Summary of
FDA Information:
Approval Date: November 20, 1997
Freedom of
Information Summary
NADA141-096
I. GENERAL INFORMATION:
NADA 141-096
Sponsor: Fort Dodge Animal Health
9401 Indian Creek Parkway
Overland Park, KS 66210
Generic Name: Difloxacin hydrochloride
Trade Name: DICURAL® TABLETS
Marketing Status: Rx
II. Indications for
Use:
DICURAL® (difloxacin hydrochloride) TABLETS are indicated for
the management of
diseases in dogs associated with bacteria susceptible to difloxacin.
Efficacy Confirmation: Clinical efficacy was
confirmed in dogs with skin and
soft tissue infections (wounds and
abscesses) and
urinary tract infections (cystitis). Specific bacterial pathogens isolated in clinical field trials are listed in Table 4 in the
Clinical Efficacy section of
the FOI Summary.
III. Form(s), Route of
Administration, and
Recommended Dosage(s):
The dose range of
difloxacin in dogs is 5 to 10 mg/kg (2.3 to 4.6 mg/lb) once a day for
2-3 days beyond cessation of
clinical signs to a maximum of
30 days.
Three tablet sizes are available for
ease of
administration: DICURAL® Tablet Tablet Color Body Weight of
Dog
11.4 mg Blue 5 lb (2.3 kg)
45.4 mg White 20 lb (9.0 kg)
136 mg Orange 60 lb (27.2 kg)
The 11.4 mg and
the 45.4 mg tablets are single scored and
the 136 mg tablet is double scored for
more accurate dosing.
Dogs should be administered difloxacin hydrochloride at 5 to 10 mg/kg body weight. For the treatment of
skin and
soft tissue infections, DICURAL® TABLETS should be given for
at least two to three days beyond the cessation of
clinical signs for
a maximum of
30 days. For treatment of
urinary tract infections, DICURAL® TABLETS should be administered for
at least 10 consecutive days. If no improvement is noted after at least five days of
therapy, then the clinical case should be re-evaluated and
a different course of
therapy should be considered.
Dose Rationale: The dose range of
5 to 10 mg/kg was
established based upon the clinical efficacy demonstrated at the
5 mg/kg dose and
by the linear kinetics of
difloxacin up to 60 mg/kg. In addition, the
10 mg/kg dose was
found to be a dose well within the established safety margin of
the drug.
The negligible drug accumulation evident in the
pharmacokinetic studies coupled with the lack of
adverse reactions evident in the
clinical field and
target animal safety studies support administration of
a dose within the dose range up to a maximum of
30 days duration of
therapy.
IV. Effectiveness:
A. Dose Titration
Identification: Dose Titration Study for
Testing the Effect of
Difloxacin (Abbott Compound A56619) in Dogs (Escherichia coli - Klebsiella pneumoniae Model).
Study Director:
John N. Berg, DVM, PhD
College of
Veterinary Medicine
University of
Missouri-Columbia
Columbia, MO
General Design:
Purpose: To determine the effective dose of
difloxacin for
the treatment of
an infected dermal wound.
Animals: Forty-eight mixed breed dogs, male and
female, weighing 14.5 to 24.5 kg, were
placed into
four replicates (12 dogs/replicate) and
each replicate was
randomly allotted into
four treatment groups.
Dose Levels and
Regimen: Two surgical wounds (lateral neck and
abdominal midline) were
created in the
dogs and
were
inoculated with a mixed culture broth of
Escherichia coli and
Klebsiella pneumoniae.
The four treatment groups received a placebo or
difloxacin capsule at 2.5, 5, or
7.5 mg/kg body weight, respectively, once a day for
seven consecutive days, beginning eight hours after inoculation of
the wounds.
Pertinent Observations and
Measurements: Individual clinical appearance, rectal temperature, appetite, and
wound appearance were
monitored for
13 days following inoculation of
the wound.
The parameters were
scored, with each score tailored to the parameter according to severity. In addition, individual blood samples were
collected for
the determination of
total and
differential WBC count, total RBC count and
hematocrit.
