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Veterinary Drugs

 
Product and
NADA/ANADA Number
Trade Name
Ingredients
butorphanol
141-047
Torbugesic-SA (butorphanol) Veterinary Injection
butorphanol
Butorphanol tartrate
200-239
Delorex®
Butorphanol tartrate

                                                                   
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Summary of 
FDA Information:

Approval Date: July 5, 1994 Freedom of
Information Summary NADA 141-047 I. GENERAL INFORMATION: NADA 141-047 Sponsor: Fort Dodge Laboratories 800 5th Street N.W. Fort Dodge, IA 50501-0518 Generic Name: butorphanol Trade Name: TORBUGESIC-SA (butorphanol) Veterinary Injection Marketing Status: Rx II. INDICATIONS FOR USE TORBUGESIC-SA (butorphanol tartrate, USP) is indicated for
the relief of
pain in cats caused by major or
minor trauma. or
pain associated with surgical procedures. III. DOSAGE The recommended dosage in cats is 0.4 mg of
butorphanol. per kilogram body weight (0.2 mg/lb) given by subcutaneous injection.
This is equivalent to 1.0 mL of
Torbugesic-SA (2 mg/mL) per 10 lbs body weight. Pre-clinical model studies and
clinical field trials in cats demonstrated that the
analgesic effects of
butorphanol persist in the
majority of
responding cats for
approximately 3 to 6 hours following subcutaneous injection. In the clinical field trials. the average onset of
action was
approximately 20 minutes following subcutaneous injection.
The butorphanol dosage may be repeated up to 4 times per day for
up to 2 days. IV. EFFECTIVENESS: A. Dose - Response Study In Cats Title: Subcutaneous Dose-Response of
Butorphanol for
Somatic and
Visceral Analgesia in the
Cat. Investigator: Donald C. Sawyer, DVM, PhD Michigan State University East Lansing, Michigan 48824 General Design of
the Investigation The purpose of
the study
was to evaluate the analgesic effects of
butorphanol in the
cat. Test animals included 8 healthy female domestic cats, approved for
use in these studies by the Michigan State University All University Committee on Animal Facilities and
Care.
The cats were
trained for
the experimental procedures and
housed in individual cages in a room without other animals. To induce somatic responses, electrodes were
secured to either shaved forelimb with self-adhering wrap. For stimulation of
visceral receptors, a 12F Foley catheter with a 42 mL balloon incorporated, was
inserted approximately 7 cm into
the colon.
The levels of
somatic and
visceral stimulation to elicit a minimum response were
determined during training sessions for
each individual cat. For somatic responses, mild electrical currents in increments of
0.05 milliamps were
applied to the electrode until at least 2 of
the following were
observed; a blink, movement of
the leg, or
flinch. To ensure that the
electrode stimulus was
at a low level, it was
periodically tested on the investigator's finger.
The feeling was
described as a tingling sensation. For visceral responses, the
balloon in the
colon was
inflated with air in 3 mL increments until the cat strained as if preparing to defecate, and

was usually accompanied by panting or
heavy breathing.
The animals in the
study
served as their own controls and
control baseline readings were
established in each cat during a 15 to 20 minute control period prior to every experiment during which
several subthreshold inflations of
the balloon were
given, randomly interspersed with threshold inflations in a 5:1 ratio. Since the sights and
sounds and
movements were
the same whether pain was
elicited or
not, the
cat could not learn to anticipate a painful stimulus. If, during the control period, an uncharacteristic amount of
air was
required to elicit a response, the
experiment would not be continued.
There was
negligible drift in baseline values during the entire experimental period.
The procedure was
blinded by virtue of
the fact that the
person inflating was
different from
the person observing and
recording the response. Dosage form of
butorphanol used in the
study
was a 2 mg/mL injectable solution prepared by the investigator by dilution (with sterile saline) of
the 10 mg/mL butorphanol preparation supplied.
Thus the dosage form used was
identical in concentration to that proposed to be marketed. Dosages and
routes of
administration of
butorphanol were
0.2, 0.4, and

