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© 2006 Betterchem.com
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Approval Date:
December 18, 1987
Freedom of
Information Summary
NADA 140-579
I. GENERAL INFORMATION:
| NADA |
140-579 |
| Sponsor: |
Hoffmann-LaRoche, Inc.
Nutley, NJ 07110 |
| Generic Name: |
Lasalocid sodium
Oxytetracycline (monoalkyl trimethyl ammonium salt) |
| Trade Name: |
Bovatec®
Terramycin |
| Marketing Status: |
OTC |
II. INDICATIONS FOR USE
For improved feed efficiency,
increased rate of weight gain and reduction of the incidence and severity
of liver abscesses in beef cattle fed in confinement for slaughter.
III. DOSAGE
| A. |
DOSAGE FORM |
Medicated Feed |
| B. |
ROUTE OF ADMINISTRATION |
Oral |
| C. |
RECOMMENDED DOSAGES: |
Lasalocid sodium: 10 to 30 g/ton of Type C feed for improved feed efficiency;
25 to 30 g/ton of Type C feed for improved feed efficiency and increased
rate of weight gain.
Oxytetracycline (monoalkyl trimethyl ammonium salt): 75 mg per head
per day.
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IV. EFFECTIVENESS
Lasalocid is approved (21 CFR 558.311;
47 FR 34133/4, August 6, 1982) for improved feed efficiency and increased rate
of weight gain in beef cattle fed in confinement for slaughter. Oxytetracycline
(OTC) is approved (21 CFR 558.450) for reduction of the incidence and severity
of liver abscesses in beef cattle weighing over 400 lbs.
A. Pivotal Studies
1. Study C-109
This was a 108 day feedlot study
conducted by Mr. Michael Wittler, Colorado Beef Research Feedlot, Lamar, Colorado.
One hundred sixty-eight English crossbred steers with average initial weight
of 792 lb were blocked by weight and randomly allotted to the following treatment
groups: 1) negative control; 2) lasalocid 30 g/t, 3) lasalocid 30 g/t + OTC
75 mg/hd/day, and 4) OTC 75 mg/hd/day. There were six pens of seven animals/pen
per treatment. The steers were fed an 82% concentrate ration consisting of steam
flaked corn, alfalfa hay, magoferm, mineral supplement and drug supplement.
Feed was mixed and fed once daily. Data recorded consisted of individual fasted
weights at day one and 108 of test period, pen weights at 28 and 56 days, total
feed consumption per pen, and incidence of liver abscesses per pen. The following
results were reported:
(Eds. note: The following table
consists of 5 columns.)
Control Las Las + OTC OTC
N 42 42 42 42
ADG(lb) 3.62 3.80 3.67 3.65
ADFI(lb) 27.61 27.94 25.97 27.39
F/G 7.68 7.41 7.09 7.49
Liver Abs. 15/42 9/42 7/42 4/42
2. Study C-205 This was a 182
day feedlot study conducted by Dr. Rodney Preston, Texas Tech University, Lubbock,
Texas. One hundred twenty crossbred steers (Hereford, Angus and exotic crosses)
with average initial weight of 578 lb were blocked by breed and randomly assigned
to the following treatments: 1) negative control, 2) OTC 75 mg/hd/day, and 3)
lasalocid 30 g/t + OTC 75 mg/hd/day. There were five pens of eight animals/pen
per treatment. The steers were fed an 88% concentrate ration consisting of milo,
cottonseed hulls, alfalfa hay, molasses, mineral/vitamin mix and drug supplement.
Animals were weighed at 0, 28, 56, 98, 126 154 and 182 (last day on test) days
on test. Total feed consumption per pen was determined at time of animal weighing.
Liver abscess scores and carcass quality data were recorded. The following results
were reported:
(Eds. note: The following table
consists of 4 columns.)
