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© 2006 Betterchem.com
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Approval Date:
May 22, 1992
Freedom of
Information Summary
NADA140-853
I. GENERAL INFORMATION:
| NADA |
140-853 |
| Sponsor: |
A. L. Laboratories, Inc.
One Executive Drive
PO Box 1399
Fort Lee, NJ 07024 |
| Generic Name: |
Bacitracin methylene disalicylate, narasin |
| Trade Name: |
BMD®, Monteban® |
| Marketing Status: |
OTC |
II. INDICATIONS FOR USE
For the prevention of coccidiosis caused by Eimeria tenella, E. necatrix,
E. acervulina, E. maxima, E. mivati , and E. brunetti , 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 uses of these two approved Type
A medicated articles, bacitracin methylene disalicylate as per 21
CFR 558.76 and narasin as per 21 CFR 558.363 into Type C medicated
feed. Bacitracin methylene disalicylate Type A medicated articles
are marketed as a medicated premix containing 10, 25, 30, 40, 50,
60 and 75 grams/lb bacitracin. Narasin Type A medicated articles are
marketed as a medicated premix in concentrations of 36, 45, 54, 72
and 90 grams/lb.
Bacitracin methylene disalicylate is added to finished broiler Type
C medicated feed at concentrations ranging from 10-50 grams/ton and
narasin at concentrations from 54-72 grams/ton of feed.
|
| B. |
ROUTE OF ADMINISTRATION |
Orally in the feed. |
| C. |
RECOMMENDED DOSAGES: |
|
| |
Narasin |
54-72 grams/ton |
| |
Bacitracin methylene disalicylate |
10-50 grams/ton |
IV. EFFECTIVENESS:
Non-Interference Study
A series of seven well-controlled battery experiments was conducted to evaluate
the anticoccidial effectiveness of narasin when fed in combination with
bacitracin methylene disalicylate to broiler chickens. The studies (listed below)
were conducted at Lilly Research Laboratories, PO Box 708, Greenfield, IN
46140.
Experiment No. T2N8C86A0 - Eimeria acervulina challenge
Experiment No. T2N8C86A1 - Eimeria maxima challenge
Experiment No. T2N8C86A2 - Eimeria necatrix challenge
Experiment No. T2N8C86A3 - Eimeria brunetti challenge
Experiment No. T2N8C86A4 - Eimeria mitis/E. mivati challenge
Experiment No. T2N8C86A5 - Eimeria tenella challenge
Experiment No. T2N8C86A6 - Mixed Eimeria species challenge
Investigators:
K. W. Bafundo, Ph.D. and J. D. Donovan
Greenfield Laboratories
PO Box 708
Greenfield, IN 40140
Monitor:
Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603
Eight-day old Hubbard White Mountain broiler cockerels were used in each
experiment. Chicks were housed in a coccidia free environment prior to the
initiation of each experiment. Stainless steel batteries especially designed
for anticoccidial effectiveness evaluation were used in these experiments.
Water and medicated feed were supplied ad libitum and proper ambient
temperature and a constant lighting schedule were maintained for the duration
of each experiment.
A typical broiler starter ration was used in these
experiments. Medicated feed was administered for two days prior to coccidial
exposure. All rations were assayed for bacitracin methylene disalicylate and
narasin.
Two days after initiation of medicated feeding the birds were
inoculated with coccidia. In six experiments inoculation was by single
species challenge, i.e., one experiment for each of the six species of
Eimeria approved for narasin. In the seventh experiment, all six species were
combined as the mixed inoculum of Eimeria tenella, E. necatrix, E.
acervulina, E. maxima, E. mivati and E. brunetti . Inocula were
intended to produce clinical coccidiosis in the infected nonmedicated birds. The
treatment regimen is delineated below.
- Infected, non-medicated controls
- Narasin (60 ppm)
- Narasin + Bacitracin methylene disalicylate (60 + 110 ppm)
Each treatment was replicated four times using four birds per replicate.
Parameters measured were, mortality, weight gain, feed efficiency and intestinal
lesion scores. Experiments were conducted for 7 days post inoculum.