The primary parameter of
efficacy was
lesion healing.
Scoring System:
Lesion Scores:
0 = no signs of
inflammation
1 = slight swelling and
/or pain on palpation
2 = moderate swelling, pain on palpation, erythema
3 = severe swelling, extreme pain on palpation, erythema
5 = death of
dog Added scores:
purulent discharge, 1 point added to daily score
dehiscence of
suture line, 1 point added to daily score
Clinical Appearance Scores:
0 = alert, afebrile, normal appetite
1 = slight depression yet responsive to stimuli
2 = depression poor response to stimuli
3 = severe depression, recumbent, no response to stimuli
5 = death of
dog Added Scores: elevated temperature (> or
= 1°F), 1 point added to score
Culture Scoring System:
0 = No growth
1 = Growth from
TSB subculture only
2 = Colony log count 2
3 = Colony log count 3
4 = Colony log count 4
5 = Colony log count 5
6 = Colony log count 6
7 = Colony log count 7
The lesions on the neck were
examined culturally on post-infection days 1, 2, 3, 6, 9, and
at necropsy (day 13).
The abdominal lesions were
examined at necropsy only.
The isolated colonies were
identified as either Escherichia coli or
Klebsiella pneumoniae and
given a score based on their respective log counts. At the conclusion of
the study
the dogs were
euthanatized and
necropsied.
The incisions were
re-opened and
the tissues were
examined grossly and
via culture for
signs of
residual infection.
Results: At the end of
the study
the clinical and
culture scores were
combined and
the results from
the four groups were
compared statistically.
The summary of
the mean lesion healing scores were
:
Lesion Healing Scores (Combined)* Treatment Group
(mg/kg) Mean Clinical Score Mean Culture Score
E. coli & K. pneumoniae
0 3.96a 8.08a
2.5 3.44ab 6.52b
5.0 2.92b 4.44c
7.5 3.23b 4.46c
*The mean clinical combined score was
based on the neck and
abdominal lesion scores plus clinical signs. Different letters (a, b, or
c) within a column indicate the means are significantly different (P<0.05).
Difloxacin administered orally at 5.0 mg/kg bodyweight was
found to be an effective dose for
the treatment of
Escherichia coli and
Klebsiella pneumoniae induced dermal wound infections.
B. Dose Confirmation
Identification: Trial no. P146 - Dose Confirmation Study for
Testing the Efficacy of
Difloxacin (Abbott Compound A56619) Against Skin Wound Infection in Dogs (E. coli - Klebsiella pneumoniae Model).
Study Director:
Robert J. Harman, DVM, MPVM
HTI Bio-services, Inc.
Ramona, CA
General Design:
Purpose: To confirm the effectiveness of
difloxacin administered at 5.0 mg/kg against induced dermal wound infections in dogs.
Animals: Twenty-four dogs, male and
female, weighing 13.6 to 24.5 kg, were
allotted randomly into
two treatment groups of
12 dogs each.
Dose Levels and
Regimen: Two surgical wounds (lateral neck and
abdominal midline) were
induced in the
dogs and
were
infected with a mixed culture of
Escherichia coli and
Klebsiella pneumoniae.
The two treatment groups were
administered a placebo or
difloxacin in capsules at 5.0 mg/kg body weight once a day beginning eight hours post-infection for
seven consecutive days.
Pertinent Observations and
Measurements: The parameters that were
observed daily beginning on day 1 and
continuing through day 13, and
scored according to a standardized scoring method (See Dose Determination Study) were
general clinical appearance, appearance of
wounds, wound cultures, rectal temperature and
appetite.
The lesions on the neck were
examined culturally on post-infection days 1, 2, 3, 6, 9, and
at necropsy (day 13).
The abdominal lesions were
examined at necropsy only.
The dogs were
monitored for
13 days following inoculation and
then euthanatized and
necropsied.
The primary parameter of
efficacy was
lesion healing.
