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© 2006 Betterchem.com
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Approval Date:
September 1, 1992
Freedom of
Information Summary
NADA 134-830
I. GENERAL INFORMATION:
| NADA |
134-830 |
| Sponsor: |
A. L. Laboratories, Inc.
One Executive Drive
PO Box 1399
Fort Lee, NJ 07024
|
| Generic Name: |
Bacitracin zinc, monensin sodium |
| Trade Name: |
Albac®, Coban® |
| Marketing Status: |
OTC |
II. INDICATIONS FOR USE
As an aid in prevention of coccidiosis
caused by Eimeria necatrix, E. tenella, E. acervulina, E. brunetti, E.
maxima and E. mivati; for increased rate of weight gain, and
for improved feed efficiency in broiler chickens.
III. DOSAGE
| A. |
DOSAGE FORM |
This NADA provides for the combined use of two approved Type A medicated
articles, bacitracin zinc as per 21 CFR 558.78 and monensin as per
21 CFR 558.355, to make Type C medicated feed. Bacitracin zinc is
marketed as a Type A medicated article containing 50 grams bacitracin
activity/lb. Monensin is marketed as a Type A medicated article in
concentrations of 45 and 60 grams monensin sodium/lb.
Bacitracin zinc is added to finished broiler Type C medicated feed
at concentrations from 4-50 grams bacitracin/ton and monensin at concentrations
of 90-110 grams monensin sodium/ton of feed.
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| B. |
ROUTE OF ADMINISTRATION |
Orally in the feed. |
| C. |
RECOMMENDED DOSAGES: |
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Bacitracin zinc
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4-50 grams per ton |
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Monensin sodium: |
90-110 grams per ton |
IV. EFFECTIVENESS
Non-Interference Study
Two adequate and well-controlled
battery experiments were conducted to evaluate the anticoccidial effectiveness
of monensin when fed in combination with bacitracin zinc to broiler chickens.
The studies (listed below) were conducted at the experimental poultry farm
of the University of Georgia, Department of Poultry Science, Athens, GA.
Experiment Nos. GA-B-118-85;
GA-B-118-85/2
Investigator:
Larry R. McDougald, Ph.D.
Department of Poultry Science
University of Georgia
Athens, GA 30602
Monitor:
Ralph V. Fell, Ph.D.
Route 9, Box 42
Pine Bluff, AR 71603
Four hundred Arbor Acres x Peterson broiler chicks were caged in environmentally-controlled
animal rooms. Each cage contained 10 wing-banded chicks (5 males and 5 females).
Each of the five treatments (Table 1) were replicated four times in each
of the two studies. The chicks were fed an unmedicated broiler starter feed
until they were 12 days-of-age. At 12 days-of-age, chicks were weighed,
stratified by body weight, randomly allocated to cages and provided medicated
feed. At 14 days-of-age, the chicks were weighed and inoculated by oral
gavage with mixed cultures of coccidia. The infective cultures were E.
mitis, E. necatrix and E. brunetti in experiment GA-B-118-85
and E. acervulina, E. maxima and E. tenella in experiment
GA-B-118-85/2. The coccidia species that were used were recent isolates
obtained from commercial poultry farms in the United States.
Data, including death losses,
intestinal lesion scores, dropping scores, weight gain and feed consumption
were recorded over the 2 weeks following infection (Table 1). The infections
reduced weight gains in the infected controls when compared with the uninfected
controls. Treatment with monensin was effective in improving weight gain
in all instances, whether it was used alone or in combination with bacitracin
zinc. Lesion scores were recorded for the upper, mid and cecal areas of
the gut. Monensin was effective in controlling coccidiosis caused by the
six species of Eimeria in the broiler chickens. The use of bacitracin
zinc with monensin did not interfere with the anticoccidial action of monensin.
(Eds. note: The following
table consists of 10 columns.)
Table 1
Anticoccidial activity of Monensin in combination with Bacitracin zinc
against mixed Eimeria spp. infections in broiler chickens.
