Summary of
FDA Information:Approval Date: September 26, 1990
Freedom of
Information Summary
NADA 140-269
I. GENERAL INFORMATION:
NADA 140-269
Sponsor: Fort Dodge Laboratories
800 5th Street, NW
Fort Dodge, IA 50501-0518
Generic Name: Ketoprofen
Trade Name: Ketofen(TM)
Marketing Status: Rx
II. INDICATIONS FOR USE:
Ketofen(TM) is indicated for
the alleviation of
inflammation and
pain associated with musculoskeletal disorders in the
horse.
III. FORM, ROUTE OF ADMINISTRATION, DOSAGE:
Ketofen(TM) is supplied as a sterile injectable solution containing 100 mg ketoprofen per mL in an aqueous formulation containing L-arginine, citric acid to adjust pH, and
benzyl alcohol as a preservative.
The recommended dosage is 1.0 mg per pound (1 mL/100 lbs) of
body weight once daily. Treatment is administered by intravenous injection and
may be repeated for
up to five days.
IV. EFFECTIVENESS:
A. Pivotal Blinded Dosage Determination Studies
Investigators:
Doyne Hamm, DVM
E. Wynn Jones, MRCVS, PhD
Jack Hamm, PhD
Research for
Animal Health
Route 13, Box 203, Hunt Lane
Fayetteville, AR 72701
The objectives of
these studies were
to select an appropriate model for
dose-response efficacy testing in the
horse and
to determine an appropriate intravenous dosage for
further clinical testing of
ketoprofen in that model.
Test animals included 14 previously healthy mature horses, 10 geldings and
4 mares, ranging in body weight from
804 to 974 pounds.
The left carpal joint of
each horse was
surgically prepared and
0.7 ml Freund's complete adjuvant was
injected into
the intercarpal space.
This procedure is known to result in acute inflammation of
the joint which
, if left untreated, progresses to chronic degenerative arthritis. After seven days, by which
time swelling, heat, pain, and
lameness had developed in all study
animals, each horse was
given a single intravenous injection of
ketoprofen at the
randomly assigned dosage of
0 (placebo), 0.5, 1.0 or
1.5 mg/lb body weight. Four (4) horses were
treated at each of
the 0.5, 1.0 and
1.5 mg/lb dosage while two (2) horses received the placebo treatment.
Controls were
given placebo (vehicle not containing ketoprofen) injections at the
rate of
1 mL/100 lb body weight.
Dosage form was
ketoprofen injectable solution containing 100 mg ketoprofen per ml, identical to the formulation to be marketed.
Dosages, routes of
administration, and
duration were
0 (placebo), 0.5, 1.0 or
1.5 mg/pound body weight given intravenously as a single injection and
evaluated for
30 hours after treatment.
This study
was blinded by having the treatment administered by one individual and
the post treatment observation made by a second individual.
Pertinent parameters measured before each treatment and
4, 8, 12, 16, 24, and
30 hours after each treatment were
the following:
Temperature, pulse rate, and
respiratory rate
Angle of
flexion at rest (degrees)
Maximum flexion permitted (degrees)
Stride length (distance between steps at a walk)
Clinical lameness score (0-3, where 0=normal, 3=severe)
Circumference of
inflamed joint (measured with a tape measure)
Results of
the study
revealed that all dosages of
ketoprofen were
active, and
lower dosage of
0.5 mg/lb was
less effective than dosages of
1.0 and
1.5 mg/lb and
these were
not different from
each other.
The following table lists the mean data after the initial intravenous treatment, four horses per ketoprofen group and
two placebo treated controls.
(Eds. note: The following table consists of
10 columns.)
