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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 128-686 Bio-Cox® - supplemental approval (February 3, 1997 )

Approval Date: February 3, 1997

I. GENERAL INFORMATION:

NADA 128-686
Sponsor: Hoffmann-La Roche
340 Kingsland Street
Nutley, New Jersey 07110-1199
Generic Name: salinomycin sodium
Trade Name: Bio-Cox®
Marketing Status:  
Effect of Supplement: To add roaster and replacement (breeder and layer) chickens to the label claim for the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati.

II. INDICATIONS FOR USE

BROILER, ROASTER, REPLACEMENT (BREEDER AND LAYER) CHICKENS

For the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E acervulina, E. maxima, E. brunetti, and E. mivati.

QUAIL

For the prevention of coccidiosis caused by Eimeria dispersa and E. lettyae.

III. DOSAGE

A. DOSAGE FORM Type A medicated article to be mixed with feed to produce a Type C medicated feed.
B. ROUTE OF ADMINISTRATION This drug is administered orally by adding the Type A medicated article to feed to make a complete feed (Type C medicated feed).
C. RECOMMENDED DOSAGES:  
  BROILER, ROASTER, REPLACEMENT (BREEDER AND LAYER) CHICKENS 40 to 60 g/ton of Type C medicated feed
  QUAIL 50 g/ton of Type C medicated feed

IV. EFFECTIVENESS:

Salinomycin is presently approved in NADA 128-686 for use in broilers with the following claim: Salinomycin 40-60 g/ton for the "prevention of coccidiosis caused by E. acervulina, E. brunetti, E. maxima, E. mivati, E. necatrix, and E. tenella."

The present supplement to approved NADA 128-686 demonstrates that salinomycin at 40-60 g/ton is an effective anticoccidial in battery studies and is a safe and effective anticoccidial under commercial conditions in layer replacement chickens.

No new data were required to support use in roasters. Efficacy data in broilers and target animal safety data in broiler breeders support the claim for use in roasters.

The new claim will be: "For the prevention of coccidiosis caused by E. tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati." Salinomycin will be used at 40-60 g/ton. Salinomycin will not be fed to chickens producing eggs for food or to chickens over 16 weeks of age.

A. Battery Efficacy Studies in Layer Replacement Chickens

A total of 4,840 healthy two-week-old, DeKalb, layer replacement chickens were used in 11 adequate, well-controlled, battery studies conducted in a uniform environment with continuous artificial illumination to test the effectiveness of salinomycin in layer replacement chickens.

These studies (Table I) were conducted to determine the effective medication level of salinomycin in layer replacement chickens. In each of the 11 trials, a pretrial titration utilizing a 1X, 2X, and 3X dose level of oocysts was conducted to properly set the dose level for each trial.

Female birds were randomized by weight and assigned to cages with 10 birds/cage. There were 4 replicates per treatment group. The medication levels, started two days before infection, were 0, 20, 40, 60, and 90 g/ton salinomycin. Evaluations were by lesion scores (preselected birds), dropping scores, weight gains, feed conversion, and coccidiosis mortality.

There were 5 trials using a mixture of E. acervulina/mivati, E. maxima, E. brunetti, E. necatrix, and E. tenella. There were two trials each using single species of E. tenella, E. brunetti, and E. necatrix.

The investigators involved in the above studies were as follows:

Shi E. Cheng, D.V.M., Ph.D.
A. H. Robins Research Farm
1407 Cummings Drive
P.O. Box 26609
Richmond, VA 23261-6609

Kevin M. Kilgore, B.S.
A. H. Robins Research Farm
1407 Cummings Drive
P.O. Box 26609
Richmond, VA 23261-6609

Patricia C. Gerber, A.A.S.
A. H. Robins Research Farm
1407 Cummings Drive
P.O. Box 26609
Richmond, VA 23261-6609

Thomas A. Sheets
A. H. Robins Research Farm
1407 Cummings Drive
P.O. Box 26609
Richmond, VA 23261-6609

These studies demonstrate that the effective medication level for layer replacement chickens is salinomycin at 40-60 g/ton. The medication level of 20 g/ton was too low to be an effective anticoccidial agent and the level of 90 g/ton was a highly effective anticoccidial agent, but depressed weight gain, indicating slight toxicity. Results for the approved dosage levels of 40-60 g salinomycin per ton of feed are presented in Table I.

Ed. note:  The following table has 7 columns.

