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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 141-088 HISTOSTAT®, BMD® - original approval

Approval Date: June 17, 1998

I. GENERAL INFORMATION:

NADA141-088
Sponsor:Alpharma, Inc.
One Executive Drive
Fort Lee, NJ 07024
Generic Name:Nitarsone, Bacitracin methylene disalicylate
Trade Name:HISTOSTAT®, BMD®
Marketing Status:Over the Counter (OTC)

 

II. INDICATIONS FOR USE:

As an aid in the prevention of blackhead, and for increased rate of weight gain and improved feed efficiency in growing turkeys.

 

III. DOSAGE

A.DOSAGE FORMThis NADA provides for the combined use of these two Type A medicated articles, nitarsone as per 21 CFR § 558.369 (d), and bacitracin methylene disalicylate as per 21 CFR § 558.76 (d)(1)(i). Nitarsone is supplied as a Type A medicated article in a single concentration of 50 percent activity drug ingredient nitarsone. Bacitracin methylene disalicylate is supplied as a Type A medicated article in concentrations of 10, 25, 30, 40, 50, 60, or 75 grams bacitracin activity per pound.
B.ROUTE OF ADMINISTRATIONOral, via the feed.
C.RECOMMENDED DOSAGES: 
 NitarsoneNitarsone is added to growing turkey feed at 0.01875% as an aid in the prevention of blackhead.
 Bacitracin methylene disalicylateBacitracin methylene disalicylate is added to growing turkey feed at concentrations from 4 to 50 grams/ton for increased rate of weight gain and improved feed efficiency.
 NOTESDiscontinue use 5 days before slaughtering for human consumption to allow for elimination of the drug from edible tissue. Use as the sole source of organic arsenic. Dangerous for ducks, geese, and dogs. Adequate drinking water must be provided near feeders at all times. Overdosage or lack of water may result in leg weakness or paralysis.

 

IV. EFFECTIVENESS:

In accordance with the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Animal Drug Availability Act of 1996, if the active ingredients or animal drugs intended for use in combination in animal feed have previously been separately approved for the particular uses and conditions of use for which they are intended for use in combination, FDA will not refuse to approve an NADA for the combination on effectiveness grounds unless the Agency finds that the NADA fails to demonstrate that 1) there is substantial evidence to demonstrate that any active ingredient or animal drug intended only for the same use as another active ingredient or animal drug in the combination makes a contribution to the labeled effectiveness, 2) each of the active ingredients or animal drugs intended for at least one use that is different from all other active ingredients or animal drugs used in the combination provides appropriate concurrent use for the intended target population, or 3) where the combination contains more than one nontopical antibacterial active ingredient or animal drug, there is substantial evidence that each of the nontopical antibacterial active ingredients or animal drugs makes a contribution to the labeled effectiveness (21 USC §512(d)(4)(D)).

Nitarsone, as provided by Alpharma Inc., has previously been separately approved for use in growing turkey feed as an aid in the prevention of blackhead (21 CFR §558.369 (d)). Bacitracin methylene disalicylate, as provided by Alpharma Inc., has previously been separately approved for use in growing turkey feed for increased rate of weight gain and improved feed efficiency (21 CFR §558.76 (d)(1)(i)). Effectiveness for each drug, nitarsone and bacitracin methylene disalicylate, when administered alone in accordance with its approved uses and conditions of use, is demonstrated in Alpharma Inc.’s approved NADAs 7-616 and 46-592, respectively. Because nitarsone and bacitracin methylene disalicylate each have at least one use that is different from all other animal drugs used in the combination, the NADA must also demonstrate that nitarsone plus bacitracin methylene disalicylate provide appropriate concurrent use for the intended target population. The use of nitarsone plus bacitracin methylene disalicylate provides appropriate concurrent use because these drugs are intended to treat different conditions (nitarsone, blackhead; bacitracin methylene disalicylate, performance) likely to occur simultaneously with sufficient frequency in growing turkeys. There is no more than one nontopical antibacterial (bacitracin methylene disalicylate) contained in this combination animal drug intended for use in Type C medicated feed. Nitarsone is not considered to be an antibacterial animal drug for use in growing turkeys for the purposes of 512(d)(4) of the FFDCA, because nitarsone is approved only for prevention of a protozoal disease in growing turkeys.

 

V. ANIMAL SAFETY

In accordance with the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Animal Drug Availability Act of 1996, if the active ingredients or animal drugs intended for use in combination have previously been separately approved for the particular uses and conditions of use for which they are intended for use in combination, FDA will not refuse to approve an NADA for the combination on target animal safety grounds unless there is a substantiated scientific issue specific to an active ingredient or animal drug used in the combination or a scientific issue is raised by target animal observations contained in studies submitted to the NADA for the combination and FDA finds that the application fails to establish that such combination active ingredient or animal drug is safe for the target animal.

