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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-269 Ketofen™ - original approval

Date of Approval: September 26, 1990

I. GENERAL INFORMATION:

NADA140-269
Sponsor:Fort Dodge Laboratories
800 5th Street, NW
Fort Dodge, IA 50501-0518
Generic Name:ketoprofen
Trade Name:Ketofen™
Marketing Status: 

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.

FIRST KETOPROFEN TREATMENT BY INTRAVENOUS ROUTE
(mean, n = 4 except placebo where n = 2)

ParameterDosageBeforeInflamPre
Treat
4 hr8 hr12 hr16 hr24 hr30 hr
Flexion
At
Rest
(degrees)
0.5 mg/lb0.010.01.33.86.37.57.57.5
1.0 mg/lb0.010.00.00.00.05.07.57.5
1.5 mg/lb0.08.80.00.00.01.35.05.0
PLACEBO0.010.020.020.010.010.010.010.0
Maximum
Flexion
Permitted
(degrees)
0.5 mg/lb123.846.362.556.348.847.546.347.5
1.0 mg/lb123.846.380.078.876.355.050.050.0
1.5 mg.lb118.845.078.880.078.865.058.851.3
PLACEBO122.540.047.545.040.045.047.545.0
Stride
Length
(inches)
0.5 mg/lb61.837.348.045.541.540.840.540.8
1.0 mg/lb62.037.00.351.550.344.341.540.5
1.5 mg/lb62.437.451.853.052.547.844.541.8
PLACEBO61.537.035.037.539.037.539.138.5
Clinical
Lameness
Score
(0 - 3)
0.5 mg/lb0.03.02.02.03.03.03.03.0
1.0 mg/lb0.03.01.51.01.32.33.03.0
1.5 mg/lb0.03.01.51.01.01.82.52.8
PLACEBO0.03.03.03.03.03.03.03.0
Joint
Circum-
ference
(inches)
0.5 mg/lb11.414.614.314.414.614.614.614.6
1.0 mg/lb11.415.114.213.914.114.615.015.1
1.5 mg/lb11.514.313.413.413.413.714.114.3
PLACEBO11.315.115.115.115.115.115.315.4

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.

MAXIMUM FLEXION, 1st treatmentStride Length

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 IV6 horses
Positive control (flunixin, IV6 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.

Response to Treatment
(mean, n = 6)

DrugTimeFlex Rest
(degrees)
Max Flex
(degrees)
Stride Length
(inches)
Lameness
(0 - 3)
JT Circum
(inches)
JT Heat
(0 - 3)
JT Pain
(0 - 3)
KETOPROFEN
intravenous
1.0 mg/lb
PRE INFLAM0.0118.360.70.011.30.00.0
PRE TREAT5.054.245.32.713.22.02.0
2 hours2.565.052.42.013.22.02.0
4 hours0.070.056.51.313.01.51.5
12 hours0.870.855.51.213.01.51.5
24 hours3.360.051.51.813.01.71.7
36 hours0.077.557.31.212.91.51.5
48 hours4.257.551.02.013.11.71.7
60 hours0.078.357.31.313.01.71.7
72 hours3.365.852.52.013.11.81.7
84 hours1.783.358.31.313.11.31.3
96 hours2.562.552.51.813.01.31.3
108 hours0.885.858.71.313.01.31.3
FLUNIXIN
control
0.5 mg/lb
PRE INFLAM0.0118.361.50.211.70.00.0
PRE TREAT8.347.541.43.013.92.02.0
2 hours4.263.352.91.813.82.01.8
4 hours2.574.255.71.513.81.71.7
12 hours2.572.556.51.313.71.71.7
24 hours4.257.552.32.213.81.81.8
36 hours0.074.258.61.013.81.71.7
48 hours2.566.754.31.813.81.81.8
60 hours1.777.559.71.013.81.71.7
72 hours2.566.752.51.713.61.81.8
84 hours0.085.860.51.013.61.51.5
96 hours1.769.255.31.813.81.71.7
108 hours0.094.261.31.013.51.31.3
PLACEBO
control
1 mg/100 lb
PRE INFLAM0.0118.360.00.011.40.00.0
PRE TREAT3.350.048.22.513.52.02.0
2 hours2.554.248.02.713.72.02.0
4 hours5.049.249.82.513.72.02.0
12 hours5.049.249.12.813.72.02.0
24 hours5.048.349.32.713.62.02.0
36 hours4.248.349.52.513.72.02.0
48 hours5.844.249.12.713.72.02.0
60 hours5.850.045.12.513.62.22.2
72 hours5.841.747.52.713.82.02.0
84 hours6.743.348.42.713.82.02.0
96 hours5.845.048.42.713.82.02.0
108 hours5.845.846.82.713.82.02.0

