Approval Date: March 27, 1989
I. GENERAL INFORMATION:
Norden Laboratories, Inc.
601 West Cornhusker Hwy.
Lincoln, NE 68521-3596
II. INDICATIONS FOR USE
For treatment of the following diseases caused by organisms susceptible to sulfamethazine: bacterial scours (colibacillosis) caused by Escherichia coli , necrotic pododermatitis (foot rot) and calf diphtheria caused by Fusobacterium necrophorum , bacterial pneumonia associated with Pasteurella spp. , and coccidiosis caused by Eimeria bovis and E. zurnii in ruminating beef and dairy calves.
Each Sulka S(TM) Bolus contains 5 grams of sulfamethazine.
ROUTE OF ADMINISTRATION
The bolus should be administered orally by use of a calf size balling gun.
Each bolus is formulated for an initial dose of 2 boluses per 100 pounds of body weight for the first 24 hour treatment period. Follow up therapy consists of one bolus per 100 pounds of body weight administered at 24 hour intervals for up to 4 additional consecutive days.
The efficacy of the Norden sulfamethazine bolus was established by meeting the requirements set forth in a notice published in the Federal Register of July 5, 1984 (49 FR 27543). In that notice, the sulfonamide requirements for blood levels were established at 8 milligrams percent or more.
A bioavailability study was conducted. The data from this study and the blood level data from a residue depletion study were used to satisfy the requirements set out ln the July 5, 1984 Federal Register notice (49 FR27543). These studies were conducted by John Murphy, Norden Laboratories, Inc., 601 W. Cornhusker Hwy., Lincoln, NE.
A bioavailability study was conducted in which ten young Holstein calves, ranging in weight from 130 to 235 pounds, were administered sulfamethazine boluses. Each calf received an initial oral "loading" dose of 100 mg per pound body weight. This initial dose was followed with a supporting oral dose of 50 mg per pound body weight every 24 hours for the next four consecutive days. This dosing procedure was in accordance with the proposed product labeling. Plasma samples were obtained at 0, 2, 4, 6, 24, 48, 72, 96 and 120 hours post treatment (i.e., after the initial "loading" dose) Additional samples were taken at 124, 128, 132, 144, 150 and 168 hours for the purposes of collecting depletion data for a future residue study.
Additional blood level data were gathered from a residue depletion study in which 24 Holstein calves, ranging in weight from 100 to 300 lbs., were administered sulfamethazine boluses at the same dosage regime as described above. Plasma samples were obtained at 0, 2, 4, 6, 24, 48, 72, 96, and 120 hours post treatment (i.e., after the initial "loading" dose).
The plasma free sulfamethazine levels for 33 out of the 34 calves from both studies were greater than 8 mg percent by 6 hours post-treatment. The therapeutic blood level for sulfamethazine was maintained throughout the five day treatment period in each study. Please refer to Table 1 for the mean sulfamethazine plasma levels at critical sampling periods. There were no adverse effects observed in either of the studies.
(Eds. note: The following table consists of 9 columns.)
TABLE 1 Mean Plasma Sulfamethazine Levels (mg %)
|Hours Following Initial Treatment|
SUMMARY The bioavailability data obtained in these studies demonstrate sulfamethazine Plasma levels > or = 8 mg percent. The results of these studies show that Norden's sulfamethazine bolus is bioequivalent to the DESI reviewed drug based on the bioavailability data. The therapeutic blood levels of sulfamethazine in this species are well established and documented in published scientific literature as cited in the July 5, 1984 Federal Register notice (49 FR 27543).
V. ANIMAL SAFETY
No animal safety studies are required for the approval of NADAs for sulfonamide products within the scope of the DESI program. However, no adverse effects were observed in either the bioavailability study or the residue depletion study.
VI. HUMAN SAFETY:
Three month oral toxicity studies of sulfamethazine in rats and Beagle dogs were submitted on February 15, 1974, in compliance with FDA's regulations (21 CFR 510.450).
Additionally, a tissue residue study was conducted in cattle to determine the withdrawal period necessary to achieve the established tolerance of 0.1 ppm for negligible residue of sulfamethazine in uncooked edible tissues of cattle (21 CFR 556.670).