Average Live Total Lesion Total Dropping
Weight Gain(g) Mortality Scores/Bird Scores/Bird
Medication g/ton Study 1 Study 2 Study 1 Study 2 Study 1 Study 2 Study 1 Study 2
None, 0 461.4 454.9 0/40 0/40 0 0 0 0
uninfected
None, 0 357.1 127.0 1/40 27/40 4.74 12.00 7.25 15.50
infected
Monensin 90 389.7 412.1 0/40 2/40 0.69 5.30 0.75 9.25
Bacitracin Zinc 100 256.9 100.8 2/40 27/40 5.88 12.00 5.00 15.75
Monensin + 90 358.6 413.4 0/40 2/40 0.88 6.38 0.75 9.25
Bacitracin Zinc 100
Study 1, infective cultures were from field isolates of E. mitis, E. necatrix,
and E. brunetti (Study GA-B-118-85).
Study 2, infective cultures were from field isolates of E. acervulina, E. maxima
and E. tenella (Study GA-B-118-85/2).
Floor-Pen Study
Three floor-pen experiments
were conducted using 2,720 broiler chickens. Bacitracin zinc was fed at
0 or 50 grams per ton of feed in combination with monensin at 110 grams
per ton. The experiments were designed to evaluate the growth promoting
effects of bacitracin zinc when fed in combination with monensin to broiler
chickens.
Experiment No. TX-B-112-83
Investigator:
William F. Krueger, Ph.D.
Department of Poultry Science
Texas A&M University
College Station, TX 77843
Monitor:
Ralph V. Fell, Ph.D.
Route 9, Box 42
Pine Bluff, AR 71603
In this experiment, 1400 chicks were housed in a conventional, dirt-floor
broiler house on the premises of Texas A&M University, College Station,
TX. Each 8 x 10 ft pen was identically equipped with a 6 ft mechanical water
trough and hanging tube-type feeders. Chicks were reared in a 22 hr photoperiod
provided by a 40 watt incandescent light over each pen. Bedding was used
litter, topped with a 1" layer of new pine shavings.
Fifty male and 50 female day-old,
Cobb x Hubbard chicks were allocated randomly to 14 experimental pens. Treatments
were assigned to pens in a randomized block design. Treatments were randomly
assigned to blocks of contiguous pens. The 14 experimental pens allowed
for 7 replications of the two treatments. The experiment consisted of two
dietary treatments which were monensin at 110 grams/ton and monensin at
110 grams/ton plus bacitracin zinc at 50 grams/ton. The duration of the
experiment was 47 days.
Results:
The addition of bacitracin zinc to the diet increased the rate of weight
gain and improved feed efficiency over birds fed monensin alone (Table 2).
Experiment No. MO-B-114-84
Investigator:
Randall A. Primo
Ponderosa Research Company
French Village, MO 63036
Monitor:
Ralph V. Fell, Ph.D.
Route 9, Box 42
Pine Bluff, AR 71603
In this experiment, 600 birds were housed in a conventional, insulated,
curtain-sided broiler house with wire partitions and a dirt floor. Each
5 x 8 pen was equipped with an automatic water fountain, a cylindrical hanging
self feeder and a heat lamp brooder. Light to supplement natural daylight
was supplied by an incandescent light over the center of each pen. Used
litter was top-dressed with new wood shavings.
Day-old chicks were distributed
randomly by sex into 12 pens so that each pen contained 25 male and 25 female
chicks, with six replicates. For assignment of treatments to pens, the 12
pens were divided into blocks and dietary treatments assigned randomly within
each block. The experiment entailed 2 dietary treatments, i.e., monensin
at 110 grams per ton and monensin at 110 grams per ton + bacitracin zinc
at 50 grams per ton. The duration of the experiment was 48 days.
Results:
The addition of bacitracin zinc to the diet increased the rate of weight
gain and improved feed efficiency over birds fed monensin alone (Table 2).
Experiment No. ARK-B-120-84
Investigator:
Park W. Waldroup, Ph.D.
Department of Animal Sciences
University of Arkansas
Fayetteville, AR 72701
Monitor:
Ralph V. Fell, Ph.D.
