Animal & Veterinary
NADA 140-918 Stenorol®, Flavomycin® - original approval
Approval Date: March 22, 1996
I. GENERAL INFORMATION:
|Sponsor:||Hoechst-Roussel Agri-Vet Company
P.O. Box 2500
Somerville, New Jersey 08876-1258
|Generic Name:||halofuginone hydrobromide, bambermycins|
|Trade Name:||Stenorol®, Flavomycin®|
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.
|A.||DOSAGE FORM||This NADA provided for the combined use of these two Type A medicated articles, bambermycins as per 21 CFR §558.95 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. Bambermycins Type A medicated articles are supplied in concentrations of 4 and 10 grams bambermycins activity per pound.|
|B.||ROUTE OF ADMINISTRATION||Orally, via the feed.|
|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.|
|Bambermycins||Bambermycins is added to turkey feed at a concentration of 2 g/ton for increased rate of weight gain.|
|NOTES||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Feed containing this combination must be withdrawn from turkeys 7 days before slaughter.
A. Coccidial-Challenge Study No. 2365-01-20-94
A series of four independent coccidial-challenge experiments using Large White (Nicholas strain), turkey poults were conducted to determine the anticoccidial effectiveness of halofuginone hydrobromide in the presence of bambermycins. 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:
- Noninfected, nonmedicated control (NINM)
- Infected, nonmedicated control (INM)
- Infected, halofuginone hydrobromide (HAL; 1.36 g/ton)
- Infected, bambermycins (BAM; 2 g/ton)
- Infected, halofuginone hydrobromide (1.36 g/ton) + bambermycins (2 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. 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 bambermycins.
(1) Percent coccidiosis-realted 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 initiaion]]/number of birds]/days on test)
The results of statistical analyses showed that:
- 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 55%.
- For each of the four coccidial challenges, a statistically significant increase in average daily gain was observed with the HAL + BAM combination drug when compared with either the INM control (p-value <0.0001) or BAM (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).
- For each of the four coccidial challenges, no bird in the HAL treatment group or NINM controls died. One bird in the HAL + BAM combination drug treatment group in the E. gallopavonis challenge 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 12.09 Infected, nonmedicated (INM) 3.80 5.36 Halofuginone hydrobromide (HAL; 1.36 0 9.02 g/ton) Bambermycins (BAM; 2 g/ton) 5.00 5.47 Halofuginone hydrobromide (1.36 g/ton) + 1.30 9.34 Bambermycins (2 g/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 15.82 Infected, nonmedicated (INM) 6.30 6.93 Halofuginone hydrobromide (HAL; 1.36 0 15.24 g/ton) Bambermycins (BAM; 2 g/ton) 13.8 6.17 Halofuginone hydrobromide (1.36 g/ton) + 0 15.04 Bambermycins (2 g/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 11.29 Infected, nonmedicated (INM) 0 3.14 Halofuginone hydrobromide (HAL; 1.36 0 8.21 g/ton) Bambermycins (BAM; 2 g/ton) 11.30 3.93 Halofuginone hydrobromide (1.36 g/ton) + 0 7.86 Bambermycins (2 g/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
Average Daily Treatment % Mortality(1) Gain(2) (g) Noninfected, nonmedicated (NINM) 0 18.24 Infected, nonmedicated (INM) 0 7.21 Halofuginone hydrobromide (HAL; 1.36 0 12.88 g/ton) Bambermycins (BAM; 2 g/ton) 4.00 6.72 Halofuginone hydrobromide (1.36 g/ton) + 0 14.05 Bambermycins (2 g/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 bambermycins 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:
- Halofuginone hydrobromide (2.72 g/ton)
Halofuginone hydrobromide (2.72 g/ton) + Bambermycins (2 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.
- Percent mortality = (number of dead birds in a pen / number of birds started in a pen) x 100
- 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)
- 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 bambermycins significantly (P<.05) increases the rate of body weight gain in tom and hen turkeys in the presence of halofuginone hydrobromide. Bambermycins 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) Gain(3) (g) Halofuginone hydrobromide 7.14 2.51 99.93 Halofuginone hydrobromide 7.67 2.49 102.79 + Bambermycins P-values 0.810 0.126 0.049
Table 6. Least-squares means for percent mortality, average daily pen gain, and adjusted feed efficiency in hen turkeys
Adjusted Feed Average Daily Treatment % Mortality(1) Efficiency(2) Gain(3) (g) Halofuginone hydrobromide 2.36 2.47 71.35 Halofuginone hydrobromide 2.40 2.45 73.57 + Bambermycins P-values 0.970 0.149 0.023
V. ANIMAL SAFETY
The basic animal safety data for the individual drugs may be found in NADA 140-824 for halofuginone hydrobromide and NADA 44-759 for bambermycins. 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 44-759, bambermycins 46 FR 58300 - December 1, 1981).
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). Bambermycins has a no tolerance clearance (40 FR 597236, December 30, 1975).
C. Residue Depletion Noninterference Study:
The residue data supporting the approved uses of halofuginone hydrobromide and bambermycins 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 bambermycins (20 g/ton) for 85 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 VII.
TISSUE RESIDUE STUDY
Dr. Paul Griminger
Rutgers University, Cook College
Department of Nutrition
P.O. Box 231
New Brunswick, New Jersey 08903
TABLE VII - RESIDUE DEPLETION STUDY ASSAY RESULTS
Drug Tissue Withdrawal Days Concentration (ppm) Halofuginone Liver 0 0.462 (SD=0.097, N=6) Liver 2 0.063 (SD=0.019, N=6) Liver 3 0.035 (SD=0.005, N=6) Liver 4 0.012 (SD=0.004, N=6) Liver 5 0.010 (SD=0.000, N=6) Bambermycins Liver 0 ND(1) (N=6) Muscle 0 ND (N=6) Skin/Fat 0 ND (N=6)
(1) None detected - bambermycins method sensitivity = 0.0125 ppm.
The residue data supports a 7-day withdrawal period for the use of this halofuginone/bambermycins 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 bambermycins (0.1 ppm) and halofuginone hydrobromide (0.1 ppm) and then conducting assays for halofuginone hydrobromide residues. The results demonstrated no interference by bambermycins on the assay for halofuginone hydrobromide.
The sponsor conducted a noninterference study for bambermycins in liver tissue by spiking samples with halofuginone hydrobromide (0.1 ppm) and bambermycins (0.1 ppm) and then assaying these tissues for bambermycins residues. The results demonstrated no interference by halofuginone hydrobromide on the assay for bambermycins.
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 bambermycins residues. The method entitled "Quantitative Agar Well Plate Assay of Bambermycins (Flavomycin) in Organs and 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 bambermycins (2 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.
Under 21 CFR §556.308, a tolerance is established at 0.13 ppm for parent halofuginone hydrobromide in turkey liver. 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. Bambermycins has a no tolerance clearance.
The battery challenge studies demonstrated that halofuginone hydrobromide in the presence of bambermycins 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 bambermycins 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 2 g/ton of bambermycins, 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)
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