NADA 141-047 Sponsor: Fort Dodge Laboratories
800 5th Street N.W.
Fort Dodge, IA 50501-0518Generic Name: butorphanol Trade Name: Torbugesic-SA (butorphanol) Veterinary Injection Marketing Status: Prescription
II. INDICATIONS FOR USE
III. DOSAGETORBUGESIC-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.
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
B. Dose Confirmation Study
- 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.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:
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
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 (p<O.05)- Conclusions The results of this 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.
C. Controlled Field Investigations of Butorphanol ln Cats
- 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).
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:
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)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]:
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
Ed. note: The following table has 5 columns. SUMMARY OF CLINICAL PAIN SCORES IN CATSThe 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.
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 scoresSigns 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.)
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.
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
- 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%)
- 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- 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 4 mg/mL solution in 10 mL vials, more concentrated than the 2 mg/mL dosage form to be marketed. Supplies of the more concentrated solution were available and were used in this trial since all other aspects of the formulation were the same as proposed for market. 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 0.05 mL of active drug or placebo per pound of body weight.
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 83 cats were received from the seven investigators of which 40 received butorphanol and 43 received placebo. (see Appendix II, pages 32-33, 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 injection resulted in decreased vocalization, panting, aggression, withdrawal, pain on manipulation, and overall pain scores. These responses were numerically greater in the butorphanol treated cats than in placebo controls, as summarized in the following table.
BUTORPHANOL PLACEBO (n=40) (n=43)
Declaw 22 19 Abscess/cellulitis 2 5 Musculoskeletal 6 7 Neuter/Spay 1 3 Trauma 4 4 Soft Tissue Injury 1 2 Miscellaneous 4 3
Ed. note: The following table has 8 columns. BUTORPHANOL DOUBLE BLIND CLINICAL DATA SUMMARYHeart rate decreased an average of 19 and 13 beats per minute in the butorphanol and placebo groups, respectively, with wide variation in response between individuals.
NUMBER AVERAGE VALUE PARAMETER DRUG PRE POST % CHG PRE POST CHANGE
VOCALIZATION BUTORPHANOL 24 15 37.5 2.4 1.0 1.4 (0 - 4) PLACEBO 28 26 7.1 2.3 1.9 0.4 PANTING BUTORPHANOL 12 5 58.3 1.6 0.6 1.0 (0 - 4) PLACEBO 14 13 7.1 1.4 1.3 0.1 AGGRESSION BUTORPHANOL 26 11 57.7 2.2 0.7 1.5 (0 - 4) PLACEBO 21 20 4.8 2.5 2.4 0.1 WITHDRAWAL BUTORPHANOL 39 27 30.8 2.6 1.1 1.5 (0 - 4) PLACEBO 40 36 10.0 2.5 2.2 0.3 PAIN ON MANIP- BUTORPHANOL 40 33 17.5 2.9 1.3 1.6 ULATION (0 - 4) PLACEBO 43 38 11.6 3.0 2.5 0.5 OVERALL PAIN BUTORPHANOL 40 34 15.0 2.6 1.3 1.3 (0 - 4) PLACEBO 43 39 9.3 2.5 2.2 0.3
NUMBER in the above table refers to the number of cats displaying each pain parameter before and after treatment; AVERAGE VALUE refers to the average score of all cats displaying each pain parameter before and after treatment.In the butorphanol group, 79% of the cats reportedly showed analgesia (yes vs no) compared to 22% in the placebo group. Overall favorable clinical ratings (good or excellent) were given in (29/39) 74% of the butorphanol cases compared with (8/41) 20% of the placebo cases, broken down as shown below. (Note that these data came from five out of the seven investigators who enrolled 10 cases or more. Two of the investigators enrolled only one and two cases, respectively, and were not considered appropriate for inclusion in the statistical analysis. The data from these two investigators were included in the data base for evaluation of clinical safety and determination of the duration and onset of analgesia.)
The average duration of the analgesic effect was approximately 4 hours (range 1 to 7 hours), with an average onset of activity of approximately 16 minutes after injection.