0.8 mg/kg subcutaneously. Test duration. Ten minutes post injection, the
electrode testing began with a low level, 1 second stimulus. If the cat's response was
positive, the
testing ended for
that interval but was
then repeated sequentially at 10 minute intervals. If the cat's response was
negative, the
electrical stimulus was
increased by 0.05 milliamps until a positive response was
seen or
the stimulus reached 0.27 milliamps as the upper limit. If the response to balloon inflation was
positive, the
balloon was
deflated and
the testing was
terminated for
that interval. If there was
a negative response, the
balloon was
deflated and
reinflated with an additional 3 mL of
air.
This procedure was
repeated until a positive response was
observed or
until a maximum of
42 mL of
air was
injected into
the balloon. Other pertinent parameters measured were
heart rate and
respiratory rate determined before drug administration and
at the
time of
mean duration of
effect post treatment. Results Visceral Pain- Average duration of
analgesia as well as pre and
post treatment heart rates and
respiratory rates in cats treated with various dosages of
butorphanol subcutaneously are listed in the
following table. Ed. note: The following table has 7 columns. -------------------------------------------------------------------------------- Duration of
Heart Rate Respiratory Analgesia Rate ___________ ______________ ______________ Drug/Route Dosage Min + Sem Pre Rx Post Rx Pre Rx Post Rx mg/kg -------------------------------------------------------------------------------- Butorphanol/SQ 0.20 159 + 56 173 167 50 57 0.40 298 + 45 149 162 55 53 0.80 346 + 13 164 173 60 55 -------------------------------------------------------------------------------- Subcutaneous injection of
butorphanol in cats resulted in dosage dependent analgesic effects. In the visceral pain model subcutaneous dosages of
0.4 0.8 mg/kg were
required to achieve analgesia as illustrated in the
following figure: Somatic Pain- Increased threshold responses were
not produced by butorphanol at any doses tested in this somatic pain model. Statistical Analysis For purposes of
describing the dose response relationships for
butorphanol in the
visceral pain model the data were
expressed as average change across time (MEAN RESPONSE), duration of
measurable change (DURATION), and

area under
the curve (duration X response). Each of
these parameters was
subjected to ANOVA with dosage as grouping variables, at the
0.05 level of
significance.
The results, showing that subcutaneous dosage of
0.4 mg butorphanol/kg body weight shows analgesia in cats that is indistinguishable statistically from
that produced by 0.8 mg/kg is summarized in the
following tables. SUBCUTANEOUS DOSE-RESPONSE SUMMARY STATISTICS (ANOVA) -------------------------------------------------------------------------------- Parameter Dosage n Mean* -------------------------------------------------------------------------------- Mean Response SQ 0.2 mg/kg 8 5.1(a) (delta mL air) SQ 0.4 mg/kg 8 9.4(b) SQ 0.8 mg/kg 8 11.3(b) Duration SQ 0.2 mg/kg 8 191.3(a) (mean, minutes) SQ 0.4 mg/kg 8 300.O(a,b) SQ 0.8 mg/kg 8 345.0(b) Area Under SQ 0.2 mg/kg 8 1633.1(a) Curve SQ 0.4 mg/kg 8 3304.7(b) (Duration X SQ 0.8 mg/kg 8 4184.1(b) Response) -------------------------------------------------------------------------------- *Means that share a common superscript are not significantly different (pthis study
indicate that an analgesic effect of
butorphanol for
visceral pain in the
cat is obtained by subcutaneous injection of
0.4 mg/kg.
The drug had no effect on somatic pain in this study
. Adverse reactions No discomfort was
observed following butorphanol injection, but mydriasis was
noted at all doses. B. Dose Confirmation Study Title: Butorphanol Dose Confirmation Study in Cats. Investigator: Marc R. Raffe, DVM, MS Professor of
Comparative Anesthesiology College of
Veterinary Medicine University of
Minnesota St. Paul, MN. General Design of
the Investigation A dose confirmation study
was conducted to confirm the results of
the dose determination study
which indicated that 0.4 mg/kg was
an effective dose of
butorphanol in the
cat. In this experimental study
, 12 cats were
given 0 (placebo) and
0.4 mg butorphanol per kg body weight by subcutaneous injection.
The study
was conducted using a cross-over design in which
drug treatments were
randomly assigned, balanced among treatment, gender and
sequence.
The study
was conducted on a double blind basis in that the
investigator and
observer were
unaware of
the drug or
dosage given.
The randomized sequence of
treatment was
repeated after a 14 day washout period by crossing over and
administering the drug treatment or
placebo treatment.
The purpose of
the study
was to determine the analgesic activity of
butorphanol given subcutaneously at the
dosage of
0.4 mg/kg in cats, using a somatic pain model. Test animals were
12 healthy domestic cats (6 males and
6 females) ranging in age from
8 to 13 months and
weighing between 2.27 and
4.24 kg, each of
which
had a periosteal electrode surgically implanted on the wing of
the ileum; the electrodes were
connected to a variable voltage generator. To induce pain responses, five second challenges of
increasing voltage were
applied to the electrodes at 15 second intervals until avoidance behavior, usually a slight movement or
twitch, was
noted.
The voltage, amperage, and