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.

Maximum FlexionStride LengthLameness Score

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.

Effect of Ketoprofen and Flunixin on CircumferenceEffect of Ketoprofen and Flunixin on Heat

Effect of Ketoprofen and Flunixin on Lameness ScoreEffect of Ketoprofen and Flunixin on Pain Sore

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.)

Harmonic Means of Drug Effect for all Variables

              ---Subjective---         ------------------------ Objective------------------   
            dLame         dPain      dCirc  ddCirc  LCIRC  dLCIRC  dHeat  ddHeat Lheat  dLheat  
Drug     (score 0-4)   (score 0-3)   (cm)    (cm)   (cm)    (cm)    (C)    (C)    (C)    (C)
                                                                                                         
Ketoprofen    1.3             1.2         1.3      1.0     30.7     0.8      1.0     0.7     34.8    1.0     
Flunixin      1.4             1.2         1.2      0.7     29.6     0.9      1.5*    1.06*   34.0*   1.0

Since two of the parameters, lameness and pain on manipulation, were clinical scores rather than actual measurements, the significance of any differences between treatments was tested by the nonparametric Mann-Whitney U test. No significant differences between treatment groups were detected for either of the parameters at any of the post treatment times (p>0.05).

Finally, the significance of any difference between treatment groups with regard to the overall clinical evaluation of excellent, good, fair or poor was tested by contingency table analysis. No significant differences between ketoprofen and flunixin in overall clinical response were detected (p>0.05).

No adverse reactions were encountered in the study in either treatment group.

Conclusions

The results of this study confirm that ketoprofen given at dosage of 1.0 mg/lb is effective intravenously as an antiinflammatory agent, has an acceptable side effect profile, and is equivalent in effectiveness and clinical safety to the positive control drug flunixin when tested under conditions of veterinary practice.

D. Corroborative Clinical Trials

Investigators:

W.A. Grantham, DVM
799 Main St., Suite K
Half Moon Bay, CA 94019

R.M. Baker, DVM
530 Grant Ave.
Raton, NM 87740

L.R. Bramlage, DVM
Ohio State Univ.
Dept. Clinical Sciences
Columbus, OH 43210

Louie Stratton, DVM
Veterinary Teaching Hospital
Oklahoma State University
Stillwater, OK 74070

Doyne Hamm, DVM
Research for Animal Health
Route 13, Box 203, Hunt Lane
Fayetteville, AR 72701

Ernest R. Benner, DVM
Valley Veterinary Services
515 East Fifth Ave.
Ranson, WV 25438

The purpose of this study was to compare the antiinflammatory effects of ketoprofen given intravenously and intramuscularly at a dosage of 1.0 mg/lb with the effects of flunixin given by the same routes at its approved dosage of 0.5 mg/lb, under conditions of veterinary practice.

Test animals included 115 horses presented to the veterinarian during the course of his routine practice for diagnosis and treatment of inflammatory conditions of the musculoskeletal system.

Each investigator was provided with a computer generated randomized drug/route assignment list which resulted in the horses being randomly divided into four treatment groups. Case reports for 22 animals were removed from final evaluation because they did not meet protocol criteria. The remaining 93 case reports were from animals treated as follows:

     Ketoprofen (1 mg/lb) by intravenous route      26 horses
     Ketoprofen (1 mg/lb) by intramuscular route    22 horses
     Flunixin (0.5 mg/lb) by intravenous route      21 horses
     Flunixin (0.5 mg/lb) by intramuscular route    24 horses

Diagnoses, based on physical examination and x-rays if indicated, in descending order of frequency included (1) minor fractures and bone chips, (2) joint inflammation and carpitis, (3) injury inflammation, (4) post operative inflammation, (5) soft tissue inflammation, myositis, and cellulitis, and (6) laminitis. Positive controls were given flunixin at its approved dosage of 0.5 mg/lb intravenously or intramuscularly.

