Summary of
FDA Information:FOI Summary; NADA 141-063 (original); NUFLOR ® (florfenicol); May 31, 1996
--Editor's abstract
I. GENERAL INFORMATION
NADA Number: 141-063
Sponsor:
Schering-Plough Animal Health Corporation
P.O. Box 529
Kenilworth, New Jersey 07033
Accepted Name: florfenicol
Trade Name: NUFLOR ® Injectable Solution
Marketing Status:
This is a prescription product and
will include the caution statement as follows: Federal (USA) law restricts this drug to use by or
on the order of
a licensed veterinarian.
II. INDICATIONS FOR USE
NUFLOR ® Injectable Solution is indicated for
the treatment of
bovine respiratory disease (BRD) associated with Pasteurella haemolytica, Pasteurella multocida, and
Haemophilus somnus.
III. DOSAGE FORM, ROUTE OF ADMINISTRATION, AND DOSAGE
A. Dosage Form:
NUFLOR ® Injectable Solution is a sterile non-aqueous solution available in 100-, 250-, and
500-mL glass vials. Each milliliter contains 300 mg florfenicol.
NUFLOR ® Injectable Solution should be stored at controlled room temperature (15 to 30 deg.C or
59 to 86 deg.F). Protect from
freezing.
B.Route of
Administration:
NUFLOR ® Injectable Solution should be administered by intramuscular injection in the
neck.
C.Approved Dose:
NUFLOR ® Injectable Solution should be administered by intramuscular injection to cattle at a dose of
20 mg/kg body weight (3 mL/100 lb).
A second dose should be administered 48 hours later. Do not inject more than 10 mL at each site.
The injection should be given only in the
neck musculature.
IV. EFFECTIVENESS
Data from
the following dose titration, dose confirmation and
clinical field trials demonstrate that NUFLOR ® Injectable Solution is effective for
the treatment of
bovine respiratory disease when
administered intramuscularly, twice, at 20 mg/kg body weight (bw) with a 48-hour interval.
The clinical trials were
conducted in multiple geographic locations.
A . Dose Determination
1. Type of
Study: Dose titration study
in cattle with naturally-occurring bovine respiratory disease (BRD).
2. Investigator:
David T. Bechtol, D.V.M.
Agri Research Center, Inc.
Canyon, Texas 79015
3. General Design:
a. Purpose:
To establish the effective dose of
florfenicol administered twice, 48-hours apart, in the
treatment of
naturally-occurring BRD.
b. Animals:
Forty-eight (48) head of
feedlot cattle (12 per group) ranging in age from
5 to 7 months.
The initial mean weight was
approximately 160 kg.
c. Controls:
Negative control was
a non-drug placebo vehicle administered intramuscularly at 0.5 mL/10 kg body weight.
d. Diagnosis:
The diagnosis of
BRD was
based on presence of
acute clinical signs of
pneumonia with an elevated rectal temperature (104.0 F or
greater) and
respiratory rate (40 per minute or
greater) and
an illness index scored "moderately ill" or
worse (illness index was
based on presence of
depression, coughing, inappetance, and
overall clinical impression). Pre-treatment naso-pharyngeal swabs were
taken for
bacterial examination.
e. Dosage form:
The dosage form was
an injectable solution containing 300 mg florfenicol per mL.
f. Route of
administration:
Intramuscular injection
g. Doses:
The 10, 20 and
30 mg/kg groups were
dosed twice with a 48-hour interval between doses.
h. Test Duration: 12 days
i. Pertinent Parameters Measured:
Mortality, rectal temperature, and
clinical illness index were
measured and
recorded daily from
Day 0 to the day of
necropsy. Lung consolidation was
recorded and
lung swabs taken for
bacterial examination at necropsy upon natural death or
sacrifice 7 days after end of
treatment period.
4. Results:
Florfenicol prevented mortality from
respiratory disease at all dose levels tested. Mortality in the
non-medicated control group was
25% (3/12). As summarized in Table 4.1, the
20mg/kg dose group showed the greatest drop in rectal temperature and
the lowest lung consolidation score at necropsy among the 3 florfenicol dose groups.
