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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-270 Sulfamethazine Sustained Release Bolus - original approval

I. GENERAL INFORMATION:
NADA140-270
Sponsor:Medico Industries, Inc.
P.O. Box 338
Elwood, Kansas 66024
Generic Name:sulfamethazine
Trade Name:Sulfamethazine Sustained Release Bolus
Marketing Status: 

II. INDICATIONS:

Sulfamethazine Sustained Release Bolus is indicated for the treatment of the following diseases in beef cattle and nonlactating dairy cattle: Bovine respiratory disease complex (shipping fever complex) associated with Pasteurella spp.; bacterial pneumonia associated with Pasteurella spp.; necrotic pododermatiris (foot rot) and calf diphtheria caused by Fusobacterium necrophorum; colibacillosis (bacterial scours) caused by Escherichia coli; coccidiosis caused by Eimeria bovis and E. zurnii; acute mastitis and metritis caused by Streptococcus spp.

III. DOSAGE FORM:

Sulfamethazine Sustained Release Bolus is a solid dosage form containing 30 grams of sulfamethazine per bolus. It is available in 50 count boxes. The recommended dosage is presented below:

DOSAGE AND ADMINISTRATION:

Sulfamethazine Sustained Release Boluses should be administered at the rate of 150 mg/lb body weight on the first day of treatment. Each bolus will treat 200 lbs of body weight. The bolus is scored to allow breaking for more accurate dosing, however, it must not be crushed. The bolus should be lubricated prior to administration and care taken to ensure the entire dose has been swallowed.

Observe animal following dosing to ensure regurgitation does not occur. If regurgitation occurs, clean regurgitated material and readminister. If this is not practical, administer a new bolus.

DOSAGE SCHEDULE:

Body WeightNo. BolusesBody WeightNo. Boluses
200 lbs1700 lbs3.5
300 lbs1.5800 lbs4
400 lbs2900 lbs4.5
500 lbs2.51000 lbs5
600 lbs3  

NOTE: Sulfamethazine Sustained Release Boluses are designed to provide a therapeutic sulfamethazine level in approximately 6 hours, and persist in providing this level for 72 hours (3 days). After 72 hours, all animals should be re-examined for persistence of observable disease signs. If signs are present, consult a veterinarian. It is strongly recommended that a second dose be given to provide for an additional 72 hours of therapy. No further doses should be administered.

IV. ANIMAL EFFICACY:

Efficacy for this product was established based on meeting the requirements of the July 5, 1984 Federal Register publication concerning 21 CFR 510.450 sulfonamides. In that publication, 80 ppm was established as the minimum effective blood level for sulfamethazine. A bioavailability study was performed to satisfy the Agency requirements. The study was conducted by TechAmerica Research Center, 225 Commerce Drive, Fort Collins, Colorado 80524.

Ten healthy crossbred cattle, four males and six females weighing 620-920 pounds were acclimated two weeks prior to the start of the study. On day O, each animal was administered one bolus per 200 pounds of body weight. Venous blood samples were collected prior to treatment and at 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours posttreatment.

Mean blood levels at 6 hours posttreatment were 95.7 ppm. Maximum blood levels averaged 277.2 ppm and occurred at 24 hours posttreatment with the exception of one animal at 36 hours. Mean blood level at 72 hours was 99.7 ppm. Thus, the study meets bioavailability requirement of the Center for Veterinary Medicine's July 5, 1984 Federal Register announcement. The table below identifies all time points and mean blood levels.

Ed. note: The following table has 12 columns.

SULFAMETHAZINE SUSTAINED RELEASE CATTLE BOLUS BIOAVAILABILITY STUDY

Hours Post-treatment0468122436487296120
Mean Blood Levels (ppm)0.055.395.7126.4193.1276.7240.0198.699.729.12.6

V. ANIMAL SAFETY:

To establish the safety of the product, a safety study was conducted in cattle. The study was conducted by TechAmerica Research Center, 225 Commerce Drive, Fort Collins, Colorado 80524.

Twenty-four healthy crossbred cattle weighing 330-650 pounds were acclimated two weeks prior to initiation of the study. The animals were randomly assigned to four groups with three males and three females in each group.

The animals in Groups II, II and IV were treated at 1, 3 and 5 times the recommended rate of one bolus per 200 pounds body weight. Treatments were administered at day O, 3 and 6. The animals in Group I received a water flush at the same treatment intervals.

Physical and clinical observations were conducted throughout the study as well as blood and urine analyses. The animals were sacririced for gross examination and tissue collection on day 22. Tissues collected for histological evaluation included the liver, kidney, thyroid and urinary bladder.

