Summary of
FDA Information:
Approval Date: July 17, 1987
Freedom of
Information Summary
NADA 139-472
I. GENERAL INFORMATION:
NADA 139-472
Sponsor:
Fermenta Animal Health Co.
7528 Auburn Road
Painesville, Ohio 44077
Generic Name: Tiamulin
Trade Name: DENAGARD Antibiotic Premix (Type A Medicated Article)
DENAGARD 5 Medicated Premix (Type A Medicated Article)
DENAGARD 10 Medicated Premix (Type A Medicated Article)
Marketing Status: over-the-counter (OTC)
II. INDICATIONS FOR USE
For the control of
swine dysentery associated with Treponema hyodysenteriaesusceptible to tiamulin. For increased rate of
weight gain from
weaning to 125 pounds body weight.
III. DOSAGE
A. DOSAGE FORM Premix
B. ROUTE OF ADMINISTRATION Oral via feed
C. RECOMMENDED DOSAGES: 35 g/t for
control of
swine dysentery; 10 g/t for
increased rate of
weight gain from
weaning to 125 lbs bwt.
IV. EFFECTIVENESS
Effectiveness trials were
conducted with tiamulin-medicated feeds prepared from
three tiamulin premixes.
These included the 25% tiamulin premix (DENAGARD), a formulation of
tiamulin in cornstarch (TIAMUTIN®-Sandoz) and
a tiamulin-extruded formulation (DYNAMUTILIN®-Squibb).
The formulations have been shown to be equivalent on the basis of
blood level bioequivalency studies.
a. CONTROL OF SWINE DYSENTERY
(1) Pivotal Studies
The effectiveness of
DENAGARD (tiamulin) premix for
the control of
swine dysentery associated with Treponema hyodysenteriaesusceptible to tiamulin has been demonstrated by the results of
three well-controlled laboratory and
field trials conducted in three states with 512 pigs.
Dose determination trials with tiamulin at 20, 35 and
50 g/t were
conducted in the
laboratory (induced infection) and
in the field (natural infections).
No adverse reactions to tiamulin were
observed in any of
these trials.
Individual trial summaries follow.
TEST: MDA 012483
STUDY TYPE: Laboratory Dose Titration
INVESTIGATOR:
T. J. Kennedy, Ph.D.
AEF Research, Inc.
5492 Kennedy Drive, Route 3
Waunakee, Wisconsin
The purpose of
this trial of
randomized block design was
to evaluate tiamulin at 20, 35, and
50 g/t of
feed vs. nonmedicated controls for
the control of
swine dysentery. Forty-eight crossbred pigs, 28 barrows and
20 gilts, averaging 34 pounds in weight were
allotted 6 pigs per pen, 2 pens per treatment on the basis of
weight and
sex. All pigs were
infected on test days 0 and
40 by feeding infective material (colonic tissue and
contents) taken from
pigs with clinical signs of
swine dysentery. Medicated feed was
self-fed from
after infection on test day 0 to test termination on Day 63.
A tiamulin premix was
used to prepare medicated feed in this trial.
Throughout the trial, pigs were
observed and
individually rated daily for
general appearance, dehydration, diarrhea and
presence of
blood in feces. Weight gains and
feed consumption were
determined periodically throughout the test. All pigs were
examined for
the presence of
treponemes on test days 1, 7, 14, 28, 42, and
56 by dark field microscopic examination of
rectal swab material.
Results of
this study
were pooled with results from
the other pivotal studies and
statistical analysis appears later in this summary.
(Eds. note: The following table consists of
5 columns.)
Table 1 MDA 012483
Tiamulin, g/t
Item 0 20 35 50
Number of
pigs 12 12 12 12
Mortality, % 0 0 0 16.7
Average daily gain, lb 0.52 1.08 0.95 0.95
Average daily feed, lb 2.249 3.282 3.045 2.796
Gain/feed 0.239 0.332 0.316 0.343
Treponemes, % of
exams 61.7 21.7 1.7 5.4
Days with bloody feces, % 22.7 0 0 0.8
Pig days with bloody feces, % 11.8 0 0 0.2
Days with diarrhea, % 68.8 28.2 0.8 0
Pig days with diarrhea, % 29.3 7.6 0.2 0
Average daily diarrhea score 0.624 0.118 0.002 0
No mortality due to swine dysentery occurred. Blood observed briefly, at 50 g/t was
due to ulcerative colitis.