Dosage forms, dosages, and duration were ketoprofen injectable solution containing 100 mg ketoprofen per ml, identical to the formulation to be marketed, and flunixin 50 mg/ml, obtained from commercial sources. Ketoprofen was given at a dosage of 1.0 mg/lb intravenously or intramuscularly and flunixin was given at its approved dosage of 0.5 mg/lb intravenously or intramuscularly. Both drugs were given daily for five days.

Pertinent parameters measured daily before each of the five treatments and 24 hours after the last treatment were the following:

  • Clinical lameness score (0-3, where 0=normal, 3=severe)
  • Pain on palpation or compression (present or absent)
  • Pain on flexion, extension, or rotation (present or absent)
  • Swelling (0-3, where 0=normal, 3=severe)
  • Heat (present or absent)
  • Reaction after each injection (present or absent)
  • Overall efficacy evaluation (excellent, good, fair, or poor)
  • Side effects (yes or no, if yes specify)

Results of the study indicated that ketoprofen was equivalent in effectiveness to the approved reference control drug flunixin by both routes of administration. Case reports from 93 of the horses were considered complete and acceptable for evaluation. Among these 93 horses the diagnoses were as follows: minor fractures and bone chips (29 cases), joint inflammation and carpitis (24 cases), injury inflammation (18 cases), post operative inflammation (10 cases), soft tissue inflammation, myositis, and cellulitis (9 cases), and laminitis (3 cases). The results illustrating parallel responses are presented in the following figures.

Lameness ScorePain on Palpation

Pain on FlexionClinical Swelling

Joint Heat

Results of overall efficacy evaluation (excellent, good, fair or poor) are presented in the following chart.

Efficacy Evaluation

No post injection reactions were observed other than swelling apparently due to injection of part of the dosage outside the vein on two occasions in the ketoprofen IV group.

Statistical analysis were conducted on the data by analysis of covariance with age, sex, duration, chip, nerve, therapy, and surgery as covariates, and also by analysis of variance. With each analysis the following contrasts were tested for significance: (1) ketoprofen IM vs IV, (2) flunixin IM vs IV, (3) ketoprofen vs flunixin averaged over routes of administration, (4) ketoprofen IV vs flunixin IV, and (5) ketoprofen IV vs all flunixin. These analyses were performed on the means after adjustment for any differences that may exist in the covariates between treatment groups. Additionally, the same analyses were performed on average values over time, the difference between pretreatment and post treatment (day 5) values, and for the linear slope over time.

Fewer significant differences between ketoprofen and the positive control flunixin at the 0.10 level of significance were detected than would be expected by chance alone. For ketoprofen, between IM and IV administration, only 15 of 112 tests were significant, about the number expected by chance. However, of the 15 significant differences, 13 favored the IM route of administration such that any differences, although small, would seem to favor the IM route of administration.

Conclusions based on results of the study were that ketoprofen given at a dosage of 1.0 mg/lb is as effective as the positive control drug flunixin and is clinically effective whether administered intramuscularly or intravenously.

E. Corroborative Blood Level Studies

Investigators:

Dr. Stan Mares
Fort Dodge Laboratories
Pharmaceutical Research and Development
Fort Dodge, IA 50501

Dr. John Eppley
Fort Dodge Laboratories
Pharmaceutical Research and Development
Fort Dodge, IA 50501

The purpose of these studies was to determine serum levels of the ketoprofen following administration by the intravenous and intramuscular route. The dosage selected for the intravenous and intramuscular route was 1 mg/lb ketoprofen, which is the dose determined by the dose titration studies as the effective dose and was the dosage used in the clinical efficacy studies.