The data
from these experiments are summarized in Tables I through VII. These data
demonstrate that birds fed narasin in combination with bacitracin methylene
disalicylate had reduced lesion scores when compared to infected nonmedicated
birds. The addition of bacitracin methylene disalicylate to feeds had no adverse
effect on the ability of narasin to control coccidial infection. Thus bacitracin
methylene disalicylate was compatible with
narasin when the drugs are fed to growing broiler chickens.
(Eds. note: The following table consists of 6 columns.)
TABLE I
Summary of Experiment No. T2N8C86A0
EIMERIA ACERVULINA
Treatment Dose Mortality Weight Gain F/G Lesions Scores
(ppm) (%) (g) Intestines
Infected controls* 00 0.0 249.1 1.768 3.75
Narasin 60 0.0 276.0 1.578 0.06
Narasin + 60 0.0 295.8 1.487 0.13
BMD 110
* Chicks were infected with 250,000 Eimeria acervulina oocysts.
(Eds. note: The following table consists of 6 columns.)
TABLE II
Summary of Experiment No. T2N8C86A1
EIMERIA MAXIMA
Treatment Dose Mortality Weight Gain F/G Lesions Scores
(ppm) (%) (g) Intestines
Infected Controls* 00 0.0 261.4 1.646 4.00
Narasin 60 0.0 291.4 1.552 0.38
Narasin + 60 0.0 283.6 1.517 0.31
BMD 110
* Chicks were infected with 50,000 Eimeria maxima oocysts.
(Eds. note: The following table consists of 6 columns.)
TABLE III
Summary of Experiment No. T2N8C86A2
EIMERIA NECATRIX
Treatment Dose Mortality Weight Gain F/G Lesions Scores
(ppm) (%) (g) Intestines
Infected Controls* 00 0.0 222.3 1.779 3.50
Narasin 60 0.0 253.3 1.623 0.38
Narasin + 60 0.0 276.4 1.516 0.38
BMD 110
* Chicks were infected with 100,000 Eimeria necatrix oocysts.
(Eds. note: The following table consists of 6 columns.)
TABLE IV
Summary of Experiment No. T2N8C86A3
EIMERIA BRUNETTI
Treatment Dose Mortality Weight Gain F/G Lesions Scores
(ppm) (%) (g) Intestines
Infected Controls* 00 0.0 176.1 2.155 4.00
Narasin 60 0.0 261.8 1.614 2.19
Narasin + 60 0.0 263.1 1.583 1.81
BMD 110
* Chicks were infected with 100,000 Eimeria brunetti oocysts.
(Eds. note: The following table consists of 6 columns.)
TABLE V
Summary of Experiment No. T2N8C86A4
EIMERIA MITIS/EIMERIA MIVATI
Treatment Dose Mortality Weight Gain F/G Lesions Scores
(ppm) (%) (g) Intestines
Infected Controls* 00 0.0 248.1 1.677 3.44
Narasin 60 0.0 276.2 1.547 1.25
Narasin + 60 0.0 286.0 1.455 0.69
BMD 110
* Chicks were infected with 100,000 Eimeria mitis/E. mivati oocysts.
(Eds. note: The following table consists of 6 columns.)
TABLE VI
Summary of Experiment No. T2N8C86A5
EIMERIA TENELLA
Treatment Dose Mortality Weight Gain F/G Lesions Scores
(ppm) (%) (g) Intestines
Infected Controls* 00 0.0 279.0 1.553 2.75
Narasin 60 0.0 272.0 1.521 1.69
Narasin + 60 0.0 293.6 1.507 0.44
BMD 110
* Chicks were infected with 100,000 Eimeria tenella oocysts.
(Eds. note: The following table consists of 7 columns.)
TABLE VII
Summary of Experiment No. T2N8C86A6
EIMERIA ACERVULINA, E. MAXIMA, E. MITIS/MIVATI, E. BRUNETTI,
E. NECATRIX, AND E. TENELLA
Treatment Dose Mortality Weight Gain F/G Lesions Scores
(ppm) (%) (g) Intestine Cecal
Infected Controls* 00 0.0 199.8 1.846 8.94 1.1
Narasin 60 0.0 251.6 1.564 0.75 0.1
Narasin + 60 0.0 283.7 1.472 0.00 0.0
BMD 110
* Chicks were infected with a mixed inoculum Eimeria acervulina,
E. maxima, E. mitis/E. mivati, E. brunetti, E. necatrix
and E. tenella oocysts.