No adverse reactions to the test drug were
observed.
TEST: MDA 052783A-2
STUDY TYPE: Field Dose Titration
INVESTIGATOR:
Eugene Nemechek, D.V.M.
905 Oak Forest Drive
Wilson, North Carolina 27893
This trial was
conducted to evaluate continuous medication with tiamulin at 20, 35, and
50 g/t for
the control of
swine dysentery under
practical conditions on a farm with a recent history of
the disease.
A total of
240 crossbred pigs averaging 71.9 lb and
approximately 11 weeks of
age were
used in this test of
randomized block design.
There were
two replications of
thirty pigs per treatment. Pigs were
weighed and
randomly allotted to pens and
treatments were
randomly assigned to pens within replications. Observations and
ratings for
diarrhea (0-3) and
presence of
blood in feces were
recorded at least twice weekly. Pigs that died were
weighed and
a postmortem exam conducted to establish cause of
death. After swine dysentery was
confirmed present among non-medicated control pigs, the
controls were
fed feed containing tiamulin at 35 g/t for
the final 3 weeks of
the 57-day trial to reduce unnecessary animal loss.
No signs of
toxicity or
adverse reactions to tiamulin were
observed in this trial.
The results of
this trial were
pooled with the other pivotal studies and
statistical analysis appears later in this summary.
(Eds. note: The following table consists of
5 columns.)
Table 2 Test MDA 052783A-2
Treatment, g/t
Item 0* 20 35 50
Number of
pigs allotted 60 60 60 60
Deaths:
(1) Due to swine dysentery 2 0 0 0
(2) Total 6 4 2 0
Average daily gain, lb 1.57 1.64 1.62 1.76
Average daily feed, lb 4.63 4.62 4.38 4.81
Gain/feed 0.339 0.355 0.369 0.365
Average daily diarrhea score 0.4560 0.2599 0.1214 0.0628
Pig days with diarrhea, % 39.6 25.3 12.2 6.2
Test days with diarrhea, % 64.8 48.9 18.5 19.1
Pig days with bloody feces, % 2.8 0.9 0 0
Test days with bloody feces, % 24.5 9.4 0 0
* Tiamulin administered at 35 g/t for
last three weeks of
trial.
TEST: MDA 041884
STUDY TYPE: Field Dose Titration
INVESTIGATOR:
Marianne Ash, D.V.M.
P.O. Box 11
Camden, Indiana 46927
A field trial was
conducted in a commercial swine operation in Indiana utilizing the tiamulin premix to evaluate continuous medication at 20, 35, and
50 g/t (active ingredient) in controlling swine dysentery in pigs housed in a facility in which
the disease repeatedly occurred.
A total of
224 crossbred barrows and
gilts average 50.2 lbs were
randomly allotted to 8 pens in each of
2 similar adjacent rooms in a completely confined growing-finishing facility. Pens in these rooms were
formed by solid partitions over a completely slotted floor.
In 3 of
the 4 test treatments, pigs were
continuously fed feed mixed to contain tiamulin at 20, 35, and
50 g/t over the total 13-week test period.
The fourth treatment, nonmedicated controls, was
maintained as such for
five weeks after the start of
the trial when
swine dysentery was
diagnosed present on the basis of
clinical signs and
observations at necropsy. Control pigs were
then fed tiamulin at 35 g/t to test end.
Observations and
ratings for
diarrhea (0-3) and
the presence of
blood in the
feces were
recorded at least once weekly. Pigs which
died were
weighed and
a postmortem examination performed to determine cause of
death. Results of
the 91-day trial are summarized in the
following table.
No signs of
adverse reactions or
toxicity due to tiamulin were
observed.
Results of
this study
were pooled with results from
the other pivotal studies and
statistical analysis appears later in this summary.
(Eds. note: The following table consists of
5 columns.)
