Approval Date: December 23, 1988
Freedom of Information Summary
NADA 138-903
I. GENERAL INFORMATION:
NADA 138-903 Sponsor: Syntex Agribusiness, Inc.
3401 Hillview Avenue
Palo Alto, CA 9430Generic Name: fenprostalene Trade Name: Porcilene; (fenprostalene) sterile solution Marketing Status: II. INDICATIONS FOR USE
Porcilene® (fenprostalene) sterile solution is indicated for use in sows and gilts pregnant at least 112 days for the induction of parturition.
III. DOSAGE
A. DOSAGE FORM Sterile PEG 400 solution B. ROUTE OF ADMINISTRATION Individually administered subcutaneously (SC) C. RECOMMENDED DOSAGES: Porcilene® sterile solution is supplied at a concentration of 0.25 mg fenprostalene per ml with 0.25 mg fenprostalene (equivalent to 1 ml Porcilene® Sterile Solution) injected subcutaneously once per animal.
IV. EFFECTIVENESS
A. Pivotal Studies:
The new animal drug application on which fenprostalene is based contains adequate and well-controlled studies demonstrating the effectiveness of the new animal drug for the indications for use as given in Part II above.
1. Dose Response Studies:
The following three investigators conducted a total of five dose titration studies to determine the most efficacious dose of fenprostalene for inducing parturition in swine.
Julian H. Edwards, D.V.M.
P.O. Box 10
Scotland Neck, NC 27874
Paul A. Martin, D.V.M.
Vet Med Research Center
Iowa State University
Ames, IA 50011
Thomas A. Miller, D.V.M.
P.O. Box 306
Milford, IN 46542
The studies were conducted under similar protocols except for the dose range of the drug given to the animals.
For each study, pregnant sows and gilts with known breeding dates were selected from existing herds in the area and randomly assigned to either a sham control group or to one of several fenprostalene dose groups. Numbers of animals entered into each study and dose group are given as follows:
(Eds. note: The following table consists of 10 columns.)
-----------------------Fenprostalene (mg)----------------------- Study 0 .03125 .0625 .125 .25 .50 .75 1.0 1.25 Miller 480.1 16 16 16 16 16 16 480.3 20 20 21 20 19 Edwards 480.1 16 14 16 15 13 13 480.3 20 20 20 18 20 Martin 480.2 16 17 18 17 18 17All sows and gilts were injected s.c. on day 112 of gestation (except eight animals in Martin's 480.2 study which were injected on Day 113). Animals were moved into the farrowing house on approximately Day 111 of gestation and housed in accordance with customary practices in use at each test station.Data recorded for each study included time from treatment to parturition, duration of labor, total number piglets born (alive and dead), birth and weaning weights and post-treatment rebreeding rate. The mean interval between injection of fenprostalene and initiation of parturition for each study is shown as follows:
(Eds. note: The following table consists of 10 columns.)
Mean Interval Between Injection and Initiation of Parturition (Hrs) Study 0 .03125 .0625 .125 .25 .50 .75 1.0 1.25 Miller 480.1 83.1 28.1 24.3 26.9 24.6 23.6 480.3 58.5 64.4 38.1 33.5 39.0 Edwards 480.1 82.3 28. 7 28.4 34. 7 29.1 24.4 480.3 94.7 49.7 44.3 38.5 29.9 Martin 480.2 49.7 61.4 51.2 31.0 29.8 28.8Results from each of the above studies show a reduction in mean interval to parturition when .125 mg fenprostalene or more is administered.The data from the studies were pooled by analysis of variance in three steps as follows:
a. The studies where dose levels 0, .03125, .0625, .125, and .25 were all present were analyzed together, using only those doses. Least square means for time to parturition were determined to be 67.7, 58.5, 44.5, 34.3, and 32.9 for Groups 0, .03125, .0625, .125, and .25 mg, respectively. A significant effect (P = .04) was seen for dose. Using linear plateau models, it was concluded that the .125 and .25 mg doses were superior to lower doses and, although not significant, the .25 mg dose was numerically better.
