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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 141-065 Aviax™, BMD® - original approval

Approval Date: October 18, 1996

I. GENERAL INFORMATION:

NADA141-065
Sponsor:Pfizer Inc.
235 East 42nd Street
New York, New York 10017
Generic Name:Semduramicin, Bacitracin methylene disalicylate
Trade Name:Aviax ™, BMD®
Marketing Status:Over the Counter (OTC)

 

II. INDICATIONS FOR USE

For the prevention of coccidiosis caused by Eimeria acervulina, E. brunetti, E. maxima, E. mivati/mitis, E. necatrix, and E. tenella, and for improved feed efficiency in broiler chickens.

 

III. DOSAGE

A.DOSAGE FORMThis NADA provided for the combined use of these two Type A medicated articles, semduramicin as per 21 CFR §558.555, and bacitracin methylene disalicylate as per 21 CFR §558.76. Semduramicin is supplied as a Type A medicated article in a single concentration of 22.7 grams of semduramicin activity per pound. Bacitracin methylene disalicylate is supplied as a Type A medicated article in concentrations 30, 50, and 60 grams of bacitracin activity per pound.
B.ROUTE OF ADMINISTRATIONOrally, via the feed.
C.RECOMMENDED DOSAGES: 
 SemduramicinSemduramicin is added to broiler chicken feed at a concentration of 22.7 g/ton for the prevention of coccidiosis caused by Eimeria acervulina, E. brunetti, E. maxima, E. mivati/mitis, E. necatrix, and E. tenella.
 
 Bacitracin methylene disalicylateComplete feed containing these two compounds is to be fed continuously as the sole diet. For broiler chickens only. Do not feed to laying hens.
 NOTESComplete feed containing these two compounds is to be fed continuously as the sole diet. For broiler chickens only. Do not feed to laying hens.

 

IV. EFFECTIVENESS:

A. Coccidial-Challenge Studies No.'s 2211S-60-93-120, -121, -122, -124, -125, and 95-103, -124, and -132.

Efficacy of semduramicin in the presence of bacitracin methylene disalicylate.

A series of eight independent coccidial-challenge experiments using crossbred broiler chickens were conducted to determine the anticoccidial effectiveness of semduramicin in the presence of bacitracin methylene disalicylate. Chickens were challenged with recent (less than three years old) field isolates of Eimeria acervulina, E. brunetti, E. maxima, E. mivati/mitis, E. necatrix, and E. tenella as individual infections, and as a mixed infection of all six 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, crossbred broiler chickens were raised in a coccidiosis-free environment, under environmentally controlled conditions, and on a nonmedicated diet until 11 to 13 days-of-age. Both genders were evaluated for each species of Eimeria. Birds were uniquely identified, assigned to treatment groups (four pens of each sex per treatment), and fed the appropriate medicated diet.

Each experiment consisted of five treatments:

  1. Noninfected, nonmedicated
  2. Infected, nonmedicated
  3. Infected, semduramicin (SEM; 22.7 g/ton)
  4. Infected, bacitracin methylene disalicylate (BMD; 50.0 g/ton)
  5. Infected, semduramicin (SEM; 22.7 g/ton) + plus bacitracin methylene disalicylate (BMD; 50.0 g/ton)

The noninfected/nonmedicated treatment groups served as environmental controls in a randomized complete block design. Blocks were comprised of contiguous cages. Noninfected/nonmedicated treatment-sex subclasses were assigned randomly to cages throughout the battery. On study-day zero (11 to 13 days-of-age), 576 healthy broiler chickens were assigned to growing/finishing battery cages, within a block, by body weight within sex. A total of eight male or eight female chickens were housed per cage. Experimental batteries were located in an environmentally controlled facility. Chickens were maintained under continuous lighting provided by vertically mounted fluorescent lights.

Experimental diets were prepared from a uniform, 23 % crude protein, broiler starter ration. Experimental diets and water were offered ad libitum from throughout the study. Nutritional composition and drug concentration of the experimental diets were verified by appropriate chemical analyses. On study-day 2, noninfected/nonmedicated 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% reduction in body weight and 2.5 unit increase in lesion scores in infected/nonmedicated chickens when compared to noninfected/nonmedicated chickens. Cages and birds were observed twice daily, and data recordings were made during the pre-infection period and during the post-infection period of 5 to 6 days. The investigator and personnel involved in the recording of observations and animal care were blinded to the identity of infected treatment groups. At 5 to 6 days post-inoculation (study-day 7 to 8) birds were weighed, and the experiment terminated. Intestinal lesions were scored by the Johnson and Reid (1970) method for the appropriate zone for each study.

