NADA 138-456

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CVM FOI…

Approval Date: December 17, 1986

Freedom of Information Summary
NADA 138-456
I. GENERAL INFORMATION:

NADA 138-456

Sponsor:
A.L. Laboratories, Inc.
452 Hudson Terrace
PO Box 1621
Englewood Cliffs, NJ 07632

Generic Name: Bacitracin Methylene Disalicylate, Monensin Sodium

Trade Name: BMD®, Coban®

Marketing Status: OTC

II. INDICATIONS FOR USE

For improved feed efficiency and as an aid in the prevention of coccidiosis caused by Eimeria necatrix, E. tenella, E. acervulina, E. brunetti, E. maxima and E. mivati .

III. DOSAGE

A. DOSAGE FORM

Medicated finished feeds manufactured from approved premixes for broiler chickens.

BMD® 25, 40 and 50 grams bacitracin activity per pound of premix.
Coban® each pound contains 45 grams monensin as monensin sodium.

B. ROUTE OF ADMINISTRATION

For oral administration via the feed for growing broiler chicken

C. RECOMMENDED DOSAGES:

Bacitracin methylene disalicylate: : 4-50 grams per ton

Coban:
110 grams per ton

NOTES Bacitracin methylene disalicylate 4-50 grams per ton in combination with 110 grams per ton monensin.

IV. EFFECTIVENESS

Six floor pen experiments were conducted using approved protocols and 23,676 broiler chickens. Bacitracin methylene disalicylate at 0, 10, 25 and 50 grams per ton of feed was used in five of the experiments, while 0, 5 and 50 grams per ton was used in one. Roxarsone at 0, 11.3, 22.7 and 45.4 grams per ton was used in five of the experiments, while 0 and 45.4 grams per ton was used in one. Monensin sodium at 110 grams per ton was included in all experimental feeds. The experiments were designed to test the effects of bacitracin methylene disalicylate in the presence of monensin on body weight gains and feed efficiency.

A description of the six experiments follows:

Experiment No: FV-B-29/30-87

Investigator:

Ralph V. Fell, Ph.D.
Box 488
Sheridan, AR 72150

The 56-day experiment was conducted at the S.B. Penick Animal Research Farm, French Village, MO, from January 3, to February 28, 1974. The experiment consisted of 16 dietary treatments with three replicates of 70 one day old Vantress X Hubbard broiler chickens placed randomly, half male and half female in 48 pens. Each 9' x 6' pen was identically equipped with an infrared brooder, two tube type hanging feeders, and three Hart drinking cups. The floors were concrete and covered with wood shavings. The building was enclosed, continuously lighted and fan ventilated. The desired levels of drugs being studied were added to typical broiler starter/finisher rations and fed for the entire growing period except that monensin was withdrawn from the feed for the last five days.

Experiment No: FV-B-29/30-74

Investigator:

Ralph V. Fell, Ph.D.
Box 488
Sheridan, AR 72150

The second of the 56-day experiments was conducted concurrently with FV-B-29-74 in a second house at the S.B. Penick Animal Research Farm, French Village, MO, from January 3 to February 28, 1974. This experiment consisted of 16 dietary treatments with two replicates of 80 one day old Vantress X Hubbard broiler chickens, placed randomly, half male and half female, in 32 pens. Each 6' x 10' pen was identically equipped with an infrared brooder, two type hanging feeders and three Hart drinking cups. Wood shavings were used as litter. The building was enclosed, continuously lighted and fan ventilated. The desired levels of drugs being studied were added to typical broiler starter/finisher rations and fed for the entire growing period, except that monensin was withdrawn from the feed for the last five days.

Experiment No: GA-B-53-77

Investigator:

Robert K. Page, D.V.M.
Department of Avian Medicine
College of Veterinary Medicine
University of Georgia
Athens, GA

Monitor:

Ralph V. Fell, Ph.D.
Box 488
Sheridan, AR 72150

This 56-day experiment was conducted at Winder, GA under the supervision of Dr. Robert K. Page from February 24, to April 20, 1976. The experiment consisted of 16 dietary treatments with three replicates of 60 one day old Hubbard X Hubbard broiler chickens, half male and half female in each of 48 pens. Each 5' x 10' pen was identically equipped with thermostatically controlled brooders, self feeders and drinking fountains. New wood shavings were spread over built-up litter.