Pasteurella haemolytica was
isolated from
39 (81%) of
the 48 pre-treatment naso-pharyngeal swabs of
the cattle used in this study
. Pasteurella multocida was
found in 16 (33%) of
the same 48 swabs. Pasteurella haemolytica was
isolated from
8 of
the 60 post-treatment lung swabs. All pathogens (Pasteurella) isolated from
either naso-pharyngeal or
lung swabs were
sensitive to florfenicol.
(Eds note: The following table consists of
4 columns).
Table 4.1.
Rectal temperature reduction and
percent lung consolidation following
treatment with florfenicol injectable solution in cattle with
naturally-occurring BRD.
__________________________________________________________________________
Rectal temperature Percent
(Degrees F) reduction Lung
since Day 0 Consolidation
______________________________
1 day 7 days 7 days post-Tx
Dose(mg/kg) post-Tx post-Tx (or at death)
__________________________________________________________________________
0 1.7 1.5 17.9
10 1.7 1.9 11.7
20 2.4 2.4 7.9
30 2.1 1.0 12.1
__________________________________________________________________________
5.Conclusions:
Under the conditions of
this study
, the
dose of
20 mg florfenicol/kg bw was
shown to be an effective dose for
the treatment of
bovine respiratory disease when
administered twice, 48 hours apart, by the intramuscular route.
6. Adverse Reactions:
There were
no adverse reactions in any treatment group.
B. Dose Confirmation
1. Type of
Study:
Field trial in cattle with naturally occurring bovine respiratory disease (BRD).
2. Investigator:
M.I. Wray, Ph.D.
Horton Feedlot and
Research Center
Wellington, Colorado 80549
3. General Design:
a. Purpose:
To confirm the therapeutic efficacy of
florfenicol administered twice, 48 hours apart, by the intramuscular route at the
dose of
20 mg/kg body weight, for
the treatment of
naturally occurring bovine respiratory disease complex.
b. Animals:
Fifty (50) mixed-breed beef calves (25 per group) approximately 6 months old with an approximate initial mean weight of
190 kg.
c. Control:
Control was
a non-drug placebo (normal saline) administered twice, 48 hours apart.
d. Diagnosis:
The diagnosis of
BRD was
based on acute clinical signs of
pneumonia with an elevated rectal temperature (104 F or
greater) and
respiratory rate (40 per minute or
greater). Pretrial nasal swabs were
taken for
bacterial examination.
e. Dosage Form:
The dosage form was
an injectable solution containing 300 mg florfenicol per mL.
f. Route of
administration:
Intramuscular injection
g. Doses:
Negative control (0 mg/kg) and
20 mg/kg administered twice with a 48 hour interval.
h. Test Duration:
29 days
i. Pertinent Parameters Measured:
Mortality from
Day 0 to Day 28, and
overall treatment success on Day 28 were
the primary variables for
assessing efficacy.
4. Results:
A significant reduction in mortality was
observed in the
florfenicol-treated group. Mortality in the
florfenicol-treated group was
4% (1/25), whereas mortality in the
non-medicated control group was
48% (12/25). Also, as summarized in Table 4.2, significantly more treatment successes were
observed in the
florfenicol group (72%) than in the
control group (24%).
Pasteurella haemolytica was
isolated from
25 (50%) of
the 50 pre-treatment naso-pharyngeal swabs in this study
. Pasteurella multocida was
found in 6 (12%) of
the same 50 swabs. Haemophilus somnus was
isolated in only one swab.
All pathogens isolated from
the naso-pharyngeal swabs were
sensitive to florfenicol.
(Eds note: The following table consists of
4 columns).
Table 4.2.
Percent initial treatment success, relapse, and
overall treatment success
in cattle with naturally-occurring respiratory disease treated with
intramuscular florfenicol in 2 doses 48 hours apart.
_________________________________________________________________________________________
Dose Initial Treatment Relapse Overall Treatment
(mg/kg) Success (Days 4 to 10) (Days 11 to 28) Success (Day 28)
_________________________________________________________________________________________
0 32 (8/25) 8 (2/25) 24 (6/25)
20 84 (21/25) 12 (3/25) 72 (18/25)
_________________________________________________________________________________________
5. Statistical Analysis:
For qualitative variables, the
exact p-values of
the Wilcoxon Midrank test were
computed using methods suggested by Mehta, et. al. (Biometrics 40:819-825; 1984), which
provided a one-tailed test for
the equivalence of
the florfenicol group against placebo with respect to the ordered categorical responses. For mortality the Fisher's Exact Test was
used. All the analyses were
performed separately for
each observation day.