Response variables of interest were mortality, body weight, and lesion score. There was no significant mortality in any of the inoculated groups. Weight gain per bird* and average lesion score were statistically evaluated using either general linear models or mixed model methodology.

*Weight gain per bird = (Body weight at study termination or at the time of death from coccidiosis - body weight at study initiation/number of surviving chicks + number of chicks dying from coccidiosis)

The comparison between noninfected/nonmedicated and infected/nonmedicated controls was made, then the data for noninfected/nonmedicated controls were excluded from further analyses. Preplanned comparisons between treatments were conducted to evaluate the effectiveness of semduramicin in preventing coccidiosis (prevention of weight gain depression and increased lesion scores) in the presence of bacitracin methylene disalicylate.

The results of the statistical analyses of the data from these experiments are depicted in Tables 1 to 8. Semduramicin in the presence of bacitracin methylene disalicylate was effective for relieving weight gain depression and reducing lesion scores in broiler chickens infected with
E. acervulina, E. brunetti, E. maxima, E necatrix, and E. tenella.

Semduramicin in the presence of bacitracin methylene disalicylate was effective for relieving weight gain depression, but not for reducing lesion scores in broiler chickens infected with E. mitis. Because lesions in chickens infected with E. mitis are often very slight, and sometimes are difficult to assess, weight gain was judged to be a more important indicator of effectiveness; thus, primary emphasis was placed on the weight gain variable for assessment of efficacy of the combination against E. mitis.

Table 1. Least squares means for weight gain and lesion scores for broiler chickens inoculated with E. acervulina
(study 2211S-60-95-132)

Preplanned Treatment ContrastsWeight gain per bird (g)*Average lesion score*
Noninfected, nonmedicated vs.
Infected, nonmedicated
274.6(a)
240.4(b)
0.00(a)
1.68(b)
SEM+BMD vs.
Infected, nonmedicated
268.8(a)
240.4(b)
0.34(a)
1.68(b)
SEM+BMD vs.
SEM
268.8(a)
257.6(a)
0.34(a)
0.26(a)
SEM+BMD vs.
BMD
268.8(a)
243.1(b)
0.34(a)
1.59(b)

*Means with different superscripts are significantly different (P<0.05).

Table 2. Least squares means for weight gain and lesion scores for broiler chickens inoculated with E. brunetti 
study 2211S-60-93-124)

Preplanned Treatment ContrastsWeight gain per bird (g)*Average lesion score*
Noninfected, nonmedicated vs.
Infected, nonmedicated
250.7(a)
112.4(b)
0.00(a)
2.94(b)
SEM+BMD vs.
Infected, nonmedicated
260.5(a)
112.4(b)
0.67(a)
2.94(b)
SEM+BMD vs.
SEM
260.5(a)
240.7(b)
0.67(a)
0.52(a)
SEM+BMD vs.
BMD
260.5(a)
112.5(b)
0.67(a)
2.67(b)

*Means with different superscripts are significantly different (P<0.05).

Table 3. Least squares means for weight gain and lesion scores for broiler chickens inoculated with E. maxima
(study 2211S-60-93-121)

Preplanned Treatment ContrastsWeight gain per bird (g)*Average lesion score*
Noninfected, nonmedicated vs.
Infected, nonmedicated
231.6(a)
 
0.00(a)
 
SEM+BMD vs.
Infected, nonmedicated
189.8(a)
129.7(b)
1.62(a)
2.78(b)
SEM+BMD vs.
SEM
189.8(a)
177.5(a)
1.62(a)
1.67(a)
SEM+BMD vs.
BMD
189.8(a)
139.8(b)
1.62(a)
2.58(b)

*Means with different superscripts are significantly different (P<0.05).

Table 4. Least squares means for weight gain and lesion scores for male broiler chickens inoculated with E. mitis
(study 2211S-60-93-120)

Preplanned Treatment ContrastsWeight gain per bird (g)*Average lesion score*
Noninfected, nonmedicated vs.
Infected, nonmedicated
309.0(a)
220.8(b)
0.00(a)
0.81(b)
SEM+BMD vs.
Infected, nonmedicated
293.4(a)
220.8(b)
0.22(a)
0.81(b)
SEM+BMD vs.
SEM
293.4(a)
293.6(a)
0.22(a)
0.28(a)
SEM+BMD vs.
BMD
293.4(a)
266.6(b)
0.22(a)
0.42(a)

*Means with different superscripts are significantly (P0.05) different.