TABLE I E. tenella - Low Infection

                      Weight    Weight    Feed    Feed                       
Treatment  Dropping    Gain      Gain     Conv.   Conv.    Lesion    Coccidiosis  
  g/ton     Score*    Day 7     Day 14    Day 7   Day 14   Score**    Mortality            
--------------------------------------------------------------------------------                                                                                  
     0       10.0      40.6     121.0     5.01     3.78     9.9         12.5%     
    40        2.8      67.9     140.2     3.25     3.06     3.0          0.0      
    60        1.8      67.2     139.6     3.22     2.98     0.4          0.0      
E. tenella - High Infection
                      Weight    Weight    Feed    Feed                       
Treatment  Dropping    Gain      Gain     Conv.   Conv.    Lesion    Coccidiosis  
  g/ton     Score*    Day 7     Day 14    Day 7   Day 14   Score**    Mortality            
--------------------------------------------------------------------------------                                                                                  
     0       11.9      35.1     109.3     7.61     5.29    11.3         55.0%     
    40        4.5      59.3     135.1     3.60     3.35     4.5          6.3%      
    60        1.1      66.8     140.5     3.06     3.05     1.8          0.0      
E. brunetti - Low Infection
                      Weight    Weight    Feed    Feed                       
Treatment  Dropping    Gain      Gain     Conv.   Conv.    Lesion    Coccidiosis  
  g/ton     Score*    Day 7     Day 14    Day 7   Day 14   Score**    Mortality            
--------------------------------------------------------------------------------                                                                                  
     0       10.3      26.2     106.7     6.13     3.82     7.1          2.5%     
    40        3.4      52.4     131.6     3.92     3.43     2.4          0.0      
    60        1.9      59.2     136.4     3.55     3.19     1.3          0.0      
E. brunetti - High Infection
                      Weight    Weight    Feed    Feed                       
Treatment  Dropping    Gain      Gain     Conv.   Conv.    Lesion    Coccidiosis  
  g/ton     Score*    Day 7     Day 14    Day 7   Day 14   Score**    Mortality            
--------------------------------------------------------------------------------                                                                                  
     0       11.9      20.3     100.7    10.72     4.30     8.5         11.3%     
    40        4.3      47.9     126.1     4.78     3.43     2.5          0.0      
    60        2.5      57.5     132.4     4.45     3.35     1.6          0.0      
E. necatrix - Low Infection
                      Weight    Weight    Feed    Feed                       
Treatment  Dropping    Gain      Gain     Conv.   Conv.    Lesion    Coccidiosis  
  g/ton     Score*    Day 7     Day 14    Day 7   Day 14   Score**    Mortality            
--------------------------------------------------------------------------------                                                                                  
     0       20.8      20.9      85.1     6.71     5.18    10.8         55.0%     
    40        8.8      55.0     120.4     3.69     3.35     2.6          0.0      
    60        5.6      62.2     123.9     3.15     3.20     1.4          0.0      
E. necatrix - High Infection
                      Weight    Weight    Feed    Feed                       
Treatment  Dropping    Gain      Gain     Conv.   Conv.    Lesion    Coccidiosis  
  g/ton     Score*    Day 7     Day 14    Day 7   Day 14   Score**    Mortality            
--------------------------------------------------------------------------------                                                                                  
     0       23.3      16.7      80.0     7.78     5.97    11.4         58.8%     
    40        7.5      53.6     113.1     3.88     3.39     3.5          0.0      
    60        5.1      59.5     119.9     3.37     3.21     2.1          0.0      
Mixed - Low Infection
                      Weight    Weight    Feed    Feed                       
Treatment  Dropping    Gain      Gain     Conv.   Conv.    Lesion    Coccidiosis  
  g/ton     Score*    Day 7     Day 14    Day 7   Day 14   Score**    Mortality            
--------------------------------------------------------------------------------                                                                                  
     0       13.5      21.2      89.3     6.84     4.33    19.1         18.5%     
    40        3.7      58.7     128.9     3.17     3.11     7.2          0.0      
    60        1.7      62.6     131.2     2.94     2.94     4.9          0.0      
Mixed - High Infection
                      Weight    Weight    Feed    Feed                       
Treatment  Dropping    Gain      Gain     Conv.   Conv.    Lesion    Coccidiosis  
  g/ton     Score*    Day 7     Day 14    Day 7   Day 14   Score**    Mortality            
--------------------------------------------------------------------------------                                                                                  
     0       17.3      15.7      77.4     7.90     5.72    21.9         42.5%     
    40        4.9      51.7     124.3     3.27     3.26     8.9          1.0      
    60        2.6      57.7     125.8     2.97     3.31     5.2          1.0      
*Dropping Score - Sum of dropping scores Days 5-9
**Lesion Score - Sum of Score for 3 birds/pen