Results: Lesion healing for
the difloxacin-treated dogs was
significantly different by Day 5 and
Days 5 & 6 combined (p<0.05) using the Wilcoxon Rank Sum Test for
treatment differences. However, after Day 6, the
control animals were
self-curing and
differences in lesion healing scores were
not seen.
The summary of
the lesion healing scores were
:
Mean Clinical Scores (Combined)* Treatment Group (mg/kg) Day 5 Day 6 Day 5 & 6
0 4.7a 4.3a 4.5a
5.0 3.5b 3.2a 3.3b
* The mean clinical scores were
based on the neck and
abdominal lesion scores plus clinical signs for
the 12 dogs in each group.
The higher the score the more severe was
the case. Different letters (a or
b) within a column indicate that the
means are significantly different (P<0.05).
The administration of
difloxacin at 5.0 mg/kg bodyweight was
determined to be efficacious for
the treatment of
Escherichia coli and
Klebsiella pneumoniae infections in skin wounds when
compared to placebo treated dogs based on combined lesion healing scores.
C. Bioequivalence of
Difloxacin HCl Capsules and
Tablets
Identification: Study no. 92-304-085 - Bioequivalence of
Difloxacin HCl Capsules and
Tablets Following Oral Administration to Dogs.
Study Director:
In-Life Phase:
Beth Reagan, AAS
Liberty Research
Waverly, NY
Analytical Phase:
John Byrd, Ph.D.
Southwest Bio-Labs
Las Cruces, NM
Statistical Phase:
Thomas Keefe, Ph.D.
Envirostat Associates
Fort Collins, C0
General Design:
Purpose: To determine the relative blood level bioavailability of
the tablet and
capsule formulations when
equal doses of
each were
administered.
Animals: Two test groups of
10 dogs (each consisting of
5 males and
5 females), ages 11 to 15 months, weighing 6.8 to 10.4 Kg, were
used for
this study
.
Dose Levels and
Regimen: A two-period crossover design was
used for
the study. Dogs were
fasted 12 hours prior to dosing until 6 hours after dosing. Water was
available ad libitum. All animals were
administered equivalent single doses of
difloxacin capsules or
tablets at 5 mg base equivalent per kilogram body weight.
The start of
each test period was
separated by a 14-day washout period.
Pertinent Observations and
Measurements: Plasma from
blood samples collected before dosing (0 hour) and
at 11 sampling times after dosing (0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 and
48 hours) were
assayed by HPLC methods to determine circulating plasma concentrations of
difloxacin.
Results: Based on a criterion that the
90% confidence interval for
the difference between product means be within plus or
minus 20% of
the capsule product mean, the
difloxacin HC1 tablet product was
found to be bioequivalent to the difloxacin capsule product with respect to the Area Under the Concentration curve (AUCtau) from
zero through the time (tau) corresponding to the last quantifiable concentration.
This criterion was
also satisfied by the supplementary pharmacokinetic parameters: elimination half-life (T1/2), AUCinfinity, and
MRTinfinity.
Thus, the
rate and
extent of
bioavailability of
the tablet and
capsule formulations were
determined to be equivalent.
Therefore, the
dose determination data, originally generated with the capsule formulation, was
determined to be applicable to the tablet formulation.
Table 1. Mean Plasma Pharmacokinetic Parameters of
the Tablet and
Capsule after a Single Oral Administration at 5 mg/kg. Pharmacokinetic
Parameter Units Mean Value
Tablet Capsule
AUCinfinity mcg·hr/mL 14.5 16.2
AUCtau mcg·hr/mL 13.7 15.4
AUMCinfinity mcg·hr2/mL 162.5 183.4
AUMCtau mcg·hr2/mL 120.1 140.6
MRTinfinity hr 10.7 10.9
Elimination Half-Life (T1/2) hr 9.3 9.4
Maximum Concentration (Cmax) mcg/mL 1.8 2.1
Maximum Time (Tmax) hr 2.8 2.3
D.