Table 5. Least squares means for weight gain and lesion scores for female broiler chickens inoculated with E. mitis
(study 2211S-60-95-103)

Preplanned Treatment ContrastsWeight gain per bird (g)*Average lesion score*
Noninfected, nonmedicated vs.
Infected, nonmedicated
272.3(a)
140.5(b)
0.00(a)
1.88(b)
SEM+BMD vs.
Infected, nonmedicated
179.6(a)
140.5(b)
0.55(a)
1.88(b)
SEM+BMD vs.
SEM
179.6(a)
184.2(a)
0.55(a)
0.53(a)
SEM+BMD vs.
BMD
179.6(a)
139.5(b)
0.55(a)
1.93(a)

*Means with different superscripts are significantly (P0.05) different.

Table 6. Least squares means for weight gain and lesion scores for broiler chickens inoculated with E. necatrix
(study 2211S-60-93-122)

Preplanned Treatment ContrastsWeight gain per bird (g)*Average lesion score*
Noninfected, nonmedicated vs.
Infected, nonmedicated
182.2(a)
144.2(b)
0.00(a)
2.66(b)
SEM+BMD vs.
Infected, nonmedicated
160.2(a)
144.2(b)
1.51(a)
2.66(b)
SEM+BMD vs.
SEM
160.2(a)
168.9(a)
1.51(a)
1.47(a)
SEM+BMD vs.
BMD
160.2(a)
136.3(b)
1.51(a)
2.69(b)

*Means with different superscripts are significantly different (P<0.05).

Table 7. Least squares means for weight gain and lesion scores for broiler chickens inoculated with E. tenella
(study 2211S-60-95-124)

Preplanned Treatment ContrastsWeight gain per bird (g)*Average Cecal lesion score*
Noninfected, nonmedicated vs.
Infected, nonmedicated
322.8(a)
162.4(b)
0.00(a)
2.94(b)
SEM+BMD vs.
Infected, nonmedicated
294.3(a)
162.4(b)
0.47(a)
2.94(b)
SEM+BMD vs.
SEM
294.3(a)
288.0(a)
0.47(a)
0.52(a)
SEM+BMD vs.
BMD
294.3(a)
162.6(b)
0.47(a)2.86(b)

*Means with different superscripts are significantly different (P<0.05).

Table 8. Least squares means for weight gain and lesion scores for broiler chickens inoculated with E. acervulina, E. brunetti, E. maxima, E. mitis, E. necatrix, andE. tenella 
(study 2211S-60-93-125)

Preplanned Treatment ContrastsWeight gain per bird (g)*Upper lesion score*Middle lesion score*Lower lesion score*Cecal lesion score*
Noninfected, vs.
Infected, nonmedicated
279.9(a)
133.9(b)
0.00(a)
1.00(b)
0.00(a)
2.73(b)
0.00(a)
1.17(b)
0.00(a)
1.61(b)
SEM+BMD vs.
Infected, nonmedicated
244.9(a)
133.9(b)
0.58(a)
1.00(b)
1.36(a)
2.73(b)
0.34(a)
1.17(b)
1.00(a)
1.61(b)
SEM+BMD vs.
SEM
244.9(a)
227.1(b)
0.58(a)
0.66(a)
1.36(a)
1.17(a)
0.34(a)
0.31(a)
1.00(a)
1.02(b)
SEM+BMD vs.
BMD
244.9(a)
138.4(b
0.58(a)
1.00(a)
1.36(a)
2.66(b)
0.34(a)
1.33(b)
1.00(a)
1.95(b)

*Means with different superscripts are significantly different (P<0.05).

These data support the efficacy of semduramicin in the presence of bacitracin methylene disalicylate against field strains of monospecific Eimeria species, or a mixed Eimeria species challenge.

B. Floor-Pen Nonchallenge Studies

Efficacy of bacitracin methylene disalicylate in the presence of semduramicin.

Six floor-pen experiments were conducted under simulated field-use conditions to investigate the growth promoting effects of bacitracin methylene disalicylate in the presence of semduramicin. The experiments were conducted at different geographic locations and under varying climatic conditions and animal production practices. The experiments used crossbred broiler chickens. The floor-pen studies were conducted by:

Dr. Carey Quarles
1401 Duff Drive, Suite 700
Colorado Quality Research, Inc.
Fort Collins, CO 80524
Studies 2311S-60-93-116, and -126 Dr. Terry TerHune
Health Management Service
3346 Ave. 248
Tulare, CA 93274
Studies 2311S-60-93-145, and -149

Dr. Park Waldroup
Department of Poultry Science
University of Arkansas
Fayetteville, AR 72701
Studies 2311S-60-93-157, and -158

Each study evaluated two treatments with 12 replicate pens per treatment. Treatments were:

  1. Semduramicin (SEM; 22.7 g/ton)
  2. Semduramicin (SEM; 22.7 g/ton)
  3. Bacitracin methylene disalicylate (BMD; 50 g/ton)

All study directors and personnel involved with animal care and data collection were blinded to treatment identity.