The results of
all statistical tests were
declared significant at the
alpha = 0.05 level.
6. Conclusion:
Under the conditions of
this study
, florfenicol administered twice intramuscularly, 48 hours apart, at a dose of
20 mg/kg body weight, was
a safe and
effective treatment of
bovine respiratory disease.
7. Adverse Reactions:
There were
no adverse reactions in either treatment group.
C. Field Investigations
1. Type of
Study:
Field trials were
conducted at 4 locations in cattle with spontaneously occurring bovine respiratory disease (BRD).
2. Investigators:
M.I. Wray, Ph.D. E.G. Johnson, DVM
Horton Feedlotand Research Center Johnson Research Center
Wellington, Colorado 80549 Parma, Idaho 83660
J.C. Johnson, DVM D. Bechtol, DVM
Schering-Plough Animal Health Agri Research Center
Elkhorn Research Center Canyon, Texas 79015
Elkhorn, Nebraska 68022
3. General Design:
a. Purpose:
The efficacy of
florfenicol, administered by intramuscular injection at a dose of
20 mg/kg body weight, repeated at 48hr, for
the treatment of
naturally-occurring BRD was
tested in positively-controlled field investigations at several locations.
b. Animals:
One hundred five (105) mixed-breed beef calves that were
approximately 6 months old and
weighed an average of
193 kg were
used at each trial location. At each trial; site, 70 calves were
injected with florfenicol and
35 with the control product.
c. Control:
The control product was
an approved oxytetracycline injectable solution administered for
4 consecutive days, at the
dose of
10mg oxytetracycline per kg body weight (4.5 mg/lb).
d. Diagnosis:
The diagnosis of
BRD was
based on acute clinical signs of
pneumonia with an elevated rectal temperature (104 F or
greater) and
respiratory rate (40 per minute or
greater). Pretreatment nasal swabs were
taken for
bacterial examination.
e. Dosage Form:
The test article was
an injectable solution containing 300 mg florfenicol per mL.
f. Test article:
Florfenicol injectable solution was
administered twice by intramuscular injection at a 48-hour interval at a dose of
20 mg/kg body weight.
h. Test Duration:
29 days
i. Parameters Measured:
Mortality from
Day 0 to Day 28, and
overall treatment success on Day 28 were
the primary variables for
assessing efficacy.
4. Results:
Day 28 treatment success was
significantly greater in the
florfenicol-treated groups than in the
oxytetracycline groups at all locations. Initial treatment success, relapse, and
overall treatment success are summarized in Table 4.3.
Mortality was
significantly lower in the
florfenicol groups at the
Nebraska and
Texas trial locations. No significant difference in mortality was
noted at the
Colorado or
Idaho trial locations. Percent mortality is summarized in Table 4.4.
(Eds note: The following table consists of
4 columns).
Table 4.3.
Percent initial treatment success, relapse, and
overall treatment success
in cattle with naturally-occurring respiratory disease treated with
intramuscular florfenicol in 2 doses 48 hours apart.
_____________________________________________________________________________________
Dose Initial Treatment Relapse Overall Treatment
(mg/kg) Success (Days 4 to 10) (Days 11 to 28) Success (Day 28)
_____________________________________________________________________________________
Colorado
10 OTC(a) 49 (17/35) 0 (0/35) 49 (17/35)
20 FFC(b) 74 (51/69) 0 (0/69) 74 (51/69)
Nebraska
10 OTC(a) 31 (11/35) 0 (0/35) 31 (11/35)
20 FFC(b) 91 (63/69) 12 (8/69) 80 (55/69)
Idaho
10 OTC(a) 31 (11/35) 0 (0/35) 31 (11/35)
20 FFC(b) 71 (50/70) 9 (6/70) 63 (44/70)
Texas
10 OTC(a) 24 (8/33) 0 (0/33) 24 (8/33)
20 FFC(b) 83 (58/70) 9 (6/70) 74 (52/70)
_____________________________________________________________________________________
(a) (OTC) oxytetracycline
(b) (FFC) florfenicol
(Eds note: The following table consists of
5 columns).