FIRST KETOPROFEN TREATMENT BY INTRAVENOUS ROUTE
(mean, n = 4 except placebo where n = 2)
Before Pre
Parameter Dosage Inflam. Treat 4 hr 8 hr 12 hr 16 hr 24 hr 30 hr
Flexion 0.5 mg/lb 0.0 10.0 1.3 3.8 6.3 7.5 7.5 7.5
At Rest 1.0 mg/lb 0.0 10.0 0.0 0.0 0.0 5.0 7.5 7.5
(degrees) 1.5 mg/lb 0.0 8.8 0.0 0.0 0.0 1.3 5.0 5.0
PLACEBO 0.0 10.0 20.0 20.0 10.0 10.0 10.0 10.0
Maximum 0.5 mg/lb 123.8 46.3 62.5 56.3 48.8 47.5 46.3 47.5
Flexion 1.0 mg/lb 123.8 46.3 80.0 78.8 76.3 55.0 50.0 50.0
Permitted 1.5 mg.lb 118.8 45.0 78.8 80.0 78.8 65.0 58.8 51.3
(degrees) PLACEBO 122.5 40.0 47.5 45.0 40.0 45.0 47.5 45.0
Stride 0.5 mg/lb 61.8 37.3 48.0 45.5 41.5 40.8 40.5 40.8
Length 1.0 mg/lb 62.0 37.0 50.3 51.5 50.3 44.3 41.5 40.5
(inches) 1.5 mg/lb 62.4 37.4 51.8 53.0 52.5 47.8 44.5 41.8
PLACEBO 61.5 37.0 35.0 37.5 39.0 37.5 39.1 38.5
Clinical 0.5 mg/lb 0.0 3.0 2.0 2.0 3.0 3.0 3.0 3.0
Lameness 1.0 mg/lb 0.0 3.0 1.5 1.0 1.3 2.3 3.0 3.0
Score 1.5 mg/lb 0.0 3.0 1.5 1.0 1.0 1.8 2.5 2.8
(0 - 3) PLACEBO 0.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0
Joint 0.5 mg/lb 11.4 14.6 14.3 14.4 14.6 14.6 14.6 14.6
Circum- 1.0 mg/lb 11.4 15.1 14.2 13.9 14.1 14.6 15.0 15.1
ference 1.5 mg/lb 11.5 14.3 13.4 13.4 13.4 13.7 14.1 14.3
(inches) PLACEBO 11.3 15.1 15.1 15.1 15.1 15.1 15.3 15.4
Among the parameters measured, maximum flexion and
stride length appeared to be the most sensitive in separating dosage effects as illustrated graphically in the
following figures.
During the study
there were
no observed adverse reactions in the
treated horses.
Statistical analysis of
the data was
performed by analysis of
variance and
the Student-Newman-Keuls and
Duncan's Multiple Range procedures on change from
baseline (preinflammation) at each observation time at the
0.05 level of
significance. In general, for
parameters listed in the
above tables, the
mean values in the
1.0 and
1.5 mg/lb ketoprofen groups were
significantly (p<0.05) different from
those in placebo and
0.5 mg/lb groups between about 4 and
16 hours after treatment but were
never significantly different from
each other.
Conclusions drawn from
the study
were that the
adjuvant arthritis model is appropriate for
dose determination of
ketoprofen and
that 1 mg/lb is an effective dosage intravenously.
B. Pivotal Controlled Efficacy, Dosage Confirmation Study
Investigators:
Doyne Hamm, DVM
E. Wynn Jones, MRCVS, PhD
Jack Hamm, PhD
Research for
Animal Health
Route 13, Box 203, Hunt Lane
Fayetteville, AR 72701
The purpose of
this study
was to compare the antiinflammatory effects of
ketoprofen given at the
previously titrated dosage of
1.0 mg/lb intravenously with the effects of
an approved reference control drug and
placebo in an equine adjuvant arthritis model.
Test animals included 18 previously healthy mature horses of
quarter horse type represented by both sexes, randomly divided into
three treatment groups as follows:
Ketoprofen 1 mg/lb IV 6 horses
Positive control (flunixin, IV 6 horses
Negative control (placebo) 6 horses
The left carpal joint of
each horse was
surgically prepared and
0.7 ml Freund's complete adjuvant was
injected into
the intercarpal space.
This procedure is known to result in acute inflammation of
the joint which
, if left unteated, progresses to chronic degenerative arthritis. After five to seven days, by which
time swelling, heat, pain, and
lameness had developed in all study
animals, treatment was
initiated on each horse according to the treatment group to which
it had been randomly assigned. Horses were
treated with ketoprofen injectable solution containing 100 mg ketoprofen per ml, identical to the formulation to be marketed, at a dosage of
1 mg/lb IV. Controls were
given placebo (vehicle not containing ketoprofen) intravenous injections at the
rate of
1 mg/100 lb body weight. Positive controls were
given flunixin (Banamine, Schering, 50 mg/ml) obtained from
commercial sources, at its approved dosage of
0.5 mg/lb IV. Both drugs and
placebo were
given daily for
five days.
This study
was blinded by having the treatment administered by one individual and
the post treatment observation made by a second individual.