Route 9, Box 42
Pine Bluff, AR 71603
In this experiment, 720 chicks were housed in a conventional steel-truss
building with an insulated roof and sidewalls and a three-foot sidewall
curtain. Pens were 7 x 8 ft and contained two hanging tube-type feeders,
an automatic water fount and an infrared gas brooder. Used litter was top-dressed
with new litter. Day-old, sexed chicks were randomly distributed by sex
into the pens so that each pen contained 30 males and 30 females. The 12
pens allotted to this study permitted 6 replications of each of the 2 dietary
treatments as follows: monensin at 110 per ton and monensin at 110 grams
per ton + bacitracin zinc at 50 grams per ton. Treatments were assigned
randomly to pens within each of the 6 blocks of pens. The duration of the
experiment was 49 days.
Results:
The addition of bacitracin zinc to the diet increased the rate of weight
gain and improved feed efficiency over birds fed monensin alone (Table 2).
(Eds. note: The following
table consists of 6 columns.)
Table 2
Performance Response Of Broiler Chickens To Bacitracin Zinc When Fed
With Monensin
Monensin, 110 g/ton
Monensin, 110 g/ton + BZn, 50 g/ton
Mean Mean
No. Weight Feed/ Weight Feed/
Reps Gain (lb) Gain Gain (lb) Gain
TX-B-112-83 7 3.59 2.25 3.77 2.11
MO-B-114-84 6 4.19 2.26 4.26 2.20
ARK-B-120-84 6 4.34 2.11 4.52 2.02
Grand Mean 4.04 2.21 4.18 2.11
Summary of Floor-Pen Study
The three floor-pen experiments,
using 2,720 broiler chickens were conducted in different geographical locations
to determine the growth promoting effects of bacitracin zinc in combination
with monensin. The studies were designed and conducted to simulate varying
conditions such as climate, geographical location, weather, management practices,
and degree of disease contamination of the premises.
Consistent with pen size 25
to 50 chicks of each sex were selected at random and assigned to pens. Six
or 7 replicates were used per treatment group. Bacitracin zinc at 0 and
50 grams per ton of feed was used in combination with monensin at 110 grams
per ton of feed in each study.
A pooled statistical analysis
of the three experiments was conducted. The data demonstrate that the addition
of bacitracin zinc to the diet at 50 grams per ton increased the rate of
weight gain and improved feed efficiency significantly (p < .05) when
compared to chicks fed monensin alone.
Summary of Effectiveness
Studies
The results of the effectiveness
studies qualify this application for range approval for the drug combination
under CVM's Drug Combination Policy, revised October, 1983. The data demonstrate
that both drugs contributed to the effectiveness of the combination drug.
These data support approval
of this application for the use of monensin at 90 to 110 grams per ton and
bacitracin zinc at 4 to 50 grams per ton as an aid in the prevention of
coccidiosis caused by Eimeria acervulina, E. brunetti, E. maxima, E.
mivati, E. necatrix, and E. tenella and for increased rate of
weight gain and improved feed efficiency in broiler chickens.
V. ANIMAL SAFETY
The basic animal safety data
for the individual drugs may be found in the parent NADAs (98-452 for bacitracin
zinc and 38-878 for monensin). The effectiveness studies shown in Section
IV demonstrate that no ill effects occurred when the drugs were combined
indicating that they are as safe when fed in combination as when fed alone.
This application is in accord with the Center's Target Animal Safety Guidelines.
Additional safety studies were not required because: (1) The drugs have
been approved singly and (2) adequate documentation has been provided to
show that these components are compatible in combination when used in broiler
chicken feeds. Therefore, based on the data in the original NADAs, the non-interference
study, the floor pen efficacy studies, and the drug residue elimination
study, this combination of drugs may be safely fed to broiler chickens.
VI. HUMAN SAFETY:
A. Toxicity Tests
The toxicology data that support
the safety of residues of bacitracin zinc are filed in the parent NADA 98-452
sponsored by A. L. Laboratories, Inc. (approved April 5 1976, 41 FR 14367).
The toxicology data for monensin are contained in the parent NADA 38-878
sponsored by Elanco Products Co. (approved May 20, 1970, 35 FR 7734).
