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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 141-066 Aviax™, 3-Nitro® - original approval

Approval Date: November 7, 1997

I. GENERAL INFORMATION:

NADA141-066
Sponsor:Pfizer Inc.
235 East 42nd Street
New York, New York 10017
Generic Name:semduramicin, roxarsone
Trade Name:Aviax™, 3-Nitro®
Marketing Status:Over the Counter (OTC)

 

II. INDICATIONS FOR USE:

For the prevention of coccidiosis in broiler chickens caused Eimeria acervulina, E. brunetti, E. maxima, E. mivati/mitis, E. necatrix, including some field strains of E. tenella that are more susceptible to semduramicin combined with roxarsone than semduramicin alone.

 

III. DOSAGE

A.DOSAGE FORMThis NADA provides for the combined use of two Type A medicated articles, semduramicin as per 21 CFR 558.555 and roxarsone as per 21 CFR 558.530. Semduramicin is supplied as a Type A medicated article in a single concentration of 22.7 grams of semduramicin activity per pound. Roxarsone is supplied as a Type A medicated article in concentrations of 45.4, 90, and 227 grams of roxarsone activity per pound.
B.ROUTE OF ADMINISTRATIONOrally, via the feed.
C.RECOMMENDED DOSAGES:

Semduramicin 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.

Roxarsone is added to broiler chicken feed at a concentration of 45.4 g/ton for the prevention of coccidiosis caused by some field strains of E. tenella that are more susceptible to semduramicin combined with roxarsone than semduramicin alone.

Complete feed containing these two compounds is to be fed continuously as the sole diet. Withdraw 5 days prior to slaughter. For broiler chickens only. Do not feed to laying hens. Use as the sole source of organic arsenic. Poultry should have access to drinking water at all times. Drug overdosage or lack of water intake may result in leg weakness or paralysis.

 

IV. EFFECTIVENESS:

A. Coccidial-challenge studies No.'s 2211S-60-93-114, -117, and -118

Effectiveness of roxarsone in the presence of semduramicin.

A series of three independent coccidial-challenge experiments using crossbred broiler chickens were conducted to determine the anticoccidial effectiveness of roxarsone in the presence of semduramicin. Chickens were challenged with recent (less than three years old) field isolates of E. tenella to demonstrate the efficacy of roxarsone in the presence of semduramicin for the prevention of coccidiosis in broiler chickens caused by some field strains of E. tenella that are more susceptible to roxarsone combined with semduramicin than semduramicin alone. 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.

One-day-old, sexed, crossbred broiler chickens were raised in a coccidiosis-free environment, under environmentally controlled conditions, on a nonmedicated diet until 12 days of age. Birds were then uniquely identified, assigned to one of four treatment groups, and fed the appropriate medicated diet.

Each experiment consisted of four treatments:

  1. Noninfected, nonmedicated (NINM)
  2. Infected, nonmedicated (INM)
  3. Infected, semduramicin (SEM; 22.7 g/ton)
  4. Infected, semduramicin (SEM; 22.7 g/ton) + roxarsone (ROX; 45.4 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 throughout the battery.

On study-day zero (11 to 13 days-of-age), 384 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 E. tenella 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 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 6 days post-inoculation (study-day 8) birds were weighed, and the experiment terminated. Cecal lesions were scored by the Johnson and Reid (1970) method for the appropriate zone.

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 bird2 and average lesion score were statistically evaluated using either general linear models or mixed model methodology. 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 roxarsone in preventing E. tenella coccidiosis (weight gain depression and increased lesion scores) in the presence of semduramicin.

The results of the statistical analyses of the data from these experiments are depicted in Tables 1 to 3. In study 2211S-60-93-114 (Table 1), a significant sex by treatment interaction was observed and the analyses were conducted separately for each sex. The noninfected/nonmedicated vs. infected/nonmedicated comparison indicated that there was an adequate infection in both sexes.
The SEM + ROX vs. infected/nonmedicated comparison, and the SEM + ROX vs. SEM comparison shows that the two-way combination was effective for reducing lesion scores in both sexes, and for relieving weight gain depression.