time (in seconds) required to elicit the response were
recorded as measures of
pain threshold. Each experiment consisted of
four baseline measurements of
pain threshold at 15 minute intervals prior to injection of
test material at the
designated dosage. Following injection, measurements of
pain threshold were
made at 15 minute intervals for
a total of
360 minutes. Control treatment consisted of
a placebo injection followed by evaluation of
pain threshold as above. Diagnosis of
pain was
based on overt avoidance behavior, usually a slight movement or
twitch, that occurred when
threshold voltage was
reached. Dosage form was
an injectable solution of
butorphanol at a concentration of
2 mg/mL, identical to that to be marketed. Placebo injection consisted of
vehicle only, without active drug. Dosages, routes of
administration and
duration were
0 (placebo control) or
0.4 mg/kg subcutaneously followed by observation periods of
six hours. Pertinent parameters measured at each observation time (every 15 minutes) included the following: volts required to elicit a response amperage required to elicit a response time required to elicit the response heart rate (recorded every 30 minutes) respiratory rate mental awareness (subjective assessment on a scale of
-2 = very depressed, to +2 = very agitated) Results Butorphanol at a dosage of
0.4 mg/kg body weight had the effect of
increasing pain threshold (both volts and
amperage) required to elicit a response to the electrode simulation.
The effect of
butorphanol on the pain threshold using the somatic pain model is illustrated in the
following figures.
Threshold voltages post-treatment were
significantly higher for
butorphanol treated cats as compared to placebo at 30 minutes and
from 90 minutes through 135 minutes by the univariate ANCOVA (P<0.05, two-sided test).
The repeated measures ANCOVAs also found a statistically significant effect of
treatment (higher voltages for
butorphanol) in the
first and
second one-hour periods. Using one sided tests, results are also significant (P<0.05) at 15 minutes, 45 minutes, 75 minutes, 150 minutes, and

315 minutes. Amperages post-treatment were
significantly (P<0.05) higher for
butorphanol as compared to placebo at 30 minutes through 60 minutes and
from 90 minutes through 150 minutes using the univariate ANCOVA test. Amperages were
also found to be significantly higher in the
first three one-hour periods by the repeated measures ANCOVA analysis. Using one-sided tests, results are also significant (P<0.05) at 15 minutes, 75 minutes, 210 minutes, 240 minutes, and

270 minutes. Although there were
some additional statistically significant findings for
the other parameters in this study
(mental awareness score, reaction time, heart rate, respiratory rate), these occurred much less often (i.e., sporadically), were
observed later in the
study
(relative to treatment administration), and

are not believed to be related to butorphanol. Statistical analysis The study
data were
analyzed using a univariate and
repeated analysis of
covariance (ANCOVA) for
cross-over designs; the terms included in the
model were
replicate, sex, treatment, period, sequence, cat (within replicate, sex and
sequence combination), time, all interactions of
the former terms with time, and

the baseline taken just prior to treatment as a covariate. Because the plots of
mean values indicated differences between treatments in early time points (one to three hours posttreatment), and

