was at least 41%.
  2. For each of the four coccidial challenges, a statistically significant increase in average daily gain was observed with the HAL + BMD combination drug when compared with either the INM control (p-value <0.0001) or BMD (p-value <0.001). The average daily gain of the combination drug was not statistically different from that of HAL (two-sided p-value > or = 0.27).  
  3. For each of the four coccidial challenges, no bird in the HAL + BMD combination drug treatment group or HAL treatment group or NINM controls died of coccidiosis.

Means for percent coccidiosis-related mortality and least-squares means for average daily gain are presented in Tables 1 to 4.

Table 1. Least-squares means for percent mortality and average daily gain of growing turkeys inoculated with Eimeria gallopavonis

Average Daily
Treatment                                  %  Mortality(1)   Gain(2) (g)
Noninfected, nonmedicated (NINM)                0.0             24.49
Infected, nonmedicated (INM)                    7.5              9.89
Halofuginone hydrobromide (HAL; 1.36            0.0             22.49        
g/ton)
Bacitracin methylene disalicylate              13.75             8.77
 (BMD; 50g/ton)
Halofuginone hydrobromide (1.36 g/ton) +        0.0             22.35        
Bacitracin methylene disalicylate (50g/ton)

(1) Due to coccidiosis
(2) 6 days post-inoculation.

Table 2. Least-squares means for percent mortality and average daily gain of growing turkeys inoculated with Eimeria adenoeides 

Average Daily
Treatment                                  %  Mortality(1)   Gain(2) (g)
Noninfected, nonmedicated (NINM)                0.0             27.48      
Infected, nonmedicated (INM)                   11.25            14.36
Halofuginone hydrobromide (HAL; 1.36            0.0             25.30        
g/ton)
Bacitracin methylene disalicylate               8.75            12.80
 (BMD; 50g/ton)
Halofuginone hydrobromide (1.36 g/ton) +        0.0             26.91        
Bacitracin methylene disalicylate (50g/ton)

(1) Due to coccidiosis
(2) 6 days post-inoculation.

Table 3. Least-squares means for percent mortality and average daily gain of growing turkeys inoculated with Eimeria meleagrimitis 

Average Daily
Treatment                                  %  Mortality(1)   Gain(2) (g)
Noninfected, nonmedicated (NINM)                0.0             30.48
Infected, nonmedicated (INM)                    0.0             17.94
Halofuginone hydrobromide (HAL; 1.36            0.0             26.58        
g/ton)
Bacitracin methylene disalicylate               0.0             16.59
 (BMD; 50g/ton)
Halofuginone hydrobromide (1.36 g/ton) +        0.0             25.76        
Bacitracin methylene disalicylate (50g/ton)

(1) Due to coccidiosis
(2) 6 days post-inoculation.

Table 4. Least-squares means for percent mortality and average daily gain of growing turkeys inoculated with Eimeria adenoeides, E. meleagrimitis, and E. gallopavonis

(Mixed Infection) 

Average Daily
Treatment                                  %  Mortality(1)   Gain(2) (g)
Noninfected, nonmedicated (NINM)                0.0             30.48
Infected, nonmedicated (INM)                    0.0             17.94
Halofuginone hydrobromide (HAL; 1.36            0.0             26.58        
g/ton)
Bacitracin methylene disalicylate               0.0             16.59
 (BMD; 50g/ton)
Halofuginone hydrobromide (1.36 g/ton) +        0.0             25.76        
Bacitracin methylene disalicylate (50g/ton)

(1) Due to coccidiosis
(2) 6 days post-inoculation.

B. Floor-Pen Nonchallenge Studies

Three floor-pen experiments were conducted under simulated field-use conditions to investigate the growth promoting effects of bacitracin methylene disalicylate in the presence of halofuginone hydrobromide. The experiments were conducted at different geographic locations and under varying climatic conditions and animal production practices. The experiments used 1,844 (1060 hens and 784 toms) Large White (Nicholas strain) turkeys. The floor-pen studies were conducted by:

Mr. Randall Primo
Ponderosa Research Co.
French Village, MO 63036
Study No. 2365-11 Dr. Carey Quarles
Colorado Quality Research
1401 Duff Dr., Suite 700
Ft. Collins, CO 80524
Study No. 2365-12

Mr. Michael Sims
Virginia Scientific Research, Inc.
1790-10 East Market St.
Harrisonburg, VA 22801
Study No. 2365-13

Each floor-pen experiment was designed as a randomized complete block; with blocks consisting of a series of contiguous floor-pens. Treatments were:

  1. Halofuginone hydrobromide (2.72 g/ton)  

  2. Halofuginone hydrobromide (2.72 g/ton) + Bacitracin methylene disalicylate (50 g/ton)

For each floor-pen experiment, day-old, sexed, poults were obtained from a commercial turkey hatchery. Poults were allocated to floor-pens, within a block, by sex. The number of birds allocated to pens varied from 15 to 24 hens and 12 to 16 toms; depending on the predominate commercial practice in the geographic location where the study was conducted. Treatment-sex subclasses were randomly assigned to pens within a block. Twelve to 20 replicates (6 or 10 of each sex) were conducted per treatment.