The desired level of drugs being studied were added to a typical broiler starter/finisher ration and fed for the entire growing period except that monensin was withdrawn from the feed for the last five days.

Experiment No: 306-572-1-14

Investigators:

B.F. Schlegel, D.V.M.
Wheeler, AR

and

D.L. Gard, Ph.D.
Eli Lilly & Company
Greenfield, IN 46140

This 50-day experiment was conducted at facilities leased by Eli Lilly & Company, Wheeler, AR, beginning on December 8, 1971. The experiment consisted of six dietary treatments with the negative controls being replicated six times and the other four treatments being replicated four times. One hundred one day old male broiler chickens were placed randomly in each of 28 pens. Each 8' x 10' pen was equipped with area gas brooders, incandescent light, two 18" tube feeders and one 18" diameter automatic waterer. Reused litter was provided. The pens were in a building which had a concrete block foundation, wood frame walls, insulated ceiling, concrete floor and thermostatically controlled glass curtains. The desired levels of drugs being studied were added to a typical starter/finisher broiler ration and fed for the entire growing period except monensin was withdrawn from the feed for the last five days.

Experiment No: 306-572-2-2

Investigators:

B.F. Schlegel, D.V.M.
Wheeler, AR

and

D.L. Gard, Ph.D.
Eli Lilly & Company
Greenfield, IN 46140

This 61-day experiment was conducted at the same facilities as the previous experiment beginning February 28, 1972. The experiment consisted of 16 dietary treatments. Four treatments were replicated three times and the other 12 treatments were replicated 4 times. One hundred Vantress X Arbor Acre broiler chickens, half male and half female, were randomly distributed to each of the 60 pens. The desired level of drugs being studied were added to a typical starter/finisher broiler ration and fed for the entire growing period except monensin was withdrawn from the feed for the last five days.

Experiment No: 306-572-2-7

Investigators:

B.F. Schlegel, D.V.M.
Wheeler, AR

and

D.L. Gard, Ph.D.
Eli Lilly & Company
Greenfield, IN 46140

This 58-day experiment was conducted at the same facilities as the previous experiment beginning May 9, 1972. The experiment consisted of 16 dietary treatments. Four treatments were replicated three times and the other 12 treatments were replicated four times. One hundred Vantress X Arbor Acre broiler chickens, half male and half female, were distributed randomly in each of the 60 pens. The desired levels of drugs being studied were added to typical broiler and starter/finisher rations fed for the entire growing period except monensin was withdrawn from the feed for the last five days.

Floor Pen Experiments Summary

Six adequate and well controlled floor pen experiments, using approved protocols and 23,676 broiler chickens (in five experiments equal numbers of males and females, in one experiment all males) were conducted under conditions simulating actual field use to determine the growth promoting effects of bacitracin methylene disalicylate in the presence of monensin. Although these experiments were originally designed as titration studies, for purposes of this submission, only the highest levels of bacitracin methylene disalicylate (50 grams per ton) in the presence of monensin (110 grams per ton) are considered.

The efficacy data were evaluated according to the combination drug guidelines revised October 1983: Drugs approved individually at a range and codified in the CFR are not required to be titrated in the combination. However, each drug's contribution to the combination must be demonstrated by data from studies conducted with the maximum approved drug level. For the NADA, data from two treatment groups from each of the 6 trials are adequate to satisfy these requirements. Treatment one (1) monensin at 110 g/ton; Treatment two (2) monensin 110 g/ton plus BMD at 50 g/ton.

The data for each of the above two treatments from the six trials were pooled for analysis for weight gain and feed efficiency. The analysis for weight gain showed no difference (p = 0.10) between the two treatments. The analysis of the feed to gain data showed a significant difference (p < 0.01) between the two treatments due to BMD.

The data from the non-interference studies and the six floor pen studies qualify the application for approval for the prevention of coccidiosis and for improved feed efficiency. The CVM policy outlined in the October 1983 revised guidelines permits the quantity of the range for BMD codified in 21 CFR 558.75 (e)(i), which is 4 to 50 g/ton for use in combination with monensin at 110 g/ton.