PROPORTION OF CATS EVALUATED AS EXCELLENT OR GOOD
INVESTIGATOR BUTORPHANOL PLACEBO
Bradshaw 6/ 7 0/ 9 Bruck 10/10 0/10 Goldston 4/ 5 0/ 5 Gruss 6/10 5/10 Malsby 3/ 7 3/ 7
- Statistical analysis Statistical analysis was conducted on data generated by five of the seven investigators who reported on 10 cases or more (see table above). Among these investigators there appeared to be differences in efficiency of detecting analgesic response to butorphanol. The difference between treatment groups with regard to satisfactory response (excellent or good) was tested using Fisher's exact test. The treatment differences (in favor of butorphanol) were significant (p<0.01) for investigators Bradshaw, Bruck, and Goldston, but not for Gruss and Malsby.
The significance of the apparent differences between butorphanol and placebo for the changes (pretreatment - post treatment) for each of the response variables listed in the summary table above was tested by the non-parametric Mann Whitney U test at the nominal 0.05 level of significance. The analgesic responses were significantly (p< 0.05) greater in butorphanol-treated cats than in placebo controls with regard to all individual clinical score parameters.
The significance of the difference between dosage groups with regard to change in heart rate was tested by 2-factor analysis of variance with treatment and investigator as grouping variables. The difference in heart rate reduction between butorphanol and placebo was not significantly different (p> 0.05) nor was there significant investigator-treatment interaction.
- 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 74% 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 6/40 (15%) 12/43 (28%) Mydriasis 2/40 (5%) 0/43 (0%) Disorientation 1/40 (2.5%) 0/43 (0%)
E. Clinical Evaluation of Butorphanol as an Analgesic in Cats
- Objectives This was a preliminary, open field investigation, the purpose of which was to determine whether or not butorphanol injection would provide clinically detectable analgesia in the cat, what the clinical signs of pain in cats would be, and whether subcutaneous dosage of 0.1 mg/lb (0.2 mg/kg) would be as effective as 0.2 mg/lb (0.4 mg/kg) under conditions of veterinary practice. These studies were conducted partly to refine the dosage to be recommended for larger scale clinical testing.
- Investigators:
Stanley L. Blazejewski, DVM Michael Christopher, DVM Route #1 2081 Marietta Highway Chadd's Ford, PA 19317 Canton, GA 30114 Steve Bruck, DVM Mark Lowe, DVM 4240 Slate Hill Road Rte. 1, Box 461G Marcellus, NY 13108 Homosassa, FL 32646 Robert Malsby, Jr., DVM Albert Smith, DVM 3007 Canton Road, N.E. 3050 Berkmar Drive Marietta, GA 30060 Charlottesville, VA 22901 Dale Eckert, DVM Cecil E. Moore, DVM Lexington Road, P.O. Box 108 8131 Old Kings Road, South Versailles, KY 40383 Jacksonville, FL 32217 Nancy Freeborough, DVM Charles H. Wood Jr, DVM 120 Julian Plaza Mclntire Plaza Syracuse, NY 13210 Charlottesville, VA 22901 Harvey A. Phillips, DVM Jesse Webster, DVM P.O. Box 205 1309 E. Washington Ave. Ashland, VA 23005 Vinton, VA 24179 Richard T. Goldston, DVM James K. Hicks, DVM 3295 62nd Avenue, North 3507 U.S. 19St. Petersburg, FL 33702 Spring Hill, FL 33526- General Design of the Investigation: . Cats entering the study could be of any age, weight, sex, or breed that presented with pain, which could be the result of trauma or originate from painful surgical procedures.
Prior to administration of butorphanol, investigators were asked to list those clinical signs suggestive of pain. After treatment investigators were asked to record their observations that indicated the cat Was in less pain. Investigators then evaluated the analgesic effect as "excellent", "good", "fair", or "poor" as defined in the protocol (refer to pages 13 and 18 of the FOI Summary for definitions). Investigators also noted the number of minutes following injection that analgesia was first noted and the approximate duration of analgesia.
Test drug was supplied as a 0.5 mg/mL formulation of butorphanol in 10 mL vials. Dosing schedules were provided to each investigator for assignment of either 0.1 or 0.2 mg/lb dosages to each case. Cats were dosed as needed, but no sooner than every 6 hours.
- Results Case reports on a total of 58 cats were received of which 36 were given 0.1 mg/lb, 21 were given 0.2 mg/lb. One cat was inadvertently given 0.05 mg/lb and was excluded from the study.