because of
the biological plausibility that efficacy would be most apparent shortly after drug administration, the
analysis was
segmented into
repeated measures ANCOVA for
each one hour period (two hours for
heart rate). Although this approach has the
disadvantage of
slightly increasing the overall false-positive rate. it allows one to detect treatment differences that would be diluted (at later times after drug administration, when
blood levels of
butorphanol decline) by a single overall ANCOVA. Significant treatment effects were
denoted by a (conservative two sided test) P value less than 0.05. Plots of
the pertinent parameters as functions of
time and
drug dose were
also constructed. Conclusions drawn from
the study
The results of
this study
indicate that a butorphanol dosage of
0.4 mg/kg given subcutaneously in cats is effective in producing analgesia to somatic pain.
The statistical results (Univariate and
repeated measures analyses) indicate that butorphanol significantly (P<0.05, two sided test) increases the threshold Voltage at several time points significantly so in the
first one hour after injection and
marginally (P=0.0575) in the
second hour. Amperages were
significantly increased at an even greater number of
points, with significant (P<0.05, two sided test) effects seen in the
first two hours post-treatment and
marginally (P=0.0734)in the third hour.
The only adverse reaction-reported was
pain on injection.
The following table shows the incidence of
pain with injection of
vehicle placebo and
butorphanol. Treatment No. of
Cats No. of
Cats Eliciting Pain without Pain -------------------------------------------------------------------------------- Vehicle Placebo 11 1 Butorphanol 6 6 -------------------------------------------------------------------------------- Four cats developed lead wire infections during the study
which required treatment with antibiotics (amoxicillin or
amoxicillin/clavulanate). C. Controlled Field Investigations of
Butorphanol ln Cats Title: Clinical Evaluation of
Butorphanol Tartrate as an Analgesic in Cats (Blinded Study) Investigators: Randal Bradshaw, DVM Mark Lowe, DVM Waterlick Plaza Rte. 1, Box 461G Lynchburg, VA 24502 Homosassa, FL 32646 Steve Bruck, DVM Carol Moon, DVM 4240 Slate Hill Road 9758 Gayton Road Marcellus, NY 13108 Richmond, VA 23233 Wayne Carter, DVM Albert Smith, DVM Georgetown Road 3050 Berkmar Drive Charlottesville, VA 22901 Charlottesville, VA 22901 Dale Eckert, DVM Robert Stein, DVM Lexington Road, P.O. Box 108 2217 Kensington Avenue Versailles, KY 40383 Snyder, NY 14226 Nancy Freeborough, DVM Charles H. Wood Jr., DVM 120 Julian Plaza Mclntire Plaza Syracuse, NY 13210 Charlottesville, VA 22901 John Gruss, DVM Jesse Webster, DVM Box 67 1309 E. Washington Ave. Earlysville, VA 22936 Vinton, VA 24179 Denise Van Cleef, DVM 1910 N. Wickham Rd. Melbourne, FL 32935 General Design of
the Investigation The purpose of
the study
was to evaluate the effectiveness and
side effect profile of
butorphanol given at a dosage of
0.4 mg/kg (0.2 mg/lb) by subcutaneous injection for
alleviating pain in cats, under
conditions of
veterinary practice. Test animals were
cats of
any age, weight, or
breed which
were
diagnosed by the veterinarian as experiencing pain.
The pain could be the result of
major or
minor trauma, or
originate from
painful surgical procedures such as declaws and
castrations.
The study
was controlled by use of
a placebo (sterile buffered saline) injection to provide a negative control group of
cats with pain similar to the population receiving the active drug, butorphanol.
The study
was blinded by providing the investigators with coded vials containing either butorphanol or
a placebo solution.
The diagnosis of
pain in the
cats was
of necessity based on the behavioral changes observed in the
animals by the investigators.
These behavioral changes may be manifest by aggressive behavior or
by withdrawal or
depression, and

may be expressed by obscure signs such as loss of
appetite and
unwillingness to urinate or
by more obvious signs such as biting, licking or
scratching at a painful lesion, lameness, or
aggressive behavior when
an injured area is manipulated. Accordingly, the
pain intensity was
standardized by use of
a scoring system on a 0 - 4 (normal to severe) basis on individual signs of
pain including vocalizing, panting, aggression, withdrawal, and

