I. General Information
NADA Numbers: 139-876, 140-288
Sponsor Name/Address: The Upjohn Company, Agricultural Division
Sponsor Number: 000009
Generic Name: melengestrol acetate
Trade Name: MGA®100/200 Premix, MGA® 500 Liquid Premix
Generic Name: lasalocid sodium
Trade Name: Bovatec®
Marketing Status: OTC
II. Indications for Use
For increased rate of weight gain, improved feed efficiency and suppression of estrus (heat) in heifers fed in confinement for slaughter.
III. Dosage Form, Route of Administration, and Recommended Dosage Form: Feed
Route of Administration: Oral
melengestrol acetate - 0.25 to 0.5 mg/head/day
lasalocid sodium - 10 to 30 g/ton of air dried complete feed
Approval has been granted to feed 0.25 to 0.5 mg melengestrol acetate (MGA) per head per day in combination with 10 to 30 g lasalocid per ton of air dried complete feed, when each additive is provided via separate supplements or a supplement containing melengestrol acetate is fed in combination with a complete feed containing lasalocid.
The supplement containing melengestrol acetate provided at a rate of 0.5 to 2.0 pounds per head may be top-dressed onto or mixed with the feed containing lasalocid.
This clearance does not provide for the mixing of melengestrol acetate and lasalocid premixes together in a common supplement or in a complete ration offered for sale by the feed manufacturer.
IV. Effectiveness (In compliance with combination approval claims)
The efficacy of melengestrol acetate for increased rate of weight gain, improved feed efficiency and suppression of estrus (heat) in heifers fed in confinement for slaughter is well documented and approved (21 CFR 558.342). Further, the effectiveness of lasalocid for improved feed efficiency and increased rate of weight gain of feedlot cattle is established and approved (21 CFR 558.311). For these applications, the efficacy of melengestrol acetate and lasalocid when co-administered was established by conducting a series of field trials under a common protocol. These trials were designed to evaluate the performance of feedlot heifers fed each drug separately and in combination.
A. Pivotal Study
A feedlot heifer study consisting of field trials at nine locations with three replications per location was conducted to generate animal performance data on the combination of melengestrol acetate and lasalocid. Results of each study are reported as well as a summary and statistical analysis of the pooled data from all nine field investigations.
1. Type of Study
- Clinical (field) trials
2. Investigator names and addresses by location:
Trial No. 540-9665-0-JFM-83-002
Steve Rust, Ph.D.
Montana Ag Experiment Station
Route 1, Box 131
Huntley, MT 59037
Trial No. 540-9665-0-JFM-83-003
David Bechtol, D.V.M.
Palo Duro Agri. Division
Canyon, TX 79015
Trial No. 540-9665-0-JFM-004
Thomas R. Schriemer, B.S.
The Upjohn Company
Kalamazoo, MI 49001
Trial No. 540-9665-0-JFM-83-005
Steve Rust, Ph.D.
Montana State University
Bozeman, MT 59717
Trial No. 540-9665-0-JFM-83-006
Jack Riley, Ph.D.
Dept. of Animal Science - Industry
Weber Hall KSU
Manhattan, KS 66506
Trial No. 540-9665-0-JFM-83-007
Richard Luther, Ph.D.
Panhandle State University
Goodwell, OK 73939
Donal R. Gill, Ph.D.
005 Animal Science
Oklahoma State University
Stillwater, OK 74074
Trial No. 540-9665-0-JFM-83-009*
Elvin Thomas, Ph.D.
Dept. of Animal & Dairy Sciences
Auburn, AL 36830
Trial No. 540-9665-0-JFM-83-010
Wilton Heinemann, Ph.D.
Research & Extension Center
Washington State University
P.O. Box 30
Prosser, WA 99350
Trial No. 540-9665-0-JFM-84-001
Steve Schmidt, Ph.D.
Dept. of Animal and Dairy Sciences
Auburn, AL 36830
*This trial was cancelled shortly after it was started for reasons unrelated to the safety and efficacy of the compounds. There were no data generated as a result of this trial.
3. General design of each field investigation
- Purpose of the field investigations: To evaluate the effect of melengestrol acetate and lasalocid sodium on the performance of feedlot heifers when fed singly and in combination.
(1) Species: bovine
Number/group: The number of heifers per treatment group varied from location to location, and ranged from 6 to 14 animals per pen (Table 1).