Table 4.4.
Percent mortality in cattle with naturally-occurring respiratory disease
treated with intramuscular florfenicol in 2 doses 48 hours apart.
_________________________________________________________________________
Percent Mortality
________________________________________________________
Dose
(mg/kg) Colorado Nebraska Idaho Texas
_________________________________________________________________________
10 OTC(a) 9 (3/35) 17 (6/35) 0 (0/35) 15 (5/33)
20 FFC(b) 1 (1/69) 0 (0/69) 0 (0/70) 1 (1/70)
_________________________________________________________________________
(a) (OTC) oxytetracycline
(b) (FFC) florfenicol
5. Microbiology
In the Colorado field trial, Pasteurella haemolytica was
isolated from
81 (77%) of
the 105 pre-treatment naso-pharyngeal swabs in this study
. Pasteurella multocida was
found in 11 (10%) of
the same 105 swabs. All pathogens isolated from
the naso-pharyngeal swabs were
sensitive to florfenicol with an MIC90 of
2 and
1 ug/mL for
P. haemolyticaand P. multocida, respectively.
In the Nebraska field trial, Pasteurella haemolytica was
isolated from
75 (71%) of
the 105 pre-treatment naso-pharyngeal swabs of
the cattle used in this study
. Pasteurella multocida was
found in 3 (3%) of
the same 105 swabs. All pathogens isolated from
the naso-pharyngeal swabs were
sensitive to florfenicol with an MIC90 of
2 ug/mL for
P. haemolytica.
The MIC90 values for
the three P. multocida isolates were
1 ug/mL or
less.
In the Idaho field trial, Pasteurella haemolytica was
isolated from
40 (38%) of
the 105 pre-treatment naso-pharyngeal swabs of
the cattle used in this study
. Pasteurella multocida was
found in 50 (48%) of
the same 105 swabs. All pathogens isolated from
the naso-pharyngeal swabs were
sensitive to florfenicol.
In the Texas field trial, Pasteurella haemolytica was
isolated from
79 (75%) of
the 105 pre-treatment naso-pharyngeal swabs of
the cattle used in this study
. Pasteurella multocida was
found in 9 (9%) of
the same 105 swabs. Haemophilus somnus was
isolated in 3 of
those swabs (3%). All pathogens isolated from
the naso-pharyngeal swabs were
sensitive to florfenicol. MIC90 values for
florfenicol were
4 ug/mL for
P. haemolytica, and
2 ug/mL for
P. multocida.
6. Statistical Analysis:
For qualitative variables, the
exact p-values of
the Wilcoxon Midrank test were
computed using methods suggested by Mehta, et. al. (in Biometrics, 40 (3), September 1984, 819-825), which
provided a one-tailed test for
the equivalence of
the florfenicol group against positive control with respect to the ordered categorical responses. For mortality the Fisher's Exact Test was
used. All the above analyses were
performed separately for
each observation day.
The results of
all statistical test were
declared significant at the
alpha = 0.05 level.
7. Conclusion:
Under the conditions of
this study
, florfenicol administered twice intramuscularly, 48 hours apart, at a dose of
20 mg/kg body weight, was
a safe and
effective treatment of
bovine respiratory disease.
8. Adverse Reactions:
There were
no adverse reactions in either treatment group at any of
the four field trial locations.
G. Field Investigation - Haemophilus somnus
1. Type of
Study:
Field trial in cattle with naturally-occurring bovine respiratory disease (BRD).
2. Investigator:
Dr. Kee Jim
Feedlot Health Management Services
Postal Bag Service #5
Okotoks, Alberta TOL 1TO, Canada
3. General Design:
a. Purpose:
To confirm the therapeutic efficacy of
florfenicol administered twice, 48 hours apart, by the intramuscular route at the
dose of
20 mg/kg body weight, for
the treatment of
naturally-occurring bovine respiratory disease associated with Haemophilus somnus.
b. Animals:
One hundred twenty-five (125) auction-derived, 5 to 10 month old, mixed-breed beef steers, weighing an average of
278 kg, were
used in the
study
. Eighty-four (84) steers were
treated with NUFLOR Injectable Solution and
41 were
treated with a control product.
c. Control:
The control product was
saline administered according to the NUFLOR Injectable Solution dosage regimen.
d. Diagnosis:
Diagnosis of
BRD and
subsequent entrance into
the study
was based on rectal temperature >= 105 F for
two consecutive days and
the absence of
clinical signs referable to organ systems other the respiratory system.