In each of these studies, vaccinated, one-day-old male and female chickens were allocated to 48 pens (12 blocks of 4 pens each) with equal numbers of each sex per pen. The total number of chickens varied from 52 to 62 per pen in these studies in accordance with pen size and local commercial specifications for square footage per bird. Each bird was uniquely wingbanded prior to placement in pens where feed and water were offered ad libitum.

Experimental diets were prepared from uniform, 23 % (starter), 20% (grower), and 18% (withdrawal) crude protein, broiler rations. Diets were formulated to be representative of local diets, and met or exceeded NRC nutritional recommendations. Nutritional composition and drug concentration of the experimental diets were verified by appropriate chemical analyses.

Pens and birds were observed twice daily during the course of the study. Mortalities and culls were identified and their weights recorded. On day 0 and day 45, pens were selected in successive order by block, remaining feed was weighed, and the birds in each pen were grouped and weighed by sex. Average final pen weight and feed:gain were analyzed using general linear models.

Results from the pooled analysis of the data from the floor-pen studies are presented in Table 9.

The analyses of the pooled data indicate that bacitracin methylene disalicylate improved feed efficiency in broiler chickens in the presence of semduramicin. Bacitracin methylene disalicylate did not increase the rate of weight gain in broiler chickens in the presence of semduramicin.

Table 9. Least squares means for average final weight and feed efficiency in broiler chickens

Treatment groupsAverage final weight/bird (kg)*Feed:Gain ration*
SEM2.168(a)1.931(a)
SEM + BMD2.205(a)1.903(b)

*Means with different superscripts are significantly different (P<0.05).

 

V. ANIMAL SAFETY:

Basic animal safety for semduramicin and bacitracin methylene disalicylate is demonstrated in the individually approved NADAs 140-940 and 46-592, respectively, when each drug is fed alone. The floor pen efficacy studies referenced in Section IV demonstrated that no adverse effects were observed, indicating that the drugs were safe when fed in combination. Adequate studies are provided to show that these compounds are compatible in combination when used in broiler chickens. Based on the data in the original NADAs, the presented battery and floor pen efficacy studies, and the tissue residue depletion studies, the combination of drugs was determined to be safe when fed to broiler chickens.

 

VI. HUMAN SAFETY:

A. Toxicity Tests: Data in the parent NADAs demonstrate that these drug products do not constitute a hazard to human health when used in accordance with approved labeling. The basic safety data for semduramicin and bacitracin methylene disalicylate are included in approved NADAs 140-940 and 46-592, respectively.

B. Tolerances and Safe Concentrations of Residues:

The tolerance for residues of bacitracin methylene disalicylate in uncooked tissues of chickens is established at 0.5 ppm (21 CFR §556.70). The safe concentration of semduramicin in chicken muscle tissue is established at 360 ppb in NADA 140-940.

C. Residue Depletion Noninterference Studies:

Experiment No. 2511S-60-90-010 was conducted to support approval of the use of semduramicin (25 ppm) and bacitracin methylene disalicylate (10-50 g/ton) in broiler feed.

Mr. R. Michael Bodden
Hazleton Laboratories America, Inc.
P. O. Box 7545
Madison, WI 53707
Study No. 2511S-60-90-010

In Exp. 2511S-60-90-010 residues of semduramicin, roxarsone (arsenic), and bacitracin methylene disalicylate were determined after feeding a three-way combination of semduramicin + roxarsone + bacitracin methylene disalicylate at 22.7 g/ton, 45.4 g/ton, and 50.0 g/ton, respectively, for 44 days followed by a 5-day withdrawal period. In Exp. 2511S-60-94-152, residues for roxarsone (arsenic) were determined following feeding of the same combination for 38 days followed by a 5-day withdrawal period.

Newly hatched broiler chickens were equally divided by sexes and fed either a nonmedicated or medicated diet until the scheduled day of withdrawal. Birds formerly on the medicated diet were then fed a nonmedicated diet for an additional 5 days (withdrawal period). To simulate the time of transporting birds to a slaughter processing facility, birds were held off feed and water for 6 hours prior to slaughter for each scheduled withdrawal time period followed in the study.