There were a total of eight (8) mature horses utilized in these studies. Weight of the animals ranged from 590 to 930 pounds. All horses used in the studies were maintained at the Fort Dodge Laboratories facilities. They were housed in outdoor facilities and received care and maintenance consistent with good laboratory management practices. The studies consisted of two sets of four (4) horses each. The first set of four (4) horses were randomly assigned to receive the ketoprofen twice by the same parenteral route of administration with a 16-day interval between treatments. Blood samples were collected at 0, 5, 15, and 30 minutes and at 1, 2, 4 and 6 hours post injection. Serum was separated from the samples and transported to the analytical laboratory for analysis by a validated HPLC assay method.

The second set of four (4) horses were handled as a separate trial. These four (4) horses were randomly assigned to treatment by either the intravenous administration or the intramuscular administration of ketoprofen at the dosage of 1.0 mg/lb. After a three (3) day time period, all four (4) animals were again treated by cross-over (the horses who received the intravenous treatment for the first dosage were retreated by the intramuscular route and vise-versa.) Blood samples were collected at 0, 1, 2, 4, 10, 20 and 40 minutes and at 1, 2, 4, 6, and 8 hours post treatment. Serum was separated and analyzed by a validated HPLC assay method.

For all studies the individual animal had pretreatment blood samples collected which served as a control for that animal. No untreated control animals were utilized during these blood level studies.

During these trials there were no observed local or systemic adverse reactions in any of the treated horses.

Results of the blood level studies are illustrated graphically in the following charts depicting all values from all eight (8) horses. Since this was a corroborative study with a limited number of horses involved, no statistical analysis was performed.

Ketoprofen Intravenous Blood LevelsKetoprofen Intramuscular Blood Levels

Conclusions based on results of these studies were that following IM or IV administration ketoprofen reached measurable, albeit variable, serum concentrations in the horse.

 

V. ANIMAL SAFETY

A. Pivotal Subacute (15 day) Safety 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

J. Beasley, DVM, PhD, ACVP
Veterinary Science Department
University of Arkansas
Fayetteville, AR 72701

The purpose of the study was to determine the safety of ketoprofen given at 0, 1x, 3x, and 5x the recommended dosage for 3x the recommended treatment period in horses as the intended target species.

Test animals included 24 horses of both sexes including geldings, of quarter horse or thoroughbred type, ranging in age from 2 to 8 years, and in body weight from 705 to 930 pounds. The horses were randomly divided into four groups, six horses per group. The study was blinded in that neither the veterinarian making the observations, nor the laboratory performing the tests, had prior knowledge of the dosage administered.

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), 1.0, 3.0, or 5.0 mg/lb body weight given intravenously daily for 15 consecutive days.

Parameters measured before treatment, on days 5, 10, and 15 during treatment, and 7 days after treatment included a battery of blood chemistry tests, fecal analysis for occult blood, urinalysis, and hematology (Listed in Table 1 and Table 2). Additionally, BSP liver function tests were performed before treatment and on the last day of treatment and two animals from each dosage group were euthanized and necropsied one week after treatment.

(Eds. note: The following table consists of 3 columns.)

PIVOTAL SUBACUTE (15 DAY) SAFETY STUDY IN HORSES

BLOOD CHEMISTRY AND HEMATOLOGY RESULTS TABLE

Parameters                               Normal Values (1,2,3)    Results

Blood Chemistry Tests:                                                                 
Glucose                                        4.16 - 6.39 mol/l            N          
Blood Urea Nitrogen (BUN)                      10 - 24 mg/dl                S          
Total Protein                                  52 - 79 g/l                  N          
Albumin                                        26 - 37 g/l                  N          
Bilirubin Total                                1 -2 mg/dl                   N          
Alkaline Phosphatase                           143 - 395 U/l                N          
Serum Clutamate-Oxaloacetate Transaminase      226 - 366 U/l                N          
(SGOT)                                                                                 
Sodium                                         132 - 146 mmol/l             N          
Potassium                                      2.4 - 4.7 mmol/l             N          
Creatinine, Serum                              106 - 168 µmol/l or          N          
                                               1.2 - 1.9 mg/dl                               
Blood Urea Nitrogen (BUN)/Creatine Ratio       5 - 20                       S          
Albumin/Globulin (A/G) Ratio                   0.62 - 1.46                  N          
Globulin                                       26.2 - 40.4 g/l              N          
Calcium                                        11.2 - 13.6 mg/dl            N          
Phosphorus                                     3.0 - 7.0 mg/dl              N          
Brom Sulfone Phthalate (BSP) % Retention       <10%                         N          

