Approval Date: December 1, 1997
I. GENERAL INFORMATION
Hoffmann-La Roche Inc. (formerly American Cyanamid)
340 Kingsland Street
Nutley, New Jersey 07110
chlortetracycline, sulfathiazole, and penicillin
Aureozol® 500 Granular
- Generic Names: Chlortetracycline, sulfathiazole and penicillin
- Trade Name: AUREOZOL® 500 Granular
- Dosage Form: Type A Medicated Article
- How Supplied: 50 lb. (22.7 kg) or 10 lb. (4.54 kg) bag
- How Dispensed: Over-the-counter (OTC)
Label Claim of Amount of Active Ingredient(s):
- Chlortetracycline calcium complex equivalent to chlortetracycline HCl: 40 g/lb. of Type A Medicated Article
- Sulfathiazole: 8.8% (40 g/lb.) of Type A Medicated Article
- Penicillin (from procaine penicillin): 20 g/lb. of Type A Medicated Article
- Route of Administration: Orally in complete feed.
- Labeled Dosage: Mix 2.5 pounds of AUREOZOL 500 into each ton (907.2 kg) of complete swine feed (providing 100 grams chlortetracycline, 100 grams of sulfathiazole and 50 grams of penicillin per ton of feed).
- Species: Swine
Indications for Use:
- Pre-Starter and Starter Feeds: Administer to swine in a complete feed for reduction of the incidence of cervical abscesses; treatment of bacterial swine enteritis (salmonellosis or necrotic enteritis caused by Salmonella choleraesuis and vibrionic dysentery); maintenance of weight gains in the presence of atrophic rhinitis; increased rate of weight gain and improved feed efficiency from 10 pounds of body weight to 6 weeks post-weaning. For swine raised in confinement (dry lot) or on limited pasture.
- Grower and Finisher Feeds: Administer to swine in a complete feed for reduction of the incidence of cervical abscesses; treatment of bacterial swine enteritis (Salmonellosis or necrotic enteritis caused by Salmonella choleraesuis and vibrionic dysentery); maintenance of weight gains in the presence of atrophic rhinitis; increased rate of weight gain from 6 to 16 weeks post-weaning. For swine raised in confinement (dry lot) or on limited pasture.
- CSP 500 Fermazole Brand
- Chlortetracycline (as hydrochloride), Sulfathiazole,
- Penicillin (from Procaine Penicillin)
- NADA 39-077
- Boehringer Ingelheim (Formerly Fermenta Animal Health Company)
II. TARGET ANIMAL SAFETY AND DRUG EFFECTIVENESS
In accordance with the provisions of the Federal Food, Drug and Cosmetic Act, as amended by the Generic Animal Drug and Patent Restoration Act and the Center's first policy letter (53 FR 50460, December 15, 1988) and the Center's fifth policy letter (June 18, 1990, 55 FR 24645), Hoffmann-La Roche, Inc. is entitled to the approval of the generic chlortetracycline, sulfathiazole and penicillin combination. In vivo bioequivalence studies were required for the approval of this generic chlortetracycline, sulfathiazole, and penicillin combination because the pioneer's combination product is a non-granular premix and the generic product is a granular premix product. The active ingredients are also produced using the same manufacturing processes as the pioneer active ingredients. The manufacturing site for the production of the generic combination is an approved alternate manufacturing site for the pioneer product. The combination of chlortetracycline, sulfathiazole, and penicillin is codified under 21 CFR § 558.155.
Experiment P-93-5 was conducted by the American Cyanamid Company's Agricultural Research Division, Princeton, NJ 08543-0400 (Hoffmann-La Roche Inc. Purchased this ANADA from American Cyanamid) to compare the blood levels of chlortetracycline (CTC), sulfathiazole and penicillin in growing pigs given feed containing either CSP 500 Fermazole Brand nongranular premix (Fermenta Animal Health Company) or AUREOZOL 500 granular premix (manufactured at the time of the study by American Cyanamid Company). A total of 42 pigs (24 gilts and 18 barrows) were included in this experiment which was conducted in seven phases with six pigs of a single sex in each phase. Within each phase the six pigs were randomly assigned to either Treatment A, which was given feed containing CSP 500 Fermazole Brand nongranular premix, or Treatment B, which was given feed containing AUREOZOL 500 granular premix. Overall, a total of 21 pigs fed CSP 500 nongranular premix and 21 pigs fed AUREOZOL 500 granular premix successfully completed the study.