Pertinent parameters measured before adjuvant injection, before treatment, 2, 4, 12, and
24 hours after the first treatment, and
twice daily throughout the study
period were
the following:
General health (temperature, pulse rate, and
respiratory rate)
Angle of
flexion at rest (degrees)
Maximum flexion permitted (degrees)
Stride length (distance between steps at a walk)
Clinical lameness score (0-3, 0=normal, 3=severe)
Circumference of
inflamed joint (measured with a tape measure)
Joint heat (0-3, where 0=normal, 3=severe)
Pain on palpation (0-3, where 0=normal, 3=severe)
Results of
the study
indicated that ketoprofen by the intravenous route of
administration was
equivalent in effectiveness to the approved reference control drug flunixin.
The mean results for
each parameter at each measurement time are present in the
following table. During the study
there were
no adverse reactions in the
treated horses.
(Eds. note: The following table consists of
9 columns.)
Response to Treatment
(mean, n = 6)
Flex Rest Max Flex Stride Length Lameness JT Circum JT Heat JT Pain
Drug Time (degrees) (degrees) (inches) (0 - 3) (inches) (0 - 3) (0 - 3)
KETOPROFEN PRE INFLAM 0.0 118.3 60.7 0.0 11.3 0.0 0.0
intravenous PRE TREAT 5.0 54.2 45.3 2.7 13.2 2.0 2.0
1.0 mg/lb 2 hours 2.5 65.0 52.4 2.0 13.2 2.0 2.0
4 hours 0.0 70.0 56.5 1.3 13.0 1.5 1.5
12 hours 0.8 70.8 55.5 1.2 13.0 1.5 1.5
24 hours 3.3 60.0 51.5 1.8 13.0 1.7 1.7
36 hours 0.0 77.5 57.3 1.2 12.9 1.5 1.5
48 hours 4.2 57.5 51.0 2.0 13.1 1.7 1.7
60 hours 0.0 78.3 57.3 1.3 13.0 1.7 1.7
72 hours 3.3 65.8 52.5 2.0 13.1 1.8 1.7
84 hours 1.7 83.3 58.3 1.3 13.1 1.3 1.3
96 hours 2.5 62.5 52.5 1.8 13.0 1.3 1.3
108 hours 0.8 85.8 58.7 1.3 13.0 1.3 1.3
FLUNIXIN PRE INFLAM 0.0 118.3 61.5 0.2 11.7 0.0 0.0
control PRE TREAT 8.3 47.5 41.4 3.0 13.9 2.0 2.0
0.5 mg/lb 2 hours 4.2 63.3 52.9 1.8 13.8 2.0 1.8
4 hours 2.5 74.2 55.7 1.5 13.8 1.7 1.7
12 hours 2.5 72.5 56.5 1.3 13.7 1.7 1.7
24 hours 4.2 57.5 52.3 2.2 13.8 1.8 1.8
36 hours 0.0 74.2 58.6 1.0 13.8 1.7 1.7
48 hours 2.5 66.7 54.3 1.8 13.8 1.8 1.8
60 hours 1.7 77.5 59.7 1.0 13.8 1.7 1.7
72 hours 2.5 66.7 52.5 1.7 13.6 1.8 1.8
84 hours 0.0 85.8 60.5 1.0 13.6 1.5 1.5
96 hours 1.7 69.2 55.3 1.8 13.8 1.7 1.7
108 hours 0.0 94.2 61.3 1.0 13.5 1.3 1.3
PLACEBO PRE INFLAM 0.0 118.3 60.0 0.0 11.4 0.0 0.0
control PRE TREAT 3.3 50.0 48.2 2.5 13.5 2.0 2.0
1 mg/100 lb 2 hours 2.5 54.2 48.0 2.7 13.7 2.0 2.0
4 hours 5.0 49.2 49.8 2.5 13.7 2.0 2.0
12 hours 5.0 49.2 49.1 2.8 13.7 2.0 2.0
24 hours 5.0 48.3 49.3 2.7 13.6 2.0 2.0
36 hours 4.2 48.3 49.5 2.5 13.7 2.0 2.0
48 hours 5.8 44.2 49.1 2.7 13.7 2.0 2.0
60 hours 5.8 50.0 45.1 2.5 13.6 2.2 2.2
72 hours 5.8 41.7 47.5 2.7 13.8 2.0 2.0
84 hours 6.7 43.3 48.4 2.7 13.8 2.0 2.0
96 hours 5.8 45.0 48.4 2.7 13.8 2.0 2.0
108 hours 5.8 45.8 46.8 2.7 13.8 2.0 2.0
Maximum flexion, stride length, and
clinical lameness appeared to be the most sensitive parameters in demonstrating treatment effects as illustrated graphically in the
following figures.
