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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-578 Solu-Tet 324 - original approval

Approval Date: February 26, 1991

I. GENERAL INFORMATION:

NADA 140-578
Sponsor: Vetri-Tech, Inc.
P. O. Box 324
Montvale, NJ 07645
Generic Name: tetracycline hydrochloride
Trade Name: Solu-Tet 324
Marketing Status:  

 

II. INDICATIONS FOR USE:

Chickens:

Control of chronic respiratory disease (CRD) and air sac infection caused by Mycoplasma gallisepticum and Esherichia coli; infectious synovitis caused by Mycoplasma synoviae susceptible to tetracycline.

 

III. Dosage Form: Water soluble powder

Route of Administration: Orally in drinking water

Recommended Dosage: 25 mg/pound of body weight per day in divided doses for 7 to 14 days.

 

IV. EFFICACY:

Pivotal Study

1. Type of Study: Parallel Bioequivalency

2. Name and Address of Investigator:

Colorado Animal Research Enterprises, Inc.
6200 East County Road 56
Fort Collins, CO 80524

3. General Design

a. Purpose:

To compare the bioequivalency of Vetri-Tech's SOLU-TET 324 to the National Academy of Science/National Research Council (NAS/NRC) reviewed reference product (VETQUAMYCIN-324; Pfizer, Inc.) by measuring blood levels of tetracycline in broilers which had been medicated via drinking water according to label directions.

b. Test Animals

1. Species and Number per Group: Broiler breeder chickens (Indian River Cornish Rocks) were used in three groups as follows:

Group 1 (VETQUAMYCIN): 54 birds
Group 2 (SOLU-TET): 54 birds
Group 3 (Control): 12 birds

2. Subgroups: Chickens in each group were equally represented by males and females. The mean body weights of chickens at the beginning of the adjustment period (four weeks old) ranged from 331-341 grams for females and 358-374 grams for males. All birds were ranked within sex according to weight and randomly assigned to treatment groups with weight and sex stratification.

c. Type of Control Used: Twelve unmedicated birds were utilized as negative controls to detect background antibiotic blood levels and to generate recovery data.

d. Diagnosis: As this was a bioequivalency study, diagnostic methods were not applicable.

e. Dosage Form: SOLU-TET 324 is a soluble powder to be added to the drinking water of poultry.

f. Route of Administration: Orally via drinking water.

g. Dosages Used: Test and reference products were administered at a concentration which provided approximately 25 mg tetracycline hydrochloride per pound of body weight per day.

h. Test Duration: Medicated water was provided continuously for 13 consecutive days.

i. Parameters Measured: The following parameters were measured: weight gains (overall and average daily), feed consumption, water and drug consumption, drug blood levels.

4. Results: Assayed blood levels of tetracycline hydrochloride (TCH) for SOLU-TET and VETQUAMYCIN treated birds are presented in Tables 1 and 2, respectively, while background blood levels of TCH in control birds are given in Table 3. Blood levels were generally about twice the level of the assay method's detection limit. Mean assayed blood levels of TCH from SOLU-TET medicated birds ranged from 0.136 to 0.154 ppm over the three bleeding periods. The VETQUAMYCIN medicated birds averaged 0.146 to 0.180 ppm TCH over the three bleeding periods. Comparing mean TCH blood levels of the two medicated groups on each bleeding day, the SOLU-TET birds had slightly higher (0.006 ppm higher) TCH levels on day 7, 0.044 ppm lower TCH levels on day 10, and 0.004 ppm lower TCH levels on day 13. No TCH was detectable in the control birds at any bleeding period.

Values for other evaluation parameters (food, water and drug consumption, weight gains and feed efficiency) were similar for the two treatment groups.

Ed. note: The following table has 8 columns.

Table 1. Assayed blood levels of tetracycline hydrochloride (TCH)
from SOLU-TET 324 medicated broilers.

Females Males _________________ _________________ Bleeding Assayed(a) Assayed(b) Time Blood Level Blood Level Mean of (Days Post- Bird of TCH Bird of TCH Females Treatment) Battery Cage Number (ppm) Number (ppm) and Males

7 A 2 420 .092 685 .092 18 379 .293 494 .120 19 366 .174 496 .084 B 2 395 .179 696 .101 18 394 .125 562 .097 19 391 .221 538 .286 C 3 367 .151 660 .075 7 388 .221 682 .114 17 324 .159 653 .148

Mean .179 .124 .152

10 A 13 386 .118 44 .146 17 364 .095 439 .083 21 319 .136 434 .079 B 3 372 .124 671 .115 16 380 .093 442 .157 20 428 .191 664 .143 C 1 411 .260 675 .165 6 321 .100 453 .260 20 426 .095 898 .083

Mean .135 .137 .136

13 A 3 385 .165 665 .165 8 356 .(b) 489 .092 16 344 .141 495 .173 B 5 425 .135 430 .162 13 376 .118 39 .276 21 365 .181 592 .169 C 14 313 .145 594 .141 16 338 .181 548 .106 21 346 .141 525 .135

Mean .151 .158 .154

Overall Mean .155 .140 .147

a Detection limit for 7, 10 and 13 day assays = .070, .072 and .076 ppm, respectively. b Not able to obtain blood. Ed. note: The following table has 8 columns. Table 2. Assayed blood levels of tetracycline hydrochloride (TCH) from Vetquamycin medicated broilers.