B. Field Studies - Layer Replacement Chickens

Three adequate and well-controlled field studies, utilizing 84,265 pullets, were conducted under conditions of actual use to determine the effect of feeding salinomycin at 60 g/ton for 16 weeks. The objective of the studies was also to evaluate safety at the highest use level under commercial conditions. The studies were conducted in two geographical locations and three pullet operations.

In these studies, nine houses were used. The square footage per bird was 0.75-0.90. Each house had used litter which was top dressed with wood shavings prior to placing the pullets. The studies were designed to simulate varying conditions, such as differences in geographical location and climate, changes in weather, and differences in management practices and degree of contamination of the premises. In each of the studies, the pullets grew normally and entered egg production at the same time as other pullets the same age. There were no signs of toxicity or side effects and livability was normal. In summary, salinomycin, at the highest level of 60 g/ton, was effective in preventing coccidiosis, there was no evidence of toxicity, and birds were brought into egg production in the way practiced by the growers with good results.

1) STUDY No. 85-071:

a. Type of Study: Clinical Efficacy

For the evaluation of salinomycin as an anticoccidial in commercial scale growing of replacement chickens intended for use as cage layers.

b. Investigators:

Dr. Larry R. McDougald
Professor, Poultry Science
University of Georgia
Livestock-Poultry Building
Athens, GA 30602

Larry Thomason
Thomason Egg Farm
Calhoun, GA 30701

c. General Design of Investigation:

a) Objective:

To evaluate the safety and efficacy of salinomycin at 60 g/ton in layer chickens grown under commercial production in the United States.

b) Test Animals:

34,568 one-day old Hyline W-36 breed of single comb White Leghorns

c) Dosage Form:

Type A medicated article

d) Route of Administration:

Salinomycin premix was mixed with feed at 2 lb/ton (60 g/ton). The birds were started on feed containing the drug at day one.

e) Dosage Used:

60 g/ton

f) Test Duration:

16 weeks

g) Pertinent Parameters Measured:

  • Intestinal lesion scores at 31 days of age
  • Mortality
  • General observations
  • Body weight
  • Microscopic exam of litter to determine Eimeria oocysts

d. Results:

The birds developed normally and were brought into egg production at 22 weeks of age. The lesion scores were low. The microscopic observations indicated the presence of E. acervulina and E. maxima. The mortality pattern was normal for the farm.

e. Conclusion:

The results demonstrate that salinomycin is suitable for use as an anticoccidial in Leghorn pullets intended as cage layers.

f. Adverse Reactions:

No adverse drug reactions were observed.

2) STUDY No. 85-072:

a. Type of Study: Clinical Efficacy

For the evaluation of salinomycin as an anticoccidial in commercial scale growing of replacement chickens intended for use as cage layers.

b. Investigators:

Dr. Larry R. McDougald
Professor, Poultry Science
University of Georgia
Livestock-Poultry Building
Athens, GA 30602

Jack Self
Cal-Maine Foods
P.O. Box 2960
Jackson, MS 39207

c. General Design of Investigation:

a) Objective:

To evaluate the safety and efficacy of salinomycin at 60 g/ton in layer chickens grown under commercial production in the United States.

b) Test Animals:

16,560 one-day old commercial type White Leghorns Hyline W-36

c) Dosage Form:

Type A medicated article

d) Route of Administration:

Salinomycin premix was mixed with feed at 2 lb/ton (60 g/ton). The birds were started on feed containing the drug at day one.

e) Dosage Used:

60 g/ton

f) Test Duration:

16 weeks

g) Pertinent Parameters Measured:

  • Lesion scores
  • Mortality
  • General observations
  • Diseases or conditions diagnosed

d. Results:

The egg production was considered normal at 22 weeks of age. The general appearance of the birds was normal. Seven of 20 intestines examined presented lesions corresponding to E. tenella and E. maxima. The mortality was considered usual compared with previous years.

e. Conclusion:

The study confirms that salinomycin at 60 g/ton is effective against natural infection of Eimeria spp.

f. Adverse Reactions:

No adverse drug reactions were observed.