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

TABLE 1 SUMMARY OF RESPONSE OF BROILERS TO BACITRACIN-MD WHEN FED WITH MONENSIN Coban 110 g/ton+ Coban 110 g/ton --BMD 50 g/ton-- No. Average Feed/ Average Feed/ Reps. Weight Gain Weight Gain FV-B-29-74 3 3.86 2.19 3.83 2.15 FV-B-30-74 2 3.89 2.20 4.01 2.15 GA-B-52-77 3 3.82 2.22 3.85 2.18 306-572-2-7 3 3.43 2.05 3.43 2.03 306-572-2-02 3 3.70 2.06 3.83 2.05 306-572-1-14 4-6 2.93 2.05 2.99 2.00 ---- ---- ---- ---- Average 3.60 2.13 3.66 2.09
Effectiveness - Non-Interference
An experiment was conducted using 125 broiler chickens to determine whether bacitracin methylene disalicylate interferes with the anti-coccidial activity of monensin. This study was conducted in batteries by:

M.E. Callender and D.J. Donovan
Elanco Products Company
A Division of Eli Lilly and Company
Greenfield, In

Monensin at 0.0121% (110 gpt) was effective in controlling a mixed species infection of Eimeria acervulina, E. brunetti, E. mivati, E. necatrix and E. tenella . The addition of bacitracin methylene disalicylate at 0.011% (110 gpt) did not interfere with the anti-coccidial properties of monensin. The infective inoculum produced mortality rates of 96% and 100% among birds which received no drug treatment or only bacitracin methylene disalicylate. Four percent (1/25) of the birds which received either monensin or monensin plus bacitracin methylene disalicylate in combination with monensin did not adversely affect mean weight gain, feed conversion, intestinal lesion scores or cecal lesion scores. A summary of the data is presented in Table 2.

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

SUMMARY TABLE 2 Mean Weight Gain Intestinal Cecal Percent Survivor Feed Lesion Lesion Test Group Mortality(1) (gm)(2) Conversion(3) Score(4) Score(5) Monensin (0.0121%) 4 134 1.84 .46 .96 Bacitracin methylene 100 -- -- -- 4.0 disalicylate (0.011%) Monensin (0.0121%) + 4 127 1.94 .04 1.56 Bacitracin methylene disalicylate (0.011%) Infected controls 96 -- -- -- 3.96 Noninfected, nontreated controls 0 155 1.66 -- -- (1) Due to coccidiosis. (2) Pens 4, 10, 16, 22, 28 omitted from this calculation due to waterer malfunction. (3) Only pens which contained five birds for the entire test period. (4) Birds sacrificed seven days after inoculation. (5) All surviving birds plus all which died later than 100 hrs. after infection.
V. ANIMAL SAFETY

The basic animal safety data for the individual drugs may be found in the original NADA 46-592 for bacitracin methylene disalicylate, NADA 38-878, for monensin and its referenced INADs and MFs, including NADA 49-463. Safety for the combination of bacitracin methylene disalicylate and monensin was demonstrated by the results of the non-interference study conducted by Elanco Products Co. and the results of six floor pen studies described in Section IV.

This application is in accord with the Animal Safety Guidelines. 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 drugs are compatible in combination when used in broiler chicken feeds. Therefore, based on the data in the original NADAs, the non-interference studies and the drug residue elimination study, it is concluded that this combination of drugs may be safely fed to broiler chickens.

VI. HUMAN SAFETY:

It has been established in the original NADA (46-592 for bacitracin methylene disalicylate and 38-878 for monensin) that these products are not a hazard to human health when used according to approved labeling. Tolerances for residues of bacitracin methylene disalicylate are established at 0.5 ppm negligible residue in uncooked chicken tissue (21 CFR 556.70). Safe concentrations for total residues of monensin in chickens are 1.5 ppm in muscle, 3.0 ppm in skin with adhering fat and 4.5 ppm in liver [FR Vol. 50, No. 155 (32394) August 12, 1985]. The tissue residue data supporting uses of bacitracin methylene disalicylate and monensin have been presented in the original applications for each.

The drug residue depletion study as presented was conducted by Elanco Products Co. Sexed, day-old Penobscot broiler chicks were used in a 56-day study. Chicks were allotted to pens by grab sample from each compartment of the shipping boxes so that each pen received 50 males or 50 females. The floor pens provided 0.9 square feet per bird.

Each pen was bedded with clean, ground corn cobs. Feed and water was provided ad libitum. Feed was provided to each pen in two hanging feeders. The chicks were fed typical broiler starter and finisher rations. At 56 days the medicated feeds were replaced with non-medicated feeds.

Room temperature was maintained at 70° ± 5° F. Supplemental heat was provided by thermostatically controlled infrared heat lamps. Continuous light was provided. Ventilation was provided by 2 attic and 4 window fans.