Under the condition of this tudy, the product did not result in any adverse effects other than a transitory inappetence when administered three times (days O, 3 and 6) at the recommended rate of one bolus per 200 pounds of body weight. When administered at three and five times the recommended level, anorexia, reduced water consumption, weight loss, weakness, and the death of one animal in the 5X dosage group occurred. The changes were most pronounced following the third treatment, but most animals had fully recovered by the end of the study. Further, the results of histopathological evaluation demonstrated that the test material did not cause any chronic lesions consistent with sulfonamide toxicity.

It was concluded that under he conditions of this study, Medico's Sulfamethazine Sustained Release Bolus is safe when administered at the recommended level of one bolus per 200 pounds body weight for three treatments (two treatments recommended).

The following tables and charts summarize body weight, feed and water consumption changes durlng the study. The hematology and serum chemistry changes are summarized statistically.

Ed. note: The following table has 9 columns.

SAFETY STUDY WITH SULFAMEETHAZINE SUSTAINED-RELEASE BOLUSES

Table 2. Percent Change in Average Daily Feed Consumption in Pounds

 GROUP IGROUP IIGROUP IIIGROUP IV
DAYDAILY%CHDAILY%CHDAILY%CHDAILY%CH
Pre-Tx Average11.8 1O.1 10.5 9.8 
110.3-12.78.7-13.95.5-47.65.1-48.0
212.77.68.7-13.97.1-32.44.4-55.1
312.34.27.5-25.74.7-55.23.3-66.3
413.816.97.5-25.73.0-71.42.6-73.5
513.111.09.5-5.93.9-62.92.3-76.5
611.80.05.4-46.52.8-73.31.2-87.8
715.228.86.4-36.61.3-87.60.4-95.9
816.035.69.0-10.93.1-70.51.1-88.8
915.733.16.7-33.73.7-64.81.3-86.7
1014.926.37.9-21.84.3-59.00.7-92.9
1114.422.09.6-5.06.0-42.91.6-83.7
1218.153.411.311.96.3-40.03.8-61.2
1314.926.311.311.96.3-40.03.8-61.2
1413.615.312.321.86.4-39.01.6-83.7
1514.825.412.725.77.9-24.83.5-64.3
1617.447.513.230.710.71.95.0-49.0
1714.220.310.0-1.011.37.64.8-51.0
1814.119.59.8-3.010.3-1.96.6-32.7
1917.346.614.947.511.26.76.4-34.7
2014.835.413.129.711.812.48.9-9.2
2114.321.211.311.99.4-10.57.9-19.4

%CH is defined as the percent difference berween the pre-treatment average and each subsequent day for the duration of the study, days 1-21.

Ed. note: The following table has 9 columns.

SAFETY STUDY WITH SULFAMETHAZINE SUSTAINED-RELEASE BOLUSES

Table 3. Percent Change in Average Daily Water Consumption in Gallons

 GROUP IGROUP IIGROUP IIIGROUP IV
DAYDAILY%CHDAILY%CHDAILY%CHDAILY%CH
Pre-Tx Average5.47 4.45 5.18 4.25 
15.551.53.30-25.83.23-37.61.58-62.8
25.33-2.64.654.53.60-30.53.00-29.4
36.009.73.90-12.43.23-37.62.10-50.6
46.009.73.83-13.91.05-79.71.28-69.9
57.2031.64.889.72.33-55.02.03-52.2
65.25-4.03.00-32.62.03-60.81.28-69.9
76.3816.63.23-27.41.43-72.41.35-68.2
87.2833.13.15-29.22.03-60.81.08-74.6
96.7523.44.582.92.48-52.11.53-64.0
106.9026.13.83-13.93.60-30.51.26-70.4
116.0811.24.20-5.61.95-62.40.99-76.7
127.2031.65.5524.74.58-11.62.43-42.8
137.3534.43.98-10.63.60-30.53.06-28.0
146.2313.96.1538.23.15-39.21.08-74.6
155.856.95.4823.14.13-20.31.80-57.6
168.5957.05.9333.35.10-1.52.70-36.5
175.480.24.35-2.24.88-5.82.97-30.1
186.3015.24.807.94.88-5.82.52-40.7
196.6020.75.8531.56.3823.24.14-2.6
207.8844.16.4544.95.03-2.93.5117.4
216.9026.15.1816.45.231.43.96-6.8

%CH is defined as the percent difference berween the pre-treatment average and each subsequent day for the duration of the study, days 1-21.