3) STUDY No. 85-205:

a. Type of Study: Clinical Efficacy

For the evaluation of salinomycin as an anticoccidial in commercial scale growing of replacement chickens intended for use as cage layers.

b. Investigators:

Dr. Larry R. McDougald
Professor, Poultry Science
University of Georgia
Livestock-Poultry Building
Athens, GA 30602

Douglas Grubs
Farm Fresh Eggs
Newborn, GA 30262

c. General Design of Investigation:

a) Objective:

To evaluate the safety and efficacy of salinomycin at 60 g/ton in layer chickens grown under commercial production in the United States.

b) Test Animals:

33,137 one-day old commercial type White Leghorns Hyline W-36

c) Dosage Form:

Type A medicated article

d) Route of Administration:

Salinomycin premix was mixed with feed to provide 60 g salinomycin/ton of feed. The birds were started on feed containing the drug at day one.

e) Dosage Used:

60 g/ton

f) Test Duration:

16 weeks

d. Results:

The birds developed normally throughout the starting and growing period and they entered egg production at 22 weeks of age. The overall mortality was 3.9% including culling and death losses to all causes.

e. Conclusion:

The study confirms that salinomycin at 60 g/ton is effective against natural infection of Eimeria spp.

f. Adverse Reactions:

No adverse drug reactions were observed.

V. ANIMAL SAFETY

Refer to the FOI Summary for the original approval of salinomycin in broiler chickens (NADA 128-686 and 21 CFR 558.550). The studies covered the evaluation of salinomycin in broiler chickens from day one of age to marketing.

The safety of salinomycin in layer replacement and broiler breeder chickens was determined in a target animal safety study utilizing medication levels of 0, 60, 90, and 120 g/ton salinomycin, and a medication period of 16 weeks. The study was designed to evaluate 1x, 11/2x, and 2x because of the narrow margin of safety of salinomycin in poultry. Hatchability, fertility, and teratology was determined in these chickens following the medication period.

STUDY No. 84-181:

1) Type of Study: Target Animal Safety

2) Investigator:

Dr. Carey L. Quarles
Colorado Quality Research, Inc.
2629 Redwing Road, Suite 315
Fort Collins, Colorado 80526

3) General Design of Investigation:

a) Objective: To determine the safety of salinomycin at 60, 90, and 120 g/ton on the performance of cage layer and broiler replacement chickens raised on floor pens.

b) Test Animals: 1000 one-day old (40-46 g) short comb White Leghorn (Hy-Line) and 920 broiler breeders (Arbor Acres) were randomly assigned into 4 treatments: 40 female and 10 male Leghorns and 36 female and 10 male broiler breeders per treatment.

c) Treatments

Salinomycin was administered at 60, 90, and 120 g/ton. Diets were available free choice throughout the test for the layer replacement chickens. Diets for the broiler breeders were fed free choice for the first 28 days and then the feeding followed the recommendations of the Arbor Acres Breeder Management Guide which limits the feed consumption to control body weight within a desired range. One group did not receive drug treatment. Birds were placed on 4-5 inches new wood shavings.

d) Parameters:

Body weight and feed consumption were measured at Days 28, 84, and 112. Mortality was recorded and necropsy was performed on the dead birds. Daily observations were made of feathering, abnormal behavior, and litter moisture.

One preselected female and male from each group were used for hematological studies. The following blood parameters were measured: total WBC, RBC, Hct, Hb, and clotting time at 4 days and 16 weeks. At 16 weeks (112 days), 3 females and 1 male were randomly selected from each treatment for histopathological examination. At 16 weeks of age, 3 males and 3 females were randomly selected for determination of salinomycin in skin/fat (tissue residue).

At 16 weeks a group of 20 randomly selected female layer replacements (4/each pen) from each treatment were placed in laying cages. At 20, 24, 28, and 32 weeks of age all eggs for 3 consecutive days were saved for evaluation of egg weights, shell thickness, interior egg quality (yolk color, blood and meat spots, albumen thickness, and organoleptic tests). Weekly feed intake and feed/egg ratios were determined for these birds.

At 16 weeks, 32 females and 3 males from each treatment group (broiler breeder) were selected and housed in 4 different pens. Birds were subjected to a standard management program as recommended by Arbor Acres Breeders. When the birds came into production, all eggs for 10 days were collected and set for hatchability and fertility data for 4 consecutive 28-day periods. Fertility and hatchability were determined. Following hatching, a random sample of 25 chickens were wing banded and grown to 28 days of age for a teratologic examination.

