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Freedom of Information Summary
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 Recommended Dosage:
melengestrol acetate - 0.25 to 0.5 mg/head/day 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 a. Clinical (field) trials 2. Investigator names and addresses by location:
Trial No. 540-9665-0-JFM-83-002 *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 a. 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. b. Test animals (1) Species: bovine (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). c. Control groups 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. d. Diagnosis. Not applicable. e. Dosage form (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. f. Route of drug administration (1) Oral g. Dosages: The dosages used int he field study were: melengestrol acetate, 0.5 mg/head/day; lasalocid, 30 gm/ton of air dried feed. h. 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 Mean Starting Days on Estrus Detection
Trial No. Number/Pen Wt./Lbs. Test (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. 4. Results 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 EstrusTreatment 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 GainTreatment 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 EfficiencyTreatment 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). 6. Conclusions 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. 2. Investigator:
A.D. Hall, Ph.D., D.V.M. 3. General Study design: a. 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. b. Test animals 1) Species: bovine 2) Breed: Hereford c. Dosage used: 1) Control...no drugs 2) 1X... 0.5 mg melengestrol acetate per head per day 3) 3X... 1.5 mg melengestrol acetate per head per day 4) 5X... 2.5 mg melengestrol acetate per head per day e. Routes of administration: Oral f. Test duration: 90 days g. 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 The following serum chemistry parameters were measured:
Aspartate aminotransferase Urine specimens were collected via paracentesis from the urinary bladder at the time of necropsy. The following parameters were measured:
Specific gravity 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: Brain Diaphragm
Pituitary Rumen
Thyroids Reticulum
Adrenals Omasum
Pancreas Abomasum
Ovaries Duodenum
Uterus Jejunem
Mammary gland Ileum
Mediastinal lymph node Cecum
Mesenteric lymph node Colon
Lung Heart
Liver (one section from each
Gall bladder atrium and ventricle)
Kidneys Aorta (and small arteries)
Urinary bladder Bone
Spleen 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. 4) Results 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. 5) Conclusions 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: Melengestrol Acetate Lasalocid _________________ __________ NADA 34-254 NADA 96-298 NADA 39-402 NADA 124-309 NAD 138-792 INAD 1707 INAD 4 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. Location: Michigan L. F. Krzeminski, Ph.D. 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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