The pooled data was also evaluated with respect to the variability (variances and ranges) of the response time. The least squares means for variances and ranges of time to parturition for Groups 0, .03125, .0625, .125, and .25 were 1420.5, 1124.7, 912.4, 365.9, and 154.0 for variances and 143.1, 107.9, 100.3, 71.2, and 56.3 for ranges, respectively. The results of these analyses indicate that the overall variability of the interval to parturition was significantly reduced (P = .11 and P = .05 for variances and ranges, respectively). Again, using linear plateau models, Groups .125 and .25 were seen to provide the optimum dose with Group .25 numerically better.
b. The three studies where dose levels 0, .25 and .50 mg were all present were analyzed, again using only those doses. Least square means for time to parturition were calculated to be 71.7, 28.9, and 27.2 for Groups 0, .25, and .50 mg, respectively. The effect for dose was significant at P = .02 and there were significant differences between the control and .25 mg (P= .01) and .50 mg (P= .01) groups but not between the .25 and .50 mg groups (P= .87).
The pooled data was also evaluated with respect to the variability (variances and ranges) of the response time. The least squares means for variances and ranges of time to parturition for Groups 0, .25, and .50 mg were 1261.3, 98.1, and 114.6 for variances and 133.0, 40.5, and 37.7 for ranges, respectively. The results of these analyses indicate that the variability of the interval to parturition was significantly reduced (P= .03 for variances and ranges) with either the .25 or .50 mg groups.
c. Lastly, the two trials where dose levels 0, .25, .50, .75, 1.0, and 1.25 were all present were analyzed. Least squares means for time to parturition were calculated to be 82.7, 28.5, 26.4, 30.7, 26.8, and 24.1 for Groups 0, .25, .50, .75, 1.0, and 1.25 mg, respectively. The effect for dose was significant at P = .0001. There were no significant differences between non-zero doses.
As above, the pooled data was evaluated with respect to the variability (variances and ranges) of the response time. The least squares means for variances and ranges of time to parturition for Groups 0, .25, .50, .75, 1.0, and 1.25 mg were 1529.2, 112.8, 132.7, 165.7, 87.7, and 104.09 for variances and 144.8, 40.1, 39.9, 41.6, 34.0, and 39.0 for ranges, respectively. There were no significant differences between non-zero doses.
The data indicated steady reduction in interval to parturition, variation in the time to parturition, and ranges of time to parturition with increasing dose of fenprostalene through the .25 mg level with a significant positive response through .125 mg. Little or no additional response was seen above the .25 mg level.
It is held that for this type of claim, it is more important that a sufficient quantity of drug be administered to be reasonably certain of inducing parturition within a short time frame than it is to administer the "minimum effective dose." Consequently, it is concluded that the .25 mg dose is superior to the .125 dose on the basis that it provides a margin of assurance that virtually all susceptible animals in the proposed treatment population will be induced to farrow in the minimum amount of time.
No differences were detected between the treated and control groups in duration of labor, percent born alive, birthweight, or weaning weight for the induced farrowing. Also, no differences were detected in rebreeding rate, litter size at birth, percent born alive, and litter size at weaning for the subsequent untreated pregnancy and farrowing. There were no adverse reactions observed among the fenprostalene-treated animals.
2. Clinical Field Trials:
The following five investigators conducted a total of six clinical field trials under various protocols to determine the efficacy of fenprostalene for induction of parturition in swine.
Lee Edgerton, Ph.D.
University of Kentucky
Dept. of Animal Sciences
Ag. Science Bldg., South
Lexington, KY 40546-0215
Julian H. Edwards, D.V.M.
P.O. Box 10
Scotland Neck, NC 27874
Richard N. Goddard, D.V.M.
P.O. Box 384
Sommerville, TN 38068
Thomas A. Miller, D.V.M.
P.O. Box 306
Milford, IN 46542
A total of 415 gestating sows and gilts of breeds common to the area were used. At each location, animals with known breeding dates were injected SC on approximately 112 days of gestation with either fenprostalene or carrier.
Parameters measured were time of treatment to farrowing, duration of parturition, number of pigs born alive and dead, litter weights at weaning, and number dying between birth and weaning. The mean interval between injection of fenprostalene and initiation of parturition for each trial is shown as follows:
(Eds. note: The following table consists of 5 columns.)
Days(s) Mean Response Trial Injected Dose N Time (hrs) 560.1(1) 112-114 F (.25 mg) 17 26.3* (Edgerton) C 17 61.2 560 112 F (.5 mg) 18 29.2* (Edgerton) C 18 84.1 560.1(2) 112-114 F (.5 mg) 18 32.6 (Edgerton) C 19 72.2 598 114 F (.5 mg) 49 25.7 (Miller) C 51 44.1 598 109-115 F (.5 mg) 54 35.5 (Goddard) C 54 66.4 598 112-113 F (.5 mg) 50 25.9 (Edwards C 50 62.0 P < .001 (determined by t-test)
Results from each of the above studies demonstrate a significant reduction in mean interval to parturition when either .25 or .5 mg fenprostalene is administered on Day 112.