Control OTC Las + OTC
N 39 40 38
ADG(lb) 2.03 2.12 2.18
ADFI(lb) 21.3 21.1 21.3
Feed/Gain 10.49 9.96 9.77
Liver Ab. 5/39 2/40 6/38
3. Study C-207 This was a 132
day feedlot study conducted by Dr. Don Gill, Panhandle University Feedlot, Goodwell,
Oklahoma. One hundred twenty steers (734 lb average initial weight) were randomly
assigned to the following treatment groups: 1) control, 2) OTC 75 mg/hd/day, and
3) OTC 75 mg/hd/day + lasalocid 30 g/t. There were five pens of eight animals/pen/treatment.
The steers were fed a 95% concentrate ration consisting of whole shelled corn,
cottonseed hulls, soybean mean, limestone, and drug supplement. Feed was mixed
and fed twice daily. Animals were weighed (shrunk) on days 1 and 132 of study.
Interim weights and feed consumption were taken at 28, 62, 111 and 132 days. Carcass
and liver abscess data were taken at slaughter. The following results were reported:
(Eds. note: The following table
consists of 4 columns.)
Control OTC Las + OTC
N 39 39 40
ADG(lb) 2.80 2.73 3.02
ADFI(lb) 19.0 18.3 18.9
Feed/Gain 6.80 6.71 6.26
Liver Ab. 4/39 2/39 0/40
4. Study C-225 This was a 145
day feedlot study conducted by Dr. Dallas Horton, Horton Feedlot and Res. Ctr.,
Wellington, Colorado. One hundred twenty Hereford X Angus crossbred steers with
average initial weight of 712 lb. were blocked by weight and randomly assigned
to the following treatments: 1) Control, 2) OTC 75 mg/hd/day, and 3) lasalocid
30 g/t + OTC 75 mg/hd/day. There were five pens of eight head/pen/treatment. The
steers were fed an 85% concentrate ration consisting of corn, corn silage and
drug supplement. Diet was adjusted from 40 % to 85% corn over a three week period.
Data reported included individual zero and 145 day weights, 28 day interim pen
weights, feed consumption (corrected for weigh backs) and carcass and liver abscess
data. The following results are reported:
(Eds. note: The following table
consists of 4 columns.)
Control OTC Las + OTC
N 39 39 40
ADG (lb) 2.65 2.68 2.66
ADFI (lb) 17.63 17.49 17.56
Feed/Gain 6.65 6.53 6.60
Liver Ab. 20/39 18/39 14/40
5. Study C-226 This was a 128
day feedlot study conducted by Dr. Donald Hinman, Univ. of Idaho, Caldwell, Idaho.
One hundred twenty steers (Hereford and Hereford X Angus) with average initial
weight of 725 lb. were randomly assigned to the following treatments: 1) control,
2) OTC 75 mg/hd/day, 3) lasalocid 30 g/ton + OTC 75 mg/hd/day. There were five
pens of eight head/pen/treatment. The steers were fed an 85% ration of barley,
alfalfa, corn silage, molasses, and drug supplement. Data recorded consisted of
initial and final weights, 28 day interim weights, feed consumption, and carcass
liver abscess data. The following results were reported:
(Eds. note: The following table
consists of 4 columns.)
Control OTC Las + OTC
N 40 40 40
ADG (lb) 2.58 2.64 2.62
ADFI (lb) 17.84 18.29 18.04
Feed/Gain 6.92 6.94 6.90
Liver Ab. 16/40 11/40 11/40
6. Study C-83-27 This was a
90 day feedlot study conducted by Dr. Steven Rust, Montana State University, Huntly,
Montana. One hundred seventy six steers of British origin (avg. initial weight
of 794 lb) were allocated by weight, breed, and previous implant type to the following
treatment groups: 1) control, 2) OTC, 3) lasalocid, and 4) OTC + lasalocid. The
steers were fed a 90% concentrate diet consisting of barley, alfalfa silage, and
supplement. Individual weights were taken initially and at end of trial. Daily
feed consumption, carcass quality, and liver abscess data were recorded. The following
results were reported:
(Eds. note: The following table
consists of 5 columns.)