Hematology:                                                                            
White Blood Count                              5.5 - 12.5 (x10^3 per µl)    N          
Red Blood Count                                5.5 - 12 (x10^6 µl)          N          
Hemoglobin                                     8 - 19 gm/dl                 N          
Hematocrit (PCV)                               24 - 52 % µl                 N          
Polys                                          2.5 - 62 (x10^3 per µl)      N          
Bands                                          0 - 2.0 (x10^3 per µl)       N          
Lymphocytes                                    1.2 - 6.0 (x10^3 per µl)     S          
Monocytes                                      0 - 0.8 (x10^3 per µl)       N          
Eosinophil                                     0 - 1.0 (x10^3 per µl)       N          
Basophil                                       0 - 0.17 (x10^3 µl)          S          
Platelet Count                                 1 - 6 (x10^5 µl)             S          
Activated Partial Thromboplastin Time (True    42 - 70 Seconds              N          
APTT) (=APTT - APTT Control)                                                           

Fecal Analysis:                                                                        
Occult Blood                                   *                            N          

Urinalysis:                                                                            
Urine pH                                       7 - 9                        N          
Protein                                        *                            N          
Glucose                                        *                            N          
Ketones                                        *                            N          
Bilirubin                                      *                            N          
Blood                                          *                            N          
Urobilinogen                                   *                            N          
Specific Gravity                               1.020 - 1.050 Units          S          
Bile Pigments                                  *                            N          
Bile Salts                                     *                            N          
N   No significant difference from pretreatment baseline
    values and published normal values among dose groups
    on any of the sampling days.
S   A Duncan's Range Test indicated a possible difference
    (from pretreatment baseline values) among dose groups
    on one sampling day.  However, upon further statistical
    analysis, this finding was considered to occur by random
    chance, and is therefore not of clinical significance.
(1) Clinical Biochemistry of Domestic Animals,
    4th ed., 1989, J.J. Kaneko
(2) Veterinary Laboratory Medicine - Clinical Pathology,
    2nd ed., 1986, J.R. Duncan, K.W. Prasse
(3) Current Therapy in Equine Medicine, 2nd ed.,
    1987, N.E. Robinson

Results were that all animals remained healthy throughout the study and no reactions were observed clinically. Blood chemistry, urinalysis, and hematology determinations likewise failed to indicate consistent deviation from normal values. Occult blood was detected in feces on only two occasions, in a horse of the placebo group and in a horse of the 1 mg/lb group, both on day 10. BSP half lives did not change appreciably during the study period in any of the dosage groups. At necropsy, gross lesions that were observed were randomly distributed among all dosage groups including placebo. These included excess peritoneal fluid (6 cases), ulcers at the margo plicatus in the stomach (5 cases) and pylorus (6 cases), slightly swollen kidney (2 cases), nodules in lung (3 cases), and internal parasites (2 cases).

Since it is well known that gastrointestinal ulceration is a potential toxic effect of any nonsteriodal antiinflammatory agent, an independent pathologist (Dr. James R. Rooney, University of Kentucky) was consulted to review the histopathology slides of the ulcers noted above and to submit an opinion as to whether or not they represented a treatment effect. Dr. Rooney's opinion corroborated the findings of Dr. Beasley, namely that the ulcer lesions encountered were coincidental, not uncommon in horses as a result of bots (stomach worms) for example, and not related to ketoprofen treatment at any dosage.

Statistical analysis of the numerical data was conducted by analysis of variance at the 0.05 level of significance according to the following outline:

(Eds. note: The following table consists of 2 columns.)