The following table shows the clinical conditions which necessitated analgesic therapy and the number of cases that received each dose of butorphanol with each condition:
The most frequent signs of pain noted by the investigators were vocalizing, withdrawal, aggression, and panting, which subsided following butorphanol treatment at either dosage. Mean heart rate declined after treatment in both treatment groups. The numbers of cats displaying each parameter before and after treatment and the average heart rates before and after treatment are summarized in the following table.
0.1 mg/lb 0.2 mg/lb (n=36) (n=21)
Declaw 11 6 Abscess/cellulitis 6 3 Musculoskeletal 9 5 Neuter/Spay 2 2 Trauma 3 2 Soft Tissue Injury 3 1 Miscellaneous 2 2
Ed. note: The following table has 7 columns. Summary of Study on Butorphanol Analgesia in CatsThe onset of analgesia was similar in both dosage groups, averaging approximately 17 minutes in the 0.1 mg/lb group and 24 minutes in the 0.2 mg/lb group. The duration of analgesia was approximately 5 hours (range 3 to 8 hours) in the 0.1 mg/lb group and 4 hours (range 1.5 to 6.5 hours) in the 0.2 mg/lb group. The following observations which the investigators felt were indicative of pain relief in the cats following butorphanol treatment were noted:
0.1 mg/lb 0.2 mg/lb __________________________ ____________________________ percent percent pre Rx post Rx change pre Rx post Rx change
Vocalizing 23 7 70 16 3 81 Withdrawal 27 5 81 16 4 75 Aggression 9 3 66 10 1 75 Panting 5 0 100 5 1 80 Heart Rate (mean) 162 153 5.5 190 182 4.2
OBSERVATION 0.1 mg/lb 0.2 mg/lbThe investigators rated the overall analgesic effect as 'excellent' or "good" in 78% (28/36) of the cats given butorphanol at 0.1 mg/lb, and in 95% (20/21) of the cats in the 0.2 mg/lb dosage group.
More comfortable 31/36 (86%) 20/21 (95%) Smoother convalescence 27/36 (75%) 18/21 (86%) Shorter recovery period 14/36 (39%) 9/21 (43%) Management easier 27/36 (75%) 16/21 (76%) Faster return to normal attitude 23/36 (63%) 17/21 (81%)Due to the limited number of cases and the paucity of numerical criteria for evaluation, statistical analysis was not performed.
Adverse effects noted consisted of pain on injection, dilation of pupils (mydriasis), disorientation, sedation, and swallowing and licking (see following table):
CLINICAL SIGN 0.10 mg/lb 0.20 mg/lb
Pain on Injection 6/36 (17%) 1/21 (5%) Mydriasis 6/36 (17%) 2/21 (10%) Disorientation 3/36 (8%) 2/21 (10%) Sedation 1/36 (8%) 0/21 Swallowing/Licking 1/36 (3%) 1/21 (5%)- Conclusions Results of this study indicated that: 1) butorphanol is an effective analgesic in the cat, 2) analgesia can be detected by careful observation of behavioral signs, and 3) that the 0.2 mg/lb subcutaneous dosage gives a satisfactory analgesic response which is more dependable than the lower dosage tested. On the basis of these study results it was decided that in future studies the list of signs of pain should be expanded, that each sign should be given a numerical score in order to provide data for statistical analysis, and that 0.2 mg/lb (0.4 mg/kg) is the preferred clinical dosage.
V. ANIMAL SAFETY
A. Subacute Toxicity Study of Butorphanol in Cats
B. Range Finding Safety Study of Butorphanol in Cats
- Title: Twenty-One Day Subcutaneous Safety Evaluation of Butorphanol in Cats
- Investigator:
J.A. Botta, Jr., DVM, PhD
T.P.S. Inc.
10424 Middle Mt. Vernon Road
Mt. Vernon, IN 47620- General Design of the Investigation The purpose of the study was to evaluate the effects of butorphanol injected subcutaneously to cats at levels of 1, 3, or 5 times the anticipated clinical dosage of 0.4 mg/kg.
