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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-448 Terramycin + Bio-Cox - original approval

Approval Date: April 13, 1990

I. GENERAL INFORMATION

NADA 140-448
Sponsor: Roussel-Uclaf
235 East 42nd St.
New York, NY 10017
Generic Name: oxytetracycline + salinomycin sodium
Trade Name: Terramycin + Bio-Cox
Marketing Status:  

 

II. INDICATIONS FOR USE

As an aid in the reduction of mortality due to air sacculitis (air sac infection) caused by Escherichia coli sensitive to oxytetracycline and for the prevention of coccidiosis caused by Eimeria necatrix, E. tenella, E. acervulina, E. brunetti, E. mivati and E. maxima .

 

III. DOSAGE FORM

Currently approved Type A Medicated Articles of Terramycin manufactured by Pfizer under NADA 8-804 (approved by letter dated 5/5/53) and Bio-Cox manufactured by A.H. Robins under NADA 128-686 (48 FR 30616, July 5, 1983) serve as the dosage formulations.

These Type A Medicated Articles are used to manufacture Type C Medicated broiler chicken feeds containing 500 g/ton of oxytetracycline (from Terramycin) and range of 40 to 60 g/ton of salinomycin sodium (from Bio-Cox) to be fed for 5 days as the sole ration.

 

IV. EFFECTIVENESS

The original NADA for Bio-Cox (salinomycin sodium) contained adequate data to establish that salinomycin sodium at a range of 40 to 60 g/ton in finished feed is safe and effective for the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti and E. mivati . Terramycin (oxytetracycline) is approved at 500 g/ton in the finished feed as an aid in the reduction of mortality due to air sacculitis (air sac infection) caused by Escherichia coli sensitive to oxytetracycline. In the present NADA it has been established that the combination of Terramycin at 500 g/ton and Bio-Cox at 40 to 60 g/ton does not interfere with the efficacy of the individual drugs.

A. Non-Interference Studies

Three separate studies were conducted utilizing 14-16 day old broiler chickens to test for non-interference of Terramycin with the anticoccidial effectiveness of Bio-Cox. In each study the birds were divided into five treatment groups: I- uninfected, unmedicated; II- infected, unmedicated; III- infected, salinomycin 40 g/ton; IV- infected, oxytetracycline 500 g/ton; V- infected, oxytetracycline 500 g/ton plus salinomycin 40 g/ton. An additional group of infected, unmedicated birds was included in each study solely for documentation of the infection.

In the first study (Table 1) the infected treatment groups were challenged with an inoculum of E. acervulina / mivati, E. maxima and E. tenella . In the second two studies (Tables 2 and 3) the infected treatment groups were challenged with an inoculum of E. necatrix, E. brunetti and E. acervulina / mivati . This arrangement facilitated identification of lesions. Treatment effects were based on mortality, dropping scores, lesion scores, weight gain, feed conversion and live bird weight.

The results of the above studies (Tables 1,2 & 3) demonstrate that oxytetracycline at 500 g/ton in Type C Medicated feed of broiler chickens does not interfere with the anticoccidial activity of salinomycin sodium when fed at its lowest approved level.

The investigators involved in the studies were:

S.E. Cheng, D.V.M., Ph.D.
M.D. Sims
K.L. Puffenbarger, M.S.
A.H. Robins Co.
Research & Development Division
Richmond, Virginia 23220

(Eds. note: The following table consists of 12 columns.)