Statistical analysis of
the data was
performed by analysis of
variance and
Duncan's Multiple Range procedure on change from
baseline (preinflammation) at each observation time at the
0.05 level of
significance. Responses in ketoprofen IV, and
flunixin treated animals were
significantly (p<0.05) better than those in placebo controls but were
not significantly different among drug treatment groups.
Conclusions based on results of
the study
were that ketoprofen, given at a dosage of
1.0 mg/lb intravenously, shows marked antiinflammatory activity in horses, equivalent to that of
the approved reference control drug flunixin.
C. Pivotal Blinded Clinical Trials
Investigators:
Drs. Anthony and
Sally Prickett
720 40th Avenue
Cumming, IA 50061
W.A. Grantham, DVM
799 Main St., Suite K
Half Moon Bay, CA 94019
Doyne Hamm, DVM
Research for
Animal Health
Route 13, Box 203, Hunt Lane
Fayetteville, AR 72701
Michael J. Betley, DVM
PO Box 231
Barrington, IL 60010
The purpose of
this study
was to determine the clinical antiinflammatory effects and
side effect profile of
ketoprofen given at the
proposed dosage of
2.2 mg/kg (1 mg/lb) intravenously for
5 consecutive days in horses with musculoskeletal inflammatory disorders, under
conditions of
veterinary practice.
Test animals included horses of
either sex and
of any age that, in the
routine course of
the investigators' practice, were
presented for
diagnosis and
treatment of
non-infectious inflammatory conditions of
the musculoskeletal system from
the elbow or
stifle joint distal.
Diagnoses, based on physical examination and
x-rays if indicated, included various inflammatory condition characterized as follows:
Conditions less than 2-4 weeks duration
Lameness of
American Association of
Equine Practitioners (AAEP) grad 2 or
more, or
marked pain on palpation
Swelling or
heat clinically greater than corresponding contralateral side
Horses with a tentative diagnosis of
any of
the following conditions:
Traumatic arthritis/synovitis
Tendonitis/desmitis
Osteochondritis dessicans
Osselets
Soft tissue swelling
Post surgical inflammation and
swelling
Horses with inflammatory conditions of
over 4 weeks duration; horses that had received antiinflammatory or
other anti-arthritic drugs within the previous 14 days; fracture cases exceptpost surgical cases; and
horses with a tentative diagnosis of
laminitis, splints, osteitis, or
navicular disease; were
not included in the
study
. Dosage form, dosage, and
duration.
The investigational drug ketoprofen was
supplied as a sterile, 100 mg/ml solution, identical to the formulation to be marketed, in glass vials each containing 50 ml.
The control drug flunixin, 50 mg/ml obtained from
commercial sources, was
supplied in 50 ml glass vials identical to those containing ketoprofen. Ketoprofen was
given at a dosage of
1.0 mg/lb intravenously and
flunixin was
given at its approved dosage of
0.5 mg/lb intravenously. Both drugs were
given daily for
five days.
The study
was blinded by providing each investigator with numbered vials containing either ketoprofen or
flunixin. Both products were
clear, colorless aqueous solution, packaged in identical vials, and
the recommended dosage of
each corresponds to 1 ml/100 lb of
body weight was
given intravenously. Consecutive numbers from
1 to 100 were
randomly assigned to either control or
test substance vials in a 50:50 ratio.
The substances were
supplied to investigators as kits each containing 10 vials numbered consecutively and
randomly but equally divided between ketoprofen and
flunixin.
The coding system was
known only to Pharmaceutical Development personnel who prepared the test substances and
was
not broken until the data were
analyzed.
Pertinent parameters measured included general physical examinations and
observations for
any apparent side effects daily just prior to the scheduled treatment. Complete evaluation of
lameness and
pain on palpation, as well as measurement of
circumference and
thermography of
lesion site and
corresponding contralateral site, was
conducted before treatment, on the 3rd day after initiation of
treatment, and
again 24 hours after the 5th and
final treatment was
as follows:
Lameness, evaluated on a subjective 0-4 scale where
0=normal
no detectable lameness
1=slight
subtle lameness without overt head movement,
2=moderate
easily recognizable, head-bobbing lameness
3=severe
definite lameness observed at a walk and
at a trot
4=extreme
non weight-bearing on affected limb
Pain on palpation, evaluated on a 0-3 scale where
0=normal
no response to firm pressure
1=slight
digital pressure at site of
lesion induces muscle tremors and
/or slight avoidance movement
2=moderate
digital pressure at site of
lesion induces definite limb withdrawal
3=severe
attempted digital pressure induces marked withdrawal
Swelling, circumference of
affected part measured with a tape measure as compared with the circumference of
the corresponding site on the opposite limb. Heat (thermography), Skin temperature at a predesignated and
marked position over the lesion site, and
at the
equivalent position on the contralateral limb of
the horse, was
measured and
recorded. For this purpose microprobe thermometers (Sensortek(TM), BAT-12), equipped with skin surface probes (similar to miniature stethoscopes) were
procured, tested for
accuracy and
provided to each investigator.