Experimental diets were prepared from uniform basal turkey rations. Rations were formulated based on the predominate commercial practice in the geographic location where the study was conducted, for the age and sex of poults being fed.
The nutritional composition and drug concentration of the experimental diets were verified by appropriate chemical analyses. Experimental diets and water were offered ad libitum from a day-of-age until seven days prior to collection of final body weight data.

Response variables of interest were mortality, body weight and feed consumption. Data was analyzed separately for tom and hen turkeys. Percent mortality(3), adjusted feed efficiency(4), and average daily pen gain(5) were statistically evaluated using mixed model methodology. Percent mortality was analyzed using an arcsine, square root transformation. The homogeneity or errors among locations was evaluated using a Bartlett's test on the mean square errors from each location. The data from all three studies were pooled for determination of treatment effects.

(3) Percent mortality = (number of dead birds in a pen / number of birds started in a pen) x 100

(4) Adjusted feed efficiency = total feed consumed in a pen / (body weight of live birds at the end of the experiment + body weight of dead birds at the time of death)

(5) Average daily pen gain = ([body weight of live birds in a pen / number of live birds]/days on test)

The analyses of the pooled data indicate that bacitracin methylene disalicylate significantly (P<.05) increases the rate of body weight gain in tom and hen turkeys in the presence of halofuginone hydrobromide. Bacitracin methylene disalicylate did not improve feed efficiency in either sex in the presence of halofuginone hydrobromide. There was no difference in the mortality rates between the treatment groups in either sex. The least-squares means are presented in Tables 5 and 6.

Table 5. Least-squares means for percent mortality, average daily pen gain, and adjusted feed efficiency in tom turkeys

                            Adjusted Feed    Average Daily

         Treatment            Mortality(1) %   Efficiency(2)   Pen Gain(3) (kg)
Halofuginone hydrobromide         7.11              2.51             .100
Halofuginone hydrobromide         7.06              2.47             .103       
+ Bacitracin methylene                                                          
disalicylate
P-values                           .992              .083            .036    

Table 6.  Least-squares means for percent mortality, average daily pen gain,

and adjusted feed efficiency in hen turkeys

Adjusted FeedAverage Daily

         Treatment            Mortality(1) %   Efficiency(2)   Pen Gain(3) (kg)
Halofuginone hydrobromide         2.41              2.46             .071      
Halofuginone hydrobromide         2.96              2.44             .074       
+ Bacitracin methylene                                                          
disalicylate                                                                    
P-values                           .460              .069            .028    

 

V. ANIMAL SAFETY

The basic animal safety data for the individual drugs may be found in NADA 140-824 for halofuginone hydrobromide and NADA 46-592 for bacitracin methylene disalicylate. The effectiveness studies described in Section IV demonstrate that no ill effects occurred when the drugs were combined; indicating that they are as safe when fed in combination as when fed alone.

This application is in accord with the CVM's Target Animal Safety Guidelines for New Animal Drugs (June 1989). Additional safety studies were not required because: (1) the drugs have been approved singularly and (2) adequate documentation has been provided to show that these compounds are compatible in combination when used in turkey feeds. Therefore, based on the data in the original NADA's, the non-interference studies, the floor-pen efficacy studies and the drug residue elimination study, it is concluded that this combination of drugs may be safely fed to growing turkeys.

 

VI. HUMAN SAFETY

A. Toxicity Tests:

The original NADA's contain FOI summaries and complete information that demonstrate that food from animals fed these products is safe for human consumption. (NADA 140-824, halofuginone hydrobromide 54 FR 28051 - July 5, 1989; NADA 46-592, bacitracin methylene disalicylate 21 CFR §558.76).

B. Tolerances and Safe Concentrations of Residues:

Halofuginone hydrobromide has an established tolerance in turkeys of 0.13 ppm for parent halofuginone (marker residue) in liver (the target tissue). The safe concentrations for total residues of halofuginone hydrobromide in the uncooked edible tissues are 0.10 ppm in muscle, 0.30 ppm in liver, and 0.20 ppm in skin with adhering fat (21 CFR § 556.308). Tolerances for residues of bacitracin methylene disalicylate are established at 0.5 ppm, negligible residue, in uncooked edible tissues (21 CFR § 556.70) with muscle as the target tissue.