Table 1 Anticoccidial Activity, of Salinomycin in Combination wih Oxytetracyline Against a Mixed Elmeria Infection in 2-Week-Old Chicks (Experiment 84-095)

                                                      Average
                                    Coccidiosis-     Dropping                                        Average Live-
Treatment3                            Induced         Score1      ----------Weight Gain----------     Bird Weight      Feed Conversion       Total
  Group      Medication Infection    Mortality       D-4 - D-6   Day 5    Day 6    Day 7    Day 14     on Day 14       Day 7    Day 14   Lesion Scores2   
    
    I          None                           0/40             0.00        1859      2225      2606       6097            926            1.52       1.52           0.0         
               Uninfected 
 
    II         None                           2/40             1.55        1527      1525      1724       5180            835            2.10       1.85           6.0         
               Mixed 
 
    III        40 g/ton Salinomycin           0/40             0.35        1711      2009      2332       5575            866            1.72       1.70           1.2 
               Mixed 
 
    IV         500 g/ton Oxytetracycline      0/40             O.85        1741      1997      2261       5630            877            1.76       1.71           4.7       
               Mixed 
 
    V          40 g/ton Salinomycin +         0/40             0.30        1829      2094      2467       6092            918            1.71       1.65           O.8 
               500 g/ton Oxytetracycline        
               Mixed

1 Pen dropping scores assigned using a scale of 0 to 4 (Morehouse and Baron, 1970).

2 Lesion scores assigned using a score of 0 to 4 (Johnson and Reid, 1970) for each area of the small intestine and ceca

3 Infected treatment groups were challenged with an inoculum of E. acervulina / mivati, E. maxima and E. tenella.

(Eds. note: The following table consists of 12 columns.)

Table 2 Anticoccidial Activity, of Salinomycin in Combination wih Oxytetracyline Against a Mixed Elmeria Infection in 2-Week-Old Chicks (Experiment 84-096)

Average Coccidiosis- Dropping Average Live- Treatment3 Induced Score1 ----------Weight Gain---------- Bird Weight Feed Conversion Total Group Medication Infection Mortality D-4 - D-6 Day 5 Day 6 Day 7 Day 14 on Day 14 Day 7 Day 14 Lesion Scores2 I None 0/40 O.O 1727 1987 2270 5644 949 1.74 1.66 0.0 Uninfected II None 2/40 1.7 1176 1137 1311 4440 831 2.45 2.10 6.O Mixed III 40 g/ton Salinomycin 0/40 O.O 1708 1975 2334 5747 964 1.75 1.71 l.8 Mixed IV 500 g/ton Oxytetracycline 0/40 O.9 1336 1679 2052 5315 921 1.90 1.80 5.2 Mixed V 40 g/ton Salinomycin + 0/40 O.O 1756 2090 2420 5873 980 1.71 1.66 1.6 500 g/ton Oxytetracycline Mixed

1 Pen dropping scores assigned using a scale of 0 to 4 (Morehouse and Baron, 1970).

2 Lesion scores assigned using a score of 0 to 4 (Johnson and Reid, 1970) for each area of the small intestine and ceca

3 Infected treatment groups were challenged with an inoculum of E. acervulina / mivati, E. maxima and E. tenella.

(Eds. note: The following table consists of 11 columns.)

Table 3 Anticoccidial Activity, of Salinomycin and Salinomycin plus Roxarsone in Combination wih Oxytetracyline Against a Mixed Elmeria Infection in 2-Week-Old Chicks (Experiment 85-195)

                                                      Average
                                    Coccidiosis-     Dropping                                         
Treatment3                            Induced         Score1       Weight Gain (Average/Chick)           Feed Conversion       Total
  Group      Medication Infection    Mortality       D-4 - D-6   Day 5    Day 6    Day 7    Day 14       Day 7    Day 14   Lesion Scores2   
    
  
    I          None                           0/40             0.0         1746      2112      2415       6004           1.50       1.48           0.0         
               Uninfected 
 
    II         None                           3/40             2.45        1120       765       725       4119           2.68       2.20           5.7         
               Mixed 
 
    III        40 g/ton Salinomycin           0/40             O.O         1906      2336      2729       6870           1.45       1.45           1.6 
               Mixed 
 
    IV         500 g/ton Oxytetracycline      0/40             0.35        1934      2338      2689       6505           1.42       1.48           3.7
               Mixed 
 