Safety Study with Sulfa-methazine Sustained-Release Boluses in Cattle

TABLE 4 Statistical Analysis (p<O.05)* of Mean Hematology and Serum Chemistry Results

CategoryParameterDaySignificantly Different
From Control (Group I)
HematologyT. Leukocytes6IV
Lymphocytes6III, IV
Monocytes6III, IV
Basophils6III
T. Leukocytes10II, III, IV
Seg. Neutrophils10II, III, IV
Lymphocytes10III, IV
Monocytes10III
T. Leukocytes15IV
Seg. Neutrophils15II, III, IV
T. Leukocytes21IV
Hemoglobin21IVc
Serum ChemistryCreatinine6III, IV
Creatinine10IV
T. Protein15IV
T. Protein21IV

*One-way ANOVA and Dunnett's test for significant differences between control and experimental groups. (See Appendices XII and XIII.)

VI. HUMAN SAFETY:

Medico Industries, Inc. was a sponsor of the sulfamethazine toxicology studies conducted by the Animal Health Institute (AHI) which supported the 0.1 ppm residue in tissue. Authorization to reference that data, submitted under AHI's MF #3623, was provided to the Agency. Further, the Food and Drug Administration has established a tolerance of 0.1 ppm for negligible residues of sulfamethazine in uncooked edible tissues of cattle (21 CFR 556.670). A tissue residue study was conducted in cattle to determine the withdrawal period necessary to achieve the 0.1 ppm tolerance. The study was conducted by TechAmerica Research Center, 225 Commerce Drive, Fort Collins, Colorado 80524.

Twenty healthy crossbred cattle weighing 500-700 pounds were acclimated for two weeks prior to the study. The animals were randomly assigned to five sacrifice groups containing two males and two females per group. All animals were dosed at the rate of one bolus per 200 pounds body weight, once at day 0 and again 72 hours later.

Groups I through V, respectively, were sacrificed at 168, 216, 120, 144 and 192 hours following initial treatment, corresponding to 4, 6, 2, 3 and 5 days after the final 72 hour treatment. Approximately 200 g of skeletal muscle and liver, and both kidneys were collected from each animal. Sulfamethazine concentrations from these tissue samples were determined by an extraction procedure followed by analysis using high pressure liquid chromatography with ultraviolet detection. An internal standard ratio method was used to calculate the sample sulfamethazine concentrations. Calibration standards were prepared by spiking control tissue samples with known concentrations of sulfamethazine.

To validate the method of analysis, samples of each tissue (liver, kidney and muscle) were prepared with two concentration ranges of sulfamethazine, 0.05 - 0.5 mcg/g and 3 - 60 mcg/g. These ranges were used to encompass the expected levels in actual samples. The prepared samples were analyzed according to the previously described procedure with the desired linearity being achieved. To determine no sulfamethazine levels remained, the prepared samples were re-extracted using the same procedure. Results of prepared samples demonstrated no detectable levels in the lower concentration range and less than 2% of known levels from the 30 mcg/g liver sample. Results from actual samples showed analogous values.

Results of the residue analysis and subsequent statistical analysis demonstrated an overall withdrawal time for Medico's Sulfamethazine Sustained Release Bolus of 8 days (8 days in liver, 7 days in muscle and kidneys). The 8 day withdrawal period was determined from individual data which, when analyzed statistically, demonstrates that 99% of an infinite number of treated animals will have tissues which deplete to the residue tolerance of 0.1 ppm in 8 days using the 95% confidence level. The following table summarizes the mean and standard deviation values for sulfa methazine levels at the sacrifice intervals for kidney, liver and muscle.

Summary of Tissue Residue Levels With Sulfamethazine Sustained Release Boluses In Cattle

Group Mean Tissue Residue Levels

GroupDay* Kidney (ug/g)Liver (ug/g)Muscle (ug/g)
III2Mean73.60069.50039.425
 S.D.11.33910.5746.058
IV3Mean16.94521.0436.898
 S.D.8.8148.2273.230
I4Mean2.1804.5850.990
 S.D.1.3072.7010.536
V5Mean0.2970.8630.117
 S.D.0.1620.4760.054
II6Mean0.1630.1390.023
 S.D.0.0110.0400.019

* Day of sacrifice.

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA comply with the requirements of 512 of the Act and demonstrate that Sulfamethazine Sustained Re]ease Bolus, when used under its proposed conditions of use, is safe and effective for the ]abeled indications.

Approval of the application poses no increased human risk from exposure t0 residues of sulfamethazine because the number of food-producing animals receiving medication will not significantly increase and because the drug is already regulated at the requested use level. According]y, this approval does not require a complete reevaluation of human safety data supporting the drug's use.

The labeling for this product contains adequate directions for its use by a layman. In addition, most sulfonamide products for use in food-producing animals are approved for over-the-counter sale. Accordingly, this product is approved for over-the-counter sale.

Figures:

Percent Change, Mean Body Weight

Percent Change, Feed Consumption

Percentage Change, Water Consumption

VIII. LABELING (Attached)

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