• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Animal & Veterinary

  • Print
  • Share
  • E-mail

NADA 141-034 Flavomycin® - supplemental approval (March 14, 1994)

Approval Date: March 14, 1994

I. General Information:

NADA NUMBER: 141-034

Sponsor:

Hoechst-Roussel Agri-Vet Co.
P.O. Box 2500
Route 202-206
Somerville, NJ 08876-1258

Agent and United States Address:
Hoechst-Roussel Agri-Vet Co.
P.O. Box 2500
Route 202-206
Somerville, NJ 08876-1258

Established Name: Bambermycins

Trade Name: Flavomycin®

Marketing Status: OTC

Effect of Action: A previous approval for bambermycins (58 FR 54286; October 21, 1993) provided for the use of bambermycins in complete feeds for increased rate of weight gain and improved feed efficiency of cattle fed in confinement for slaughter. This approval provides for the same dosage range of 10 to 20 mg bambermycins/head/day for increased rate of weight gain in pasture cattle (slaughter, stocker and feeder cattle) when fed daily in a least one pound of supplemental feed (Type C Medicated feed).

 

II. Indications for Use:

For increased rate of weight gain in pasture cattle (slaughter, stocker and feeder cattle) when fed daily in at least one pound and not more than ten pounds of supplemental feed (Type C Medicated feed).

Dosage Form(s), Route(s) of Administration, and Recommended Dosage:

Flavomycin® is supplied as three (3) Type A Medicated Articles in 50 lb. multi-walled bags. The Type A Medicated Articles contain 2 g bambermycins per pound, 4 g bambermycins per pound, and 10 g bambermycins per pound. The drug is administered orally by mixing the Type A Medicated Article into supplemental cattle feed (Type C Medicated Feed) to provide not less than 10 nor more than 20 mg bambermycins per head per day.

The resultant supplemental feed containing bambermycins is to be fed continuously through the period in which the cattle are consuming pasture.

 

III. Effectiveness:

Pivotal Dose Titration Studies:

This New Animal Drug Application is based on adequate and well-controlled studies demonstrating the effectiveness of bambermycins for increased rate of weight gain in cattle consuming pasture. Five (5) pivotal dose titration studies were conducted using a randomized complete block design and 1300 growing calves. The studies are summarized and evaluated below for significant differences in rate of weight gain. The 1300 test animals used in these five (5) pasture studies were fullbred or crossbred animals of European and exotic breeds. At three (3) study locations, there were five (5) test blocks in which each block consisted of s1X (6) adjacent pastures. S1X (6) treatments, 0, 10, 20, 40, 60 and 80 mg bambermycins per head per day, were randomly assigned to the pastures within each block. Ten (10) steers or heifers were randomly assigned to each pasture. At two (2) study locations, there were five (5) test blocks in which each block consisted of four (4) adjacent pastures. Four (4) treatments, 0, 5, 10 and 20 mg bambermycins head per day, were randomly assigned to the pastures within each block. Ten (10) steers or heifers were randomly assigned to each pasture. Hence, at each of the five (5) study locations, each treatment tested was replicated five (5) times, and for the five (5) combined locations, eighteen (18) blocks of steers and seven (7) blocks of heifers were tested. The initial animal weights ranged from 160 to 320 kgs, and the studies were terminated when the animals reached 250 to 410 kgs. Feeding periods ranged from 92 to 107 days.

During the studies the cattle were rotated across pastures within a block to minimize any effect(s) of pasture conditions. Each animal received daily .45 or .90 kg of supplemental feed containing bambermycins to provide the assigned treatment dosage. Bambermycins was administered daily via hand feeding supplemental feed. The five (5) studies are summarized as follows:

Trial No. 946-17

Investigator:

Robert W. Lee
KanTech Research Foundation
P.O. Box 1036
Garden City, Kansas 67846

Monitor:

Lawrence E. Deetz
Hoechst-Roussel Agri-Vet Company
P.O. Box 2500
Route 202-206
Somerville, New Jersey 08876-1258

