I. GENERAL INFORMATION:
| NADA |
140-954 |
| Sponsor: |
Hoechst-Roussel Agri-Vet Company
Route 202-206 North
Somervile, New Jersey 08876-1258 |
| Generic Name: |
Fenbendazole Lincomycin |
| Trade Name: |
Safe-Guard®, Type "A" Medicated Article (Premix)
Lincomix®, Type "A" Medicated Article (Premix) |
| Marketing Status: |
OTC |
II. INDICATIONS FOR USE
Fenbendazole is indicated for the removal of:
Lungworms:
Metastrongylus apri, Metastrongylus pudendotectus .
Check verbatim label for Type 'A" products.
Gastrointestinal worms:
large roundworms (Ascaris suum ) adult and
larvae (L3
& L4
stages; liver, lung and intestinal forms), nodular worms (Oesophagostomum
dentatum, O.
quadrispinulatum ), small stomach worms (Hyostrongylus rubidus ) adult and larvae
(L2, L3,
L4 stages; intestinal mucosal forms), and whipworms (Trichuris suis )
Kidneyworms: Stephanurus dentatus, adult and larvae
Lincomycin is indicated for:
- increased rate of weight gain in growing-finishing swine
- for control of swine dysentery; for use in swine on premises with a history of
swine
dysentery, but where symptoms have not yet occurred
- for treatment swine dysentery
- for reduction in the severity of swine mycoplasmal pneumonia caused by
Mycoplasma
hyopneumoniae .
III. DOSAGE
| A. |
DOSAGE FORM |
Fenbendazole and lincomycin are marketed as separate Type
"A" medicated articles. The fenbendazole Type A medicated
article is sold in three concentrations: 40, 80, or 200 grams of fenbendazole
activity per kilogram. Lincomycin Type "A" medicated article
is sold in two concentrations: 20 and 50 grams of lincomycin per pound.
|
| B. |
ROUTE OF ADMINISTRATION |
oral via the feed. |
| C. |
RECOMMENDED DOSAGES: |
|
| |
Fenbendazole |
|
| |
10 to 80 g/ton |
To provide a total dose of 9 mg/kg of body weight; the
total dose is divided over a period of 3 to 12 days. |
| |
Lincomycin |
|
| |
20 g/ton |
For increased rate of gain in growing-finishing swine.
|
| |
40 g/ton |
For control of swine dysentery. For use in swine on premises
with a history of swine dysentery, but where symptoms have not yet occurred.
|
| |
100 g/ton |
For treatment of swine dysentery. |
| |
200 g/ton |
For reduction in the severity of swine mycoplasmal pneumonia
caused by Mycoplasma hyopneumoniae. |
| |
NOTES |
The resultant feed containing both drugs is then fed as
the sole ration. Feed containing lincomycin at 100 or 200 g/ton must
be withdrawn 6 days prior to slaughter. |
| |
|
|
IV. EFFECTIVENESS
The efficacy data for each individual drug are located in its parent NADA. The
Freedom of
Information (FOI) Summary contains a summary.
(Eds. note: The following table consists of 4 columns.)
Fenbendazole NADA 131-675 49 FR 3845 Jan. 31, 1984
55 FR 48230 Nov. 20, 1990
Lincomycin NADA 97-505 41 FR 26855 Jun. 30, 1976
47 FR 52145 Nov. 19, 1982
51 FR 12137 Apr. 9, 1986
55 FR 23423 Jun. 8,1990
Lincomycin is a continuous use production drug (fed longer than 14 days) and
fenbendazole is a short term therapeutic treatment. The study required for this
type of
approval is one that demonstrates the effectiveness of fenbendazole when fed
in
combination with lincomycin (see Center for Veterinary Medicine Staff Manual
Guide , IV.
Supplemental Policies, Guide 1240.4145, dated 4/16/90).
A controlled critical experiment was conducted using 80 pigs which were
experimentally
infected. The experiment demonstrated significant differences in parasite
removal and is
summarized below.
Eighty pigs were experimentally infected with Ascaris suum and
Trichuris suis .