4) Results:

The results from the testing were: no clinical pathological or hematological effects, no gross pathology or histopathology, no teratologic effects, no adverse effects of percent hatch or egg quality, no adverse effects on weekly feed intake or feed/egg ratio, and no adverse effects on growth or feed conversion at the use level. The only adverse effects noted at 90 and 120 g/ton were lower body weight and slightly poor feathering in two pens of layers and 3 pens of broiler breeders at Days 28 and 84 and in 2 pens of broiler breeders at Day 112. The tissue residue of salinomycin in skin/fat was <116 ppb, which is well below the acceptable upper limit of 200 ppb.

5) Conclusion:

The study conducted in layer and broiler breeder replacement chickens demonstrates that salinomycin at 60 g/ton is safe to the target birds.

VI. HUMAN FOOD SAFETY:

A. Data to Support Human Safety

Refer to the FOI Summary in the original approval of salinomycin in broiler chickens. Safety for the approved drug salinomycin has been demonstrated by data submitted in the parent NADA 128-686.

Safe concentrations for total residues of salinomycin in the edible tissues of chickens are 0.6 ppm for muscle, 1.8 ppm for liver, and 1.2 ppm for skin/fat. The upper limit for residues of parent salinomycin in skin/fat is 200 ppb at zero withdrawal (NADA 128-686).

B. Residue Depletion/Non-interference Studies

Six Leghorn chickens (3 males, 3 females) and 6 broiler breeders (3 males, 3 females) were maintained on feed containing 60 g/ton salinomycin from 1 day of age. On Day 112 of the experiment, the chickens were removed from feed and held 6 hours before sacrifice. Abdominal skin/fat was collected from each bird for analysis of salinomycin with an HPLC procedure. Validation data were provided for control skin/fat samples that had been spiked with salinomycin at 125, 275, 450, 600, 750 and 925 ppb. Over those concentrations the recoveries ranged from 94.6% to 103.5%, with an average of 100.5%.
All the samples from broiler breeder chickens and 3 of 6 samples from the Leghorns were found to be less than 100 ppb. The samples from the 3 remaining Leghorns were 107, 140, and 100 for an average of 116 ppb. For all the samples, the average would be less than 116 ppb. The results of this study show, therefore, that residues in skin/fat of treated chickens at zero withdrawal are below the upper limit of 200 ppb.

C. Regulatory Method

A regulatory analytical methodology for salinomycin is not required.

VII. AGENCY CONCLUSIONS:

The data submitted in support of this supplemental NADA comply with the requirements of section 512 of the Act and demonstrate that salinomycin sodium, when used under the proposed conditions of use, is safe and effective for the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E acervulina, E. maxima, E. brunetti, and E. mivati in roaster and replacement (layer and broiler breeder) chickens.

Based on tissue residue studies, a zero day withdrawal period is assigned for roaster and replacement (layer and broiler breeder) chickens treated with salinomycin sodium at the recommended dosage.

The original approval of salinomycin sodium was as an over-the-counter drug. Adequate directions for use have been written for the layman, and the conditions for use prescribed on the labeling are likely to be followed in practice. Therefore, the Center for Veterinary Medicine (CVM) has concluded that this product shall retain over-the-counter marketing status.

Under the Center's supplemental approval policy 21 CFR 514.106(b)(2), this is a Category II change. The approval of this change did not require a reevaluation of the safety or effectiveness data in the parent application.

Under section 512(c)(2)(F)(iii) of the FFDCA, this approval for food producing animals qualifies for THREE years of marketing exclusivity beginning on the date of approval because the supplemental application contains substantial evidence of the effectiveness of the drug involved, any studies of animal safety, or, in the case of food producing animals, human food safety studies (other than bioequivalence or residue studies) required for the approval of the application and conducted or sponsored by the applicant. The THREE years of marketing exclusivity applies only to the claim for use in roaster and replacement (breeder and layer) chickens for the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E acervulina, E. maxima, E. brunetti, and E. mivati.

VIII. LABELING (Attached)

The following labeling is attached.

  • Facsimile Type A medicated article labeling
  • Facsimile bluebird labeling for Type C medicated article

Copies of applicable labels may be obtained by writing to the:

Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857

Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.