This study was conducted using 300 yearling steers. The cattle were fed supplemental feed for 104 days on native buffalograss pastures. There were 10 animals per pasture and 5 replications of each treatment. The results were as follows:

Ed. note:  The following table has 7 columns

Bambermycins (mg/hd/day)

0.0    10.0    20.0    40.0   60.0   80.0

Average Daily Gain (kgs.)   0.762   1.033   0.927   0.927  0.973  0.893

Trial No. 946-18

Investigator:

Terry Klopfenstein
Department of Animal Science
236 Marvel Baker Hall
University of Nebraska
Lincoln, Nebraska 68583

Monitor:

Lawrence E. Deetz
Hoechst-Roussel Agri-Vet Co.
P.O. Box 2500
Route 202-206
Somerville, New Jersey 08876-1258

This study was conducted using 120 yearling steers and 180 yearling heifers. The cattle were fed supplemental feed for 107 days on native smooth brome pastures. There were 10 animals per pasture and 5 replications of each treatment. The results were as follows:

Ed. note:  The following table has 7 columns.

Bambermycins (mg/hd/day)

0.0    10.0    20.0    40.0    60.0   80.0

Average Daily Gain (kgs.)   0.690   0.742   0.793   0.771   0.812  0.788

Trial No. 946-19

Investigator:

Ed G. Johnson
Johnson Research
Route 1
Parma, Idaho 83660

Monitor:

Lawrence E. Deetz
Hoechst-Roussel Agri-Vet Co.
P.O. Box 2500
Route 202-206
Somerville, New Jersey 08876-1258

A study was conducted using 180 yearling steers and 120 yearling heifers. The cattle were fed supplemental feed for 106 days on irrigated rescue and ladino clover pastures. There were 10 animals per pasture and 5 replications of each treatment. The results were as follows:

Ed. note:  The following table has 7 columns.

Bambermycins (mg/hd/day)

0.0   10.0   20.0   40.0   60.0   80.0

Average Daily Gain (kgs.)      0.777  0.773  0.842  0.843  0.863  0.856

Trial No. 946-20

Investigator:

William E. Kunkle
University of Florida
231 Animal Science Building
Gainesville, Florida 32611

Monitor:

Lawrence E. Deetz
Hoechst-Roussel Agri-Vet Co.
P.O. Box 2500
Route 202-206
Somerville, New Jersey 08876-1258

A study was conducted using 120 yearling steers and 80 yearling heifers. The cattle were fed supplemental feed for 96 days on wheat and ryegrass pastures. There were 10 animals per pasture and 5 replications of each treatment. The results were as follows:

Ed. note:  The following table has 5 columns.

Bambermycins (mg/hd/day)

0.0     5.0    10.0    20.0

Average Daily Gain (kgs.)     0.876   0.884   0.903   0.945

Trial No. 946-21

Investigator:

William C. Ellis
Colonial Farms
704 Encinas Place
College Station, Texas 77845

Monitor:

Lawrence E. Deetz
Hoechst-Roussel Agri-Vet Co.
P.O. Box 2500
Route 202-206
Somerville, New Jersey 08876-1258

A study was conducted using 200 yearling Holstein steers. The cattle were fed supplemental feed for 92 days on coastal bermudagrass and bahiagrass pastures. There were 10 animals per pasture and 5 replications of each treatment. The results were as follows:

Ed. note:  The following table has 5 columns.

Bambermycins (mg/hd/day)

0.0     5.0    10.0    20.0

Average Daily Gain (kgs.)      0.465   0.469   0.505   0.602

Results of Efficacy Studies:

A randomized complete block design was used for all studies and the data were pooled by mixed model analysis of variance to determine the significance of the effect of bambermycins on average daily gain (ADG). A pooled analysis of the three (3) studies that tested bambermycins at O, 10, 20, 40, 60 and 80 mg/head/day demonstrated that there was no improvement in average daily gain at dosages above 20 mg bambermycins/head/day which established the maximum effective dosage as 20 mg/bambermycins/head/day. Therefore, because an improvement in average daily gain was not observed with the 40, 60 and 80 mg/head/day dosages of bambermycins, a pooled statistical analysis of the five (5) studies was conducted for treatments O, 5, 10 and 20 mg bambermycins per head per day. Results of the pooled analysis demonstrated that bambermycins fed at 10 and 20 mg/head/day significantly increased (P< .05) the average daily gain (ADG) of steers and heifers consuming pasture when compared with the control steers and heifers. Steers and heifers responded similarly to the treatments. Approval of the dosage range of 10 to 20 mg bambermycins/head/day was based on the best fitting Andersen-Nelson linear plateau model. This was a linear model, on which 10 mg bambermycins/head/day was the first dose tested that was significantly better than controls. Results from the unweighted pooled analysis are presented in the following table.

Ed. note:  The following table has 5 columns.

POOLED ANALYSIS

Bambermycins (mg/hd/day)

0.0      5.0     10.0     20.0

Average Daily Gain (kgs.)      0.729    0.750    0.806    0.835

 

IV. Target Animal Safety:

Pivotal Study No. 9034b - Target Animal (Cattle) Safety Study with Bambermycins (Flavomycin®) in Pasture Cattle

Investigator:

John W. Byrd
Southwest Bio-Labs, Inc.
401 N. 17th St., Suite 11
Las Cruces, NM 88005

Monitor:

Robert J. Grant
Hoechst-Roussel Agri-Vet Co.
P.O. Box 2500
Route 202-206
Somerville, New Jersey 08876-1258

The pivotal Target Animal Safety study was conducted using thirty-two (32) yearling beef steers and heifers weighing between 450 and 650 pounds at study initiation.

Species and Strain - Cattle, English crossbred calves Weight - 450 to 650 lbs (204 to 295 kg)

Number per Group - 4/sex/group

Dosage Form - Oral

Dosage Used - O, 20, 100, 300 mg/head/day

Frequency - Fed continuously

Start Date - July 31, 1991

End Date March 3, 1992

The highest approved use level of bambermycins is 20 mg/hd/day. This was established as the 1X dose level. Multiples of the highest use level were then tested as follows (mg/hd/day): control (0.0 mg), 1X (20.0 mg), 5X (100.0 mg), and 15X (300 mg). Bambermycins was fed continuously from study initiation to slaughter for the 1X, 5X, and 15X groups. The duration of treatment for these groups was 160 days or a normal growing period for pasture steers and heifers.

The control, 1X, 5X and 15X cattle were observed once daily for general appearance, abnormal behavior, respiration, depression, anorexia, abnormal discharge, trauma or injury, urine or feces abnormalities and abnormal skin or hair coat. Blood samples were collected prior to initiation of treatments (-55 and -34 days) and on days 29, 57, 85, 113, 141 and just prior to slaughter (day 161). The following assays and cell counts (hematology) were done on all samples.

Serum Chemistries

  • Alkaline phosphatase
  • Serum glutamate pyruvate transaminase (SGPT or ALT)
  • Serum glutamate oxaloacetate transaminase (SGOT or AST)
  • Creatine phosphokinase
  • Albumin
  • Total Protein
  • Globulin
  • Total bilirubin, direct bilirubin, indirect bilirubin
  • Serum blood urea nitrogen
  • Creatinine
  • Cholesterol
  • Glucose
  • Calcium
  • Phosphorus
  • Bicarbonate
  • Chloride
  • Potassium
  • Sodium
  • Albumin/globulin ratio
  • BUN/creatinine ratio
  • Sodium/potassium ratio
  • Amylase
  • Sorbitol dehydrogenase

Hematology

  • White blood cell count
  • Red blood cell count
  • Hemoglobin
  • Hematocrit (Packed cell volume)
  • Mean corpuscular volume
  • Mean corpuscular hemoglobin
  • Mean corpuscular hemoglobin concentration
  • Platelet count
  • Neutrophil segments
  • Lymphocytes
  • Monocytes
  • Eosinophils
  • Basophils
  • Partial thromboplastin

Two males and two females from the control, 1X, 5X and 15X groups were sacrificed at the end of the study and the weights of the major organs (liver, kidneys, rumen, reticulum, abomasum, omasum, large intestine, small intestine, adrenal glands, thyroid/parathyroid glands, pituitary gland) were obtained. Tissues from the control and 15X groups underwent histopathological examination and included: liver, kidneys, rumen, reticulum, abomasum, omasum, large intestine, small intestine, adrenal glands, thyroid/parathyroid glands, pituitary gland, bone with marrow, and bone marrow smear. A complete necropsy was conducted on each animal.