The pigs
were randomly assigned to 8 treatment groups of 10 each; each treatment
group
contained 2 replicates of 5 each. The analysis of the data shows a significant
reduction (p
<.05) in the number of parasites present in animals receiving fenbendazole.
The treatment
groups and data are summarized in Table 1.
This study was conducted by T.S. van Veen, Veterinary Clinical Center, Michigan
State
University, East Lansing, Michigan 48824.
(Eds. note: The following table consists of 4 columns.)
Table 1.
Mean Number of Ascaris suum and Trichuris suis .
Treatment Group Ascaris suum Trichuris suis
Control 9.3 (18.4) 133.9 (90.36)a
FBZ 3 mg/kg x 3 days 0.0 (0.0)b 6.3 (6.98)b
FBZ 1.5 mg/kg x 6 days 0.0 (0.0)b 0.5 (1.58)c
FBZ 75 mg/kg x 12 days 0.0 (0.0)b 99.8 (85.57)a
FBZ 3 mg/kg x 3 days 0.0 (0.0)b 1.6 (2.01)b,c
LI 200 g/ton
FBZ 1.5 mg/kg x 6 days 0.0 (0.0)b 6.2 (19.26)b,c
LI 200 g/ton
FBZ 75 mg/kg x 12 days 0.0 (0.0)b 2.1 (3.45)b
LI 200 g/ton
LI 200 g/ton 4.0 (7.96)a 88.7 (65.42)a
Note:
FBZ = fenbendazole, LI = lincomycin.
Numbers in parentheses are standard deviation.
Means within columns with different superscripts are different p < 0.5.
From these data it can be concluded that the efficacy of fenbendazole against
A. suum and T. suis is not altered by the concurrent use of
lincomycin.
V. ANIMAL SAFETY
The target animal safety data for each individual drug are located in its
parent NADA. The FOI contains a summary of the data.
(Eds. note: The following table consists of 4 columns.)
Fenbendazole NADA 131-675 49 FR 3845 Jan. 31, 1984
55 FR 48230 Nov. 20, 1990
Lincomycin NADA 97-505 41 FR 26855 Jun. 30, 1976
47 FR 52145 Nov. 19, 1982
51 FR 12137 Apr. 9, 1986
55 FR 23423 Jun. 8,1990
The New Animal Drug Application upon which approval of fenbendazole in
combination
with lincomycin is based contains an adequate and well-controlled study
demonstrating the
safety of the combination when administered in the feed to pigs.
This study was designed to evaluate the target animal safety aspects of animals
treated
with various dosages of fenbendazole and lincomycin. Forty pigs weighing
approximately
35 lbs were divided into 4 groups of 10 pigs each. Treatment regimens reflected
0, IX, 3X
or 5X the suggested maximum dosage treatments (fenbendazole = 3 mg/kg for 3
days, 9
mg/kg for 9 days, or 15 mg/kg for 9 days, lincomycin = 200 g/t, 600 g/t or 1000
g/t for 21
days).
This study was conducted by T. S. van Veen, Veterinary Clinical Center,
Michigan State
University, East Lansing, Michigan 48824.
Parameters measured included body weight (weekly), clinical observations
(daily), clinical
chemistry and hematology (onset, middle, and termination of study). The latter
two
parameters included complete blood count, activated partial thromboplastin
time, serum
chemistry profile, and serum electrolyte profile. None of the parameters
measured at any
dosage were outside of physiological ranges.
This study demonstrates normal physiological function (used as a measure of
safety) when
fenbendazole and lincomycin are administered concomitantly in feed to pigs.
VI. HUMAN SAFETY:
A. Toxicity Tests:
The original NADA's and FOI summaries for each drug demonstrate that food
from
animals fed these products is safe for human consumption.
(Eds. note: The following table consists of 4 columns.)
