Date of Approval: August 20, 1996
I. GENERAL INFORMATION:
Fermenta Animal Health Company
10150 N. Executive Hills Boulevard
Kansas City, Missouri 64153-2314
tiamulin hydrogen fumarate + chlortetracycline (equivalent to chlortetracycline hydrochloride)
Denagard® 10; chlortetracycline premixes
II. INDICATIONS FOR USE
For the control of swine dysentery associated with Serpulina hyodysenteriae susceptible to tiamulin and for treatment of swine bacterial enteritis caused by Escherichia coli and Salmonella choleraesuis sensitive to chlortetracycline and treatment of bacterial pneumonia caused by Pasteurella multocida sensitive to chlortetracycline.
- DOSAGE FORM - Finished Type C combination medicated swine feed manufactured from separate Type A or Type B medicated articles containing tiamulin hydrogen fumarate, NADA 139-472 (21 CFR 558.600), and Type A or Type B medicated articles containing chlortetracycline, equivalent to chlortetracycline hydrochloride (21 CFR 558.128) or a Type B combination medicated article.
- ROUTE OF ADMINISTRATION - oral administration in feed
- RECOMMENDED DOSAGES: tiamulin hydrogen fumarate: 35 g/ton in finished Type C medicated feed
chlortetracycline: 400 g/ton (10 mg/lb body weight daily in divided doses) in finished Type C medicated feed
Effectiveness of Component Premixes
The approved original NADA 139-472 for DENAGARD® 10 (tiamulin) Premixes contained data to establish that this product was effective for the control of swine dysentery associated with Serpulina hyodysenteriae when fed continuously at 35 g/ton of feed.
Label claims for chlortetracycline premixes accepted through the Drug Efficacy Study Implementation (DESI) of findings of the National Academy of Science and National Research Council (NAS/NRC) include use in swine feed at 400 g/ton (10 mg per pound body weight daily in divided doses) for treatment of bacterial enteritis caused by Escherichia coli and Salmonella choleraesuis and treatment of bacterial pneumonia caused by Pasteurella multocida when fed for 14 days (61 FR 35949).
Blood Level Non-interference Study
- Objective: This study was conducted to determine whether the presence of tiamulin hydrogen fumarate in feed at 35 g/ton compromises the bioavailability of chlortetracycline present in the same swine feed and thus interferes with its therapeutic activity.
S. Rogers, S. Stroh, J. Petty and W. Reynolds
Fermenta Animal Health Company Research Center
Fort Collins, Colorado 80524
- Design and Methods: Thirty-two pigs were divided into 2 groups of 16 for a cross-over blood level study. Sixteen pigs were dosed orally with chlortetracycline (CTC) at 13 mg/lb. The second group of 16 pigs was dosed orally with chlortetracycline at 13 mg/lb plus tiamulin hydrogen fumarate at 1.2 mg/lb.
- Test Article Administration: For the purposes of this study, the assumed dose of CTC provided by the mixing into feed at 400 mg/ton was considered to be between 12.7 and 13.5 mg/lb. A middle dose of 13 mg/lb was used. The dose of tiamulin hydrogen fumarate (1.2 mg/lb) was approximated from the ratio of the drugs in the finished product (400:35 g/ton = 11.4 g/ton). The ratio of CTC to tiamulin hydrogen fumarate doses used for this study (10.8) was slightly different from the ratio of the drugs in the finished product. These dose differences were considered within acceptable limits and biologically inconsequential to the purposes of the non-interference study.
- Samples: Blood samples were collected prior to dosing and at 0, 1, 2, 3, 4, 6, 9, 12, 18, 24, 36, 48, and 60 hours post-dosing. Serum from the collected samples was microbiologically assayed for chlortetracycline activity. Two weeks later the treatments administered to the 2 groups were reversed and blood samples were collected for assay as before.
Results: The post-dosing time to reach maximum chlortetracycline concentration in serum (TMAX), maximum concentration found in serum (CMAX) and area under the concentration x time curve (AUC) were determined. For pigs treated with chlortetracycline alone the TMAX, CMAX and AUC were 2.5 ± 1.0 hour, 2.23 ± 0.65 ug/mL and 16.59 ± 4.41, respectively. When the pigs were dosed with both CTC and tiamulin the TMAX, CMAX and AUC values were 2.9 ± 1 hour, 2.55 ± 0.76 mcg/mL and 19.22 ± 6.54, respectively.
No signs of toxicity or adverse reactions to the drugs administered were observed.
- Conclusions: There was no indication that the administration of tiamulin had interfered with the therapeutic activity of chlortetracycline based on the level of chlortetracycline found in blood.
Field Investigation of Combined Use
- Objective: This study was conducted to determine whether the presence of chlortetracycline at 400 g/ton (10 mg/lb body weight daily in divided doses) adversely affects the clinical effectiveness of tiamulin at 35 g/ton for the control of swine dysentery associated with Serpulina hyodysenteriae.
Kent Schwartz, D.V.M., M.S.