Source of Variation    Degrees of Freedom

Total                             95
   Among Horses                   23
      Dose Groups                  3
      Horses within Groups        20
   Within Horse                   72
      Treatment Day                3
      Treatment Day x Dose         9
      Error                       60

In addition to the overall analysis, a separate analysis was conducted for each of the four treatment days. This amounted to a simple one-way analysis of variance with dose groups as the defining factor. Duncan's multiple range analysis followed any significant differences indicated by the various analyses of variance. No significant (p<0.05) relevant dose related effects were detected. Conclusions of the study were that no evidence of any toxic effects of ketoprofen dosage in horses was encountered, even when the drug was given at up to five fold multiples of the recommended dosage for three times longer than that recommended by the proposed labeling. It was thus demonstrated that an ample margin of safety is associated with ketoprofen when used as directed in horses.

B. Pivotal Drug Tolerance Test

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

J. Beasley, DVM, PhD, ACVP
Veterinary Science Dept.
University of Arkansas
Fayetteville, AR 72701

The purpose of the study was to further characterize the margin of safety of ketoprofen by assessing the response in horses to toxic doses of the drug.

Test animals included 4 horses of both sexes, of quarter horse type, ranging in age from 2 to 5 years, and in body weight from 800 to 945 pounds. The horses were randomly divided into two groups, two horses per group. The study was blinded in that neither the veterinarian making the observations, one the laboratory performing the tests, had prior knowledge of the dosage administered.

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 15 to 25 mg/lb (15 and 25 times the recommended dosage, two horses per dosage) intravenously daily for five consecutive days.

Parameters measured before treatment and 24 hours after each of the five treatments included physical examination for signs of toxicity, a battery of blood chemistry tests, fecal analysis for occult blood, urinalysis, and hematology (Listed in Table 1 and 2). The animals were euthanized and necropsied after treatment.

(Eds. note: The following table consists of 4 columns.)

Pivotal Drug Tolerance Test at 15X and 25X Overdose in Horses Laboratory Test

Results Table I

                                                                 15x Group     25x Group
Parameters                                Normal Values (1,2,3)   Results       Results

Blood Chemistry Tests:                                                                 
Glucose                                        4.16 - 6.39 mmol/l           N                N
Total Protein                                  52 - 79 g/l                  N                N
Albumin                                        26 - 37 g/l                  N                N
Bilirubin Total                                1 -2 mg/dl                   N                N
Sodium                                         132 - 146 mmol/l             N                N
Potassium                                      2.4 - 4.7 mmol/l             N                N
Creatinine, Serum                              106 - 168 µmol/l or          N                N
                                               1.2 - 1.9 mg/dl
Blood Urea Nitrogen (BUN)/Creatine Ratio       5 - 20                       N                N
Globulin                                       26.2 - 40.4 g/l              N                N
Calcium                                        11.2 - 13.6 mg/dl            N                N
Phosphorus                                     3.0 - 7.0 mg/dl              N                N
Albumin/Globulin (A/G) Ration                  0.62 - 1.46                  N                N

Hematology:                                                                                  
White Blood Count                              5.5 - 12.5 (x10^3 per µl)    N                N
Red Blood Count                                5.5 - 12 (x10^6 µl)          N                N
Hemoglobin                                     8 - 19 gm/dl                 N                A
Hematocrit (PCV)                               24 - 52 % µl                 N                A
Polys                                          2.5 - 62 (x10^3 per µl)      N                N
Bands                                          0 - 2.0 (x10^3 per µl)       N                N
Lymphocytes                                    1.2 - 6.0 (x10^3 per µl)     N                A
Monocytes                                      0 - 0.8 (x10^3 per µl)       N                N
Eosinophil                                     0 - 1.0 (x10^3 per µl)       N                N
Basophil                                       0 - 0.17 (x10^3 µl)          N                N
Platelet Count                                 1 - 6 (x10^5 µl)             N                N
Activated Partial Thromboplastin Time (True    42 - 70 Seconds              N                N
APTT) (=APTT - APTT Control)                                                                 
      
Fecal Analysis:                                                                              
Occult Blood                                   *                            N                A
      