Table 3 MDA 041884
Treatment, g/t
Item 0* 20 35 50
Number of
pigs allotted 56 56 56 56
Deaths:
(1) Due to swine dysentery 8 1 0 0
(2) Total 9 3 0 0
Average daily gain, lb 1.43 1.57 1.58 1.57
Average daily feed, lb 4.06 4.31 4.38 4.38
Gain/feed 0.352 0.364 0.361 0.359
Average daily diarrhea score 0.1824 0.0540 0.0094 0.0098
Pig days with diarrhea, % 9.38 2.81 0.52 0.73
Test days with diarrhea, % 25.0 32.4 1.5 6.1
Pig days with bloody feces, % 4.5 2.3 0.1 0.2
Test days with bloody diarrhea, % 17.6 17.6 1.5 3.0
* After five weeks on test, pigs were
administered 35 g tiamulin/ton
until test end.
STATISTICAL ANALYSIS
Statistical analysis of
the most meaningful parameters consistent among the trials was
conducted.
The parameters were
percent test days with diarrhea, percent pig days with diarrhea and
average diarrhea scores.
a. Because of
the number of
0 percentages and
other small percentages, the
arcsin of
the square root of
the proportion was
used to transform the data.
The value of
1/(4 X n) was
substituted for
zero values before transformation.
b.
The use of
Bartlett's test for
homogeneity of
variance found that the
variances from
location to location are homogeneous (P>.005) for
all parameters. No weighted analysis was
necessary.
c. An analysis of
variance of
the transformed data included effects for
location, reps within location, treatment, treatment by location and
error. For the three parameters analyzed, the
treatment by location effect was
always significant (P<.20) and
was
used to test the treatment effect, which
were
all significant (P<. 01).
d. Least square means derived from
these analyses were
subjected to model fitting, both linear plateau models as well as polynomial models. Two models, linear and
Model III-2 (linear response from
0 - 35 gm/ton and
plateau from
35 to 50 gm/ton), showed nearly equal characteristics of
optimum fit for
all parameters. Both models had R-squares greater than .93, all had coefficients that significantly contributed to the model and
all had insignificantly little variation left to explain by fitting a different model.
The linear model indicated the optimum dose to be 50 gm/ton whereas the Model III-2 indicated 35 gm/ton. Observing the means and
graphs, it appeared that the
response at 50 gm/ton was
somewhere between the plateau and
a straight linear relationship. It is not generally recommended to use pairwise testing in dose titration studies to determine the optimum dose, but in this case, the
lack of
significance between the 35 and
50 gm/ton levels (P>.40) would point to 35 gm/ton being a sufficient dose.
(2) Corroborative Studies
Four trials involving 673 pigs are included as supporting evidence of
effectiveness of
tiamulin for
the control of
swine dysentery.
These trials were
conducted in Iowa (2), Missouri, and
Wisconsin.
Tiamulin was
tested at concentrations ranging from
20 to 50 g/t in the
feed. Each trial included infected nonmedicated controls and
3 of
the 4 trials included a positive control treatment (lincomycin).
The results of
these trials support the conclusions reached in the
pivotal efficacy studies.
No adverse reactions to tiamulin were
observed in these trials.
Individual trial summaries follow.
TEST: SR44 -214
STUDY TYPE: LABORATORY EFFECTIVENESS
INVESTIGATORS:
J. Hayden, D.V.M.
G.
Thompson, Ph.D.
Gray Summit, Missouri
The purpose of
this trial was
to evaluate tiamulin at 35 g/t in feed for
the control of
swine dysentery. Mixed breed barrows and
gilts averaging 72.4 lbs and
about 15 weeks of
age were
randomly allotted 8 per pen to 12 pens.
Three pens were
nonmedicated controls; 9 pens were
fed tiamulin at 35 g/t beginning after deliberate infection on Test Day 0. Pigs were
weighed individually on Test Days -2, 49, and
at test end on Day 70. Daily observations were
made and
pen groups rated for
diarrhea and
presence of
bloody feces. Two pigs per pen (25%) were
checked for
spirochetes by dark field microscopic examination of
rectal swabs taken on Test Days 0, 49 and
63. Bacterial culture of
swab material for
T. hyodysenteriaewas also performed on Days 49 and
63 and
on pigs with bloody feces on other days. Results of
the 70-day trial are summarized below.
(Eds. note: The following table consists of
3 columns.)