Test animals were 24 young adult domestic shorthair cats of random
source, of both sexes (8 males, 16 females), weighing 1.7 to 4.5 kg at initiation. The cats were individually housed in metal cages in an >environmentally controlled facility, and provided with Purina cat chow and fresh water ad libitum. The cats were randomly sorted by a computer generated (RANAN) randomization program into 4 dosage groups of 6 cats per group, each group represented by 2 males and 4 females.The dosage form used was an injectable formulation containing 2 mg butorphanol per mL, identical to the formulation to be marketed, supplied in glass vials containing 10 mL. The control substance was sterile saline for injection, USP.
Dosages, routes, and test duration were 0 (saline placebo given in a volume equal to the highest dosage of butorphanol), 0.4, 1.2, and 2.0 mg butorphanol per kg body weight, given by subcutaneous injection 4 times daily during the first 6 days of the investigation (which is 3 times the recommended duration of use of 2 days), then once daily for 15 additional days, for a total of 21 days of dosing. These dosages represent O, 1, 3, and 5 times the anticipated clinical subcutaneous dosage of 0.4 mg/kg.
Pertinent parameters measured included clinical observations twice daily and during the first hour after dosing, monitoring of body weights and food consumption, physical examination including ophthalmic examination weekly, and complete blood counts and serum chemistry profiles conducted before the experiment and weekly, thereafter. Cats were euthanized and necropsied 24 - 36 hours after the last injection, for complete gross necropsy, determination of organ weights, and histopathology on major tissues and organ systems.
- Results Clinically, the only sign of drug induced toxicity was a reaction to the repeated injections by the cats as if they caused a burning or stinging sensation for a few seconds after each injection. Signs of respiratory infections (congestion and Conjunctivitis) occurred during the experimental period in controls as well as treated groups (3 cats in the control group, 4 in the 1X group, 2 in the 3X group and 2 in the 5X group). Likewise, body weight fluctuated in all treatment groups, but drug or dosage related trends were not detected, as shown in the following table:
MEAN BODY WEIGHT (grams) __________________________________ GROUP WEEK 0 WEEK 1 WEEK 2 WEEK 3Hematology and clinical chemistry results did not reveal any consistent or distinct effects associated with butorphanol treatment. At the end of week 1, the red blood cell count (6.11 X 106), hematocrit (29.2%) and hemoglobin concentration (8 g/dl) were significantly lower in the high dose females compared to the controls (8.05 X 10(6), 36.3% and 10.4 g/dl, respectively). Similar changes were not seen in the male cats or in the high dose females for the remainder of the study. A decrease in the mean total protein value was seen in the mid dose females at week 1 compared to the controls (7.2 g/dl compared to 8.6 g/dl).
0 2504 2559 2602 2563 1X 2212 2166 2349 2325 3X 2270 2309 2420 2308 5X 2446 2292 2350 2295At necropsy, there were no apparent treatment or dosage related gross tissue changes other than lesions typical of those expected in random source cats, including roundworms, tapeworms, and ocular and nasal discharge. On Histopathology, focal renal tubular dilation was noted in the high dosage group in one of two males and two of four females but not in other dosage or control groups. Histopathologic changes indicative of minimal to slight irritation were noted at the injection sites in 3 of 6 cats in the low dose group, 4 of 6 cats in the middle dose group and 6 of 6 cats in the high dose group.
- Conclusions It was thus demonstrated that an ample margin of safety is associated with butorphanol when used as directed at a dosage of 0.4 mg/kg subcutaneously in cats. The results of this study indicate that the only adverse clinical effect of subcutaneously administered butorphanol in cats at a dose of 0.4 mg/kg was pain with injection. Histopathologic changes indicative of minimal to slight irritation at the injection sites are seen at the 1X, 3X and 5X dosages, while focal renal tubule dilation is evident at 5 times the recommended dose.
Four young adult domestic shorthair cats, two males and two females. weighing between 2.1 and 2.9 kg at initiation, were given daily subcutaneous injections of butorphanol at a dosage of 2 mg/kg for one week, 4 mg/kg the following week, 8 mg/kg the following week, and 16 mg/kg the final week. A 2 mg/mL solution of butorphanol, identical to that to be marketed, was used for the 2 and 4 mg dosages, and a 10 mg/mL formulation was used for the 8 and 16 mg/kg dosages due to volume considerations. The cats were observed twice daily, during the first and last hour of the workday, and during the first hour after dosing each day for any signs of toxicity throughout the 28 day dosage period. Physical examinations were conducted pretest and. prior to necropsy. Blood samples were collected before treatment and weekly thereafter for evaluation of hematology parameters. Body weights were recorded pretest and weekly during the study. At the end of the dosing period complete serum chemistry determinations and gross postmortem examinations were conducted on all the cats. Group mean body weights were slightly depressed following four weeks of butorphanol treatment (see table below). This finding could be attributable to the drug or to the stress of frequent clinical procedures. Without a concurrent control group, no definitive conclusions could be made.