Twelve birds (6 males and 6 females), from either the nonmedicated (control) treatment of the medicated treatment were sacrificed and tissues were collected at each of the scheduled times of withdrawal. Also, tissues from the nonmedicated birds were collected and designated as "control birds, 0 hour withdrawal". Livers were collected for semduramicin analysis at 0, 6, 12, and 24 hours withdrawal, while muscle tissue was collected for bacitracin methylene disalicylate analysis at 0 and 24 hours withdrawal.

Semduramicin and bacitracin methylene disalicylate tissue assay values at the various withdrawal times is presented in Table 10. The mean residue values at each of the withdrawal times were below the established tolerances for each of the drugs. Semduramicin has a research tolerance of 400 ppb for parent drug in liver (based on parent being 37% of the safe concentration of 1080 ppb for liver).

TABLE 10. Tissue residue studies in broiler chickens using medicated feed containing semduramicin (SEM) and bacitracin methylene disalicylate (BMD)*

STUDY NO. 2511S-60-90-010 SEMDURAMICIN (ppb) - LIVER(a)

 HOURS OF WITHDRAWAL
 06122472120
MEAN21813667.6(b)53.4(c)NANA
SD123.559.1NANANANA
SE35.6517.06NANANANA
N12121212NANA

 

STUDY NO. 2511S-60-90-010 BACITRACIN (ppm) - BREAST MUSCLE(a)

 HOURS OF WITHDRAWAL
 06122472120
MEANNDLNANANDLNANA
SDNANANANANANA
SENANANANANANA
N12NANA12NANA

Note:Dietary fortification: semduramicin (22.7 g/t) plus roxarsone (45.4 g/t) plus bacitracin methylene disalicylate (50 g/t).

*Abbreviations code as follows:
SDStandard deviation
SEStandard error
NNumber of animals
NANot applicable
NRNot reported
NDLNo detectable level (assay sensitivity 0.3 ppm)

a Combined male and female data.

b Mean of four animals. Remaining eight animals show no residues (less than 40 ppb).

c Value for one animal. Remaining 11 animals show no residues (less than 40 ppb).

The following analytical procedures were used to assay for drug residues: HPLC for determination of parent semduramicin in poultry liver using vanillin post column derivitization; the silver diethyldithiocarbamate method for arsenic (AOAC method 25.048); a microbiological assay for determination of bacitracin in tissues. Validation data were collected for each assay.

D. Assay Noninterference

Along with the residue depletion studies summarized above, the sponsor conducted experiments to demonstrate assay noninterference. Thus, liver samples were spiked with 0.5 ppm bacitracin methylene disalicylate, or with 0.5 ppm bacitracin methylene disalicylate, 83 ppb semduramicin, and 2 ppm roxarsone. The recovery of bacitracin was 80% from liver containing only bacitracin methylene disalicylate, and 86% from the sample containing the combination. In a similar study for semduramicin, the sponsor found that the recovery of semduramicin at 83 ppb was 75.8% from liver spiked with semduramicin alone, and 79.1% from liver spiked with the combination.

E. Regulatory Methods

The requirement of a regulatory method to monitor for residues of semduramicin in tissues of chickens was waived under NADA 140-940. Practical analytical methods for determination of residues of bacitracin methylene disalicylate in edible tissues of chickens are on file at the Food and Drug Administration's Freedom of Information Room (Room 12A-30), 5600 Fishers Lane, 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 semduramicin (22.7 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.

Data show that at zero withdrawal residues of bacitracin methylene disalicylate are below the tolerance of 0.5 ppm in edible chicken tissues, and that residues of semduramicin are below applicable safe concentrations. Therefore, these data support the assignment of a zero withdrawal.

The battery challenge studies demonstrated that semduramicin in the presence of bacitracin methylene disalicylate prevented coccidiosis when the birds were exposed to the six major species of Eimeria infecting chickens. The data from six floor-pen nonchallenge studies demonstrate the effectiveness of bacitracin methylene disalicylate in the presence of semduramicin and roxarsone for improved feed efficiency. In accordance with CVM's guideline entitled "Guideline for Drug Combinations for Use in Animals" (October 1983), Pfizer Inc. is permitted the range of 10 to 50 g/ton of bacitracin methylene disalicylate in the Type C medicated feed for the prevention of coccidiosis caused by Eimeria acervulina, E. brunetti, E. maxima, E. mivati/mitis, E. necatrix, and E. tenella, and for improved feed efficiency in broiler chickens, 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