Table 4
Nonmedicated Tiamulin
Item Control 35 g/t
Number of
pens 3 9
Number of
pigs 24 72
Average initial weight, lb 75.0 71.5
Percent mortality 25 0
Average daily gain, lb 1.24 1.86
Average daily feed, lb 4.63 5.97
Gain/feed 0.266 0.312
Average diarrhea score (0-3) 1.9333 0.6524
Test days with diarrhea, % 99.0 61.2
Test days with bloody feces, % 61.4 6.2
Rectal swabs culture+ for
T. hyo., % 33 7
No adverse reactions to tiamulin were
observed.
TEST: MDA 052783A
STUDY TYPE: Field Dose Titration
INVESTIGATORS:
D.L. Weiss, D.V.M.
R.A. Howland, D.V.M.
Veterinary Clinic
R.F.D. #4
Fort Dodge, Iowa 50502
This field trial was
conducted to evaluate continuous tiamulin medication at 20, 35, and
50 g/t for
effectiveness in controlling swine dysentery under
practical conditions on a farm with a history of
the disease.
A total of
367 crossbred pigs, approximately half barrows and
half gilts, and
averaging 89 lbs were
sorted by weight and
origin and
assigned to a total of
8 pens in an open-front Cargill-type finishing facility.
There were
two pens per treatment.
The nonmedicated control treatment was
maintained until about six weeks after the start of
the trial when
swine dysentery was
diagnosed as present on the basis of
clinical signs and
confirmed present on the basis of
postmortem examination of
dead test pigs submitted to the state veterinary diagnostic laboratory. Control pigs were
then treated with tiamulin in the
drinking water at 60 ppm for
5 days and
put on a diet containing tiamulin at 35 g/t to test end.
Observations and
ratings for
diarrhea (0-3) and
the presence of
blood in the
feces were
recorded at least twice weekly. Pigs that died were
weighed and
a postmortem examination performed to determine cause of
death. Pleuropneumonia was
a complicating factor in this trial.
Pigs were
withdrawn from
medication and
removed from
the trial on a pen-by-pen basis as they approached market weight or
between 56 and
81 days after the start. Test results are summarized in the
following table.
Continuous medication with tiamulin in the
feed at 20, 35 and
50 g/t was
effective in controlling signs of
swine dysentery in this trial. Apparent weight gain response to levels of
tiamulin in controlling swine dysentery may have been confounded by pneumonia in this trial.
No signs of
adverse reaction or
toxicity due to tiamulin were
observed.
(Eds. note: The following table consists of
5 columns.)
Table 5 MDA 052783A
Treatment, g/t
Item 0* 20 35 50
Number of
pigs allotted 91 95 99 82
Deaths:
(1) Due to swine dysentery 2 0 0 0
(2) Total 8 7 3 1
Average daily gain, lb 1.43 1.30 1.40 1.67
Average daily feed, lb 5.41 5.12 5.43 6.96
Gain/feed 0.268 0.253 0.258 0.240
Average diarrhea score (0-3) 0.0259 0 0 0
Pig days with diarrhea, % 1.32 0 0 0
Test days with diarrhea, % 17.0 0 0 0
Pig days with bloody feces, % 0.9 0 0 0
Test days with bloody feces, % 9.8 0 0 0
* After 6 weeks, pigs were
treated with tiamulin in the
water followed
by 35 g/t in the
feed to test end.
TEST: MDA 051884
STUDY TYPE: Field (Clinical) Effectiveness
INVESTIGATOR:
Curt Daniels, D.V.M.
FIELD TRIALS
Mingo, Iowa 50168
A field effectiveness trial was
conducted to evaluate tiamulin at 35 g/t for
controlling a natural infection of
swine dysentery an a commercial swine operation. Lincomycin at 40 g/t was
used as a positive control treatment. One pen of
nonmedicated controls was
used to show that the
disease was
present in the
facility. Swine dysentery was
confirmed present in the
control pigs on the basis of
clinical signs observed during the 114-day trial and
on the basis of
gross lesions and
the presence of
Treponema hyodysenteriaein the colonic tissues of
a control pig killed for
necropsy at test end.
All pigs were
rated for
clinical signs of
swine dysentery at least twice weekly throughout the test. Weight gains and
feed consumption were
determined on test days 65 and
114. Fecal material collected by rectal swabs from
5 pigs per pen on test days 1 and
65 and
from all pigs on test day 114 were
examined for
the presence of
spirochetes by microscopic examination and
/or for
Treponema hyodysenteriaeby bacterial culturing.