Control OTC OTC + Las Las
N 43 44 44 43
ADG (lb) 3.12 3.15 3.15 3.19
ADFI (lb) 23.0 22.7 22.6 22.3
Feed/Gain 6.48 6.36 6.34 6.45
Liver Ab. 12/43 10/44 11/44 11/43
Data from Studies C-109, C-205, C-207,
C-225 and C-226 were considered acceptable in support of the effectiveness of
lasalocid in combination with OTC for improving feed efficiency and increasing
rate of weight gain in cattle fed in confinement for slaughter (Study C-83-27
was not used in the pooled analysis because the cattle had been previously treated
with hormonal implants). A total of 648 cattle were involved at five different
experimental locations. The locations and management practices employed are representative
of major cattle feeding areas and practices in the United States with exception
that none of the test cattle received growth promoting implants. The data from
the five studies was subjected to a pooled analysis of variance comparing the
combination of OTC + Lasalocid to OTC alone and to negative controls for both
ADG and Feed/Gain. The means and their standard error are presented as follows:
(Eds. note: The following table
consists of 3 columns.)
Control OTC Las + OTC
ADG (lb) 2.771 +/- 0.031 2.798 +/- 0.031 2.861 +/- 0.031
Feed/Gain 7.707 +/- 0.079 7.529 +/- 0.079 7.315 +/- 0.079
ADG and Feed/Gain were improved by
the addition of both lasalocid and OTC to the diet. ADG for the lasalocid and
OTC group was shown to be significantly better than the control group (P=0.0023)
and tended to be better than the OTC group (P=0.0777). Feed/Gain for the combination
was shown to be significantly greater than the control group (P<0.0005) and
OTC group (P<0.0313). No differences were seen between groups with respect
to carcass quality. Data from Studies C-109, C-225, C-226 and C-83-27 were considered
acceptable in support of the effectiveness of lasalocid in combination with OTC
for reducing the incidence and severity of liver abscesses in cattle fed in confinement
to slaughter. Studies C-205 and C-207 were not used because the incidence of liver
abscesses in these trials was too low to draw adequate conclusions.
The data for these studies were
subjected to a pooled analysis of variance to determine if lasalocid interfered
with the ability of OTC to control liver abscesses. The means of percentages
of animals with liver abscesses were 37.51, 24.88, and 24.45 for the control,
OTC treated, and Lasalocid + OTC treated groups, respectively. The percentages
of incidence of liver abscesses for the lasalocid + OTC and OTC groups were
significantly less than for the control group (P<0.05). No significant difference
was seen between the lasalocid + OTC and OTC groups with respect to the percentage
of incidence of liver abscesses (sensitivity to detect a change of 15% incidence
with 80% power for a one sided test at the 0.05 level of significance).
Based on the above studies, it
is concluded that OTC fed in combination with lasalocid is more effective than
OTC fed alone to feedlot cattle with respect to improving feed efficiency. Furthermore,
it is concluded that lasalocid does not interfere with the ability of OTC to
reduce the incidence and severity of liver abscesses.
With respect to the Center's Combination
Drug Guidelines (November 9, 1983), it must be demonstrated that:
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a)
Lasalocid + OTC is better than OTC for performance; and |
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b)
lasalocid + OTC is better than lasalocid for reduced liver abscesses. |
The studies cited above provide a
direct comparison between the combination and OTC alone. Lasalocid + OTC was shown
to be better than OTC alone for improving feed efficiency. No direct comparison
can be made between the combination and lasalocid alone. However, the data demonstrate
that both OTC alone and in combination with lasalocid was effective in reducing
the incidence of liver abscesses and that lasalocid does not interfere with the
ability of OTC in this respect. Furthermore, studies used for the approval of
lasalocid in feedlot cattle (see Table below) showed no effect of lasalocid on
incidence of liver abscesses. Accordingly, it is concluded that lasalocid + OTC
has been demonstrated to be better than lasalocid for reducing liver abscesses.
(Eds. note: The following table
consists of 3 columns.)
Incidence of Liver Abscesses in Feeding Trials Using
Lasalocid Alone Submitted Under NADA 96-298 Dated
October 17, 1980.