(2) Subgroup Identity: Heifers used in the field studies were non-pregnant yearlings and the breeds were typical of those commonly found in commercial feedlots. The average initial weights ranged from 674 to 826 pounds (Table 1).
Groups of heifers fed melengestrol acetate or lasalocid alone served as controls. Pairwise comparisons were made to groups of heifers fed the two drugs in combination.
- Diagnosis. Not applicable.
(1) Medicated feed: Feed was medicated using melengestrol acetate or lasalocid premixes. Final feeds were prepared using intermediate premixes which were either mixed into or top-dressed onto the bulk of the ration.
Route of drug administration
- Dosages: The dosages used int he field study were: melengestrol acetate, 0.5 mg/head/day; lasalocid, 30 gm/ton of air dried feed.
Days on test: The cattle were fed for a minimum of 90 days, the actual day of trial termination being left up to the investigator's judgement as to when the cattle had reached market weight and condition. The days on test by location are listed in Table 1.
(Eds. note: The following table consists of 5 columns.)
Table 1. General Trial Information
Location Trial No. Number/Pen Mean Starting Wt./Lbs. Days on Test Estrus Detection (Yes/No) Montana (Huntley) (A) 540-9665-0-JFM-83-002 12 790 102 Yes Texas 540-9665-0-JFM-83-003 14 707 104 Yes Michigan 540-9665-0-JFM-83-004 8 735 97 No Montana (Bozeman) (B) 540-9665-0-JFM-83-005 8 826 97 Yes Kansas 540-9665-0-JFM-83-006 6 731 92 No South Dakota 540-9665-0-JFM-83-007 8 700 126 No Oklahoma 540-9665-0-JFM-83-008 8 674 112 Yes Washington 540-9665-0-JFM-83-010 8 773 96 Yes Alabama 540-9665-0-JFM-83-001 8 728 99 No
i. Measurements taken: The following were measured:
Estrus...2X per day (AM and PM) during days 5 through 47 of the trial. Estrus was measured at five of the nine locations (Table 1).
Cattle weight...cattle were weighed at about 28 day intervals.
Feed consumption...daily feed records were maintained.
Daily observations...individual pens of cattle were observed at least once per day for general activity and physical condition of the cattle.
Performance Data: The treatment by location means for percent standing estrus, average daily gain and feed efficiency are presented in the following tables. While the study included several treatment groups, data from only those pertinent to the subject approval are included.
(Eds. note: The following table consists of 6 columns.)
Table 2. Treatment by Location Means for Percent Standing Estrus
Treatment Oklahoma Montana (B) Montana (A) Texas Washington ________________ ________ __________ __________ ________ __________ melengestrol acetate 8.33 4.17 5.56 14.29 0.00 lasalocid sodium 37.50 45.83 61.11 49.08 54.17 melengestrol acetate/ lasalocid sodium 8.33 16.67 11.11 11.90 16.67
(Eds. note: The following table consists of 10 columns.)
Table 3. Treatment by Location Means for Average Daily Gain
Treatment Alabama Oklahoma Kansas Montana* Montana** S. Dakota Texas Michigan Washington _________ _______ ________ ______ ________ _________ ________ _____ ________ __________ melengestrol acetate 2.90 2.18 3.18 2.46 2.98 3.30 3.10 3.45 2.46 lasalocid sodium 3.03 2.23 3.19 2.40 2.80 3.02 2.67 3.30 2.41 melengestrol acetate/ lasalocid sodium 3.05 2.38 3.09 2.43 2.87 3.31 3.15 3.45 2.59
(Eds. note: The following table consists of 10 columns.)
Table 4.Treatment by Location Means for Feed Efficiency
Treatment Alabama Oklahoma Kansas Montana* Montana** S. Dakota Texas Michigan Washington _________ _______ ________ ______ ________ _________ _________ _____ ________ _________ melengestrol acetate 8.30 6.91 8.21 10.06 9.17 6.52 7.28 6.98 8.48 lasalocid sodium 7.70 6.61 7.76 10.26 9.37 6.81 7.86 6.96 8.41 melengestrol acetate/ lasalocid sodium 7.47 6.19 8.02 10.07 9.14 6.56 7.26 6.93 8.17
The results from the nine individual field investigations were pooled and analyzed statistically to evaluate effectiveness. Average daily gain (ADG) and feed efficiency (FE) data were pooled from all nine locations, while estrus suppression data were pooled from five of the nine locations (Table 1).
5. Statistical analysis: Least squares analyses of variance for the transformed performance data from the nine locations and for the transformed estrus data from five locations were conducted. The results of this analysis are presented on Table 6.