    V          40 g/ton Salinomycin +         0/40             0.0         2154      2605      3012       7353           1.40       1.42           1.3          
               500 g/ton Oxytetracycline       
               Mixed

1 Pen dropping scores assigned using a scale of 0 to 4 (Morehouse and Baron, 1970).

2 Lesion scores assigned using a score of 0 to 4 (Johnson and Reid, 1970) for each area of the small intestine and ceca

3 Infected treatment groups were challenged with an inoculum of E. acervulina / mivati, E. maxima and E. tenella.

In three other studies 14-16 day old broiler chickens were used to demonstrate the non-interference of salinomycin sodium with the efficacy of oxytetracycline against E. coli infections. The studies contained the following five treatment groups: uninfected, unmedicated; infected, unmedicated; infected salinomycin 60 g/ton; infected oxytetracycline 500 g/ton; infected salinomycin 60 g/ton plus oxytetracycline 500 g/ton. The air sacs were cultured for presence of E. coli from all birds dying post infection and from survivors at study end. Lesion scores were given to all dead birds and birds sacrificed at study end based on gross observation of the air sacs, liver and heart. The results of these studies are found in Tables 4, 5a and 5b. These results demonstrate that salinomycin at 60 g/ton does not interfere with the antibacterial activity of oxytetracycline at 500 g/ton when both are fed in combination.

The investigators for these studies were as follows:

Beverly A. George, PhD
Colorado Animal Research Enterprises, Inc.
Fort Collins, Colorado

(Eds. note: The following table consists of 7 columns.)

Table 4 Antibacterial Activity of Oxytetracycline in Combination with Salinomycin Against E. coli (Study No. 611A-85-001)  

                                                          E. coli        Mean
Trt     Infection   Drug(s)*      No.       Mortality     in air sac     Lesion 
                                 Birds      N      %       N      %      Score**
                                                 
T-1          No          None          40          0     0.0       11     27.5       0.00 
T-2          Yes         None          40         22    55.0       40    100.        3.45 
T-3          Yes          S            40         27    67.5       35     87.5       3.63 
T-5          Yes          O            40         21    52.5       25     62.5       3.13 
T-6          Yes         SO            40         20    50.0       28     70.0       3.13

*
S = Salinomycin
O = Oxytetracycline

** Lesion scores assigned using a score of 0 to 4 with 4 being most severe.

(Eds. note: The following table consists of 7 columns.)

Table 5a Antibacterial Activity of Oxytetracycline in Combination with Salinomycin Against E. coli (Study No. C-626)

         E. coli                                           E. coli       Mean
Trt     Infection   Drug(s)*      No.       Mortality     in air sac     Lesion 
                                 Birds      N      %       N      %      Score**


T-1          No          None          36          0     0.0        0      0.0       0.00
T-2          Yes         None          36         12    33.3       23     63.9       2.6
T-3          Yes          S            36         11    30.6       27     75.0       2.8
T-5          Yes          O            36          5    13.9        5     13.9       2.3
T-7          Yes         SO            36          3     8.3        7     19.4       2.3

*
S = Salinomycin
O = Oxytetracycline

** Lesion scores assigned using a score of 0 to 3 with 3 being most severe.

(Eds. note: The following table consists of 7 columns.)

Table 5b Antibacterial Activity of Oxytetracycline in Combination with Salinomycin Against E. coli (Study No. C-706)

         E. coli                                           E. coli       Mean
Trt     Infection   Drug(s)*      No.       Mortality     in air sac     Lesion 
                                 Birds      N      %       N      %      Score**

T-1          No          None          36          0     0.0        0      0.0       0.00
T-2          Yes         None          36         18    50.0       29     80.6       2.5
T-3          Yes          S            36         19    52.8       35     97.2       2.7
T-5          Yes          O            36         15    41.7       18     50.0       2.6
T-7          Yes         SO            36         12    33.3       15     41.7       2.6

*
S = Salinomycin
O = Oxytetracycline

** Lesion scores assigned using a score of 0 to 3 with 3 being most severe.

 

V. ANIMAL SAFETY

The original approved NADA's for Terramycin NADA 8-804 (approved by letter dated 5/5/53) and Bio-Cox NADA 128-686 (48 FR 30616, July 5, 1983) contained adequate data to establish the safety of each drug for broiler chickens.