Route 2, Box 92
Story City, Iowa 50248
- Design, Methods, and Test Article Administration: Ninety specific-pathogen-free (SPF) pigs of modern breeding, 45 gilts and 45 barrows, were allotted 5 per pen on the basis of weight and gender. The average initial weight of the pigs was 30.3 lb. There were six pens per treatment in this test of randomized block design. The three treatments were: 1) non-medicated controls; 2) tiamulin at 35 g/ton continuously; and 3) tiamulin at 35 g/ton continuously plus CTC at 400 g/ton (10 mg/lb body weight daily in divided doses) for the first 2 weeks (Days 0 to 14) of the 42-day test. On Day 2 and on Day 3 of the test, each pig was infected by administering 40 mL of a broth growth culture of a pathogenic strain of Serpulina hyodysenteriae (108/mL) by stomach tube).
- Measurements: The pigs were observed daily for clinical signs: pig weights and feed consumption were determined weekly. When pigs died, they were weighed and a post-mortem examination conducted to determine the cause of death. Diarrhea scores were calculated by assigning numerical values of 0, 1, 2, and 3 to daily individual pig diarrhea ratings of none, mild, moderate and severe. General appearance scores were calculated by assigning values of 0, 1, 2, and 3 to individual pig daily appearance ratings of normal, thin, emaciated and moribund, respectively. Presence or absence of visible amounts of blood in feces of individual pigs was recorded daily.
Results: All deaths in the trial were due to swine dysentery. Percent pig days with diarrhea and percent test days with diarrhea over the time of concurrent feeding (Days 0 to 14) were considered the important primary variables of this study. For these criteria of efficacy the two medicated treatment groups had mean values significantly (P = 0.0001) different from that of the non-medicated control treatment. Treatment mean values for test Days 0 to 14 are summarized in Table 4.1. No signs of toxicity or of adverse reactions to the test medications were observed in this trial.
Ed. note: The following table has 4 columns.
Table 4.1. Summary data from a clinical trial evaluating the efficacy of tiamulin combined with chlortetracycline in feed for the treatment of diarrhea associated with Serpulina hyodysenteriae in pigs (swine dysentery).
Criteria Non-medicated Control Tiamulin, (35 g/ton) Tiamulin (35 g/ton) + CTC (400 g/ton) Survival, % 80 100 100 Pig days with diarrhea, % 47.4 8.4 2.0 Test days with diarrhea, % 68.9 32.0 10.0 Pig days with bloody feces, % 32.0 0.2 0.0 Test days with bloody feces, % 66.7 1.1 0.0 Appearance score (range 0 to 3) 0.548 0.036 0.013 Diarrhea score (range 0 to 3) 0.909 0.120 0.029
V. ANIMAL SAFETY
The approved NADA 139-472 for tiamulin in feed and NADA 48-761 and NADA 46-699 for chlortetracycline in feed contained adequate data to establish the safety of each drug for swine. The NAS/NRC/DESI conclusions on chlortetracycline in feed for swine indicate that safety as well as effectiveness of this level of use for swine is accepted (61 FR 35949).
The safety of the two drugs when fed together at the proposed levels to swine was demonstrated in a field investigation conducted to show noninterference of activity and also in the residue depletion study described in this document.
Based on these studies, it is concluded that the combination is safe to be fed to swine.
VI. HUMAN FOOD SAFETY
Safe Concentrations and Tolerances
Safety of the approved products, DENAGARD® 10 remixes and chlortetracycline premixes, has been established by data submitted in original applications of NADA 139-472, NADA 48-761, and NADA 46-699, respectively.
The safe concentrations of total residues of tiamulin in uncooked edible tissues of swine were originally established at 3.6 ppm in muscle, 10.8 ppm in liver, and 14.4 ppm in kidney and fat (21 CFR 556.738). The safe concentrations for tiamulin have been revised using the new food consumption factors as described in the FDA/CVM July 1994 publication entitled, "General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals" (59 FR 37499). The revised safe concentrations of total residues of tiamulin in swine are 5 ppm in muscle, 15 ppm in liver, and 30 ppm in kidney and fat.
The tolerances for chlortetracycline in swine are: 12 ppm in kidney, 6 ppm in liver, 2 ppm in muscle, and 12 ppm in fat (21 CFR 556.150). The tolerance for the tiamulin marker residue, 8-alpha-hydroxymutilin, was originally set at 0.4 ppm in swine liver (21 CFR 556.738). Using the new safe concentration of 15 ppm for tiamulin in swine liver, the tolerance for 8-alpha-hydroxymutilin is 0.6 ppm.
Study Establishing the Withdrawal Period
A residue depletion study was conducted by Fermenta Animal Health, Kansas City, Missouri. The purpose of the study was to determine the depletion of tiamulin and chlortetracycline (CTC) in pigs following administration of the antibiotics in feed at 400 g CTC/ton and 35 g tiamulin/ton for 14 days.