Trial Control (%) Las 30 g/t (%)
773 5/31 (16.1) 7/31 (22.6)
789 0/24 (0) 3/24 (12.5)
793 5/32 (15.6) 2/32 (6.2)
799 15/120 (12.5) 25/120 (20.8)
C-6 32/40 (80.0) 27/40 (67.5)
C-10 9/32 (28.1) 12/32 (37.5)
C-23 1/15 (6.7) 0/16 (0)
C-24 13/48 (27.1) 12/48 (25.0)
C-29 2/32 (6.2) 0/32 (0)
Total 82/374 (21.9) 88/375 (23.5)
The above data establish compliance
with 21 CFR 514.1 (b)(8)(v).
V. ANIMAL SAFETY
Safety studies for lasalocid in
feedlot cattle at dosages up to 5X the recommended level are reported in NADA
96-298. OTC is currently approved for cattle at 0.5 to 2.0 grams per head daily
for the prevention and treatment of the early stages of shipping fever complex.
This dose is 6.7X to 26.7X the dose presently requested.
Two hundred cattle from the studies
used in the pooled analysis for efficacy were fed lasalocid and OTC during the
entire finishing period at the highest level in the approved ranges and no adverse
effects were noted during the entire feeding period.
It is concluded that the combination
of lasalocid and OTC is safe in feedlot cattle.
VI. HUMAN FOOD SAFETY:
A. Toxicity Tests and Safe Concentration
of Residues
Toxicity metabolism and total residue
depletion studies, which are used to establish human safety for lasalocid and
oxytetracycline, are described in the FOI Summary for NADA 96-298 (approved
at 47 FR 34133/4, August 6, 1982) for lasalocid and NADA 8-804 for oxytetracycline
as individual entities.
The tolerances of oxytetracycline
are established at 0.1 ppm in the uncooked edible tissues of cattle, beef calves,
non lactating dairy cattle and dairy calves (21 CFR 556.600) with liver and
kidney as the target tissues for feed uses.
The safe concentrations of total
lasalocid residues in the livers of cattle have been established at 4.8 ppm.
A marker residue concentration of 0.7 ppm of intact lasalocid corresponds to
a total residue level of 4.8 ppm (21 CFR 556.347).
B. Residue Depletion/Noninterference
Studies
A tissue depletion study in cattle
fed lasalocid at 300 mg/head/day using feed with 30 g lasalocid/ton feed and
oxytetracycline at 75 mg/hd/day for 34 days was undertaken by Animal Science
Research, Hoffmann-LaRoche Inc., Nutley, NJ. The study was conducted at the
ASR Experiment Station (ASRES), Wrightstown, NJ using ten cattle of mixed breeds
and sexes weighing 628 to 857 lbs. The animals were allocated as shown in the
following table with the 34 day medication period from 1/13 - 2/16/87.
(Eds. note: The following table
consists of 4 columns.)
Treatment -------# of--------
(mg/hd/day) Heifers Steers
I Control (a) 0 1 1
II Lasalocid Sodium + 300 4 4
Oxytetracycline 75
(a) Purpose of control group was to supply control liver for the
analytical laboratories.
The animals were slaughtered on the
morning of 2/17/87 at ASRES, and a 3 kg liver sample and both kidneys from each
animal were collected, identified and frozen as soon as possible. The samples
were transported to the HLR Animal Science Research (ASR) Analytical/Metabolic
Labs, Nutley, NJ where the liver samples were split in half. Both kidneys and
one half liver sample from each animal were shipped frozen via overnight express
on 2/18/87 to Hazleton Labs, America Inc., Madison, WI for oxytetracycline assay.
The other one half liver sample was forwarded to the ASR analytical lab for lasalocid
assay. The hplc-fluorescence detection regulatory procedure for the determination
of sodium lasalocid in bovine liver with a sensitivity of 0.025 ppm was used by
Hoffmann-LaRoche Inc. for all bovine liver assays in this study. The hplc-fluorescence
detection tissue residue procedure for lasalocid is described in the Food Additives
Manual which is on display in FDA's Freedom of Information Public Room (Room 12A-30,
5600 Fishers Lane, Rockville, MD 20857).
The oxytetracycline tissue residue
assays were conducted by Hazleton Labs, America Inc., Madison, WI using a method
from "Antibiotic Residues in Milk, Dairy Products, and Animal Tissues:
Methods, Reports and Protocols," revised October 1968, National Center
for Antibiotic and Insulin Analysis, Food & Drug Administration, Dept. of
Health, Education and Welfare, Washington, DC modified for a sensitivity of
0.1 ppm oxytetracycline in liver and kidney.