At termination and up to 120 hours following treatment, birds of each sex were randomly selected and sacrificed for each drug to be assayed at each sampling interval. Feathers were mechanically removed. Samples of muscle, liver, kidney and skin/fat were collected from each bird, individually bagged and submitted for assay.

The summary of the tissue residue depletion study in Table 3 establishes that each drug in the presence of the other does not exceed its established safe concentration or tolerances. In addition, one drug does not interfere in the others tissue residue assay. In this study broiler chickens were fed a combination of bacitracin methylene disalicylate (50 gpt) and monensin (110 gpt) for 56 days. Edible tissues as required for each drug or combination of drugs were assayed for presence of drug residue.

Tissue assay non-interference and method validation studies for bacitracin assay were conducted by spiking control chicken tissues with bacitracin zinc standard and monensin and then assaying for bacitracin residue. The results demonstrated no interference by monensin for bacitracin (MO-B-TR-1-85). The recovery of bacitracin from the spiked tissues was 84 percent.

The non-interference of bacitracin on the determination of monensin was examined by the analysis of negative control chicken tissue fortified with the equivalent of 5.0 and 0, and 5.0 and 0.05 ppm bacitracin zinc standard and monensin, respectively (S-AAC-83-03). No interference of bacitracin on the recovery of monensin was observed. Prepared extracts of tissue fortified with the equivalent of 5.0 ppm bacitracin gave no zone of inhibition on the bioautographic plate. The recovery of monensin from tissue fortified with 5.0 ppm bacitracin and 0.05 ppm monensin was about 86% (0.043/0.05) which is on the order of the expected experimental variation.

Based upon the established no withdrawal times for monensin and bacitracin methylene disalicylate, no residues were above tolerances in any tissues from these broiler chickens. The data support no withdrawal for the bacitracin methylene disalicylate/monensin combination.

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

TABLE 3 RESIDUE DEPLETION ASSAY RESULTS Day Liver Kidney Skin/Fat Muscle Monensin Estab. Safe Conc. 4.5 -- 3.0 1.5 Monensin alone 0 none none negligible negligible + Bacitracin-MD 0 none none negligible negligible Bacitracin-MD Establish Tolerance 0.5 Bacitracin-MD alone 0 none + Monensin 0 none From Experiment CK 710 NADA 49-463 Monensin
Assay Procedure No. 5801645 for chicken tissues and eggs. Eli Lilly and Co., Greenfield Laboratories, Greenfield, IN. Antibiotics
Residues in Milk, Dairy Products and Animal Tissues: Methods, Reports, Protocols. National Center for Antibiotic and Insulin Analyses. Dept. HEW Washington, DC 20204, Rev. October 1968. Modified Method for Determination of Bacitracin in Tissues, Test Procedure Code 9A, A.L. Laboratories, Inc., Englewood Cliffs, NJ 07632.
VII. AGENCY CONCLUSIONS

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and demonstrate that monensin (110 g/ton) plus bacitracin MD (4-50 g/ton) are safe and effective for the claims indicated in Section II of this FOI Summary.

This original NADA is regarded as a Category II application under CVM's supplemental policy (42 FR 64367) which did not require reevaluation of safety and efficacy data in the parent NADAs. The drugs are to be supplied to the feed mill in individual premixes (Type A Article) for combining in finished feeds (Type C Article) within the indications and dosages approved in the parent NADAs.

Residue data show monensin is well within the established safe concentration of 4.5 ppm in liver, three ppm skin/fat and 1.5 ppm muscle of the chicken at zero withdrawal. Residue data show bacitracin MD is well below tolerance of 0.5 ppm in edible chicken tissues at zero withdrawal.

Non-interference studies demonstrate that monensin alone prevented an outbreak of coccidiosis and in the presence of bacitracin MD when the birds were exposed to the six major species of Eimeria . The data from six well controlled floor pen studies demonstrate the effectiveness of bacitracin (50 g/ton) in the presence of monensin (110 g/ton). These data qualify the application for approval under CVM's policy outlined in the combination drug guidelines revised October 1983. This policy permits the granting of range approval for bacitracin MD (4-50 g/ton) plus monensin as an aid in the prevention of coccidiosis and for improved feed efficiency in broiler chickens, as shown in Section 2 of this FOI Summary.

VIII. LABELING

1. Bag label with ingredients, analysis, and feeding directions

Copies of these 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.