Therapeutic Bioequivalence of
Difloxacin HCl Tablets and
Capsules
Identification: Study no. 93-204-001 - Therapeutic Bioequivalency of
Difloxacin HCl Tablets and
Capsules Against Induced Escherichia coli Urinary Infection in Dogs.
Study Director:
Martin Gilman, PhD
Liberty Research
Waverly, NY
General Design:
Purpose: To compare the efficacy of
the difloxacin capsules to tablets using an induced urinary infection in dogs.
Animals: Thirty-six (36) Beagle dogs one and
a half to three years of
age, weighing 7.2 to 12.1 kg, were
used in this study
.
Dose Levels and
Regimen: The dogs were
randomly allocated to one of
three treatment groups; placebo, difloxacin tablet, or
capsule. Each study
dog's bladder was
primed for
infection, and
, through a sterile urethral catheter, rinsed with sterile saline and
then inoculated with Escherichia coli.
The animals were
administered 5 mg difloxacin/kg body weight beginning on day 8 post-inoculation.
Pertinent Observations and
Measurements: Urine was
collected by cystocentesis and
cultured prior to inoculation and
on post-inoculation (PI) days 7, 12, 15 and
19. Because urine is usually sterile, bacterial elimination was
used as the primary parameter of
efficacy.
Results: On day 7 post infection (PI), it was
determined statistically that the
dogs were
uniformly infected.
The rates of
E. coli elimination (based on urine cultures) were
compared on the 5th day of
treatment (day 12 PI) and
one day following the end of
the seven day treatment schedule (day 15 PI).
The active treatments, difloxacin tablets and
capsules, administered on days 8-14 post-infection significantly eliminated E. coli on days 12 and
15 when
compared to the placebo treated dogs.
There was
not a significant difference between the two difloxacin treatment groups when
elimination rates of
E. coli on days 12 and
15 PI were
compared.
Dogs Positive for
Induced E. coli Urinary Tract Infections Treatment Group Days Post Infection*
7 12 15 19
Placebo 9a 6a 6a 3a
Tablet 10a 1b 0b 0a
Capsule 11a 0b 1b 4a
* Treatment administered on days 8-14 post-infection. Different letters (a or
b) within a column indicate the numbers are significantly different (P<0.05).
This study
demonstrated the therapeutic bioequivalence of
difloxacin tablets and
capsules administered at 5 mg/kg/day for
seven consecutive days to treat
E. coli urinary tract infection in dogs.
E. Pharmacokinetics and
Metabolism
1. Study no. Abbott-56619:2
Identification: The Metabolism and
Pharmacokinetics of
14C-Difloxacin Base in Dogs.
Study Director:
Ilmar Merits, PhD
Abbott Laboratories
North Chicago, IL
General Design:
Purpose: To study
the metabolism and
pharmacokinetics of
14C-difloxacin (radiolabeled difloxacin) base in beagle dogs.
Animals: Two male and
four female beagle dogs weighing between 6 to 10 kg and
10 to 16 months old were
used in the
study
.
Dose Levels and
Regimen: The dogs were
administered 10 mg difloxacin base/kg body weight (30 µCi/dog) orally by gavage and
3 weeks later by intravenous administration. All administrations were
made following an overnight fast. Fasting was
continued for
an additional 12 hours postdosing.
Pertinent Observations and
Measurements: After oral and
intravenous administration of
10 mg base/kg doses, both the total radioactivity and
parent drug levels in the
plasma, urine and
feces were
measured. Whole blood and
fecal samples were
combusted and
the resulting 14CO2 was
trapped in Carbo-Sorb and
was
measured by liquid scintillation. Plasma, bile and
urine samples were
added directly to the liquid scintillation cocktail and
were
counted. To assess the concentrations of
metabolites in the
blood, plasma samples were
analyzed by High Performance Liquid Chromatography (HPLC).
Results: After oral administration of
a 10 mg base/kg dose, both the total radioactivity and
parent drug levels in the
plasma peaked at 2.4 mcg/mL by 1.5 hours. Within five days after oral administration of
14C-difloxacin base, 16% of
the 14C dose was
excreted in the
urine and
80% was
eliminated in the
feces.