The summary tissue residue results
for both lasalocid and oxytetracycline are listed below.
(Eds. note: The following table
consists of 5 columns.)
Concentration of Lasalocid and Oxytetracycline in Zero Day
Withdrawal Bovine Livers and Oxytetracycline in Zero Day
Withdrawal Bovine Kidneys
----------------ppm----------------
Lasalocid Oxytetracycline
Animal Liver Liver Kidney
standard
mean deviation mean mean
S <0.025 ----- <.010* <0.010*
F 0.158** 0.243** <0.10* <0.10*
* No zones of inhibition were present
** One of the four values included in this determination
was an estimate below the limit of sensitivity.
The results of the two residue
studies show that the residues do not exceed the established safe concentration
for lasalocid and the tolerance for OTC at zero day withdrawal, the assigned
withdrawal period of lasalocid and oxytetracycline in cattle.
C. Assay Noninterference
Studies
The hplc-fluorescence procedure
was evaluated with all the common antibiotics including oxytetracycline prior
to initial submission to NADA 96-298 on October 17, 1980, and it was determined
that no antibiotic including oxytetracycline was detected in the method or interfered
with the lasalocid determination.
The method was validated to a sensitivity
of 0.1 ppm and shown to have no interference with lasalocid using a simultaneous
0.7 ppm lasalocid spike in the same tissue sample. This study also included
a 14 day stability test of oxytetracycline in frozen tissue which showed no
losses over that time period.
D. Analytical Methods for Determination
of Residues
The hplc-fluorescence detection
tissue residue regulatory procedure for the determination of sodium lasalocid
in bovine liver with a sensitivity of 0.025 ppm is described in the Food Additives
Manual which is on display in FDA's Freedom of Information Public Room (Room
12A-30, 5600 Fishers Lane, Rockville, MD 20857).
The oxytetracycline tissue residue
assays used a method from "Antibiotic Residues in Milk, Dairy Products,
and Animal Tissues: Methods, Reports and Protocols," revised October 1968,
National Center for Antibiotic and Insulin Analysis, Food and Drug Administration,
Dept. of Health, Education and Welfare, Washington, DC modified for a sensitivity
of 0.1 ppm oxytetracycline in liver and kidney.
E. 21 CFR 558.15
The following studies were conducted
to satisfy the animal and human health safety requirements of 21 CFR Section
558.15 for use of OTC at 75 to 80 mg/head/day in cattle (NADA 8-804).
Title: Effect of Oxytetracycline
of Tissue Levels, Antimicrobial Resistance and Shedding of Salmonella typhimurium
from Cattle.
Report No.: C 110184
Starting Date: April 18,
1985
Termination Date: July 18,
1985
Investigator: Colorado Animal
Research Enterprises, Inc.
Location: Ft. Collins, Colorado
Substance Tested: Oxytetracycline
administered in feed
Animals: Crossbred heifer
and steer calves, seven per treatment group.
This study was conducted to assess
the effect of oxytetracycline fed to cattle at 75 mg/hd/day on the quantity,
prevalence and duration of shedding of a tetracycline resistant Salmonella
typhimurium and to evaluate the effect of resistance characteristics and
tissue levels of the infecting organism.
Calves, weighing 500 to 600 lb,
were orally inoculated with a tetracycline resistant Salmonella typhimurium
after a four week adjustment period in the test facilities. Medicated diet feeding
was initiated to the appropriate treatment group at six days after the challenge
and was continued daily for the next eight weeks. Post challenge fecal samples
were collected twice prior to treatment initiation and 22 times during the 56
day treatment period. Collected specimens were direct-counted for quantities
of test salmonellae and enriched for detection of non-countable levels of test
salmonellae. From ten of the post challenge sampling periods, five S. typhimurium
isolates per calf tested by a microdilution, MIC method for susceptibility to
amikacin, kanamycin, carbenicillin, cefoxitin, chloramphenicol, gentamicin,
and trimethoprim/sulfamethoxazole. At study end, samples of liver, spleen and
mesenteric lymph node were surgically removed from all Salmonella-challenged
calves and were analyzed for presence of test salmonellae. This study was conducted
in compliance with US FDA Good Laboratory Practice Regulations (21 CFR 58).