Forty-five crossbred pigs, weighing approximately 50 pounds each, were used. Ten males and ten females were fed feed containing tiamulin at 35 g/ton for 14 days. Ten males and ten females were fed feed containing tiamulin at 35 g/ton and CTC at 400 g/ton for 14 days. Five pigs were feed non-medicated feed. After 14 days of test drug feeding, the medicated feed was withdrawn and replaced with non-medicated control feed. At 6, 12, 24, 36, and 48 hours after the end of medication, two male and two female pigs were killed and the appropriate tissues were assayed for residues. Results are presented in Tables 6.1 and 6.2.
Ed. note: The following table has 3 columns.
Table 6.1. Concentration (ppm) of the marker residue (8-alpha-hydroxymutilin) in the target tissue (liver) of pigs fed Type C medicated finished feeds containing tiamulin hydrogen fumarate (THF) alone and THF plus chlortetracycline (CTC).
Withdrawal Period (hours) tiamulin (35 g/ton) tiamulin (35 g/ton)
+ CTC (400 g/ton)
6 0.314 0.377 12 0.273 0.274 24 0.208 0.195 36 0.143 0.145 48 0.083 0.151 Withdrawal Period (hours) Tissue Liver Kidney Muscle Fat 6 1.55 3.55 0.38 0.16 12 0.82 1.81 0.18 0.08 24 0.57 0.98 0.10 0.04 36 0.41 0.54 0.08 0.04 48 0.47 0.56 0.07 0.04
An approved regulatory method was used for determining the tiamulin marker residue, 8-alpha-hydroxymutilin, in swine liver. This method involves extraction, derivation, and then quantitation by gas chromatography. The limit of quantitation (LOQ) is 50 ppb.
The validated microbiologic method was used to measure antimicrobial activity of chlortetracycline in swine tissue (Antibiotic Residues in Milk, Dairy Products, and Animal Tissues: Methods, Reports, and Protocols, FDA, 1968). The limit of quantitation is 0.31 ppm for muscle, 0.53 ppm for kidney, 0.52 ppm for liver, and 0.097 ppm for fat. The presence of tiamulin (and 8-alpha-hydroxymutilin in liver) did not affect the performance of the assay to measure chlortetracycline. Both methods are on file at the Center for Veterinary Medicine, Food and Drug Administration, HFV-199, 7500 Standish Place, Rockville, Maryland 20855.
VII. AGENCY CONCLUSIONS
The data submitted in support of this NADA satisfy the requirements of Section 512 of the Federal Food, Drug, and Cosmetic Act and demonstrate that tiamulin Type A medicated article (DENAGARD® 10) and approved chlortetracycline Type A medicated articles when combined to produce a Type B combination medicated article or finished Type C combination medicated feed, and when fed to swine under its labeled conditions of use, is safe and effective.
A reevaluation of underlying safety and effectiveness data in the two parent applications was not required. While it was not necessary to re-evaluate the underlying toxicity tests supporting the human food safety of the separate approvals, the safe concentration for tiamulin and chlortetracycline were revised using the new food consumption factors described in FDA/CVM July, 1994 publication entitled, "General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals" (59 FR 37 499). The revised safe concentration and tolerance for chlortetracycline are 2 ppm for muscle, 6 ppm for liver, and 12 ppm for fat and kidney. These tolerances apply to total tetracycline activity in edible tissues. The revised safe concentration of total residues of tiamulin in swine are 5 ppm in muscle, 15 ppm in liver and 30 ppm in kidney and fat. Using these new safe concentrations for tiamulin, the revised tolerance for tiamulin is 0.6 ppm for 8-alpha-hydroxymutilin (marker compound) in liver (target tissue).
A pre-slaughter withdrawal period of 2 days has been established for the use of this combination. These restrictions are based on statistical analysis of depletion data, using the upper tolerance limits containing 99 percent of the population with a 95 percent confidence limit.
Adequate directions for use of this combination product by non-veterinarians have been clearly written, and there is reasonable certainty that the conditions of use, including mixing directions, stated on the label can and will be followed by the feed mill and producer. Approved over-the-counter products containing tiamulin (DENAGARD® 10) and chlortetracycline alone are marketed for the same claims as are on the label for the combination product. The Agency is not aware of any reason why the combining of the two products would require restriction of the new product to prescription use.
The agency has carefully considered the potential environmental effects of this action and has concluded that the action is categorically excluded under 21 CFR 25.24(d)(1)(ii) from the requirement to prepare an environmental assessment (EA). The categorical exclusion applies to this action because this is a combination of previously approved drugs. The data available to the Agency do not establish that, at the expected exposure level, the substance may be toxic to organisms in the environment.
Under section 512(c)(2)(F)(ii) of the FFDCA, this approval for food producing animals qualifies for THREE years of marketing exclusivity beginning on the date of approval because the application contains reports of new clinical field investigations essential to the approval of the application and conducted or sponsored by the applicant.
VIII. APPROVED PRODUCT LABELING
Copies of the following facsimile labeling are attached to this document.
Blue Bird - Type B medicated article label.
(1) Net weight/Active Ingredients - Bag g/ton & g/lb
(2) Net weight/Active Ingredients - Bulk g/ton & g/lb
Blue Bird - Type C medicated feed label.
(3) Net weight/Active Ingredients - Bag g/ton
(4) Net weight/Active Ingredients - Bulk g/ton
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