Floor-Pen Study
Six floor-pen experiments were conducted using a total of 5,020 birds.
Bacitracin methylene disalicylate was used at 0 or 50 grams per ton of feed
in combination with narasin at 72.5 grams per ton. The experiments were
designed to evaluate the growth promoting effects of bacitracin methylene
disalicylate when fed in combination with narasin to broiler chickens.
- Experiment No. TX-B-146-86
Investigator:
Jack H. Trammel, Ph.D.
3T Research
Box 192
Hamilton, TX 76531
Monitor:
Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603
In this experiment, 840 broiler chickens were housed in a conventional type, dirt
floor broiler house on the premises of 3T Research, Hamilton, TX. Pens trial
were arranged in two rows with a center aisle. Each 5' x 10' pen was equipped
with a cylindrical hanging self-feeder, a bell-type automatic waterer and a
thermostatically controlled gas brooder. Natural light was supplemented with
incandescent lighting over the center aisle. Used litter was top-dressed with
new shavings.
Thirty male and 30 female day-old chicks were randomly allocated
to 14 experimental pens. Treatments were assigned to pens in a randomized
block design. The 14 pens allowed for 7 replications of the 2 treatments.
The experiment consisted of 2 dietary treatments, i.e., narasin 72.5 grams per
ton and narasin 72.5 grams per ton + bacitracin methylene disalicylate
50 grams per ton. Commercial mixing procedures were followed and feed samples
were assayed for drug content. Birds were on medicated feed for 46 days.
Results:
The addition of bacitracin methylene disalicylate to the diet
increased the rate of
weight gain and improved feed efficiency over birds fed narasin alone (Table
VIII).
- Experiment No. TX-B-130-85
Investigator:
William F. Krueger, Ph.D.
Department of Poultry Science
Texas A&M University
College Station, TX 77843
Monitor:
Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603
In this experiment, 1400 chicks were housed in a conventional type, dirt floor
broiler house (Random Sample Broiler House 2) on the Texas A&M University
Poultry Center. Fifty male and 50 female day-old Hubbard x Hubbard broiler
chicks were distributed randomly into 14 pens. Chicks that died during the
first week were replaced with hatch mates.
Experimental diets were prepared by
mixing the appropriate amount of each drug premix with rations formulated to
simulate commercial-type nutrient concentrations. Feed samples were assayed
for drug content.
The 14 pens permitted 7 replications (pens) of the following
2 dietary treatments: narasin 72.5 grams per ton and narasin 72.5 grams per
ton + bacitracin methylene disalicylate 50 grams per ton. Birds were on
medicated feed for 46 days.
Results:
The addition of bacitracin
methylene disalicylate to the diet increased the rate of weight gain and
improved feed efficiency over birds fed narasin alone (Table VIII).
- Experiment No. MO-B-132A-85
Investigator:
Randall A. Primo
Ponderosa Research Company
French Village, MO 63036
Monitor:
Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
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
identically 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 Arbor Acre x Peterson 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.
Chicks that died during the first week were replaced with chicks from the
same hatch.
Experimental diets were prepared by blending the appropriate amount of the
respective drug premixes with commercial-type starter and grower basal ration
formulated to meet or exceed all NRC nutrient recommendations. The experiment
entailed 2 dietary treatments, i.e., narasin 72.5 grams per ton and narasin
72.5 grams per ton + bacitracin methylene disalicylate 50 grams per ton.
The experiment ran for 48 days.
Results:
The addition of bacitracin methylene disalicylate to the diet increased the rate
of weight gain and improved feed efficiency over birds fed narasin alone
(Table VIII).
- Experiment No. MO-B-102-83
Investigator:
Randall A. Primo
Ponderosa Research Company
French Village, MO 63036
Monitor:
Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603
In this experiment, 900 birds were housed in a conventional, insulated, curtain
sided broiler house with wire partitions and dirt floor. Each 5' x 8' pen was
identically 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. Built-up
litter was stirred and top dressed with new wood shavings.
Day-old sexed
chicks were randomly distributed by sex so that each pen contained 25 male
and 25 female chicks. The 18 pens allotted to this study permitted 9 replications
of each of the 2 dietary treatments as follows: narasin 72.5 grams per ton
and narasin 72.5 grams per ton and bacitracin methylene disalicylate 50 grams
per ton.