No differences were detected in the duration of labor, percent piglets live born, percent piglets dying between birth and weaning, and weaning weights between treated and control groups.
A total of 18 adverse reactions were reported involving only slight reactions at the site of injection. These reactions consisted of a slight bruising at the injection site which disappeared after a few days. No other drug-related problems attributable to fenprostalene were reported by the investigators.
B. Corroborative Study:
A preliminary study was conducted by Dr. T.A. Miller, Milford, Indiana to evaluate various dose levels of fenprostalene for parturition induction in swine. Twenty-five pregnant gilts with known breeding dates were randomly assigned to groups (5/group) and injected s.c. either 0, 0.1, 0.2, 0.4, or 0.8 mg fenprostalene. Fenprostalene at all dose levels was efficacious in inducing parturition. Mean time from treatment to farrowing was 50.8, 30.5, 27.5, 27.5, and 19.3 hours for Groups 0, 0.1, 0.2, 0.4, and 0.8 mg, respectively.
The above results support the claim that fenprostalene effectively induces parturition in gilts.
There were no differences seen between the groups for the duration of parturition, the numbers of pigs born live/dead, and the sequence of birth for the live/dead pigs. There were no adverse reactions reported for this trial.
V. ANIMAL SAFETY
VI. HUMAN SAFETY:
A. Pivotal Study:
A combined drug tolerance and animal safety study was conducted by Dr. Doyne Hamm, Research for Animal, Inc., Fayetteville, Arkansas 72701.
The purpose of this study was to assess the safety to pregnant swine of fenprostalene when injected subcutaneously at Day 112 of gestation for induction of parturition. All females used in this study were 112 days pregnant at the time of treatment with fenprostalene. Each group was composed of two sows and two gilts which were administered fenprostalene subcutaneously at doses of 0 (Controls), 0.5 (2x), 1.5 (6x), 2.5 (10x), 5.0 (20x), or 12.5 (50x) mg/animal. Repeat injections of the specified fenprostalene doses were given at 12 and 24 hours following the initial dose if an animal had not yet farrowed. The clinical condition and the bodyweight of the dam and its piglets were monitored at scheduled intervals during the study. The time from injection to parturition, duration of labor, proportion live-born, proportion surviving between birth and weaning, and weaning weight were recorded. Blood cytology and chemistry parameters were evaluated in specimens collected on pretreatment days -7 and 0 (prior to dosing), and on posttreatment days +1, +7, +14, and +28. On study day +28 (i.e. 28 days following treatment), one sow and one gilt from each group were sacrificed and subjected to gross and histopathologic evaluations.
For the 24-hour period following treatment the 6x to 50x groups showed a mild transient increase in temperature. The 6x to 50x groups exhibited slight reactions at the sites of injection. An increase in duration of labor was seen in the 6x and above dose groups. Blood samples obtained from treated animals revealed no group-wide biologically meaningful alterations in blood cytology or chemistry values during the course of the trial. Gross and microscopic examination of the tissues derived from treated animals revealed no changes attributable to the experimental regimen except for local changes seen at the injection sites.
It was concluded that fenprostalene is safe for pregnant sows and gilts at the 0.25 mg/animal dose. At the 6x dose animals start exhibiting longer duration of labor, difficulties in farrowing, and inflammation at the injection site. Treatment with fenprostalene up to 50x (12.5 mg/animal) produced no changes in the blood and serum profiles, nor was lethal to the target animal.
VII. AGENCY CONCLUSIONS
A. Toxicity Tests and Safe Concentrations
Reference is made to NADA 128-549 Freedom of Information Summary for more detailed information on toxicity testing.
1. Utilizing a no-effect level of 8.0 mcg/kg/day established in the rhesus monkey study, safe concentrations for human consumption of edible swine tissue would be: muscle 10 ppb, fat 40 ppb, and injection site 100 ppb.
2. Pienta Assay
Fenprostalene was evaluated in a system designed to assay in vitro transformation of Syrian hamster embryo cells. Fenprostalene did not induce the appearance of any transformed colonies over the concentration range of 239 mcg/ml to 39.0 mcg/ml. This concentration range corresponded to approximately 7.7% to 78.7% survival in the transformation assay. Therefore, the test material was considered to be inactive in the in vitro transformation of Syrian hamster embryo cells assay.
The results of these studies continue to support the assignment of this drug to Category A in the Threshold Assessment.