Each phase of the experiment had a pretreatment period of at least 13 days. All pigs received nonmedicated feed during the pretreatment period. Because of the relatively large number of blood samples to be obtained, each pig received a surgically placed jugular vein catheter eight days prior to the initiation of the medicated feeding period.
Each pretreatment period was followed by a five-day treatment period during which pigs received medicated feed containing 600 ppm CTC, 600 ppm sulfathiazole and 300 ppm penicillin provided by either CSP 500 nongranular premix (Treatment A) or AUREOZOL 500 granular premix (Treatment B). Medicated feed was given at the rate of 20 g of feed per kg of body weight which provided 12 mg CTC, 12 mg sulfathiazole and 6 mg penicillin/kg of body weight per day for five consecutive days. After animals had consumed their medicated feed each day, they were provided nonmedicated feed ad libitum until approximately 15 hours prior to the next day's medicated feeding.
Blood samples were taken from each pig immediately prior to giving medicated feeds on the first and fourth day of treatment. On the fifth day of treatment (Day 5), blood samples were taken from each pig at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 18 and 24 hours following the feeding of medicated feed. On Experimental Day 6, pigs were given only nonmedicated feed and a final blood sample was obtained at a time which was equivalent to 30 hours following the last offering of medicated feed on Day 5.
Blood samples obtained following the fifth day of medication were analyzed for CTC, sulfathiazole and penicillin in order to determine the maximum concentration (Cmax) and area under the concentration-time curve (AUC) for each of the three components in pigs fed either CSP 500 nongranular premix (Treatment A) or AUREOZOL 500 granular premix (Treatment B). CTC and penicillin blood levels were determined using microbiological assay methods with a validated limit of quantification (LOQ) of 0.02 ppm for CTC and 0.02 units/ml for penicillin. Blood sulfathiazole was determined using a gas chromatographic method which has a validated LOQ of 0.10 ppm.
All animals remained in good health throughout the study. The overall consumption of medicated feed was 97% of the amount offered for pigs in both groups.
The geometric mean AUC and Cmax responses for each treatment and the percent change of response of Treatment B (generic) with respect to Treatment A (pioneer) were calculated as well as the lower and upper 90% two-sided confidence limits on the percent change in response. The statistical criterion for bioequivalence was that the confidence limits on the percent change in response must be contained in the interval of -20 to +25%.
For AUC, the statistical bioequivalence criterion was met for CTC, penicillin and sulfathiazole. For Cmax, the statistical bioequivalence criterion was met for CTC and sulfathiazole. For penicillin the upper confidence limit for Cmax was above the statistical bioequivalence criterion.
Since the penicillin Cmax was above the upper confidence limit, penicillin depletion rates were calculated using the first order kinetic model (depletion rate proportional to concentration) for penicillin blood concentration data at 2, 2.5, 3, 4 and 5 hours. The estimated rate constants, k, in units of (hours)-1 were 0.2230 for Treatment A (pioneer) and 0.2481 for treatment B (generic). The half lives, t1/2, were 3.11 hours for treatment A (pioneer) and 2.79 hours for Treatment B (generic).
Based on the methods used in this study and the importance of AUC for the determination of bioequivalence, it was concluded that AUREOZOL 500 granular premix and CSP 500 nongranular premix were bioequivalent when administered in feed to swine.
III. HUMAN FOOD SAFETY
The tolerance established for the pioneer product applies to the generic product. A tolerance of 0.1 ppm is established for negligible residues of sulfathiazole in the uncooked edible tissues of swine (21 CFR § 556.690). At 7-days withdrawal, residues of chlortetracycline and penicillin in edible tissues are also negligible. The established tolerance for residues of penicillin is zero in the uncooked edible tissues of swine (21 CFR § 556.510(b). The established tolerances for the sum of residues of tetracyclines (chlortetracycline, oxytetracycline, tetracycline) are 12 ppm in swine fat and kidney, 6 ppm in swine liver, and 2 ppm in swine muscle [21 CFR § 556.150].