Fenbendazole NADA 131-675 49 FR 3845 Jan. 31, 1984
55 FR 48230 Nov. 20, 1990
Lincomycin NADA 97-505 41 FR 26855 Jun. 30, 1976
47 FR 52145 Nov. 19, 1982
51 FR 12137 Apr. 9, 1986
55 FR 23423 Jun. 8,1990
B. Safe Concentration of Residues:
In swine a tolerance of 0.1 ppm lincomycin is established for negligible
residues in the
edible tissues (21 CFR 556.360). A tolerance for marker residues of
fenbendazole in swine
is not needed. The safe concentration for total residues of fenbendazole in
uncooked
edible tissues of swine are 5 ppm in muscle, 15 ppm in liver, 20 ppm in kidney,
and 20
ppm in skin and fat (21 CFR 556.275).
C. Residue Depletion Non-interference Study:
The residue data supporting the approved individual uses of fenbendazole and
lincomycin
have been submitted in their respective original applications. The summaries of
the study
conducted for this combination are presented in Tables 2, 3 and 4. These
summaries
establish that each drug in the presence of the tolerance(s) and that none of
the drugs
interferes with the other's tissue residue assay. The pigs in this study were
fed lincomycin
(100 g/t or 200 g/t) for 12 days prior to the withdrawal period in combination
with
fenbendazole (total dose of 9 mg/kg divided over 3 or 12 days) for 3 or 12 days
prior to
the withdrawal period. Liver and kidney were collected and assayed for
lincomycin
residues. Liver was also assayed for fenbendazole residues (fenbendazole assay
detection
limit 0.02 ppm, lincomycin assay detection limit 0.067 ppm). The tissues were
collected on
the withdrawal days indicated in Tables 2, 3 and 4.
Studies conducted by T.S. van Veen, MSU, East Lansing, Michigan 48824.
(Eds. note: The following table consists of 4 columns.)
Table 2.
Residue Depletion Assay Results of Fenbendazole (ppm);
Average values (n = 4); Standard Deviation in parentheses.
Treatment Tissue Withdrawal(hr) Concentration (ppm)
FBZ 3 days; Liver 12 .116 (0.7)
LI 200 g/ton
FBZ 12 days; Liver 12 .049 (.07)
LI 200 g/ton
FBZ 3 days; Liver 12 .992 (.90)
LI 100 g/ton
FBZ 12 days; Liver 12 .113 (.04)
LI 100 g/ton
(Eds. note: The following table consists of 4 columns.)
Table 3.
Residue Depletion Assay Results of Lincomycin (ppm);
Average values (n = 4); Standard Deviation in parentheses.
Treatment Tissue Withdrawal(hr) Concentration (ppm)
FBZ 3 days; Liver 12 .02 (.04)
LI 200 g/ton Liver 24 .00 (.00)
Liver 72 .06 (.07)
Liver 144 .00 (.00)
FBZ 12 days; Liver 12 .06 (.04)
LI 200 g/ton Liver 24 .02 (.03)
Liver 72 .15 (.20)
Liver 144 .00 (.00)
FBZ 3 days; Liver 12 .02 (.03)
LI 100 g/ton Liver 24 .00 (.00)
Liver 72 .04 (.06)
Liver 144 .00 (.00)
FBZ 12 days; Liver 12 .00 (.00)
LI 100 g/ton Liver 24 .00 (.00)
Liver 72 .00 (.00)
Liver 144 .00 (.00)
(Eds. note: The following table consists of 4 columns.)
Table 4.
Residue Depletion Assay Results of Lincomycin (ppm) in Kidney: Average
values (n=4); Standard Deviation in parentheses.
Treatment Tissue Withdrawal(hr) Concentration(ppm)
FBZ 3 days; Kidney 12 .15 (.10)
LI 200 g/ton Kidney 24 .06 (.04)
Kidney 72 .11 (.11)
Kidney 144 .00 (.00)
FBZ 12 days; Kidney 12 .09 (.06)
LI 200 g/ton Kidney 24 .08 (.01)
Kidney 72 .27 (.22)
Kidney 144 .00 (.00)
FBZ 3 days; Kidney 12 .10 (.03)
LI 100 g/ton Kidney 24 .00 (.00)
Kidney 72 .11 (.10)
Kidney 144 .00 (.00)
FBZ 12 days; Kidney 12 .08 (.01)
LI 100 g/ton Kidney 24 .01 (.02)
Kidney 72 .09 (.06)
Kidney 144 .03 (.05)
Along with the residue depletion results presented in Tables 2, 3 and 4, the
sponsor
conducted a noninterference study for the fenbendazole tissue residue study by
spiking
samples with fenbendazole and lincomycin and conducting fenbendazole assays.