MEAN BODY WEIGHT (kg) _____________________ WEEK 0 2.6 WEEK 1 2.4 WEEK 2 2.4 WEEK 3 2.4 WEEK 4 2.3The only clinical signs of toxicity noted during the first three weeks of the experiment were signs of pain ,and resentment of the daily subcutaneous injections in all cats. When dosages were increased to 16 mg/kg during the final week of the experiment, however, all of the cats responded by displaying incoordination, salivation, or mild convulsions. most evident during the first hour after injection. All cats survived the study. At the time of the terminal physical examination, one cat walked with a crab-like side motion. This observation was believed to be due to tenderness in the flank area from the test material injections.Neither hematology nor serum chemistry evaluations revealed changes suggestive of any drug toxicity. The only changes noted in the hematology data were elevations of the mean corpuscular volume (MCV) at week 1 compared to week 0 (48.3 fl compared to 45 fl) and a decrease in the MCV in the females at necropsy compared to week 0 (45.5 fl versus 48 fl). These changes in the MCV were not associated with any changes in the packed cell volume. No abnormalities were noted in the serum chemistry parameters evaluated at the time of necropsy. At gross postmortem 'examination, the only remarkable lesion was a green, semisolid exudate in the right frontal sinus of one cat.
It was concluded that daily subcutaneous injection of butorphanol at a dosage of 2 mg/kg for one week, 4 mg/kg the following week, and 8 mg/kg the following week, (5 to 20 times the recommended dose of 0.4 mg/kg) is without toxic effects in cats other than irritation at the injection site. Dosages of 16 mg/kg/day (40 times the recommended dosage), are associated with side effects of incoordination, salivation, or mild convulsions, signs believed to represent the toxic clinical syndrome of butorphanol overdosage in the cat.
VI. HUMAN SAFETY
Data on human safety, pertaining to consumption of drug residues in food, were not required for approval of this NADA. The drug is to be labeled for use in cats, which are non-food animals. Human safety relative to possession, handling, and administration: no special caution statement needed.
Vll. AGENCY CONCLUSIONS
The data 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 Torbugesic(R)-SA (butorphanol) Veterinary Injection (2 mg/mL). when used under labeled conditions of use is safe and effective. The drug is restricted to use by or on the order of a licensed veterinarian because professional expertise and proper diagnosis are required to determine when an analgesic is required in the cat and because the drug is administered by subcutaneous injection.
Under Section 512(c)(2)(F)(ii) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b(c)(2)(F)(ii)), this approval for nonfood producing animals qualifies for three years of marketing exclusivity beginning on the date of approval because the application contains reports of new clinical or field investigations (other than bioequivalence studies) essential to the approval of the application and conducted or sponsored by the applicant.