Results of
determinations and
observations made are summarized in the
following table:
(Eds. note: The following table consists of
4 columns.)
Table 6
Nonmedicated Tiamulin Lincomycin
Control 35 g/t 40 g/t
Number of
pens 1 3 3
Total number of
pigs 10 30 30
Average initial weight, lb 45.1 45.8 46.1
Mortality, % 0 0 0
Average daily gain, lb 1.549 1.533 1.529
Average daily feed, lb 4.90 4.81 4.82
Gain/feed 0.3161 0.3188 0.3170
Average diarrhea score (0-3) 0.2570 0.0000 0.500
Pig days with diarrhea, % 16.3 0.0 3.8
Test days with diarrhea, % 50.0 0.0 20.8
Test days with bloody feces, % 34.4 0.0 4.2
Exams for
spirochetes
positive/total exams(a) 4/20 3/60 6/60
(a)Combined results of
exams on days 1, 65 and
114.
Tiamulin at 35 g/t was
at least as effective as lincomycin at 40 g/t in controlling swine dysentery in this trial. No adverse reactions to tiamulin or
to lincomycin were
observed.
TEST: MDA 051884A
STUDY TYPE: Field (Clinical) Effectiveness
INVESTIGATOR:
T. J. Kennedy, Ph.D.
AEF Research, Inc.
5492 Kennedy Drive, Rt. 3
Waunakee, Wisconsin 53597
A total of
140 crossbred pigs averaging 132 pounds were
allotted 14 per pen to 10 pens for
this trial to compare tiamulin at 35 g/t with lincomycin at 40 g/t (positive control) for
effectiveness in controlling a natural infection of
swine dysentery in a hog farm operation. During the 38-day test, pigs were
rated twice weekly for
appearance, apparent dehydration and
diarrhea and
the presence or
absence of
bloody feces in the
pens was
recorded. All pigs were
weighed at the
start of
the test and
on Day 38, test end. Five pigs per pen were
examined for
treponemes by dark field microscopic examination of
rectal swab material collected on Day 0 and
again on Day 38. Results are summarized in the
table below.
(Eds. note: The following table consists of
4 columns.)
Table 7
Nonmedicated Tiamulin Lincomycin
Controls 35 g/t 40 g/t
Number pens 2 4 4
Mortality due to swine dysentery 1 0 1
Average daily weight gain, lb 1.015 1.586 1.506
Gain/feed 0.157 0.224 O.214
Average diarrhea score (0-3) 0.3490 0.0653 0.0922
Pig days with diarrhea, % 21.8 4.8 6.2
Test days with diarrhea, % 80.0 30.8 63.4
Test days with bloody feces, % 40.0 7.8 7.0
Pigs positive for
treponemes, %:
Day 0 80 85 70
Day 38 100 10 25
No adverse reactions to either tiamulin or
lincomycin were
observed.
Tiamulin at 35 g/t was
at least as effective as the positive control drug, lincomycin at 40 g/t, in controlling swine dysentery in this field trial.
b. INCREASED RATE OF WEIGHT GAIN
(1) Pivotal Studies (Three Trials: P-8-14-LT, P-9-3-NT, P-8-15-LT)
Three controlled trials with a total of
300 pigs, at an average initial weight of
23.5 lbs, were
conducted in three states to demonstrate the effectiveness of
tiamulin for
increasing rate of
weight gain to 125 lbs body weight. Tiamulin was
evaluated at levels of
2.5 to 40 g/t in the
diet.
The 0, 10 and
20 g/t treatments were
common to all three trials, while the 40 g/t level was
tested in two trials.
Analyses of
combined data from
the three pivotal studies examined average daily gain and
feed conversion values to market weight only for
the 0, 10, 20, and
40 g/t treatment groups due to the imbalance in dose groups from
location to location. Tiamulin at 10 g/t was
found in the
combined analysis to have significantly (p=.001) increased average daily gain. Feed conversion was
not significantly different among treatments.
The least squares means and
standard errors derived from
the combined analyses are as follows:
(Eds. note: The following table consists of
5 columns.)
Dose
Level ADG Feed/Gain
gm/ton LS Means s.e. LS Means s.e.