The safety of the combination of the two drugs was demonstrated in the drug residue elimination studies and the non-interference studies. There were no adverse reactions observed in any of the studies attributable to the drug combination.

The data provided evidence for the combination of Bio-Cox at 40 to 60 g/ton and Terramycin at 500 g/ton in the feed of broiler chickens and are consistent with and fulfill all the requirements for a fixed combination drug for animals as follows:

A. Each drug component makes a contribution to the claimed effects.

B. The dosages of each drug component are such that the combination of safe and effective.

C. Each drug component is utilized presently in an animal population for prevention of disease. The combination usage permits appropriate flexibility to fit drug use to the needs of individual flock management and disease prevention requirements for the same animal population.

D. The label claims are not antagonistic.

 

VI. HUMAN SAFETY

A. Toxicity tests

The toxicity studies that support the safe use of oxytetracycline in broiler chickens are filed in NADAs 8-804 and 11-034 and VMF 3651. The safe use of salinomycin in broiler chickens was established by toxicity studies described in the Freedom of Information Summary for NADA 128-686.

B. Safe concentrations of residues

The tolerances for microbiologically active residues of oxytetracycline in edible tissues of chickens are established at 1.0 ppm in muscle, liver and skin/fat and 3.0 ppm in kidney (21 CFR 556.500).

The safe concentration for total residues of salinomycin in broiler chickens are 0.6 ppm in muscle, 1.8 ppm in liver, and 1.2 ppm in skin/fat as described in the Freedom of Information Summary for NADA 128-686. The basic approval of salinomycin for use in broiler chickens (not in combination with other drugs) was granted under NADA 128-686 without a tolerance based on a marker residue. A marker residue, tolerance, and regulatory analytical method were not required for that approval because total residues of the drug in the tissues of treated chickens were shown to be well below the safe concentrations listed above in the tissues of chickens at zero withdrawal.

In an addendum to the Human Safety section of the original FOI Summary for NADA 128-686, the level of 0.2 ppm was assigned as the maximum amount of unmetabolized salinomycin that can be present in the skin/fat of treated chickens for the drug use to qualify for zero withdrawal. For the purpose of evaluating drug combinations with salinomycin, the 0.2 ppm level of salinomycin in skin/fat is used as the criterion of noninterference on the depletion of residues of salinomycin by the other drug(s) in the combination.

C. Residue depletion noninterference study

The noninterference by oxytetracycline on the depletion of residues of salinomycin and the noninterference by salinomycin on the depletion of residues of oxytetracycline was demonstrated in a study in broiler chickens conducted with the three-way combination of oxytetracycline, salinomycin and roxarsone. The chickens in that study were arranged in two groups and received either medicated feed or control feed as shown below.

(Eds. note: The following table consists of 5 columns.)

              -----------------Medication----------------- 
Treatment                                                      Birds Per
  Group       Days 0 to 36    Days 36 to 41   Days 41 to 46    Treatment 
                                                                
     I               None              None                None             40 
  
    II            Salinomycin       Salinomycin            None             80 
                  75 g/ton +        75 g/ton + 
    
                   Roxarsone         Roxarsone 
                   45 g/ton         45 g/ton + 
                
                                  Oxytetracycline 
                                    500 g/ton

For the evaluation of the two-way combination of oxytetracycline and salinomycin, chickens were killed in groups on days 41, 42 and 43 of the study to provide tissues from birds at 0, 1 and 2 days of withdrawal. The assays for residues of oxytetracycline were performed on tissues collected at 0, 1 and 2 days of withdrawal by a method based on the test organism Bacillus cereus var. mycoides for the detection of microbiologically active residues of the drug. That method had a sensitivity of 0.15 ppm for kidney, muscle and skin/fat and 0.25 for liver. Residues of salinomycin were assayed only in the skin/fat samples from chickens killed at 0 withdrawal. The analytical method for residues of salinomycin was an HPLC method for parent (unmetabolized) salinomycin developed by A.H. Robins Co. The limit of quantitation by that method is 0.1 ppm in skin/fat.