TABLE 6 - Using the MGA, lasalocid, and MGA + lasalocid treatments, the resulting significance levels were:
Parameter ______________________________________ Comparison Estrus FE ADG __________ __________ ____________ ___________ Lasalocid vs MGA + Lasalocid 0.00013 0.03091 0.00606 MGA vs MGA + Lasalocid 0.02205 0.19317 S.E. difference ±0.061458 ±0.106786 ±0.049903
The melengestrol acetate + lasalocid combination was justified since the contribution of lasalocid enhanced feed efficiency (P=0.02205). In this combination, melengestrol acetate was effective for estrus suppression (P=0.00013) and average daily gain (P=0.00606) (Table 6).
The data generated by the nine location field study demonstrated that the melengestrol acetate and lasalocid combination is justified for its effect on estrus suppression, improved feed efficiency and increased rate of weight gain. Each drug, melengestrol acetate and lasalocid, has been shown to make a significant contribution to the effectiveness of the combination.
7. Adverse Reactions
No adverse reactions due to the feeding of melengestrol acetate and lasalocid, either singly or in combination, were reported.
8. Special Issues
Compliance with combination drug policy:
a. The effectiveness and safety of melengestrol acetate and lasalocid when fed singly to feedlot cattle are well documented in their respective approved NADAs. The results of effectiveness and safety studies were submitted to the FDA in support of these respective NADAs. Such data resulted in the approval of melengestrol acetate as per CFR 558.342, and lasalocid as per CFR 558.311. Data generated in support of combination usage have demonstrated that melengestrol acetate and lasalocid fed together are effective and safe.
The data establish compliance with 21 CFR 514.1(b)(8)(v) and CVM's combination drug guidelines (November 9, 1983). The combination is justified as detailed in items 4, 5 and 6 above.
The use of untreated controls was not deemed necessary as a test for general effectiveness because the individual drugs have been previously shown to be effective and already approved at the levels tested. The treatment groups consisting of the individual drugs served as the appropriate controls for the respective two-way combination. Thus, these treatment groups essentially served as negative controls with respect to 21 CFR 514.111(a)(5)(ii)(a)(4), and the studies were properly controlled.
To justify the combination, comparisons were made which demonstrated that each drug made a statistically significant contribution to the combination. The two way combination provides a benefit that cannot be obtained by the use of each of the drugs individually.
The comparison of melengestrol acetate-lasalocid vs. melengestrol acetate for feed efficiency and rate of weight gain directly addresses the contribution of lasalocid to the combination. Significance for either variable shows that lasalocid significantly contributes to the combination.
A comparison of melengestrol acetate-lasalocid vs. lasalocid for average daily gain, feed efficiency and estrus suppression demonstrates the contribution of melengestrol acetate to the combination. Significance for any variable shows that melengestrol acetate contributes to the combination. Both the single drugs are approved and substantial evidence exists to document their effectiveness relative to untreated control.
The proposed ranges for each drug are justified when fed in combination since the highest levels proposed were tested in combination for efficiency and human and animal safety.
B. Corroborative Studies. N/A
V. Animal Safety
A. Pivotal study
The safety of melengestrol acetate and of lasalocid in the bovine have been documented as evidenced by their respective approvals (21 CFR 558.342 for melengestrol acetate and 21 CFR 558.311 for lasalocid) as feed additives. The following pivotal study was conducted to establish the target animal safety of these two additives when fed in combination.
1. A 90 day, subchronic study was conducted.
A.D. Hall, Ph.D., D.V.M.
The Upjohn Company
Kalamazoo, MI 49001
3. General Study design:
- Purpose: The purpose of this study was to evaluate the safety of the melengestrol acetate and lasalocid when fed in combination in the diet of yearling heifers at 1 to 5 times the recommended dosage.
1) Species: bovine
Number per Group: 14 control, 7 treated
2) Breed: Hereford
Sex: Female (heifers)
Weight: 284 to 378 kg initial weight
1) Control...no drugs
0.5 mg melengestrol acetate per head per day
30 g lasalocid sodium per ton of air dried feed
1.5 mg melengestrol acetate per head per day
90 g lasalocid sodium per ton of air dried feed
2.5 mg melengestrol acetate per head per day
150 g lasalocid sodium per ton of air dried feed
- Routes of administration: Oral
- Test duration: 90 days
- Parameters measured:
1) Clinical observations included twice daily health checks, daily observations, body weight, daily feed consumption.
