NADA 140-897 REVALOR®-G - supplemental approval (March 27, 1996)
Approval Date: March 27, 1996
I. GENERAL INFORMATION:
102, route de Noisy
93230 Romainville, France
trenbolone acetate and estradiol
Effect of Supplement:
Provides for the administration of REVALOR®-G in pasture steers (slaughter, stocker and feeder steers) for increased rate of weight gain.
II. INDICATIONS FOR USE
For increased rate of weight gain in pasture steers (slaughter, stocker and feeder steers).
ROUTE OF ADMINISTRATION
subcutaneous implantation on the posterior aspect of the middle one-third of the ear by means of an implant gun
The recommended dosage is one implant containing 40 mg trenbolone acetate and 8 mg estradiol. Each implant is made up of two pellets with each pellet containing 20 mg trenbolone acetate and 4 mg estradiol. Each implant is contained in one division of a multiple dose cartridge. There are ten doses in each cartridge. The cartridge is designed to be used with a special implant gun which places the implant under the skin on the posterior aspect of the ear.
The supplemental new animal drug application for REVALOR-G contains data from adequate and well-controlled studies demonstrating the effectiveness of the new animal drug for the indications for use and dosage as given in Sections 2 and 3 above.
The pivotal studies are dose titration studies in which the parameters measured are the same parameters as are measured in field investigations. Four dose titration studies were conducted in Idaho, Virginia, Nebraska, and Wyoming using a uniform protocol so that the results of the studies could be pooled and summarized. The studies were conducted in the major beef producing areas of the United States.
Name and Address of Investigators:
Dr. Daryl Meyer (Nebraska Study)
Dr. Mary Wray (Virginia and Wyoming Studies)
Horton Feedlot and Research Center
Dr. E. G. Johnson (Idaho Study)
The purpose of the studies was to evaluate the dose response for trenbolone acetate (TBA) and estradiol (E2beta) on average daily gain of steers maintained on pasture. The test animals were straight-bred and cross-bred animals of English and European breeds. For each study, 300 steers were blocked by weight (six steers/block) and randomly assigned within block to one of six treatments (50 replicates/treatment). The treatments consisted of Control (no implant), 10 mg E2beta, 40 mg TBA, 2 mg E2beta/10 mg TBA, 4 mg E2beta/20 mg TBA, and 8 mg E2beta/40 mg TBA. The steers average weights for each study were between 530 lbs. and 617 lbs. when the studies were initiated. The duration of the studies ranged between 107 and 116 days. Each steer was administered TBA and E2beta via subcutaneous implantation on the backside of the mid-ear. The steers were administered the implant once at the initiation of each study. After the cattle were implanted they were maintained together in the same pasture for the duration of the study.
Average daily gain (ADG) data for the steers are summarized in Table 1 for each of the four dose titration studies.
A randomized complete block design was used for all four studies and the data were pooled by analysis of variance to determine the significance of the effect of TBA/E2beta implants on ADG. There were significant (P < .05) linear and quadratic components in the response of average daily gain to increasing levels of the combination product with an optimal dose near 8 mg E2beta /40 mg TBA. The 8 mg E2beta /40 mg TBA treatment also was shown to be significantly (P < .05) better than 40 mg TBA alone and 10 mg E2beta alone. These data are sufficient to support the claims and dosage as provided in Sections 2 and 3.
(Eds. Note: The following table consists of 6 columns)
TABLE 1. Summary of Results for Average Daily Gain (lbs.) (Adjusted Means)+ Location
|0 / 0||1.690a||1.910a||1.782a||1.812a||1.799a|
|10 / 0||1.870b,c||2.107c||1.924b||1.953a,b,c||1.966c|
|0 / 40||1.748a||1.978a,b||1.800a||1.989b,c,d||1.870b|
|2 / 10||1.847b||2.046b,c||1.921b||2.119d||1.973c|
|4 / 20||1.954c,d||2.110c||1.997b,c||1.964a,d||2.014c,d|
|8 / 40||2.011d||2.124c||2.086c||2.005b,d||2.067d|
+ Any two means within a column not followed by the same letter are significantly different (P < .05)
++ Mean square error term was used to test all the pairwise treatment comparisons.
V. ANIMAL SAFETY
The supplemental new animal drug application for REVALOR-G references the target animal safety studies summarized in the FOI for NADA 140-992 (60 FR 4376 - January 23, 1995). The data from those studies demonstrate the safety of the new animal drug for the indications for use and dosage as given in Sections 2 and 3 above.
VI. HUMAN FOOD SAFETY:
A. Toxicity Tests and Safe Concentration
The toxicity studies summarized in the FOI from NADA 138-612 (52 FR 24994 - July 2, 1987) establish the safe concentration for TBA. The safe concentration for total residues is 50 ppb for muscle, 100 ppb for liver, 150 ppb for kidney, and 200 ppb for fat. Residues for estradiol and related esters may not exceed the following increments above the concentrations of estradiol naturally present in the untreated animals; in the uncooked edible tissues of heifers, steers, and calves, 120 parts per trillion (ppt) for muscle, 480 ppt in fat, 360 ppt for kidney, and 240 ppt for liver (21 CFR 556.240).