B. Residue and Metabolism Studies
The levels of drug related residues of fenprostalene in the tissues of swine were determined in a total residue depletion study conducted with tritium labeled fenprostalene. Eight gilts of breeding age were each administered a 0.5 mg dose of 3H-fenprostalene by subcutaneous injection. The animals were then killed in groups of two at 1, 2, 3 and 7 days post dosing. Blood, urine and feces were collected at intervals up until slaughter, and samples of liver, kidney, muscle, fat and injection site tissue were collected from each animal at the time of slaughter. The radioassays of the tissue samples yielded the mean values shown below.
(Eds. note: The following table consists of 6 columns.)
Mean* residue levels (ppb) in the tissues of gilts following a single 0.5 mg dose of 3H-fenprostalene. Days Post Dosing Liver Kidney Muscle Fat Inj Site 1 1.860 5.437 O.049 O.166 77.5 2 O.897 2.268 O.019 O.025 16.1 3 O.520 1.074 O.012 O.026 10.1 7 O.154 O.384 O.000 O.025 2.0 * The day 2 values represent a single animal due to a dosing error in the second gilt in that group.
A maximum average plasma concentration of 0.410 (± 1.33) ng equiv/ml was observed at 12 hours post dosing, and it declined to 0.117 (± 0.040) ng equiv/ml for the three gilts killed at seven days post dosing. Radio-activity amounting to 61.2% of the administered dose was recovered in the 0-72 hour urine collections of the four gilts in the day three and day seven sacrifice groups. Radioactivity in the feces of the same animals during the 0-72 hour period was an average of 14.8% of the administered dose.
The fenprostalene metabolites present in liver tissue were investigated in a separate study involving two gilts treated with 3H-fenprostalene. Each animal received a single 0.485 mg subcutaneous injection of 3H-fenprostalene, and both were killed 12 hours post dosing. A composite sample of the livers from the two gilts was subjected to a tissue work-up procedure using reverse isotope dilution, thin layer chromatography, and high pressure liquid chromatography.
The composite swine liver sample contained a fenprostalene total residue level of approximately 2 ppb, and the greater part of that residue (68%) was nonextractable radioactivity. A small part of the total residue (about 4%) was attributed to combined parent fenprostalene and fenprostalene acid, which was the only identified metabolite. Approximately 25% of the residue was attributed to unidentified acidic metabolites. Structural identification of those metabolites was considered impractical because of the small amount of radioactivity present in the tissue.
A comparison of the metabolite data summarized above was made with data from earlier studies conducted in the heifer, dog, monkey, and rat. Those studies also showed that, one day after injection of fenprostalene, the single identified major metabolite was deesterified fenprostalene. The identity of that metabolite was confirmed by GC/MS analysis in the monkey and the heifer. These data indicate that the residue present in tissues of swine have been adequately tested for toxicity.
C. Withdrawal Time and Regulatory Method
Neither a withdrawal time nor a regulatory method to monitor for residues of the drug are required with the use of fenprostalene in swine for induction of parturition because total residues of the drug do not exceed the safe concentrations in tissues at 24 hours post dosing. The human food safety evaluation of this drug use was based on the total residue values at 24 hours post dosing rather than the usual 8 to 12 hours because of an inherent withdrawal period of approximately one day from the time of drug administration to the time of parturition.
The Center for Veterinary Medicine has concluded that the data submitted in support of this New Animal Drug Application comply with the requirements of Section 512 of the Act. The data demonstrates that Porcilene® is safe and effective for induction of parturition in swine pregnant at least 112 days.
The Center has also concluded that because of the potential for adverse reactions in humans using Porcilene®, prescription labeling is required. Women of child-bearing age, asthmatics, and persons with bronchial and other respiratory problems should exercise extreme caution when handling this product. In the early stages, women may be unaware of their pregnancies. Fenprostalene is readily absorbed through the skin and can cause abortion and/or bronchiospasms.
Because this application was for a new major species, rereview of the underlying human food safety data for fenprostalene was necessary. However, data in NADA 128-549 were found to be satisfactory to assess the toxicity and establish the safe concentration for use of the drug in sows and gilts. The metabolism study in swine, compared with the metabolism studies in the heifer, dog, monkey, and rat that had been done in support of NADA 128-549, established that further metabolite testing was unnecessary. Residue studies submitted by the sponsor were adequate to establish that a withdrawal time and a regulatory method are not needed.
VIII. LABELING (Attached)
1. PORCILENE(TM) product label
2. PORCILENE(TM) carton label
3. PORCILENE(TM) package insert
Copies of these labels may be obtained by writing to the:
Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857
Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.