Table 1. Least squares means for weight gain and lesion scores for broiler chickens inoculated with a field strain of E. tenella (study 2211S-60-93-114)
Preplanned treatment
contrasts
Weight gain/bird (g)1, 2Cecal lesion score1
Noninfected, nonmedicated
vs.
Infected, nonmedicated
315.7a

260.8b
0.00a

2.27b
SEM + ROX
vs.
Infected, nonmedicated
301.6a

260.8b
1.00a

2.27b
SEM + ROX
vs.
SEM
301.6a

287.4a
1.00a

2.18b

1Means with different superscripts are significantly different (P<0.05).

2 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)

In study 2211S-60-93-117 (Table 2), the sex by treatment interaction was not significant and the data were pooled across sex for analysis. The noninfected/nonmedicated vs. infected/nonmedicated comparison indicates that there was an adequate infection. The SEM + ROX vs. infected/nonmedicated comparison shows that the two-way combination was effective for reducing lesion scores and for relieving weight gain depression. The SEM + ROX vs. SEM comparison shows that the two-way combination was effective for reducing lesion scores, and for relieving weight gain depression.

Table 2. Least squares means for weight gain and lesion scores for broiler chickens inoculated with a field strain of E. tenella (study 2211S-60-93-117)
Preplanned treatment
contrasts
Weight gain/bird (g)1Cecal lesion score1
Noninfected, nonmedicated
vs.
Infected, nonmedicated
293.9a

258.4b
0.00a

3.16b
SEM + ROX
vs.
Infected, nonmedicated
280.3a

258.4b
1.23a

3.16b
SEM * ROX
vs.
SEM
280.3a

261.5a
1.23a

2.50b

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

In study 2211S-60-93-118 (Table 3), the sex by treatment interaction was not significant, and the data were pooled across sex for analysis. The noninfected/nonmedicated vs. infected/nonmedicated comparison indicates that there was an adequate infection. The SEM + ROX vs. infected/nonmedicated comparison, and the SEM + ROX vs. SEM comparison shows that the two-way combination was effective for reducing lesion scores and for relieving weight gain depression.

Table 3. Least squares means for weight gain and lesion scores for broiler chickens inoculated with a field strain of E. tenella (study 2211S-60-93-118)
Preplanned treatment
contrasts
Weight gain/bird (g)1Cecal lesion score1
Noninfected, nonmedicated
vs.
Infected, nonmedicated
312.8a

220.9b
0.00a

3.15b
SEM + ROX
vs.
Infected, nonmedicated
284.9a

220.9b
1.35a

3.15b
SEM + ROX
vs.
SEM
284.9a

257.0b
1.35a

2.44b

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

Collectively, these data demonstrate that roxarsone in the presence of semduramicin was effective for reducing lesion scores and relieving weight gain depression. These data support the efficacy of roxarsone in the presence of semduramicin for the prevention of coccidiosis in broiler chickens caused by some field strains of E. tenella that are more susceptible to roxarsone combined with semduramicin than semduramicin alone.

 

V. ANIMAL SAFETY:

Basic animal safety for semduramicin and roxarsone is demonstrated in the individually approved NADAs 140-940 and 007-891, respectively, when each drug is fed alone.

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 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 roxarsone are included in approved NADAs 140-940 and 7-891, respectively.

B. Tolerances and Safe Concentrations of Residues:

The tolerance for residues of roxarsone (as residues of arsenic in edible tissues of chicken) are established at 0.5 ppm arsenic in muscle and 2.0 ppm arsenic in edible by-products (21 CFR 556.60). The safe concentration of semduramicin in chicken muscle tissue is established at 360 ppb in NADA 140-940.

C. Residue Depletion Noninterference Studies:

Two tissue residue depletion studies were conducted to demonstrate that there were no changes in the residue depletion pattern of semduramicin and roxarsone when fed to broiler chickens in combination. The studies were conducted by the following investigators:

Mr. R. Michael Bodden
Hazleton Laboratories America, Inc.
P.O. Box 7545
Madison, WI 53707
Study No. 2511S-60-90-010 Dr. Erica Little
Midwest Research Institute
425 Volker Blvd.
Kansas City, MO 64110
Study No. 2511S-60-94-152

In Exp. 2511S-60-90-010 residues of semduramicin and roxarsone 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 were determined following feeding of the same combination for 38 days followed by a 5-day withdrawal period.