response to manipulation. Additionally, an overall severity of
pain score was
given to each patient. Finally, the
investigators were
asked to describe in words any other signs that were
consistent with pain.
The dosage form of
butorphanol was
a 2 mg/mL solution in 10 mL vials, identical to the dosage form to be marketed.
The control placebo solution was
provided in identical vials.
The dosage of
butorphanol was
the proposed recommended dosage of
0.2 mg/lb body weight given by the proposed route of
administration, subcutaneous injection.
Thus all cats were
given 0.1 mL of
active drug or
placebo per pound of
body weight.
The protocol allowed for
the dosage to be repeated as needed but no sooner than six hours after the previous dosage and
for
not longer than seven days (the labeling indicates that butorphanol can be safety repeated up to 4 times per day for
up to 2 days because the subacute safety study
was conducted at 4 times per day for
6 days which
is 3 times the duration of
use). Pertinent parameters measured included the clinical signs of
pain as well as the clinical scores as described above, before treatment and
after treatment. Heart rate was
also determined before and
after treatment.
The investigators were
also asked to state how soon after treatment they felt analgesia had become evident and
what the duration of
analgesic activity was
. Finally, investigators were
asked to report on each case whether or
not they observed an analgesic effect (yes or
no) and
to give an overall evaluation on the following basis: EXCELLENT Injection produced a marked analgesic effect making the subject comfortable and
relaxed, improved subject's attitude, and

promoted a smoother convalescence. GOOD Injection produced a noticeable analgesic effect, making the subject somewhat more comfortable and
relaxed. FAIR Injection produced only a slight analgesic effect. POOR No noticeable analgesic effect. Results Case reports on a total of
64 cats were
received of
which
33 were
treated with butorphanol and
31 with placebo (see Appendix I, pages 30-31 for
a description of
each butorphanol-treated case).
The following table shows the clinical conditions which
necessitated analgesic therapy and
the number of
cases treated with butorphanol and
placebo for
each condition: BUTORPHANOL PLACEBO (n=31) (n=33) -------------------------------------------------------------------------------- Declaw 13 10 Abscess/cellulitis 6 7 Musculoskeletal 4 8 Neuter/Spay 2 4 Trauma 2 2 Soft Tissue Injury 2 0 Miscellaneous 2 2 Clinical pain scores before and
after treatment for
all enrolled cases are summarized in the
following table [the values below represent the mean scores (0-4) from
those cats showing that particular pain parameter, i.e., not every cat showed aggression during the study
]: Ed. note: The following table has 5 columns. SUMMARY OF CLINICAL PAIN SCORES IN CATS -------------------------------------------------------------------------------- Mean pain score (0 - 4) for
parameter indicated PLACEBO BUTORPHANOL ________________ ________________ Pain Parameter Pre Rx Post Rx Pre Rx Post Rx -------------------------------------------------------------------------------- Vocalizing 1.5 1.2 1.5 0.9 Panting 0.3 0.3 0.2 0.0 Aggression 1.6 1.3 1.4 0.7 Withdrawal 2.4 1.8 2.4 1.0 Pain on manipulation 3.3 2.4 3.2 1.7 ___ ___ ___ ___ Total score* 9.1 7.0 8.7 4.3 -------------------------------------------------------------------------------- *Average of
sum of
individual pain scores The mean overall pain score in the
placebo group was
2.8 (scale 0-4) prior to treatment and
2.2 after treatment. For butorphanol, the
mean overall pain score was
2.7 prior to treatment and
1.5 after treatment. Signs of
pain other than those listed in the
table above (ex. non-weight bearing, not eating, reluctant to move) were
noted in 18 placebo and
20 butorphanol cats prior to treatment. Improvement in these signs of
pain was
noted in 5/18 (28%) placebo-treated cats and
in 16/20 (80%) butorphanol-treated cats. Other comments noted on the case reports from
those cats responding to the drug, although difficult to quantitate, indicated that butorphanol made the subjects more comfortable, shortened the convalescence period, and

made management easier, when
compared to placebo. Finally, the
overall analgesic effect of
the drugs was
rated as satisfactory ('excellent' or
'good')in 19/28 (68%) butorphanol-treated cats compared to 7/25 (28%) placebo-treated cats. (Note that these data came from
six out of
the thirteen investigators who enrolled cases in both treatment groups, see statistical analysis.) -------------------------------------------------------------------------------- PROPORTION OF CATS EVALUATED AS EXCELLENT OR GOOD -------------------------------------------------------------------------------- INVESTIGATOR BUTORPHANOL PLACEBO -------------------------------------------------------------------------------- Bradshaw 4/4 0/1 Bruck 5/5 0/5 Carter 2/5 1/5 Gruss 3/5 3/5 Smith 2/5 1/5 Wood 3/4 2/4 -------------------------------------------------------------------------------- The average duration of
the analgesic effect was
approximately 4 hours (range 15 minutes to 8 hours), with an average onset of
activity of
approximately 16 minutes after injection. Statistical analysis Statistical analysis was
performed on data from
the six investigators (Bradshaw, Bruck, Carter, Gruss, Smith, and