Exposure to Haemophilus somnus was
confirmed at study
completion based on histopathologic lesions characteristic of
H. somnus infection, and
the results of
microbiological culture of
blood, nasal swabs, and
transtracheal washes.
e. Dosage Form:
The dosage form was
an injectable solution containing 300 mg florfenicol per mL.
f. Route of
administration:
Intramuscular.
g. Doses:
Florfenicol injectable solution and
the placebo were
administered twice with a 48 hour interval at a dose of
20 mg/kg body weight.
h. Test Duration:
15 days
i. Pertinent Parameters Measured:
Mortality was
monitored daily from
Day 0 to Day 15, rectal temperature was
measured and
recorded from
Day -1 to Day 4 and
on Day 15. Relapses were
recorded from
day 4 to day 15. An animal was
considered a treatment success if it met the entrance criteria, was
subsequently treated, and
did not relapse.
4. Results:
Microbiology:
Haemophilus somnus was
isolated in 12% (10/84) of
the nasal swabs and
/or transtracheal washes in the
NUFLOR ® Injectable Solution group and
in 7% (3/41) of
the controls. Pasteurella haemolytica was
present in 26% (22/84) and
29% (12/41) of
the nasal swabs and
/or transtracheal washes from
the NUFLOR Injectable Solution and
saline treatment groups, respectively. Pasteurella multocida was
isolated in 29% (24/84) of
the NUFLOR ® Injectable Solution group and
34% (14/41) of
the saline group.
Haemophilus somnus exposure:
Based on lung histopathology and
positive H. somnus cultures from
nasal swabs and
/or transtracheal washes, 12% (10/84) of
the calves in the
florfenicol treatment group and
15% (6/41) of
the calves in the
control group were
considered exposed to H. somnus.
Mortality:
Overall study
mortality was
1.2% (1/84) in the
florfenicol treatment group and
34% (14/41) in the
control group. In regard to the 16 animals considered exposed to H. somnus, there were
no mortalities in the
florfenicol-treated animals and
83% (5/6) mortality in control animals.
Treatment success:
As summarized in Table 4.5, there were
significantly more overall treatment successes in the
florfenicol treatment group (62%) than in the
control group (12%). In regard to animals considered exposed to H. somnus , 7 of
the 10 florfenicol-treated animals were
treatment successes, and
1 of
the 6 control animals was
a treatment success.
(Eds note: The following table consists of
3 columns).
Table 4.5.
Percent treatment success on Day 15 for
all animals on study
and for
animals exposed to Haemophilus somnus
___________________________________________________________________
Success Success
Treatment (all animals) (H. somnus-exposed)
___________________________________________________________________
saline 12 (5/41) 17 (1/6)
florfenicol 62 (52/84) 70 (7/10)
___________________________________________________________________
5. Statistical Analysis:
Overall treatment success and
mortality were
analyzed using the Cochran-Mantel-Haenszel statistic. Treatment success and
mortality for
animals exposed to H. somnus were
analyzed using the Fisher's Exact test for
2 X 2 tables.
6. Conclusion:
Under the conditions of
this study
, florfenicol administered twice, 48 hours apart, by the intramuscular route at the
dose of
20 mg/kg body weight was
a safe and
effective treatment of
bovine respiratory disease associated with Haemophilus somnus.
7. Adverse Reactions:
There were
no adverse reactions in either treatment group.
H. Pharmacokinetics
The pharmacokinetic information provided in the
labeling for
NUFLOR ® Injectable Solution was
based on the following published study
.
Lobell, R.D., Varma, K.J., Johnson, J.C., Sams, R.A., Gerken, D.F., Ashcraft, S.M.. Pharmacokinetics of
florfenicol following intravenous and
intramuscular doses to cattle. J. Vet. Pharmacol.
Therap. 17, 253-258, 1994.
The disposition of
florfenicol after single intravenous and
intramuscular doses of
20 mg of
florfenicol/kg of
body weight (b.w.) to feeder calves was
investigated. Serum florfenicol concentrations were
determined by a sensitive high performance liquid chromatographic method with a limit of
quantitation of
0.025 ug/mL.