B. Residue Depletion Study
A tissue residue study was conducted to determine the residues of estradiol and the two metabolites of TBA (17alpha-hydroxytrenbolone (17alpha-TB) and 17beta-hydroxytrenbolone (17beta-TB)). This study was conducted by Dr. Don Henricks, at Clemson University, Clemson, S.C. Eight (8) steers were treated with 140 mg trenbolone acetate and 28 mg estradiol. An additional eight (8) steers were treated with 200 mg TBA. There were also four (4) control steers in the study. In each treatment group, four steers were sacrificed 15 days after treatment and the other four steers were sacrificed 30 days after the initial implantation. Muscle, fat, liver and kidney samples were collected from each animal on each of the sacrifice dates. After collection, the samples were immediately frozen in dry ice and held frozen until they were assayed for 17alpha-TB, 17beta-TB, and estradiol residues. The following two tables summarize the results from this study. As residue levels were similar at the 15 and 30 day sampling, the results in the following two tables were averaged across both sampling dates for the treated animals. Estradiol residues were assayed in only the control steers and steers treated with 140 mg TBA and 28 mg estradiol.
In Table 2, the results from the estradiol tissue assays are summarized. The results of the estradiol assays from the treated and control animals are compared with the acceptable safe incremental increases above naturally occurring levels established in 21 CFR 556.240. The estradiol levels from the treated and control animals were many times lower than the acceptable safe incremental levels. Since the acceptable safe incremental increases of estradiol exceed the estradiol levels found in treated steers by such a wide margin, it was concluded that no pre-slaughter withdrawal period and no withholding restrictions were necessary. Thus there is no need for a regulatory tissue assay method for estradiol.
(Eds. note: The following table consists of 4 columns)
Table 2. Estradiol Levels of Treated and Control Steers Compared to Established Safe Incremental Levels
140 TBA/28 E2beta
|Muscle||120||< 6.0||< 6.0|
|Fat||480||16.1 ± 2.6||6.1 ± 1.7|
|Kidney||360||< 25.0||< 25.0|
|Liver||240||< 25.0||< 25.0|
The residues of 17alpha-TB and 17beta-TB are reported in Table 3. When the residues of the two trenbolone metabolites are compared between the two implant groups, the residues from the implant containing 140 mg TBA/28 mg estradiol are consistently lower than the residues from the steers implanted with only TBA (200 mg). Thus, implanting cattle with the combination product gave trenbolone residues that were lower compared to the residues when TBA is implanted alone. Additional information on the residues of TBA can be found in the Freedom of Information Summary for NADA 138-612 (52 FR 24994-July 2, 1987).
(Eds. note: The following table consists of 5 columns)
Table 3. Residues of 17alpha-TB and 17beta-TB Residues in Steer Tissues
|Treatment (Implant)||Tissue - Muscle||Tissue - Fat||Tissue - Liver||Tissue - Kidney|
|Control||< 15*||< 30*||< 125*||< 250*|
|140 TBA/ 28 E2beta||< 15||< 30||285.3±114.8||< 250|
|200 mg TBA||< 15||126.9±102.3||2899.0±2009.7||----|
|Treatment (Implant)||Tissue - Muscle||Tissue - Fat||Tissue - Liver||Tissue - Kidney|
|Control||< 30||< 30||< 125||< 250|
|140 TBA/ 28 E2beta||75.6±14.6||176.6±48.1||199.9±50.1||< 250|
|200 mg TBA||175.0±62.3||753.8±138.2||629.7±181.7||362.4±56.0|
*Limit of detection
C. Withdrawal Period
As discussed above, no withdrawal period is required following the use of TBA and estradiol.
D. Regulatory Method
As discussed above, no withdrawal time is required. Therefore it is not necessary to have a regulatory assay method or a confirmatory assay method for TBA or estradiol tissue residues. The respective RIA procedures for TBA and estradiol were checked for cross-reactivity with the anti-sera of the other and it was concluded that no interference existed.
VII. AGENCY CONCLUSIONS:
Adequate data were provided to demonstrate the safe and effective use of Revalor-G (ear implant containing 40 mg TBA and 8 mg estradiol) when used in pasture steers (slaughter, stocker and feeder steers) for increased rate of weight gain.
Under the Center's supplemental approval policy (21 CFR 514.106(b)(2)), this is a Category II change providing for the use of an ear implant containing 40 mg TBA and 8 mg estradiol in pasture steers. The approval of this change is not expected to have any adverse effect on the safety or effectiveness of this new animal drug. Therefore, a reevaluation of data in the parent application was not necessary.
Under section 512(c)(2)(F)(iii) of the Federal Food, Drug, and Cosmetic Act, this approval for food producing animals qualifies for three years of marketing exclusivity beginning on the date of approval because the supplemental application contains reports of new clinical investigations (other than bioequivalence or residue studies) essential to the approval of the application and conducted or sponsored by the applicant. The three years of marketing exclusivity applies only to the change for which the supplemental application was approved, i.e., use of an ear implant containing 40 mg TBA and 8 mg estradiol in pasture steers.
VIII. LABELING (Attached)
Five (5) pieces of draft labeling are attached as follows:
- Cartridge Label
- Package Insert
- Package (Box) Label
- Large Container Label
- Outer Shipping Container
Copies of these labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855