Oxytetracycline administered to
cattle in their feed at 75 mg/hd/day did not significantly increase the quantity,
duration of prevalence of Salmonella shedding, nor increase the incidence of
antimicrobial resistance in Salmonella, nor increase the presence of Salmonella
in tissue.
Title: Effect of Oxytetracycline
on the Incidence of Antimicrobial Resistance in Indigenous Fecal Coliforms from
Cattle
Report No.: C 021284
Starting Date: January 28,
1985
Termination Date: April
16, 1985
Investigator: Colorado Animal
Research Enterprises, Inc.
Location: Ft. Collins, Colorado
Substance Tested: Oxytetracycline
Animals: Crossbred heifer
and steer calves, eight per treatment group.
A study was conducted to evaluate
the effect of oxytetracycline fed to cattle at 75 mg/hd/day on the incidence
of antimicrobial resistant indigenous fecal coliforms.
Fecal samples from medicated and
non-medicated cattle were collected prior to treatment initiation to obtain
baseline data, and weekly thereafter over an eight week treatment period. Ten
coliform isolates per calf per sampling were tested by a microdilution, MIC
method for susceptibility to amikacin, ampicillin, carbenicillin, cefoxitin,
chloramphenicol, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfadiazine,
tetracycline and trimethoprim/sulfamethoxazole. This study was conducted in
compliance with US FDA Good Laboratory Practice Regulations (21 CFR 58).
The administration of oxytetracycline
in feed to cattle at 75 mg/hd/day did not significantly increase the frequency
of antimicrobial resistance in their indigenous fecal coliforms.
VII. AGENCY CONCLUSIONS:
For the purpose of the human food
safety review, this original NADA has been treated as a Category II supplement
under the Agency's Supplemental Policy (42 FR 64367; December 23, 1977). This
NADA provides for the combination use of lasalocid and OTC at the levels of
10 to 30 mg/ton of feed and 75 mg/hd/day, respectively, for increased rate
of weight gain, improved feed efficiency, and reduction of incidence and severity
of liver abscesses in beef cattle fed in confinement for slaughter. Adequate
data were submitted which show that the combination resulted in a significant
(P<.05) improvement in feed efficiency when compared to OTC fed alone and
that lasalocid does not interfere with the ability of OTC in reducing the
incidence and severity of liver abscesses. Adequate animal safety data was
provided to show that the combination is safe for the target animals to consume.
Adequate data was presented to show that OTC at a level of 75 to 80 mg/hd/day
has met the human and animal safety requirements of 21 CFR 558.15. (Higher
levels of OTC for use in cattle feed have not met the requirements for 21
CFR 558.15. Adequate data is also available to show that lasalocid for use
in cattle feed to 30 g/ton of total ration has met the requirements for 21
CFR 558.15 (NADA 96-298). No changes were made in the approved levels of either
compound or in the target animal and the noninterference of lasalocid and
OTC with the analytical methods for OTC and lasalocid, respectively, was demonstrated.
According, approval of this change is not expected to increase human exposure
to drug residues, and therefore did not require a complete re-evaluation of
the human safety data in the original applications. These production drugs
are "OTC" because the use of them does not raise any special safety
concerns or require any diagnosis.
VIII. LABELING (Attached)
1. Blue Bird Cattle Finisher (B)
Medicated Feed (Lasalocid 25-30g/ton Oxytetracycline 7.5 g/ton) product label
2. Blue Bird Cattle Finisher (B) Medicated Feed (Lasalocid 25-30g/ton Oxytetracycline
7.5 g/ton) placard
3. Blue Bird Cattle Finisher (B) Medicated Feed (Lasalocid 10-30g/ton Oxytetracycline
7.5 g/ton) product label
4. Blue Bird Cattle Finisher (B) Medicated Feed (Lasalocid 10-30g/ton Oxytetracycline
7.5 g/ton) placard
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
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