2) Clinical pathology
The following hematology parameters were measured:
- Total leukocyte count
- Total erythrocyte count
- Mean corpuscular volume
- Mean corpuscular hemoglobin
- Mean corpuscular hemoglobin concentration
Microscopic Examination: WBC differential
The following serum chemistry parameters were measured:
- Aspartate aminotransferase
- Alkaline phosphatase
- Inorganic Phosphorous
- Blood Urea Nitrogen
- Total Bilirubin
- Total Protein
- Creatinine phosphokinase
- Sorbitol dehydrogenase
Urine specimens were collected via paracentesis from the urinary bladder at the time of necropsy. The following parameters were measured:
Microscopic Examination: Formed elements
3) Gross and microscopic pathology
The following is a list of organs and tissues that were examined grossly and had a representative sample fixed in 10% neutral buffered formalin for microscopic evaluation:
- Mammary gland
- Mediastinal lymph node
- Mesenteric lymph node
- Gall bladder
- Urinary bladder
- Heart (one section from each atrium and ventricle)
- Aorta (and small arteries)
- Bone marrow (smear)*
- Gross lesions
* Bone marrow smears were made at the time of necropsy, air dried and fixed for 30 seconds or more in methanol. Slides were stained with Wrights stain.
The following organs were weighed at necropsy, paired organs weighed together:
Adrenals, liver, kidneys, and heart.
a. Clinical observations
No adverse, drug-related clinical signs were observed during this study. Although there were no significant differences in average daily gain (ADG) between treated and control animals at mid-study and at termination, there was a trend toward decreased ADG at the 3X and 5X levels of treatment.
b. Clinical pathology
Occasional statistically significant changes in several hematologic and serum chemistry parameters were detected, but all values were well within normal acceptable ranges and no dose-related trends were seen.
c. Gross and microscopic pathology
Several gross and histologic tissue changes were observed, but due to the relative even distribution of the changes in all dose groups including controls, these findings were considered to be incidental rather than drug-related.
a. Based upon the results of this study, the combination of melengestrol acetate and lasalocid sodium in the daily feed of yearling heifers appears to be non-toxic when fed for 90 days at up to 5 times the recommended dose.
VII. Human Safety
A. Drugs for use in food animals
1. Toxicity tests
Data regarding toxicity testing of melengestrol acetate and lasalocid sodium are contained in the approved NADAs for the above mentioned compounds.
2. Safe concentration of residues
Tolerances for melengestrol acetate and lasalocid sodium are published in the Code of Federal Regulations. Melengestrol acetate is currently approved under 21 CFR 558.342 for use in heifers at 0.25 to 0.50 mg/hd/day with a 48-hour withdrawal period. No residues of melengestrol acetate may be found in uncooked edible tissues of cattle with a method which detects MGA at 25 ppb (21 CFR 556.380). The tolerance for lasalocid sodium in edible tissues of cattle under 21 CFR 556.347 is 0.7 ppm with no withdrawal period.
3. Residue depletion and metabolism studies
Numerous studies have been conducted on the metabolism and depletion of residues of melengestrol acetate and lasalocid when administered as individual drugs to cattle. The results of those studies have been filed under the following submissions:
|NADA 34-254||NADA 96-298|
4. Residue depletion noninterference study
The residue study conducted with the three-way combination of melengestrol acetate, lasalocid sodium and tylosin phosphate served as the residue depletion noninterference data for the two-way combination of melengestrol acetate and lasalocid sodium.
Sponsor: The Upjohn Company
L. F. Krzeminski, Ph.D.
The Upjohn Company
G. Chen, Ph.D.
Animal Science Research
Nutley, NJ 07110
Groups of feedlot heifers were fed for 90 days with the drug combinations at the treatment levels described below.
Number of Treatment Group Animals Level Treatment* ______ __________ __________ ___________ 1 14 0 Control 2 7 1X 0.5 mg MGA + 30 g lasalocid + 10 g tylosin 3 7 3X 1.5 mg MGA + 90 g lasalocid + 30 g tylosin 4 7 5X 2.5 mg MFA + 150 g lasalocid + 50 g tylosin
*Melengestrol acetate treatment expressed as mg/head/day, lasalocid and tylosin expressed as gm/ton air dried ration.