VIII. LABELING (ATTACHED) A. Package Insert
B. 10 mL Vial Label
Copies of applicable labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855APPENDIX I Description of Cats Treated With Butorphanol (0.4 mg/kg) In Field Trial #1 (page 10 of FOI Summary)
Case Diagnosis Weight Age Sex Response Onset of Duration of Adverse (lbs) Y = years Analgesia Analgesia Reactions M= months M = months (minutes) (hours)
2 thyroid surgery 7 12Y F Good 20 4.5 3 cast./declaw 10 8M M Excellent 20 6 M, P 5 abscess 13.5 5Y M Poor 6 abscess 3.5 4M F Excellent 10 4 7 fx ilium 17.4 11Y F Poor 12 abscess 12 4.5Y M Excellent 25 8 P 15 trauma 7.25 8M F Poor 19 abscess 9.75 18M M Poor 21 cellulitis 10.5 1-2Y M Good 25 .25 S 22 fx leg 5.5 4.5M M Excellent 15 3.5 23 spay 6 10M F Poor 26 abscess 9.5 10M M Excellent 20 4-5 D, M 30 spay/declaw 6 10M F Excellent 8-10 6-8 M 31 fx leg 7.5 6M F Fair 23 1 32 hit by car 9.5 10Y F Poor 25 1.5 33 fx hip 6 5.5M M Poor 35 spay/declaw 5 6M F Excellent 20 4 36 declaw 9 4Y M Excellent 10-15 6 38 fx femur 10 9M M Fair 40 declaw 9.6 7M M Excellent 20 2.5 41 declaw 4.2 6M F Poor 42 declaw 9 1Y F Excellent 10 4 44 spay/declaw 9 2Y F Good 20 6 M, P 45 declaw 7 6M F Excellent 15 5 P 48 abscess 8 8Y F Excellent 15 none given 49 joint pain 11 9Y M Good 15 4.75 50 declaw 12 7Y M Poor 52 leg trauma 8 11Y F Poor 53 flush bladder 11.5 6Y M Excellent 7.5 5-6 D 57 declaw 9.75 5Y F Poor 59 declaw 6 5M M Excellent 10 2 P 61 spay/declaw 6 6M F Fair 25 1 62 fx leg and tail 9 4-5Y M Good 15-20 3
P = pain on injection M = mydriasis D = disorientation S = sedation APPENDIX II Description of Cats Treated With Butorphanol (0.4 mg/kg) In Field Trial #2 (page 16 of FOI Summary)
Case Diagnosis Weight Age Sex Response Onset of Duration of Adverse (lbs) Y = years Analgesia Analgesia Reactions M= months M = months (minutes) (hours)
31-3 declaw 5 5M M Poor 31-6 declaw 9 4Y M Fair 31-7 hit by car 10 3Y M Good 17 6-7 31-10 declaw 5 5M M Poor 32-2 declaw 7 8Y M Good 2 2 32-3 declaw 3 4M F Poor 32-4 declaw 9 8M M Good 15 2 33-1 declaw 15 10M M Excellent 20 3 33-3 declaw/spay 7.5 6M F Poor 33-4 declaw/spay 5.5 8M F Excellent 35 2.5 33-8 declaw/spay 6.5 5Y F Excellent 20 3.5 33-10 declaw/cast. 8 7M M Excellent 25 4 34-1 declaw 9 1Y F Good 25 4-5 34-2 fx paw 12 1Y M Excellent 8 1 P 34-3 declaw 16 3Y M Excellent 15-18 5-6 34-5 fx femur 8 3Y F Good 8-10 6 34-6 hit by car 6.5 1Y F Good 8-10 2 35-1 abscess 11 3Y M Fair 36-1 ear problem 10 15Y M Good 15 3.5 36-2 bone tumor sx 12.5 9Y M Excellent 10 5 36-6 trauma 4.4 5M F Good 30 4-5 36-7 hit by car 6.4 3Y F Excellent 10-15 4-5 36-9 pelvic trauma 11 3Y M Good 20 5 37-3 catheterization 10.6 Adult M Excellent 15 4 37-4 declaw 7.4 8M M Poor 37-6 stifle pain 9.2 17Y F Poor 37-8 bone sx 11 11Y F Poor P 37-10 declaw 6.4 11M F Fair 20 2 39-2 declaw 10 10M M Excellent 12-15 6 P 39-4 declaw 9 6Y F Excellent 12-15 6 39-5 declaw 5 3.5Y F Excellent 12-15 6 P 39-7 declaw 6.5 10M F Excellent 8-10 6 39-8 declaw 7.5 2Y M Excellent 10-12 6 40-1 shoulder exam 3.8 4M F Excellent 20 6 40-6 declaw 7.4 6M M Excellent 15 4 M 40-7 declaw 7.4 6M M Good 20 4 P, M, D 40-9 catheterization 9.4 4.5Y M Good 20 1 P 40-10 swollen leg 7.2 2Y M Excellent 20 2 41-1 declaw 10.1 1Y M Fair 15 5 41-4 abscess 9.4 1.5Y F Excellent 15-20 5
P = pain on injection M = mydriasis D = disorientation S = sedation
VIII. LABELING (Attached)
Copies of applicable labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855