Experimental diets were prepared by mixing the appropriate amount of each drug
premix with commercial-type starter and grower basal rations which were
formulated to meet or exceed all NRC nutrient recommendations. Finished feeds
were assayed for drug content. Chicks that died during the first five days
were replaced and a record of mortality was maintained thereafter. Chicks
were medicated for 49 days.
Results:
The addition of bacitracin methylene disalicylate to the diet increased
the rate of weight gain and improved feed efficiency over birds fed narasin
along (Table VIII).
- Experiment No. AR-B-119-84
Investigator:
Park W. Waldroup, Ph.D.
Department of Animal Sciences
University of Arkansas
Fayetteville, AR 72701
Monitor:
Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
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' and contained two hanging tube-type feeders, an automatic water
fount and an infrared gas brooder. Plastic feeder flats and water founts were
used during the first 7 days for supplemental feeding and water. Used litter
was top-dressed with new litter. Day-old, sexed broiler chicks were randomly
distributed by sex into the pens so that each pen contained 30 males and 30
females. Chicks that died during the first week were replaced with hatch
mates.
Brooding temperatures began at 85°F with whole-house brooding with 5 per
week reductions to a minimum of 65°. Automatic fans and sidewall curtains
were used to aid in maintaining temperature control.
The 12 pens allotted to this study permitted 6 replications of each of the 2
dietary treatments as follows: narasin 72.5 per ton and narasin 72.5 grams
per ton + bacitracin methylene disalicylate 50 grams per ton.
Finished feeds were assayed for drug content. Treatments were randomly assigned
to pens within each of the 6 blocks of pens. Chicks were medicated for 49
days.
Results:
The addition of bacitracin methylene disalicylate to the diet increased the
rate of
weight gain and improved feed efficiency over birds fed narasin alone (Table
VIII).
- Experiment No. GA-B-131-85
Monitor:
O. W. Charles, Ph.D.
Extension Poultry Science
University of Georgia
Athens, GA 30601
Monitor:
Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603
In this experiment, 560 chicks were housed in a conventional broiler house, Four
Towers Research Center, University of Georgia. Twenty male and 20 female
day-old Arbor Acre x Peterson chicks were allocated randomly to 14 pens. All
pens were equipped with automatic bell-type waterers, a circular feeder and
an electric heat bulb for brooding. Each pen received approximately 2 inches
of new litter and top dressing was applied as necessary using new pine
shavings. Medicated feeds were prepared as per standard commercial practice.
Finished feeds were assayed for drug content. Chicks were medicated for 49
days.
Seven pens were assigned to each treatment group as follows: narasin 72.5 grams
per ton and narasin 72.5 grams per ton + bacitracin methylene
disalicylate 50 grams per ton.
Results:
The addition of bacitracin methylene disalicylate to the diet increased the rate
of weight gain and improved feed efficiency over birds fed narasin alone
(Table VIII).
Summary of Floor-Pen Study
The six described floor-pen studies, using
5,020 broiler chickens were conducted in different geographical locations to
determine the growth promoting effects of bacitracin methylene disalicylate
in combination with narasin. 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 20 to 50 birds of each sex were selected at random and
assigned to pens. Six to nine replicates were used per treatment group.
Bacitracin methylene disalicylate at 0 and 50 grams per ton of feed was used
in combination with narasin at 72.6 grams per ton of feed in each study.
A pooled statistical analysis of the six studies was conducted. The data
demonstrate that the addition of bacitracin methylene disalicylate to the
diet at 50 grams per ton increased the rate of weight gain and improved feed
efficiency significantly (p ¾ .05) when compared to birds fed narasin
alone.
Summary of Effectiveness Studies
The results of the floor-pen 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 narasin at 54-72
g/ton and bacitracin methylene disalicylate at 10-50 g/ton for 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.
(Eds. note: The following table consists of 6 columns.)