Twenty-four young 105 to 255 pound dairy heifer and bull calves were administered sulfamethazine boluses with a calf size balling gun. Four additional calves (2 male, 2 female) served as non-medicated controls. The initial oral "loading" dose of 100 mg sulfamethazine per pound body weight was followed by supporting doses of 50 mg sulfamethazine per pound body weight every twenty-four hours for four additional consecutive days. This procedure was in accordance with the proposed product labeling.
The twenty-four medicated and 4 non medicated calves were appropriately divided into 7 groups of 2 male and 2 female each.
Upon sacrifice at 0, +2, +3, +4, +5, +6 and +8 days after final dosing, muscle, liver, kidney and fat tissue from both treated and untreated (control) calves were harvested. All tissue, except fat, was then analyzed for sulfamethazine residues using the Tishler/Bratton-Marshall Method A.
The data were reviewed and analyzed according to the Center for Veterinary Medicine's Guideline for Establishing a Withdrawal Period (1985). The withdrawal period was determined from the tolerance limit on a residue concentration which was below the permitted residue marker (Rm) of 0.1 parts per million (ppm). This tolerance limit provided an interval within the 99th percentile of the population, with a 95% confidence level that the interval does contain that percentile of the population.
An analysis of the data for a tolerance of 0.1 ppm resulted in a 99% statistical tolerance limit (95% confidence) of 0.07 ppm at 11 days withdrawal. Day 2 data were omitted because the data did not fall on the linear portion of the depletion curve. Day 8 data were omitted because they were below the validated portion of the assay. Thus, based on the analysis of the data for a tolerance of 0.1 ppm, a withdrawal period of 11 days has been assigned for the product.
The following table summarizes the mean and standard deviation values for sulfamethazine levels in kidney, liver, and muscle tissue at the different sacrifice periods.
(Eds. note: The following table consists of 7 columns.)
GROUP MEAN TISSUE RESIDUE LEVELS IN PPM
* Day of sacrifice following last day of dosing.
VII. AGENCY CONCLUSIONS:
The data submitted in support of this NADA satisfy the requirements of 512 of the Act and demonstrate that Sulka-S(TM) Bolus, when used under its proposed conditions of use, is safe and effective for its labeled indications.
The bioavailability study demonstrates that, when used as directed, sulfamethazine will achieve a blood level of at least 80 ppm (8 mg percent) and will maintain this level for 24 hours. The agency has determined that a blood level of not less than 8 mg percent is an effective level of sulfamethazine for the treatment of the indicated disease conditions. The tissue residue depletion study was conducted in cattle and supports a withdrawal period of 11 days. These two studies satisfied the requirements set forth in the Federal Register notice of July 5, 1984 (49 FR 27543).
Sulfamethazine products for use in food producing animals are generally over the counter (OTC) products. Accurate diagnosis can be made with a reasonable degree of certainty by the layman. Adequate directions for use have been written for the layman and the conditions of use prescribed in the labeling are likely to be followed in practice. Therefore, the agency has concluded that this sulfamethazine product be granted the over-the-counter marketing status.
Approval of this new animal drug application poses no increased human risk from exposure to residues of sulfamethazine because there are already a number of approved sulfamethazine calf boluses on the market and the number of food producing animals receiving such medication will not significantly increase as a result of approval of this NADA. In its approval decision, CVM did not take into account the preliminary results of chronic bioassays of sulfamethazine in mice and rats conducted by the National Center for Toxicological Research, see 53 FR 15886 (May 4, 1988) and 53 FR 17850 (May 18, 1988). The final results of the bioassays are expected to be available later this year. CVM will review those results and determine whether additional action with respect to the NADA for Sulka STM Bolus and the NADA's and supplemental NADA's for other sulfamethazine containing new animal drug products is necessary or appropriate.
VIII. LABELING (Attached)
- Sulka-S(TM) Bolus carton label
- Sulka-S(TM) Bolus strip packing label
- Sulka-S(TM) Bolus case label bolus cartons
- Sulka-S(TM) Bolus 50 and 100 bolus bottle label
- Sulka-S(TM) Bolus case label bolus bottles
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