Urinalysis:                                                                                  
Urine pH                                       7 - 9                        N                N
Protein                                        *                            N                A
Glucose                                        *                            N                N
Ketones                                        *                            N                N
Bilirubin                                      *                            N                N
Blood                                          *                            N                A
Urobilinogen                                   *                            N                N
Specific Gravity                               1.020 - 1.050 Units          N                N
Bile Pigments                                  *                            N                N
Bile Salts                                     *                            N                N

N   No significant difference from pretreatment baseline
    values and published normal values among dose groups
    on any of the sampling days.
A   Abnormal value; outside pretreatment baseline and
    published normal values. See text (pages 24-25) for
    discussion.
*   Non-numberic variables; measurements were recorded
    by Laboratory as Negative, Positive or Trace
(1) Clinical Biochemistry of Domestic Animals, 4th ed.,
    1989, J.J. Kaneko
(2) Veterinary Laboratory Medicine - Clinical Pathology,
    2nd ed., 1986, J.R. Duncan, K.W. Prasse
(3) Current Therapy in Equine Medicine, 2nd ed.,
    1987, N.E. Robinson

(Eds. note: The following table consists of 9 columns.)

Pivotal Drug tolerance Test at 15x and 25x in Horses Blood Chemistry Values,

Table II

Blood Chemistry Test      Horse             Pretreat (Avg.      Value at Day
and Normal Values(1,2,3)  I.D     Dosage    of 2 samples)   1        2        3        4        5
                                                                                                 
Alkaline phosphatase           A      15 mg/lb        375         432(H)    417(H)     437(H)    432(H)    388      
(AP) (iu/l)                    B      15 mg/lb        256         268       289        271       295       257      
(Normal Value 143-395)         C      25 mg/lb        181         226       318        317       324       573(H)   
                               D      25 mg/lb        396(H)      416(H)    374        335       267       263      
                                                                                                         
Serum Glutamate-               A      15 mg/lb        478*        523       484        502       446       392      
Oxaloacetate                   B      15 mg/lb        408*        434       450        395       419       356      
Transaminase                                                                                             
(SGOT) (iu/l)                  C      25 mg/lb        476*        1073(H)   3985(H)    4528(H)   6704(H)   3096(H)  
(Normal Value 226-366)         D      25 mg/lb        379*        393       391        335       284       297      
                                                                                                         
Lactate Dehydrogenase          A      15 mg/lb        367         337       319        307       367       288      
(LDH) (iu/l)                   B      15 mg/lb        365         335       338        365       407       323      
(Normal Value 162-412)         C      25 mg/lb        342         618(H)    1796(H)    2671(H)   1356(H)   1988(H)  
                               D      25 mg/lb        373         484**     426**      317       294       307      
                                                                                                         
Serum Glutamate-               A      15 mg/lb        15          17        16         16        25        21       
Pyruvate Transaminase          B      15 mg/lb        9           14        15         13        25        22       
(SGPT) (iu/l)                  C      25 mg/lb        10          41(H)     64(H)      136(H)    94(H)     122(H)   
(Normal Value 3-25)            D      25 mg/lb        7           18        15         11        10        9        
                                                                                                              
Gamma-Glutamyl-                A      15 mg/lb        18          17        17         18        17        16       
transaminase                   B      15 mg/lb        26          25        28         25        26        24       
(GGT) (iu/l)                   C      25 mg/lb        18          28        41         55(H)     60(H)     40       
(Normal Value 4-44)            D      25 mg/lb        20          18        19         18        14        16       
                                                                                                              
Amylase-Serum                  A      15 mg/lb        146         122       107        58        78        44       
(iu/l)                         B      15 mg/lb        94          68        18(L)      48        48        48       
(Normal Value 40-150)          C      25 mg/lb        60          90        65         59        51        129      
                               D      25 mg/lb        68          78        50         41        36(L)     30(L)    
                                                                                                              
Blood Urea Nitrogen            A      15 mg.lb        28(H)       24        23         18        24        33(H)    
(BUN( (mg/dl)                  B      15 mg/lb        21          18        14         19        31(H)     36(H)    
(Normal Value 10-24)           C      25 mg/lb        21          16        16         11        11        23       
                               D      25 mg/lb        20          19        23         25(H)     22        17       
  