The animals in each group were slaughtered within 16 hours following their last feeding. Perirenal fat was collected from all four treatment groups for the melengestrol acetate analysis, and liver samples were collected from the group 1 and 2 animals for the assay of lasalocid and tylosin.
a. Residues of melengestrol acetate
The samples of perirenal fat from each animal were assayed for residues of melengestrol acetate using the official AOAC gas chromatographic method which has been shown to give results comparable to the method in 21 CFR 556.380 although the limit of detection of the former method is 10 ppb. Analysis of the samples from the group 2 (1X) animals showed that all fat samples were below the 25 ppb tolerance for MGA and five of the seven samples were below the 10 ppb limit of reliable measurement of the assay. The two fat samples that gave positive responses had MGA levels of 12.7 and 13.7 ppb.
Fat samples from groups 3 and 4 (the heifers dosed at 3X and 5X levels) yielded average residue levels of 37.6 and 49.4 ppb, respectively.
b. Residues of lasalocid
The liver tissue samples from the group 2 (1X) heifers and seven of the group 1 control animals were assayed for lasalocid by the HPLC-fluorescence ce regulatory method for the drug. An average residue value of 0.09 ppm (S.D. 0.11 ppm) was obtained for the group 2 heifers, and that level is well below the 0.7 ppm tolerance for lasalocid. No positive responses were obtained for lasalocid tin the livers from the control animals.
5. Assay noninterference data
a. Melengestrol acetate assay
The data that follow were generated to demonstrate that the presence of residues of lasalocid does not interfere with the assay for MGA in bovine fat tissue. The study was also intended to show the stability of MGA in frozen tissue. Samples of freshly ground control bovine fat tissue were spiked with the combination of MGA (0.025 ppm) and lasalocid sodium (7.0 ppm).
The spiked samples were assayed in duplicate for MGA by the official AOAC method after 0, 15, 30, 45, and 60 days of storage at 0C. The percent recovery of MGA from bovine fat was 93, 82, 123, 99, and 97 for day 0, 15, 30, 45, and 60, respectively.
b. Lasalocid assay
Data demonstrating the noninterference of residues of melengestrol acetate on the HPLC-fluorescence detection assay for lasalocid were generated by Hoffmann-Laroche to support the original NADA approval for lasalocid in cattle (NADA 96-298). Those data have also been published as a journal article (J. Agricultural and Food Chemistry, 31, 75-78 (1983)) and are summarized on the following page.
Recovery Values Obtained for Lasalocid from Spiked Control Liver Samples
|Drug Combination and Fortification Level||Lasalocid Recovery|
|Lasalocid (0.1 ppm)||86% (mean of 6 assays)|
|Lasalocid (0.1 ppm) + MGA (0.11 ppm)||80.1%|
The residue depletion and assay noninterference studies presented above demonstrate that the combined feeding of melengestrol acetate and lasalocid sodium at their highest approved levels results in tissue residues below the tolerance level for each of the two drugs at 16 hours of withdrawal. The data also show that each drug in the two-way combination does not interfere with the assays for the other. This work confirms the adequacy of the 48-hour withdrawal time required for the presence of MGA in the combination and demonstrates that the use of these feed additives in combination does not pose a hazard to public health.
6. Regulatory methods
Practical regulatory methods of analysis for tissue residues of melengestrol acetate in tissues may be found in 21 CFR 556.380. A method for residues of lasalocid sodium in cattle tissues is described above in part VI 5b and has been validated in government laboratories.
VII. Agency Conclusions
For the purposes of the human food safety review, this original NADA has been treated as a Category II supplement under the Agency's Supplemental Policy (42 FR 64367). This NADA provides for the combination use of MGA and lasalocid sodium at the levels of 0.25 to 0.5 mg/head/day and 10 to 30 g/ton of feed, respectively, for increased rate of weight gain, improved feed efficiency, and suppression of estrus (heat) in heifers fed for slaughter. Adequate data were submitted which show that the combination resulted in a significant (P<.05) improvement in overall performance of heifers when compared to the performance of heifers fed either drug singly. The combination approval (0.5 mg MGA/head/day plus 30 g lasalocid/ton) for 90 days, did not produce an adverse effect./ No changes were made int the approved levels of either compound or in the target animal and the non-interference of lasalocid and MGA with the analytical methods for MGA and lasalocid, respectively, was demonstrated. Accordingly, approval of this change is not expected to increase human exposure to drug residues, and therefore did not require a complete re-evaluation of the human safety data in the original applications. These production drugs are OTC because they do not raise any special safety concerns.
Copies of applicable labels may be obtained by writing to the:
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Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855