C. Residue Depletion Noninterference Study:

The residue data supporting the approved uses of halofuginone hydrobromide and bacitracin methylene disalicylate and their respective withdrawal times of 7 and 0 days, respectively, have been submitted in their original applications. The summary of the study conducted for this combination is presented in Table VII and establishes that each drug in the presence of the other does not exceed its established safe concentration(s) or tolerance(s) and that neither drug interferes with the other's tissue residue assay. The turkeys in that study were fed the combination of halofuginone hydrobromide (2.72 g/ton) and bacitracin methylene disalicylate (100 g/ton) for 83 days prior to the withdrawal period. Liver and muscle tissue were assayed for drug residues. The tissues were collected on the withdrawal dates indicated in Table 7.

TISSUE RESIDUE STUDY

Investigator:

Dr. Carey Quarles
Colorado Quality Research, Inc.
1401 Duff Drive, Suite 700
Fort Collins, Colorado 80524

TABLE 7 - RESIDUE DEPLETION STUDY ASSAY RESULTS

Drug           Tissue    Withdrawal Days     Concentration (ppm)
HalofuginoneLiver 60;    0.393 (SD=0.087, N=6)
                Liver         2              0.207 (SD=0.100, N=6)
                Liver         3              0.108 (SD=0.043, N=6)
                Liver         4              0.060 (SD=0.019, N=6)
                Liver         5              0.034 (SD=0.011, N=6)
                
Bacitracin*     Muscle        0                0 (<0.3, N=6)
                Muscle        1                0 (<0.3, N=6)

* Sensitivity of method is 0.3 ppm.

The residue data supports a 7-day withdrawal period for the use of this halofuginone/bacitracin methylene disalicylate combination in turkeys. This withdrawal period is supported by using a statistical procedure that applies a 99% tolerance limit with a 95% confidence interval to the data.

D. Assay Noninterference:

Along with the residue depletion results in Table VII, the sponsor conducted a noninterference study for halofuginone hydrobromide in liver tissue by spiking samples with bacitracin (0.5 ppm) and halofuginone hydrobromide (0.09 ppm) and then conducting assays for halofuginone hydrobromide residues. The results demonstrated no interference by bacitracin on the assay for halofuginone hydrobromide.

The sponsor conducted a noninterference study for bacitracin in muscle tissue by spiking samples with halofuginone hydrobromide (0.3 ppm) and bacitracin (0.5 ppm) and then assaying these tissues for bacitracin residues. The results demonstrated no interference by halofuginone hydrobromide on the assay for bacitracin.

E. Regulatory Methods:

An HPLC method is used to assay tissues for halofuginone residues. The method entitled "Analysis of an Anti-Coccidial Drug, Halofuginone, in Poultry Tissue" is on file at the Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20857.

A microbiological assay method is used to assay tissues for bacitracin residues. The method entitled "Modified Microbiological Method for Determination of Bacitracin in Tissues" is on file at the Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20857.

 

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and demonstrate that halofuginone hydrobromide (1.36 to 2.72 g/ton) plus bacitracin methylene disalicylate (10 to 50 g/ton) are safe and effective for the claims indicated in Section II of this FOI summary.

Pursuant to 21 CFR § 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 efficacy 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.

Residue data show halofuginone hydrobromide is within the established safe concentrations of 0.3 ppm in liver, 0.2 ppm skin/fat and 0.1 ppm muscle of the turkey at seven days of withdrawal. Residue data show bacitracin methylene disalicylate is well below tolerance of 0.5 ppm in edible turkey tissues at seven days of withdrawal.

The battery challenge studies demonstrated that halofuginone hydrobromide in the presence of bacitracin methylene disalicylate prevented coccidiosis when the birds were exposed to the three major species of Eimeria infecting turkeys. The data from three floor-pen nonchallenge studies demonstrate the effectiveness of bacitracin methylene disalicylate in the presence of halofuginone hydrobromide for increased rate of weight gain. In accordance with CVM's guideline entitled "Guideline for Drug Combinations for Use in Animals" (October 1983), Hoechst-Roussel Agri-Vet Company is permitted the range of 10 to 50 g/ton of bacitracin methylene disalicylate, and 1.36 to 2.72 g/ton of halofuginone hydrobromide in the Type C medicated feed for prevention of coccidiosis caused by Eimeria adenoeides, E. meleagrimitis, and E. gallopavonis; and for increased rate of weight gain in turkeys, as shown in Section II of this FOI summary.

Under section 512(c)(2)(F)(ii) of the FFDCA, this approval for food producing animals qualifies for three years of marketing exclusivity beginning on the date of approval because the application contains reports of new clinical or field investigations (other than bioequivalence or residue studies) essential to the approval of the application and conducted or sponsored by the applicant.

 

VIII. LABELING (Attached)

  1. Type C medicated Feed (Blue Bird)

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