Nitarsone, as provided by Alpharma Inc., has previously been separately approved for use in growing turkey feed as an aid in the prevention of blackhead (21 CFR §558.369 (d). Bacitracin methylene disalicylate, as provided by Alpharma Inc., has previously been separately approved for use in growing turkey feed for increased rate of weight gain and improved feed efficiency (21 CFR §558.76 (d)(1)(i)). Target animal safety for each drug, nitarsone and bacitracin methylene disalicylate, when administered alone in accordance with its approved uses and conditions of use, is demonstrated in Alpharma Inc.’s approved NADAs 7-616 and 46-592, respectively. The Agency has found no substantiated scientific issue relating to the target animal safety of nitarsone or bacitracin methylene disalicylate when used in combination under this NADA and no scientific issue has been raised by target animal observations submitted as part of the NADA for this combination. Thus, pursuant to FFDCA, as amended by the Animal Drug Availability Act of 1996, no specific target animal safety study(ies) are required for approval of NADA 141-088.

 

VI. HUMAN SAFETY:

In accordance with the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Animal Drug Availability Act of 1996, if the active ingredients or animal drugs intended for use in combination have previously been separately approved for the particular uses and conditions of use for which they are intended for use in combination, FDA will not refuse to approve an NADA for the combination on target animal safety grounds unless one or more of the active ingredients or animal drugs used in the combination at the longest withdrawal for the respective active ingredients or animal drugs in the combination exceeds the established tolerance, or one or more active ingredients or animal drugs in the combination interferes with the method of analysis for another active ingredient or drug in the combination.

A. Tolerances

Safety for bacitracin MD and nitarsone has been established by data submitted to NADAs 046-592 and 7-616, respectively. Tolerances are noted below.

Bacitracin MD - Tolerances for residues of bacitracin from bacitracin MD in uncooked edible tissues of turkeys are established at 0.5 ppm, negligible residue (21 CFR 556.70).

Nitarsone - Tolerances for residues of arsenic from nitarsone in turkeys are established at 0.5 ppm in uncooked muscle and 2 ppm in uncooked edible by-products (21 CFR 556.60).

B. Residue Depletion and Assay Noninterference

On the basis of substantial scientific information showing that the likelihood of other drugs in combination with bacitracin MD altering the bacitracin residues in tissues of animals is improbable, there are no longer requirements for conducting tissue residue and analytical method noninterference studies for bacitracin MD when it is included in a combination at already approved levels. Such is the case for this combination. Radiolabeled studies confirm that the drug is recovered mostly with the feces, with only small amounts of radioactivity associated with the urine. A study of the depletion of arsenic from turkeys treated with the combination of bacitracin MD and nitarsone is summarized below.

"Total Arsenic Residues in Turkey Tissue," Report TR-430-84, March 26, 1984

Tissues were collected from turkeys reared by Randall A. Primo, Ponderosa Research Company, French Village, MO, 63036. Tissue assays were conducted by James F. Martin, Morris County Testing Laboratories, P. O. Box 1002-R, Morristown, NJ, 07960. Twenty-four turkeys, 13 weeks of age and equally mixed as to sex, were given feed containing bacitracin MD (100 g/ton) and nitarsone (0.01875%) for 4 weeks. Four groups of 6 birds (3M, 3F) were sacrificed at 0, 1, 4 and 5 days after medication was withdrawn. Samples of muscle, liver, kidney and skin/fat were collected. All tissues obtained from birds sacrificed on withdrawal periods of 0, 4 and 5 days were analyzed for total arsenic. Observed arsenic concentrations are shown in Table 1.

Table 1. Summary of Total Arsenic Concentrations (in ppm) Measured in Tissues of Turkeys Medicated with Bacitracin MD (100 g/ton) and Nitarsone (0.01875%).

Withdrawal period (days)LiverKidneyMuscleSkin/fat
01.831.070.390.23
40.480.340.180.11
50.390.290.150.12

At 5 days after the last dose, the prescribed withdrawal period for the combination, all tissues of treated birds (receiving bacitracin MD at twice the intended use level) contained total arsenic residues that were below the tolerances given in 21 CFR 556.60.

The requirement for assay noninterference data for bacitracin MD has been waived. Data to show that bacitracin does not interfere with the method for arsenic are not necessary because the analysis for arsenic involves ashing.

C. Regulatory Methods for Residues

A microbiological method is used to assay tissues for bacitracin residues. The method entitled "Modified Microbiological Method for Determination of Bacitracin in Tissues" is on file at the Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

A spectrophotometric method is used to assay tissues for arsenic resulting from nitarsone. The method entitled "Arsenic (Total) Residues in Animal Tissues, Spectrophotometric Method" is published in the Official Methods of Analysis of the AOAC, 15th Edition 973.78, page 626.

 

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA comply with the requirements of Section 512 of the FFDCA and demonstrate that nitarsone (0.01875%) plus bacitracin methylene disalicylate (4 to 50 g/ton) are safe and effective for the claims indicated in Section II of this FOI summary.

Pursuant to 21 CFR §514.106 (b)(2)(vi), this combination NADA approval is regarded as a Category II supplemental change which did not require a reevaluation of safety and efficacy data in the parent NADAs. The drugs are to be fed in Type C medicated feeds, in accordance with Section II and III of the FOI Summary and the Blue Bird labeling that is attached to this document.

Residue data show that nitarsone is within the established safe concentrations of 0.5 ppm in uncooked muscle, and 2 ppm in uncooked edible by-products at 5 days withdrawal time.

 

VIII. LABELING (Attached)

Type C medicated Feed (Blue Bird)

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