The results of the assays are shown in Table 6 below. Those data confirm that the components of the three-way combination do not interfere with the depletion of residues of oxytetracycline or salinomycin in the edible tissues of treated chickens. This allows the 24 hour withdrawal period established for the oxytetracycline (500 g/ton) and salinomycin (75 g/ton) in broiler feed.

(Eds. note: The following table consists of 6 columns.)

Table 6 Residue levels (ppm) of salinomycin* and oxytetracycline** in the tissues of chickens following the medication with the three way combination of oxytetracycline, salinomycin, and roxarsone. 

Drug                 Days of      Liver      Skin/fat        Muscle     Kidney 
                   Withdrawal 
Salinomycin                0           ----       None detected        ----        ---- 
Oxytetracycline            0        0.31 - 0.87     0.22-0.50      Ð.15 - .41   0.56 - 1.27 
                           1           Ð0.25        0.15-0.30         Ð0.15     0.21 - 0.43 
                           2           Ð0.25        0.15-0.30         Ð0.15    Ð0.15 - 0.33

* Six skin/fat samples were assayed for salinomycin

** Ranges listed are for 12 samples each

D. Assay Non Interference Studies The noninterference of salinomycin and roxarsone on the assay for oxytetracycline was demonstrated by the analysis of combined solutions of oxytetracycline, salinomycin and roxarsone containing 1.0 ppm of each drug. The recovery of oxytetracycline by that procedure was 105%.

The noninterference of oxytetracycline and roxarsone on the HPLC assay used to measure residues of salinomycin was demonstrated in a spiking study in which control skin/fat homogenate containing 0.7 ppm salinomycin was spiked with 1 ppm oxytetracycline and 2 ppm roxarsone. Analysis by the HPLC assay indicated a salinomycin level of 0.75 ppm (107% recovery), confirming the noninterference at the 0.7 ppm level.

 

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA satisfy the requirements of Section 512 of the Act and demonstrate that the combination of salinomycin sodium at concentrations of 40 to 60 g/ton (.0044 - .0066%) plus oxytetracycline at 500 g/ton (.055%) in Type C Medicated feed for broilers is safe and effective for the indications stated on the product labeling.

The tolerances for residues of oxytetracycline in edible tissue of chicken are established at 3 ppm in uncooked kidney and 1.0 ppm in uncooked muscle, liver, fat and skin (21 CFR 556.500). Safe concentrations of total residue of salinomycin in edible tissues of chickens are 0.6 ppm for muscle, 1.8 ppm for liver and 1.2 ppm for skin/fat. The data submitted in support of the NADA show that the residues of oxytetracycline were below the established tolerance in edible tissue and that the residues of salinomycin were below the safe concentration in the edible tissues. The agency has concluded that the residue composition will not be altered, based on the depletion characteristic of the drugs when used in combination.

The 24 hour withdrawal time before slaughter is satisfactory.

Adequate directions for lay use of the proposed drug combination in broiler chickens have been written for the requested claims of this NADA. Also the two drugs, salinomycin and oxytetracycline, when used separately in feed for the same uses are approved for over the counter sale, and that there is nothing about the combination of the two drugs that would require the marketing status to be changed.

 

VIII. LABELING (Attached)

  1. Blue Bird Broiler Builder Medicated Type C Medicated Feed Placard
  2. Blue Bird Broiler Builder Medicated Type C Medicated Feed Tag

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

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855