The unchanged parent drug accounted for
64% of
the 14C dose and
was
primarily excreted in the
feces.
The two major metabolites were
the ester glucuronide of
difloxacin and
the desmethyl derivative of
difloxacin, each representing about 12% of
the 14C dose.
Since 80% of
the 14C dose was
eliminated in the
feces after intravenous administration of
14C-difloxacin, biliary secretion appeared to be an important factor in the
disposition of
the compound. Renal clearance accounted for
less than 5% of
the total systemic clearance.
The ester glucuronide of
difloxacin accounted for
72-80% of
the radioactivity in the
bile and
only 6-9% was
free parent drug.
The difference between the fecal and
biliary metabolic patterns suggested that the
glucuronide of
difloxacin was
hydrolyzed in the
gastrointestinal tract and
that the
parent drug undergoes enterohepatic cycling.
2. Study no. Abbott-56619:16
Identification: The Distribution of
Radioactivity in the
Tissues of
Dogs after Oral Administration of
14C-Difloxacin Base.
Study Director:
Barbara A Bopp, PhD
Abbott Laboratories
North Chicago, IL
General Design:
Purpose: To determine the tissue concentrations of
difloxacin in dogs over a 24-hour timeframe.
Animals: Tissue distribution studies were
conducted in four male beagle dogs, weighing 10 to 12 kg and
approximately one year old.
Dose Levels and
Regimen: The dogs were
given a single oral 10 mg/kg dose of
14C-difloxacin base (47-51 µCi/dog) following an overnight fast.
Pertinent Observations and
Measurements: Selected tissue samples were
obtained from
two dogs at two hours after drug administration, from
one dog at six hours after dosing, and
from one dog at 24 hours after dosing. Tissue samples were
homogenized and
combusted.
The resulting 14CO2 was
assayed in quantified via liquid scintillation procedures.
Results: The results are presented in Table 2.
Table 2. Levels of
Radioactivity in Tissues of
Dogs 2, 6, and
24 Hours after Single Oral Administration of
10 mg/kg BW 14C-Difloxacin Base Tissue mcg equivalents/g or
mL
2 hr. 6 hr. 24 hr.
Stomach 66.69 8.47 9.89
Small Intestine 18.26 38.69 16.41
Large Intestine 4.68 7.82 102.1
Liver 10.68 7.79 4.58
Kidneys 5.00 2.75 1.48
Heart 3.80 1.61 1.05
Lungs 3.22 0.91 0.76
Spleen 3.48 1.11 1.08
Pancreas 4.50 2.19 2.17
Adrenals 2.71 1.74 1.65
Prostate 3.36 1.46 1.41
Testes 3.07 1.56 0.78
Bladder 2.98 1.84 1.70
Thyroid 4.24 2.56 2.06
Lymph Nodes 3.06 2.46 1.71
Salivary Glands 4.62 2.32 1.32
Pituitary 3.68 1.59 1.03
Brain 1.30 0.62 0.48
Cerebral Spinal Fluid 1.10 0.58 0.39
Bone 6.45 7.23 6.51
Synovial Fluid 1.12 1.75 1.52
Muscle 4.12 1.17 1.12
Fat 0.73 0.84 0.80
Blood 2.26 1.05 0.60
Plasma 2.57 1.24 0.75
Bile 1231.00 1874.00 1624.00
3. Study number Abbott-56619:15
Identification: Plasma Difloxacin Base Levels After Oral Administration of
5, 20, and
60 mg/kg/day Doses to Dogs for
3 Months.
Study Director:
G. Richard Granneman, PhD
Abbott Laboratories
North Chicago, IL
General Design:
Purpose: To study
the plasma levels of
difloxacin following oral administration of
5, 20 and
60 mg (base)/kg/day doses of
difloxacin in dogs for
3 months.
Animals: Forty-four purebred beagle adult dogs (22 males, 22 females) were
used in this study
.