TABLE VIII
Response of Broiler Chickens to Narasin and Bacitracin Methylene Disalicylate
Fed in Combination
Narasin 72.5 g/ton +
Narasin 72.5 g/ton BMD 50 g/ton
Replications Mean Wt. Feed/Gain Mean Wt. Feed/Gain
TX-B-146-86 7 4.34 1.95 4.41 1.91
TX-B-130-85 6 3.79 2.00 3.86 1.96
MO-B-132A-85 6 4.12 2.07 4.19 1.99
MO-B-102-83 9 4.28 2.18 4.45 2.09
AR-B-119-84 6 4.37 2.07 4.40 2.03
GA-B-131-85 7 3.94 2.05 4.05 2.00
Grand Mean 4.14 2.05 4.23 2.00
V. ANIMAL SAFETY
The animal safety data for bacitracin methylene disalicylate may be found
in the parent NADA 46-592 sponsored by A. L. Laboratories, Inc. (approved
March 15, 1976, 41 FR 10993); for narasin the data may be found in the parent
NADA 118-980 sponsored by Elanco Products Co. (approved August 14, 1986, 51
FR 29098). The efficacy studies shown in Section IV demonstrate that no adverse
effects were observed when the drug were combined, indicating that the drugs
are as safe when fed in combination as when fed alone.
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 compounds 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 drug residue
depletion study, it is concluded that this combination of drugs may be safely
fed to broiler chickens.
VI. HUMAN FOOD SAFETY
A. Toxicity Tests
The toxicity data that support the safety of residues of bacitracin methylene
disalicylate are filed in the parent NADA 46-592 sponsored by A. L.
Laboratories, Inc., (approved March 15, 1976, 41 FR 10993). The toxicology
data for narasin are contained in the parent NADA 118-980 sponsored by Elanco
Products Co. (approved August 14, 1986, 51 FR 29098).
B. Tolerances and Safe Concentrations of Residues
The tolerance for residues of bacitracin methylene disalicylate in uncooked
tissues of chickens is established at 0.5 ppm negligible residue (21 CFR
556.70). A tolerance for residues of narasin in chickens was not established
because total residues of the drug (parent + metabolites) are below the
safe concentrations for the drug at zero withdrawal. The safe concentrations
for total narasin residues in chicken tissues are: 0.6 ppm in muscle; 1.8 ppm
in liver; and 1.2 ppm in skin with adhering fat and fat.
C. Tissue Residue Non-Interference Studies
Data to demonstrate that the residue levels of bacitracin MD and narasin are not
adversely affected when the two drugs are fed to chickens in combination were
generated in two residue studies conducted with the three-way combination of
bacitracin MD, narasin, and roxarsone. Both studies used overdosing levels of
bacitracin MD and narasin.
The first study (LA-B-TR-1-82) was conducted for A. L. Laboratories, and it
provided data to demonstrate that residue levels of bacitracin MD are not
adversely affected by the other components of the combination. The
investigator for the dosing phase of the study was John A. Herbert, Ph.D., at
the Louisiana State University, and the assays for residues of bacitracin MD
were conducted by the Morris County Testing Laboratory, Morristown, NJ.
Sixty-five broiler chicks were fed a ration containing the combination of narasin
(90 g/ton), roxarsone (45.5 g/ton) and bacitracin MD (200 g/ton) for the
period between two to seven weeks of age. Muscle tissue was collected for the
bacitracin MD assay from six birds (three males and three females) killed at
zero withdrawal and from another group of six birds at two days of
withdrawal. The mean residue values obtained in the assay for
microbiologically active residues of bacitracin MD are shown below. The dosing
level in the study (200 g/ton) was four times the level approved under this
NADA, and all residue values reported were below the 0.5 ppm tolerance for
bacitracin MD.
(Eds. note: The following table consists of 3 columns.)
Tissue Days of Withdrawal Bacitracin MD (ppm)
muscle 0 0.40
muscle 2 0.43
The non-interference on residue levels of narasin by the other components of
the combination was demonstrated in a second residue study (MO-B-TR-3-88).
The dosing phase of the study was conducted for A. L. Laboratories, Inc., by
the Ponderosa Research Company, French Village, Missouri, with Mr. Randall A.
Primo as investigator. The narasin assays were conducted by Lilly Research
Laboratories, Greenfield, Indiana.
One hundred broiler chickens were fed a
ration containing the combination of narasin (80 g/ton), roxarsone (45.5
g/ton), and bacitracin MD (100 g/ton) from one day of age to approximately
seven weeks of age. Groups of six birds (three males and three females) were
selected and killed at zero (six hours), 24, or 48 hours of withdrawal from
the medicated feed. Samples of abdominal fat were collected from each bird
and were assayed for microbiologically active residues of narasin by Lily
Method AM-AA-CA-R108-AB-755. The mean assay results are shown below.