(H)   Above pretreatment baseline values and published normal values.
(L)   Below pretreatment baseline values and published normal values.
      However, Amylase levels are quite variable and low values are
      not considered to be clinically significant in the horse.
(1)   Clinical Biochemistry of Domestic Animals, 4th ed.,
      1989, J.J. Kaneko
(2)   Veterinary Laboratory Medicine - Clinical Pathology,
      2nd ed., 1986, J.R. Duncan, K.W. Prasse
(3)   Current Therapy in Equine Medicine, 2nd ed.,
      1987, N.E. Robinson

Results indicate that horse A, one of the animals receiving the 15 mg/lb dosage, developed severe laminitis between days 4 and 5. No other drug related lesions, abnormal laboratory results, or gross and histologic post mortem changes were noted in the 15 mg/lb group. In the 25 mg/lb group, horse C showed severe toxic signs characterized by depression, inappetence, icterus and abdominal swelling by day 3 and was euthanatized in moribund condition for necropsy on day 5. These findings were consistent with the clinical blood chemistry results. The table above shows that horse C, receiving the 25x overdose (25 mg/lb), had increased AP, LDH, SGOT, SGPT and GGT over the pre-treatment values and was positive for fecal occult blood on one sampling day. Horse D, that received the 25 mg/lb dose, showed some depression and inappetence by the end of the dosage period but did not show any meaningful changes in the blood chemistry values. In three(3) of these blood chemistry parameters, we observed that some pre-treatment values were outside of normal value limits (higher than normal for AP, SGOT and BUN). In all animals used, the Study Director clinically determined the horses to be healthy, normal animals meeting study protocol criteria and acceptable for use in this trial. Although the BUN readings for horses A and B (15 mg/lb dosage) were slightly elevated at day 4 and 5, no elevation was noted in the group receiving the 25 mg/lb dosage at day 4 and 5. Therefore these findings were not considered to be drug related. The hematology results showed minor changes in the horses receiving 25 mg/lb dose. Horse C showed elevated hemoglobin, hematocrit and lymphocyte values. The urinalysis of horse C showed the appearance of protein and blood.

The gross and histopathologic report revealed toxic manifestations only in one horse of the 25x group that exhibited severe toxic signs. This was characterized as toxic hepatitis, toxic nephritis, and adrenal necrosis and hemorrhage. No evidence of lesions attributed to treatment with ketoprofen was demonstrated in the two horses receiving the 15x dosage or the other horse of the 25x dosage group. Due to the limited number of horses (2 at each dosage level), no statistical analysis was performed.

Conclusions based on the results of the study revealed that at 15 fold overdose (15 mg/lb/day) for 5 days, one of two horses developed severe laminitis but no gross lesions or histologic changes were observed. The toxic effects observed in the horses given the 25 fold overdosage included inappetence, depression, icterus, abdominal swelling and post-mortem findings of toxic nephritis, hepatitis, and hemorrhagic necrosis of the adrenals.

 

VI. HUMAN SAFETY

Data on human food safety, pertaining to consumption of drug residues in food, were not required for approval of this NADA. The drug is approved only for use in horses that are not to be used for food and is to be labeled: Warning: not for use in horses intended for food.

Human safety relative to possession, handling, and administration: no special caution statement needed.

 

VII. AGENCY CONCLUSIONS

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and Section 514.111 of the implementing regulations. It demonstrates that Ketofen (ketoprofen), when used under its labeled conditions of use, is safe and effective.

For the safe and effective use of Ketofen (ketoprofen), it is necessary to provide a differential diagnosis of the pathology causing the clinical condition which only a trained professional can accomplish. Accordingly, we have classified Ketofen (ketoprofen) as a prescription product.

 

VIII. LABELING

  1. Ketofen(TM) 50mL Bottle Label
  2. Ketofen(TM) 100mL Bottle Label
  3. Ketofen(TM) 50mL Package Label
  4. Ketofen(TM) 100mL Package Label
  5. Ketofen(TM) Package Insert
  6. Ketofen(TM) Shipping Labels

Copies of these labels may be obtained by writing to the:

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855