Overall evaluation of
clinical response was
made of
each case at the
time of
the last (24 hour post treatment) examination according to the following criteria:
Excellent:
No detectable lameness or
swelling, horse can be returned to normal activity
Good:
Marked reduction in lameness and
swelling but horse not completely back to pre treatment condition
Fair:
Only slight reduction in lameness and
swelling
Poor:
No improvement, or
condition worsened
Results were
obtained from
a total of
52 horses, 25 treated with ketoprofen and
27 treated with flunixin, distributed among the four investigators. Both drugs showed antiinflammatory activity under
clinical conditions and
the responses were
similar.
The data are summarized in the
following table. [Editor's Note: In the following section of
this document, the
letter 'd' has been substituted for
the greek symbol Delta, as this symbol is not currently supported by HTML.]
(Eds. note: The following table consists of
5 columns.)
DOUBLE BLIND CLINICAL STUDY P315-C1 DATA SUMMARY
(mean ± sem, n=25 and
27 for
ketoprofen and
flunixin respectively)
Parameter Drug Pretreatment Day 3 Post Treatment
d Circumference* Ketoprofen 1.97 ± 0.28 1.32 ± 0.22 0.72 ± 0.16
(centimeters) Flunixin 1.77 ± 0.18 1.19 ± 0.18 0.90 ± 0.15
d Skin temperature* Ketoprofen 1.44 ± 0.21 1.00 ± 0.16 0.66 ± 0.10
(degrees centigrade) Flunixin 1.96 ± 0.31 1.23 ± 0.19 0.84 ± 0.15
Clinical Lameness Ketoprofen 2.36 ± 0.13 1.48 ± 0.16 0.92 ± 0.19
(0 - 4) Flunixin 2.15 ± 0.10 1.07 ± 0.13 0.59 ± 0.12
Pain on manipulation Ketoprofen 2.24 ± 0.16 1.44 ± 0.13 0.84 ± 0.16
(0 - 3) Flunixin 2.07 ± 0.12 1.15 ± 0.12 0.52 ± 0.10
*Difference between lesion side and
contralateral side
The above data are illustrated graphically in the
following charts.
Statistical analysis
A procedure for
comparing proportions from
mindependent samples as described by Fleiss (1981) was
used to test for
investigator effect on proportions of
"excellent" or
"good" responses (satisfactory) vs "fair" or
"poor" responses (unsatisfactory). No significant investigator effects (p>0.05) were
detected by this analysis.
Three factor ANOVA, investigator and
drug as between-subject factors and
time as a within-subject factor, of
both subjective and
objective variables was
performed using the CLR ANOVA for
the Apple® Macintosh(TM). For this analysis subjective parameters lameness and
pain scores were
expressed change relative to pretreatment, designated dLAME and
dPAIN respectively. For objective parameters circumference (CIRC) and
heat (HEAT), ANOVA was
conducted on (a) the values relative to contralateral value, designated d , (b) the change relative to pretreatment of
the values relative to contralateral value, designated dd, (c) the absolute measurements of
the lesion side, designated L, and
(d) the change relative to pretreatment of
the absolute value on the lesion side, designated dL.
No difference in response (p>0.05) between the two drugs was
detected with regard to subjective parameters. For objective parameters it appeared that the
variable circumference was
less influenced by investigator than heat. For the measurement of
circumference, CIRC, the
result was
the same whether the measurement was
compared with the contralateral site or
not. For measurement of
temperature of
the lesion, however, a difference in interpretation did arise depending on the whether the change only on the lesion side (dLHEAT) was
considered or
whether the changes relative to contralateral (dHEAT and
ddHEAT) were
considered. No drug effect was
seen for
the variable dLHEAT. Since the results of
dLHEAT are consistent with all of
the other variables measured and
since dLHEAT measures the lesion directly, it would seem that in this circumstance the use of
the contralateral site did not serve as an appropriate control.
The following table summarizes the ANOVA results described above.
(Eds. note: The following table consists of
11 columns.)
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