B. Tolerances and Safe Concentrations
of Residues
The tolerance for residues
of bacitracin zinc in uncooked tissues of chickens is established at 0.5
ppm, negligible residue (21 CFR 556.70).
A tolerance for residues of
monensin in chickens is not established because the total residues of the
drug (parent + metabolites) are below the safe concentrations for the drug
at zero withdrawal. The safe concentrations for monensin total residues
in chicken tissues are: 1.5 ppm in muscle, 3.0 ppm in skin with adhering
fat, and 4.5 ppm in liver (21 CFR 556.420).
C. Tissue Residue Non-Interference
Studies
Data to demonstrate that the
residue levels of bacitracin zinc and monensin are not adversely affected
when the two drugs are fed in combination to broilers were generated in
two residue studies. Both studies used overdosing levels of bacitracin zinc.
1. Non-interference on residues
of monensin
The first non-interference
study (CK-567) was conducted by Elanco Products Company, and it provided
data to demonstrate that residue levels of monensin are not adversely affected
by the presence of bacitracin zinc. The investigators were M.H. Gehle and
J.E. Wachtstetter.
The study was a combined residue
and efficacy trial, and it involved 600 broiler chickens which received
one of the following treatments:
A. control diet
B. bacitracin zinc at 500 g/ton
C. monensin at 110 g/ton plus bacitracin zinc at 500 g/ton.
The birds were fed the respective
diets until 56 days of age at which time groups were sacrificed at zero,
24 and 48 hours of withdrawal for the residue portion of the study. At each
of those withdrawal intervals, liver, muscle, kidney and fat samples were
collected from male and female birds. The samples were assayed for microbiologically
active residues of monensin by Lilly Method No. 5801330 to give six values
at each withdrawal interval.
Monensin residue levels in
the range of 0.025 to 0.05 ppm or 0.05 to 0.10 ppm were found in five of
the six zero withdrawal fat samples. The other fat samples and all muscle,
liver and kidney samples showed no detectable residues of monensin.
Metabolism data generated under
NADA 38-878 has shown that total residues of monensin in fat are well below
the safe concentration in that tissue when microbiologically active residues
of the drug in fat are in the range of 0.025 to 0.10 ppm. The monensin values
reported above for monensin in fat tissue confirm that total residues of
the drug are below the safe concentrations for the drug in birds fed rations
containing the monensin plus bacitracin zinc combination.
2. Non-interference on residues
of bacitracin zinc
The non-interference on monensin
residues by the presence of bacitracin zinc in the combination was demonstrated
in a second study conducted with the three-way combination of monensin,
bacitracin zinc, and roxarsone. The dosing phase of the study (MO-B-TR-1)
was conducted for A. L. Laboratories by the Ponderosa Research Company,
French Village, Missouri, with Mr. Randall A. Primo as investigator. The
assays for bacitracin zinc (CK-568) in tissues were conducted by Northvale
Analytical Laboratory, Northvale, NJ.
The study involved two pens
(12 birds each) of commercial broiler chicks. The birds in one pen were
fed a non-medicated control diet and the birds in the other pen were fed
a diet containing monensin (110 g/ton), bacitracin zinc (100 g/ton), and
roxarsone (45.5 g/ton). At 48 days of age, three male and three female birds
were withdrawn from the medicated feed for 24 hours and killed to provide
tissue samples at one day of withdrawal. Six other birds received the medicated
feed for 49 days and were killed at zero withdrawal. Breast muscle tissue
was collected, frozen, and shipped to the analytical laboratory.
Assay of the medicated and
unmedicated control muscle samples was conducted using Northvale Analytical
Laboratory Test Procedure Code No. 9A, Modified Microbiological Method for
Determination of Bacitracin in Tissues. The assays of all tissue samples
were negative (< 0.1 ppm) for microbiologically active residues of bacitracin
zinc.
The residue non-interference
studies described above confirm that, for the two-way combination of monensin
and bacitracin zinc, each drug in the presence of the other does not exceed
its approved safe concentration or tolerance. These data support a zero
withdrawal period for the use of this combination in broilers under CVM's
combination drug policy.