Wood) who had cases in both treatment groups (total of
28 cats treated with butorphanol and
25 treated with the placebo) so that a comparison of
the control and
treated groups could be made for
each investigator and
across investigators.
The data generated by the remaining seven investigators remains in the
data base for
determination of
clinical safety and
calculations of
the duration and
onset of
analgesia.
A procedure for
comparing proportions from
m independent samples as described by Fleiss (1981) was
used to test for
investigator effect [Fleiss, J.L. (1981) In: Statistical Methods for
Rates and
Proportions. 2nd ed. John Wiley & Sons, New York. pp 138-143].
This procedure was
applied both to the proportion of
cats showing an analgesic response (yes or
no) as well as proportion of
"excellent" or
"good" responses (satisfactory) vs. "fair" or
"poor" responses (unsatisfactory) between butorphanol and
placebo groups.
There was
no association (p> 0.05) between investigator and
the evaluation of
an analgesic effect (yes or
no) or
the overall evaluation of
the response of
the cats to butorphanol (excellent, good, fair, or
poor).
The determination of
the statistical significance in analgesia between placebo and
butorphanol treated patients was
performed using the zstatistic of
the difference of
two rates as described by Fleiss [Fleiss, J.L. (1981) In: Statistical Methods for
Rates and
Proportions. 2nd ed. John Wiley & Sons, New York. pp 100-111].
The difference in response between butorphanol and
placebo was
statistically significant (p<0.05) with regard to both analgesic effect (yes or
no) and
proportion of
'excellent" or
"good" responses (satisfactory) vs. "fair" or
"poor" responses (unsatisfactory). Ridit analysis was
used to take advantage of
the ordered nature of
the scoring of
analgesic response (excellent>good>fair>poor).
The statistical significance of
the difference between the mean ridit values for
the two treatments was
tested using the z-statistic and
found to be highly significant (p< 0.005). Conclusions Results of
this study
confirm clinically and
statistically that butorphanol given subcutaneously at a dosage of
0.4 mg/kg is an effective and
safe analgesic in the
cat, when
tested under
conditions of
veterinary practice. Approximately 68% of
treated cats can be expected to have a satisfactory analgesic response to the drug. Adverse Reactions The following table shows the adverse effects observed in this study
: -------------------------------------------------------------------------------- CLINICAL SIGN BUTORPHANOL PLACEBO -------------------------------------------------------------------------------- Pain on Injection 5/33 (15%) 4/31 (13%) Mydriasis 4/33 (12%) 0/31 (0%) Disorientation 2/33 (6%) 0/31 (0%) Sedation 1/33 (3%) 0/31 (0%) -------------------------------------------------------------------------------- D. Controlled Field Investigations of
Butorphanol In Cats This study
was an extension of
the study
described above, differing only in the
concentration of
butorphanol (4 mg/mL as opposed to 2 mg/mL previously used) Title: Clinical Evaluation of
Butorphanol Tartrate as an Analgesic in Cats (Blinded Study) Investigators: Randall Bradshaw, DVM John Gruss, DVM Waterlick Plaza Box 67 Lynchburg, VA 24502 Earlysville, VA 22936 Steven Bruck, DVM Mark Lowe, DVM 4240 Slate Hill Road Rte. 1, Box 46G Marcellus, NY 13108 Homosassa, FL 32646 Wayne Carter, DVM Robert F. Malsby, Jr., DVM Georgetown Road Midway Veterinary Clinic Charlottesville, VA 22901 Marietta, GA 30060 Richard T. Goldston, DVM Amy S. MacCallum, DVM 3295 62nd Ave N St. Petersburg, FL 33702

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