The
results demonstrated no interference by lincomycin on the assay for
fenbendazole.
The sponsor conducted a noninterference study for lincomycin by spiking control
tissue
samples with lincomycin and fenbendazole and then assaying these tissues for
lincomycin
content. The results demonstrated no interference by fenbendazole on the tissue
assay for
lincomycin.
E. Withdrawal Time:
The data support a zero withdrawal for fenbendazole in swine tissues. Feeds
medicated
with 100 or 200 g/t lincomycin must be withdrawn 6 days before swine are
slaughtered.
F. Category Type:
Under 21 CFR 558.3 (b)(1)(ii), fenbendazole is classified as a Category II drug
because a
withdrawal period is required for the lowest use level in cattle feed. A
withdrawal period is
also required for the use of lincomycin at 100-200 g/ton levels in swine.
Therefore,
Medicated Feed Applications (FD 1900's) will be required for the combination
of
fenbendazole and lincomycin in swine feeds.
Under Section 21 CFR 558.4 (e) when drugs from both categories are used in
combination, [Lincomycin (Category I) & Fenbendazole (Category II)] the
Category II
requirements will apply to the combination.
G. Regulatory Methods:
A microbiological assay method is used to assay tissues for lincomycin
residues. The
method titled "Determination of Lincomycin Residues in Broiler Chicken Tissues"
is on file
at the Center for Veterinary Medicine, Food and Drug Administration (HFV-199)
7500
Standish Place, Rockville, MD 20855.
An HPLC assay method is used to assay tissues for fenbendazole. This method
titled
"Determinative Procedure for the Measurement of Fenbendazole in Bovine Liver
Tissue" is
on file at the Center for Veterinary Medicine, Food and Drug Administration
(HFV-199)
7500 Standish Place, Rockville, MD 20855.
VII. AGENCY CONCLUSIONS:
The data submitted in support of this NADA, satisfy the requirements of Section
512 of the
Act and demonstrate that the combination of fenbendazole and lincomycin, when
fed to
growing swine under its labeled conditions of use, is safe and effective.
Because this drug contains a combination of two previously approved active
ingredients,
this original new animal drug application is treated as a Category II drug [21
CRF 514.106
(b) (2)]. A reevaluation of underlying safety and effectiveness data in the two
parent
applications was not required.
The sponsor demonstrated via residue depletion studies using approved
regulatory
methods, that the depletion characteristics of the marker residue for each drug
in the
combination were not significantly modified. Based on the lack of significant
change in
depletion characteristics, CVM concluded that the composition of the residue
for each drug
is not changed. The sponsor also demonstrated that the existing regulatory
method for
each drug is not interfered with by residues of the other drug. Based on the
foregoing, it
was not necessary to reevaluate the underlying toxicity tests supporting the
separate
approvals, or to require additional metabolism and total residue depletion
studies.
Adequate directions for use of this combination product by nonveterinarians
have been
clearly written, and there is reasonable certainty that the conditions of use,
including mixing
directions, as stated on the label can and will be followed by the feed mill
and producer.
Approved over-the-counter products containing fenbendazole and lincomycin alone
are
marketed for the same claims as are on the label for the combination product.
The Agency
is not aware of any reason why the combining of the two products would require
restriction
of the new product to prescription use.
Under Section 512(c)(2)(F)(ii) of the Act, this approval qualifies for a
three-year period of exclusivity to NADA's for the previously approved active
ingredients because new clinical trials, field investigations, and human food
safety data were required for approval.
VIII. LABELING
(Attached)
Copies of applicable labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855