Experiment L-2488 was conducted at American Cyanamid Company's Agricultural Research Division, Princeton, NJ, 08543-0400 to compare the depletion of sulfathiazole residues in liver in pigs given feed containing the recommended level of either AUREOZOL 500 granular premix (manufactured at the time of the study by American Cyanamid Company) or CSP 500 Fermazole Brand nongranular premix (Fermenta Animal Health Company). Sulfathiazole is the marker drug for this drug combination and the liver is the target tissue. Four nonmedicated control pigs (two barrows and two gilts) and 20 medicated pigs (10 barrows and 10 gilts) allotted in two treatment groups were used in this experiment. Pigs started the two week pretreatment period of the experiment at an average weight of approximately 88 kg.
All pigs were fed nonmedicated basal feed ad libitum during the two-week pretreatment period. Pigs identified to receive medicated feed were then switched from the basal ration to feed containing either AUREOZOL 500 granular premix (Group B) or CSP 500 nongranular premix (Group C). Both treatment feeds contained equivalent nominal concentrations of chlortetracycline (100 g/ton), sulfathiazole (100 g/ton) and penicillin (50 g/ton). Treatment feeds were fed ad libitum for seven days, with nonmedicated control pigs (Group A) continuing on nonmedicated basal feed. Animals receiving medicated feeds were randomly selected, within treatment and sex, for sacrifice at 1, 4, 7, 10 and 13 hours after withdrawal of medicated feed. One nonmedicated control pig was sacrificed at the 1, 4, 10 and 13-hour withdrawal times for medicated pigs.
Results of analysis for sulfathiazole residues in liver tissue of medicated pigs demonstrate that liver sulfathiazole concentrations were initially quite low and decreased to nondetectable levels very rapidly after withdrawal of medicated feed (see table below). At the 13-hour withdrawal time, liver sulfathiazole concentrations were below the limit of quantification (0.05 ppm) in all four pigs receiving the AUREOZOL 500 granular premix and in three of four pigs receiving CSP 500 nongranular premix.
Sulfathiazole Residue Depletion in Liver in Swine Receiving Feed Containing either AUREOZOL® 500 Granular or CSP 500 Fermazole Brand Nongranular Premix
|Withdrawal Time in Hours||Mean Liver Sulfathiazole Residues (ppm) in Swine Fed AUREOZOL 500||Mean Liver Sulfathiazole Residues (ppm) in Swine fed CSP 500|
Limit of quantitation is 0.05 ppm.
*Data not used in withdrawal time calculation due to sample handling error.The statistical method used to calculate the withdrawal time was that described by FDA: VI. Guideline for Establishing a Withdrawal Period, September, 1986. Using a statistical tolerance limit for the 99th percentile of the population with 95% confidence, a withdrawal time of 14 hours in liver was calculated for swine fed AUREOZOL 500 Granular Type A medicated article for 7 days. A withdrawal time of 15 hours in liver was calculated for swine fed CSP 500 nongranular Type A medicated article for 7 days. Since the calculated withdrawal time for the generic product is below the established withdrawal time of 7 days for CSP 500 (21 CFR § 558.155), AUREOZOL 500 is assigned a 7 day withdrawal time.
Regulatory Method for Residues
The regulatory analytical methods for detection of residues of penicillin and chlortetracycline are microbiological assay procedures (Antibiotic Residues in Milk, Dairy Products and Animal Tissues: Methods, Reports and Protocols, FDA, 1968). The regulatory method of detection for sulfathiazole residues is colorimetric. It is described in the USDA FSIS Analytical Chemistry Laboratory Guidebook-Residue Chemistry; Winter 1991, pp. 1-23 (Determinative method). The methods are on file at the Center for Veterinary Medicine, Food and Drug Administration, HFV-199, 7500 Standish Place, Rockville, Maryland 20855.
IV. AGENCY CONCLUSIONS
This ANADA submitted under section 512(b) of the Federal Food, Drug, and Cosmetic Act satisfies the requirements of section 512(n) of the Act and demonstrates that chlortetracycline, sulfathiazole, penicillin (AUREOZOL® 500 Granular) Type A Medicated Article when used under its proposed conditions of use, is safe and effective for the labeled indications.
V. APPROVED GENERIC AND PIONEER LABELING
A copy of the draft facsimile generic and approved pioneer labeling is attached to this document.
- AUREOZOL ® 500 Granular Type A Medicated Article Generic Labeling
- CSP 500 Fermazole Brand Type A Medicated Article Pioneer Label
- AUREOZOL® Type B Medicated Feed Bluebird Label
- AUREOZOL® Type C Medicated Feed Bluebird Label
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