(Eds. note: The following table consists of 3 columns.)
Tissue Days of Withdrawal Narasin (ppm)
abdominal fat 0.25 0.048
abdominal fat 1 NDR*
abdominal fat 2 NDR
* No detectable residues at the assay sensitivity of 20 ppb
Metabolism data generated under NADA 118-980 has shown that microbiologically active
residues of narasin represent one-third of the total residue present in abdominal fat at
zero withdrawal. With that relationship, the 0.048 ppm residue value listed above for zero
corresponds to approximately 0.15 ppm total residues, which is well below the 1.2 ppm
safe concentration for narasin fat tissue.
The residue non-interference studies described above confirm that each drug in the
presence of the other does not exceed its approved safe concentration or tolerance.
Therefore, 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 methylene disalicylate assay
The non-interference on the assay for bacitracin MD by the presence of residues
of narasin was demonstrated by the assay of control samples of chicken muscle
tissue that were spiked with bacitracin MD (0.5 ppm) with and without narasin
(0.5 ppm). The recovery values for the two sets of samples were comparable.
2. Narasin assay
The non-interference by residues of bacitracin MD on
the narasin assay used in the non-interference study was determined by the assay
of spiked chicken fat. Samples of control abdominal chicken fat were fortified
with narasin (0.05 ppm), bacitracin MD (0.5 ppm), and roxarsone (0.2 ppm) and
with bacitracin MD alone. The assay of those samples by Lilly Method
AM-AA-CA-R108-AB-755 gave no detectable response for the bacitracin MD-fortified
sample and an average narasin recovery of 90% for the samples fortified with the
combination.
E. Regulatory Methods
1. Bacitracin methylene disalicylate
An analytical method for microbiologically active residues of bacitracin MD in
tissues is
described in the following reports: 1) "Antibiotics 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
Tissue," Test Procedure Code 9A, A. L. Laboratories, Inc., One Executive
Drive, PO Box 1399, Fort Lee, NJ 07024.
2. Narasin
The use of narasin in broiler chickens was approved under NADA 118-980 without
the need for a tolerance or an official regulatory method. However,
analytical methods for the drug are available, and one example is the
bioautographic method used in the residue non-interference studies for
combination approved with this NADA. That method measures microbiologically
active residues of narasin and has TLC and HPLC confirmation procedures. It
is described in the following report: "Determination and Confirmation of
Narasin Residues in Chicken Target Tissue, Abdominal Fat," Method
AM-AA-CA-R108-AB- 755, Lilly Research Laboratories, Greenfield, Indiana
46140.
VII. AGENCY CONCLUSIONS
The data submitted in support of this NADA satisfy the requirements of Section
512 of the Act and demonstrate that narasin (54-72 g/ton) plus bacitracin
methylene disalicylate (10-50 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.
Residue depletion studies in this application demonstrate that residues of
narasin at 0-day withdrawal will be below the safe concentration of 1.2 ppm
in skin with adhering fat. It has been determined that measurement of parent
narasin in skin with adhering fat represents one-third of the total residue
present. Therefore, the reported 0.048 ppm level of parent narasin in skin
with adhering fat is well below one-third of the established safe
concentration of 1.2 ppm in skin with adhering fat and is appreciably different
from the previously reported values for narasin alone.
Residues of bacitracin methylene disalicylate in edible tissues are below the
tolerance of 0.5 ppm established in 21 CFR 556.70. 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 narasin
in the presence of bacitracin methylene disalicylate prevented an outbreak of
coccidiosis 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 methylene disalicylate for increased rate of weight
gain and improved feed efficiency in broiler chickens in the presence of
narasin. The policy outlined in CVM's guideline for drug combinations for use
in animals provides for the granting of range of approval for narasin (54 to
72 g/ton) for the prevention of coccidiosis caused by Eimeria acervulina, E.
brunetti, E. maxima, E. mivati, E. necatrix , and E. tenella ; for bacitracin
methylene disalicylate (10 to 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 publication of the approval
letter.
VIII. LABELING:
1. Blue Bird Broiler Ration Type C Medicated Feed package label
Copies of this label may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855
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