The extent of
serum protein binding of
florfenicol was
only 13.2% at a serum florfenicol concentration of
3.0 ug/mL. Serum concentration-time data after intravenous administration were
best described by a triexponential equation. Total body clearance and
steady state volume of
distribution were
3.75 mL/min/kg b.w. and
761 mL/kg b.w., respectively.
The terminal half-life after intravenous administration was
159 minutes.
The absolute systemic availability after intramuscular administration was
78.5% (range: 59.3-106%) and
the harmonic mean of
the terminal half-life was
1098 minutes, indicating slow release of
the florfenicol from
the formulation at the
intramuscular injection site.
I. Microbiology
Data from
fifteen studies conducted between 1990 and
1993, in the
United States, Europe, and
Canada were
used to establish an MIC data base for
florfenicol against bacteria isolated from
cattle with naturally occurring bovine respiratory disease.
The minimum inhibitory concentrations (MICs) of
florfenicol determined for
isolates of
Pasteurella haemolytica, Pasteurella multocida, and
Haemophilus somnus are shown in Table 4.6.
(Eds note: The following table consists of
4 columns).
Table 4.6.
Minimum inhibitory concentrations (MICs) of
florfenicol
against isolates from
natural infections in cattle.
___________________________________________________________________________
Organism No. isolates MIC50 (ug/mL) MIC90 (ug/mL)
___________________________________________________________________________
Pasteurella haemolytica 398 0.5 1.0
Pasteurella multocida 350 0.5 0.5
Haemophilus somnus 66 0.25 0.5
___________________________________________________________________________
V. ANIMAL SAFETY
A Drug Tolerance Test in beef calves was
conducted to determine the tolerance to and
clinical profile of
a 10X overdose (200 mg/kg) of
the intended clinical dose of
NUFLOR ® Injectable Solution.
A Target Animal Safety Study in beef calves was
conducted to address the safety of
multiple injections of
NUFLOR ® Injectable Solution at the
1X (20 mg/kg), 3X (60 mg/kg), and
5X (100 mg/kg) dose levels. An Injection Site Irritation Study was
conducted to determine the irritation potential of
the intramuscular route of
administration. In addition, a feed consumption study
was conducted to provide additional information regarding the impact of
florfenicol treatment on feed consumption in calves.
A . Drug Tolerance Test
1. Type of
Study:
This was
a 17-day study
in which
2 separate injections of
florfenicol injectable solution were
administered 48 hours apart to 4 cross-bred beef calves. Following the dosing period, the
calves were
observed and
necropsied on Day 17 (15 days following the last injection of
the test article).
2. Investigator:
Dan C. Ronning
Colorado Animal Research Enterprises
Ft. Collins, Colorado
3. General Design:
a. Purpose:
To determine the clinical profile in beef calves following a 10X overdose of
florfenicol injectable solution when
administered intramuscularly.
b. Animals:
Four cross-bred beef cattle, 2 males and
2 females, weighing 213 to 244 kg at dose initiation
c. Control:
None
e. Dosage Form:
Florfenicol injectable solution, 300 mg/mL
f. Route of
Administration:
Intramuscular injection
g. Dose:
200 mg/kg (10X the therapeutic dose) administered as two separate treatments 48 hours apart.
h. Test Duration:
17 days (includes 15 day post-dose period)
i. Pertinent Measurements/Observations:
clinical observations, physical examinations, feed and
water consumption, hematology, serum chemistries, urinalysis, fecal examinations, gross pathology, and
histopathology
4. Results
a. Clinical Observations:
Loose feces and
decreased rumen activity were
observed.
b. Feed and
water consumption:
Feed and
water intake were
decreased substantially following dosing, with a return to normal intake observed by the end of
the post-dose period.
c. Body Weight:
Body weight was
decreased during dosing with a return to normal weight gain during the post-dose period.
d. Hematology/Serum Chemistry:
Mild elevations in serum enzymes ( LDH, SGOT, SGPT, and
GGT) indicating liver and
muscle changes were
observed with a return to normal during the post-dose period.
e. Urinalysis:
A slight amount of
urinary acetone detected during dosing was
attributed to slight ketosis due to anorexia.
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