0 1.393 .0215 3.237 .0437
10 1.501 .0215 3.227 .0437
20 1.433 .0215 3.2Q7 .0437
40 1.509 .0278 3.268 .0624
Data from
trial P-9-3-NT, which
included drug concentrations of
0, 2.5, 5, 10, and
20 g/t, were
then analyzed separately to determine if levels of
less than 10 g/t should be further titrated. Least squares means for
average daily gains numerically increased from
levels of
0 to 10 g/t, but there were
no significant differences between control and
any level tested in the
study
.
No adverse drug effects were
observed in any of
these trials. Individual trial summaries follow.
TEST: P-8-14-LT
STUDY TYPE: Dose Titration
INVESTIGATORS:
G. Cromwell, Ph.D.
T. Stahley
Department of
Animal Science
University of
Kentucky
Lexington, KY
This trial was
conducted to evaluate tiamulin at 10, 20, and
40 g/t for
effect on growth performance vs. non-medicated control pigs.
Eighty Yorkshire X Hampshire crossbred pigs averaging 32.5 lb were
allotted on the basis of
weight and
sex to one of
the 4 treatments listed below.
There were
4 pens of
5 pigs per treatment in this test of
randomized block design.
A 16% protein corn-soy diet was
fed to 125 pounds followed by a 12% protein corn-soy diet to market weight.
A 25% tiamulin premix was
used to prepare tiamulin-medicated feed which
was
fed to 125 pounds. Nonmedicated feed was
fed after withdrawal of
test drug. Average daily weight gain (ADG), feed consumption (ADF), and
feed/gain values from
test initiation to an average final weight of
208 lb are presented below.
(Eds. note: The following table consists of
5 columns.)
Table 8
No.
Treatment Pigs ADG, lb ADF, lb Feed/Gain
Nonmedicated control 20 1.48 4.84 3.27
Tiamulin, 10 g/t 20 1.62** 5.37* 3.34
Tiamulin, 20 g/t 20 1.56 5.20 3.35
Tiamulin, 40 g/t 20 1.63** 5.22 3.21
* P<.05 (vs. nonmedicated controls)
** P<.01 (vs. nonmedicated controls)
Tiamulin at all levels tested numerically increased rate of
weight gain and
feed consumption, but only at 40 g/t was
feed conversion efficiency improved relative to nonmedicated controls.
No adverse reactions to tiamulin were
observed.
TEST: P-9-3-NT
STUDY TYPE: Dose Titration
INVESTIGATORS:
G. Allee, Ph.D.
J. Riley
Eureka Testing
Manhattan, Kansas
The purpose of
this trial was
to evaluate tiamulin at 2.5, 5, 10 and
20 g/t vs. nonmedicated controls for
effect on growth performance of
swine.
One hundred-twenty crossbred pigs averaging 24 lbs were
randomly assigned to pens by weight, sex and
sire.
There were
6 pigs per pen, 2 pens of
barrows and
2 pens of
gilts per treatment listed below. Treatments were
randomly assigned to pens within replications in this test of
randomized block design. Diets composed largely of
grain sorghum and
soybean meal were
self-fed throughout with feeds formulated to contain 18, 16, and
14% protein fed from
the start to 50 lbs, from
50 to 125 lbs and
from 125 lbs to market weight (200-225 lbs), respectively.
Nonmedicated pigs were
used as a negative control treatment.
A 25% tiamulin premix was
used to provide tiamulin at 2.5, 5, 10, and
20 g/t in feed which
was
self-fed to 125 lbs. Following withdrawal of
test drugs, nonmedicated feed was
fed to market weight.
The results of
this growth test are summarized below for
the total pericd of
feeding to market weight (average 210 lbs).
VIII. LABELING (attached)
1. DENAGARD® 10 Medicated Premix (Type A Medicated Article) package label
2. DENAGARD® 5 Medicated Premix (Type A Medicated Article) package label
3. Blue Bird Swine Feed (Type B) Medicated package label
4. Blue Bird COMPLETE SWINE RATION (Type C) Medicated (tiamulin 35 g/t) package label
5. Blue Bird COMPLETE SWINE RATION (Type C) Medicated (tiamulin 10 g/t) package label
6. DENAGARD® (Tiamulin) Antibiotic Premix (Type A Medicated Article) package 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
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