In both experiments, 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.

In each experiment, 12 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." For Exp. 2511S-60-90-010, livers were collected for semduramicin analysis at 0, 6, 12, and 24 hours withdrawal and for roxarsone (arsenic) analysis at 0, 72, and 120 hours withdrawal. For Exp. 2511S-60-94-152, livers were collected for roxarsone (arsenic) analysis at 0, 24, 72, and 120 hours withdrawal.

A summary of the tissue residue assay values at the various withdrawal times is presented in Table 4. 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). Semduramicin tissue assay values in Table 4 were reported from Exp. 2511S-60-94-152. Liver roxarsone (arsenic) means from Exp.. 2511S-60-90-010 were well below the tolerance limit of 2.0 ppm at each of the withdrawal times (0, 72, and 120 hours); however, these values were not reported in Table 4 because lower than expected values for arsenic were found at the 0-hour withdrawal time, which precluded the establishment of a normal depletion curve.

TABLE 4. Tissue Residue Studies in Broiler Chickens Using Medicated Feed Containing Semduramicin (SEM), Roxarsone (ROX)*
STUDY NO.HOURS OF WITHDRAWAL
06122472120
2511S-60-90-010SEMDURAMICIN (ppb) - LIVERa
MEAN21813667.6b53.4cNANA
SD123.559.1NANANANA
SE35.6517.0NANANANA
N12121212NANA
2511S-60-94-152ARSENICd (ppm) - LIVERa
MEAN0.72NANA0.440.300.16
SD0.35NANA0.130.150.08
SENRNANANRNRNR
N12NANA121212

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:

SD Standard deviation
SE Standard error
N Number of animals
NA Not applicable
NR Not reported
NDL No detectable level (assay sensitivity 0.3 ppm)

a Combined male and female data.
b Mean of four animals. Remaining eight animals showed no residues (less than 40 ppb).
c Value for one animal. Remaining 11 animals showed no residues (less than 40 ppb).
d Roxarsone contains 28.4% arsenic.

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). 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 83 ppb semduramicin, or with 0.5 ppm bacitracin methylene disalicylate, 83 ppb semduramicin, and 2 ppm roxarsone. 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.

Because the determination of arsenic involved ashing, similar work to show no effect from semduramicin was unnecessary.

E. Regulatory Methods

The requirement of a regulatory method to monitor for residues of semduramicin in tissues in chickens was waived under NADA 140-940. Practical analytical methods for determination of residues of arsenic 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 original NADA 141-066 satisfy the requirements of section 512 of the Federal Food, Drug and Cosmetic Act (FFDCA). The data demonstrate that semduramicin sodium and roxarsone in complete feed, when used for the proposed conditions, is safe and effective for the labeled indications.

The approval provides for the use of semduramicn sodium at 22.7 g/ton and roxarsone at 45.4 g/ton for the prevention of coccidiosis in broiler chickens caused by Eimeria acervulina, E. brunetti, E. maxima, E. mivati/mitis, E. necatrix, including some strains of E. tenella that are more susceptible to semduramicin combined with roxarsone than semduramicin alone.

Proper use by lay persons can be expected because poultry producers routinely use medicated feed containing an animal drug for the prevention of coccidiosis in broiler chickens. Directions are clearly written and there is reasonable certainty that the conditions of use, including mixing directions on the label, can and will be followed by the producer. The agency has concluded that this product can be approved for over-the-counter use.

Tissue depletion data demonstrates that there were no changes in the residue depletion pattern of semduramicin and roxarsone when fed to chickens in combination. The requirement of a regulatory method to monitor for residues of semduramicin in tissues in broiler chickens was waived. Analytical methods for determiantion of residues of arsenic in tissues are on file at the FDA.

Under section 512(c)(2)(F)(ii) of the FFDCA this approval for food producing animals qualifies for THREE years of marketing exclusivity begining on the date of approval because the application contains 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. Blue Bird Semduramicin/Roxarsone Type C Broiler Feed Medicated

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