Results:

The calves remained healthy and exhibited no observable adverse effects in any of the treatments. There were no adverse effects on average daily gain. The results from the remaining parameters measured were summarized as follows:

There were no changes, due to drug, in the blood chemistry or hematology variables that are of biological importance to the target animal.

No gross lesions or abnormalities, due to drug, were observed in any tissues.

There were no significant findings, due to drug, in the necropsy and histopathology reports. There were no significant differences in organ weights.

The Target Animal Safety study adequately demonstrates that there was no toxicological or pharmacological effects on the animals. These results demonstrate that bambermycins is safe when fed in supplemental feed at the approved use level.

The summary of the safety data in the NADA for bambermycins for cattle fed in confinement for slaughter, NADA 44-759 (58 FR 54286; October 21, 1993) combined with the summary of the efficacy and target animal safety data demonstrates that normal growth and no adverse effects due to the drug were observed when bambermycins is fed at the highest approved use level (20 mg/head/day).

 

V. Human Food Safety:

A. Under NADA 44-759, a supplement was recently approved (58 FR 54286; October 21, 1993) for the use of bambermycins in cattle fed in confinement for slaughter (feedlot cattle) at a dose of 10 to 20 mg/head/day without a withdrawal period, tolerance, or regulatory methods for tissue residues (58 FR 54286; October 21, 1993). No additional toxicology or residue testing were required to support the pasture cattle approval. The residue study for the feedlot approval was done in feedlot cattle at a dose of 400 mg/hd/day. Because the dose in that study was 20 times the dose to be used in pasture (and feedlot) cattle, we have no concern that the differences in diet and dosing method between feedlot and pasture cattle could cause residues of toxicological concern to be present in tissues of pasture cattle. Therefore, bambermycins will be approved for use in pasture cattle at a dose of lO to 20 mg/head/day without a withdrawal period, tolerance, or regulatory methods for tissue residues.

B. Two studies were conducted to determine the effect of bambermycins on the quantity, prevalence, and duration of salmonella shedding and on antimicrobial resistance in indigenous coliforms and salmonella in cattle (J. Anim. Sci. 44(5):734 and J. Anim. Sci. 45(6):1239). These studies were conducted to meet the requirements of 21 CFR 558.15. The use of bambermycins in cattle feed did not increase the.quantity, prevalence or duration of salmonella shedding. There was no increase in the frequency of resistance in the indigenous coliforms or salmonella.

VI. Agency Conclusions:

This NADA satisfies the requirements of section 512(b) of the Federal Food, Drug and Cosmetic Act, and demonstrates that bambermycins (Flavomycin(R)) when used under the proposed conditions of use is safe and effective for the labeled indications.

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 marketing exclusivity beginning on the date of approval because the application contains reports of new clinical or field investigations and human food safety studies (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 claim of increased rate of weight gain in pasture cattle (slaughter, stocker, and feeder cattle) for which the application was approved.

Because this application relied upon information in a previously approved application (NADA 44-759), this original application was reviewed as if it were a supplemental application. Therefore, under the Center's supplemental approval policy (21 CFR 514.106(b)(2)), this is a Category II change. This action did not require a reevaluation of the safety and effectiveness data in the parent application (NADA 44-759).


VII. Attached Labeling:

  1. The three labels for the Type A Medicated Articles (Flavomycin®-2, Flavomycin®-4, Flavomycin(R)-10) and 
  2. the Bluebird labeling for Type C Medicated feed.

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