Dose Levels and
Regimen: Dogs were
assigned into
one of
four treatment groups: vehicle control (14 animals), 5 mg difloxacin base/kg/day (8 animals); 20 mg/kg/day (8 animals) or
60 mg/kg/day (14 animals). Dogs were
fed once daily approximately 2 hours after dosing, and
the food was
removed the following morning at least 1.5 hours prior to dosing. Tap water was
available ad libitum.
Pertinent Observations and
Measurements: Plasma samples from
the treated dogs were
measured for
difloxacin base prior to and
three hours after dosing on days zero, 6, 28, 56 and
84. Plasma concentrations of
the difloxacin base were
quantified using HPLC procedures.
Results: Plasma drug levels prior to and
three hours after dosing were
linearly proportional to the administered doses.
The hour 3 difloxacin concentrations averaged across the five sampling days are shown in the
table below.
The slightly lower plasma drug concentrations and
somewhat greater variability associated with the 60 mg/kg dose is attributable to the higher frequency of
emesis in the
60 mg/kg group. Except for
random fluctuations in steady-state difloxacin concentrations, difloxacin kinetics appeared to remain constant, regardless of
the duration of
dosing. In addition, it appears that the
drug does not accumulate in the
plasma after repeated dosing.
Table 3: Mean plasma difloxacin concentrations DOSE (mg/kg) MEAN CONCENTRATIONS (µG/mL)+/- SD %CV
OBSERVED* DOSE NORMALIZED**
5 1.39 +/- 0.44 16.68 31.5
20 5.46+/- 2.32 16.38 42.5
60 15.13+/- 9.19 15.13 60.75
SD Standard Deviation
%CV Coefficient of
Variation (SD/mean concen.)
* hour 3 plasma difloxacin concentrations across the 5 day study
** average hour 3 plasma difloxacin concentrations normalized to a 60 mg/kg daily dose
F. Clinical Field Trials
The safety and
efficacy of
difloxacin tablets administered to dogs at 5.0 mg/kg body weight was
confirmed in a multi-center clinical field program. Dogs presented to the investigators with clinical signs of
bacterial infections as defined in the
protocol were
admitted into
the study
. Eighteen veterinarians located in four different geographical areas of
the U.S. (Southeast, Midwest, Northwest, and
West) conducted the clinical efficacy and
safety evaluations.
Study Investigators:
Michael Andrew, DVM, Portland, OR
Robert Blomme, DVM, Audubon, IA
Steve Callahan, DVM, Corvallis, OR
Glenn Finnell, DVM, Orlando, FL
Paul Glouton, DVM, Lilburn, GA
Richard Heers, DVM, Tulare, CA
Ken Krawford, DVM, Snellville, GA
Steven Krome, DVM, Walnut Creek, CA
Ted Lamp, DVM, Bellville, TX
Rick Lungo, DVM, Spokane, WA
Lonna Nielsen, DVM, St. Cloud, MN
Rob Privette, DVM, Kennewick, WA
Harmon Rogers, DVM, Snohomish, WA
Brian Scott, DVM, Lake Mary, FL
Roger Tsuruda, DVM, Fresno, CA
Ron White, DVM, Osceola, IA
Jim Winsor, DVM, Inver Grove Heights, MN
Robin Woodley, DVM, Oakland, CA
General Design:
Purpose: To confirm the safety and
efficacy of
difloxacin tablets when
administered to dogs using enrofloxacin (Baytril®) as a positive control.
Animals: Difloxacin was
administered to 141 dogs of
various breeds, weights and
ages.
The variety of
breeds depicted the U.S. canine population. Body weights and
ages ranged from
1.4 to 55.9 kg and
9 months to 16 years, respectively. No breed, weight or
age susceptibilities were
observed. Enrofloxacin was
used in a group of
131 dogs, as a positive control for
comparative purposes. Fifty-six (56) enrofloxacin-treated animals and
55 difloxacin-treated animals were
excluded from
clinical and
bacterial response evaluations primarily due to no initial pathogen isolation.
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