D. Assay Non-Interference
Studies
1. Bacitracin zinc assay
The non-interference on the
assay for bacitracin zinc by the presence of residues of monensin was demonstrated
by the assay of control samples of chicken muscle that were spiked with
bacitracin zinc (0.5 ppm) with and without monensin (0.5 ppm) and roxarsone
(0.5 ppm). The recovery values for both sets of samples were both about
85%, indicating no interference in the assay.
2. Monensin assay
A non-interference study on
the bioautographic method for monensin was conducted by spiking control
tissue samples with monensin and bacitracin zinc and then assaying these
tissues for monensin content. The results demonstrated no interference by
bacitracin zinc for monensin.
E. Regulatory Methods
1. Bacitracin zinc
An analytical method for microbiologically
active residues of bacitracin zinc in tissues is described in the following
reports: 1) "Antibiotic Residue in Milk, Dairy Products and Animal
Tissues: Methods, Reports, Protocols," National Center for Antibiotic
Analyses, Dept. HEW Washington DC 20204, Rev. October 1968; and 2) "Modified
Method for Determination of Bacitracin in Tissues," Test Procedure
Code 9A, A. L. Laboratories, Inc., One Executive Drive, PO Box 1399, Fort
Lee, NJ 07024.
2. The use of monensin in chickens
is approved under NADA 38-878 without the need for a tolerance or an official
regulatory method. However, analytical methods for the drug are available
such as the bioautographic methods that are used in non-interference studies
with monensin. A current bioautographic method is described in Part 5.044
of the Chemistry Laboratory Guidebook published by the United States
Department of Agriculture.
VII. AGENCY CONCLUSIONS:
The data submitted in support
of this NADA satisfy the requirements of Sections 512 of the Act and demonstrate
that monensin (90-110 g/ton) plus bacitracin zinc (4-50 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 the safety and effectiveness
data in the parent applications. 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.
A residue study referenced
in this application demonstrates that microbiologically active residues
of monensin at 0-day withdrawal will be 0.1 ppm or less in fat tissue and
generally nondetectable in other tissues when chickens are medicated with
the combination of bacitracin zinc and monensin. These levels correspond
to total residue levels (parent monensin plus its metabolites) much less
than the monensin safe concentrations of 1.5 ppm in muscle, 3.0 ppm in skin
with adhering fat, and 4.5 ppm in liver.
A second residue study, which
was contained in the application, demonstrates that microbiologically active
residues of bacitracin zinc at 0-day withdrawal will be less than the 0.5
ppm bacitracin tolerance when chickens are fed the combination of bacitracin
zinc and monensin.
Adequate information was submitted
to demonstrate non-interference between the assays for each drug. The approval
of this application will not significantly increase human exposure to drug
residues.
Non-interference studies demonstrate
that monensin in the presence of bacitracin zinc prevented an outbreak of
coccidiosis when the birds were exposed to the six major species of Eimeria.
The data from three well-controlled floor-pen studies demonstrate the effectiveness
of bacitracin zinc for increased rate of weight gain and improved feed efficiency
in broiler chickens in the presence of monensin. The policy outlined in
CVM's guideline for drug combinations for use in animals provides for the
granting of range approval for monensin (90-110 g/ton) as an aid in the
prevention of coccidiosis caused by Eimeria acervulina, E. brunetti,
E. maxima, E. mivati, E. necatrix, and E. tenella; for bacitracin
zinc (4-50 g/ton) for increased rate of weight gain and improved feed efficiency
in broiler chickens.
Section 512(c)(2)(F)(ii) of
the Federal Food, Drug and Cosmetic Act, provides a three-year period of
exclusivity to NADAs for previously approved active ingredients that require
reports of new clinical or field investigations (other than bioequivalence
or residue studies) and, in the case of food producing animals, human food
safety studies (other than bioequivalence or residue studies) essential
to the approval of the application and conducted or sponsored by the applicant.
This new animal drug application qualifies for such an exclusivity period
which will expire three years from the date of the approval letter.
VIII. LABELING
(Attached)
1. Bag label
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.
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