Females Males _________________ _________________ Bleeding Assayed(a) Assayed(b) Time Blood Level Blood Level Mean of (Days Post- Bird of TCH Bird of TCH Females Treatment) Battery Cage Number (ppm) Number (ppm) and Males

7 A 6 332 .159 687 .082 7 305 .345 569 .076 14 331 .114 534 .088 B 6 404 .170 544 (b) 7 361 .141 581 .179 14 345 .196 444 .125 C 5 358 .084 460 .106 15 336 .125 584 .070(c) 19 408 .237 549 .226

Mean(d) .175 .115 .146

10 A 1 349 .286 582 .143 5 392 .273 689 .146 9 423 .390 587 .087 B 4 389 .169 446 .169 8 340 .127 566 .087 15 326 .220 543 .248 C 8 334 .140 785 .146 13 322 .215 897 .177 18 351 .127 539 .098

Mean .216 .145 .180

13 A 4 347 .226 519 .309 15 355 .198 447 .207 20 315 .113 571 .081 B 1 384 .141 45 .135 9 303 .226 41 .126 17 406 .185 480 .088 C 2 422 .111 536 .177 4 327 .099 510 .173 9 329 .101 577 .155

Mean .156 .161 .158

Overall Mean .182 .140 .162

a Detection Limit for 7, 10 and 13 day assays = .070, .072 and .076 ppm, respectively. b Bird was euthanized on 10/27/84 (study day 4). c Actually less than the value reported but below detection limits. d A value of 1/2 of the detection limit for the values below the detection limit was used in calculating means. Ed. note: The following table has 7 columns. Table 3. Assayed blood levels of tetracycline hydrochloride (TCH) from non-medicated, control broilers.

Females Males _________________ _________________ Bleeding Assayed(a) Assayed(b) Time Blood Level Blood Level (Days Post- Bird of TCH Bird of TCH Treatment) Battery Cage Number (ppm) Number (ppm)

7 A 24 419 <.070(b) 578 <.070 B 10 335 <.070 492 <070 10 A 12 328 <.072 672 <.072 C 11 403 <.072 586 <.072 13 B 22 360 <.076 507 <.076 C 23 412 <.076 661 <.076

a Detection limit for 7, 10 and 13 day assays = .070, .072 and .076 ppm, respectively. b "<" indicates less than the value reported but below detection limits.

5. Statistical Analysis: Data derived from this study were subjected to analysis of variance. The analysis of variance of both initial body weight and body weight prior to treatment initiation found no statistically significant difference in means either between the two drug treatment groups or among the three bleeding days. Both final body weight and weight gain varied significantly among the three bleeding day groups (p < 0.001), but not between the two drug treatment groups (p = 0.282 and p = 0.134).

The difference between male and female chickens was highly significant (p < 0.001) with respect to each of four body weight variables. The mean weight gain for the control birds was slightly higher than those for the SOLU-TET and VETQUAMYCIN drug treatment groups (344.5 gm versus 336.8 gm and 323.9 gm, respectively).

The two drug treatment groups were statistically compared with respect to daily feed consumption per bird (i.e., daily feed consumption for the cage divided by the number of birds in the cage). Because of the large number of design variables and factor levels, a single analysis of daily feed consumption per bird was not possible under the currently available statistical package (SPSS, Version 8.3). Instead, two separate analyses of variance were run: 1) daily feed consumption per bird for only days 1 through 7 but all three bleeding day groups and 2) daily feed consumption per bird for days 1 through 13 but excluding those cages of birds bled on day 7. Neither analysis of variance found the difference in mean daily feed consumption between the two drug treatments to be statistically significant (p = 0.970 and p = 0.292). The mean daily feed consumption per bird was higher in the control group than both drug treatment groups (97.6 gm versus 92.6 gm). Both analyses found the increase in daily feed consumption over sampling days to be highly significant (p < 0.001) and to be not significantly different between the two drug treatment groups (p = 0.907 and p = 0.273). Feed efficiency was lower in the SOLU-TET group than in the VETQUAMYCIN group, both overall and for each bleeding day subgroup. Feed efficiency of the SOLU-TET group was also lower than feed efficiency of the control group except for the subgroups bled on day 7. None of the differences in estimated feed efficiency among the control and drug treatment groups was statistically significant.

Statistical analyses of average daily water consumption per bird found no significant difference between the two drug treatment groups nor among the bleeding day groups, but did find the variation over sampling days to be highly significant (p < 0.001).

Drug consumption per bird body weight did not vary significantly either between the two drug treatment groups or among the three bleeding days.

The assayed TCH levels in blood of non-medicated chickens were uniformly below the detection limit on each of the three bleeding days. Only one drug blood level from medicated birds was found to be below the limit of detection.

Mean assayed drug blood levels were not significantly different between the two drug treatment groups or among the three bleeding days but were significantly different between male and female chickens (0.140 and 0.169, respectively; p = 0.019).

6. Conclusions:

Results of this study indicate that SOLU-TET 324 is bioequivalent to the NAS/NRC reviewed reference product, VETQUAMYCIN-324.

7. Adverse Reactions:

No adverse reactions which could be attributed to treatment were seen in this study.

8. Special Issues:

The safety and effectiveness of this product are based upon the NAS/NRC Drug Efficacy Study Implementation (DESI) review of and bioequivalency to a pioneer product (35 FR 10966-10967, July 8, 1970). The product was initially found to be "probably effective" in the oral treatment of specified diseases in poultry caused by pathogenic microorganisms susceptible to tetracycline and later found to be effective in light of labeling revisions.

V. ANIMAL SAFETY

The safety of tetracycline hydrochloride to the target species has been confirmed through many years of worldwide use and is recognized as safe under the conditions outlined in the NAS/NRC review of the product regarding indications for use, route of administration, recommended dosages and limitations of use as specified in 35 FR 10966-10967, July 8, 1970. The Food and Drug Administration concurred with the NAS/NRC Drug Efficacy Study Implementation Group which found tetracycline to be a safe antibiotic. The safety of this product is also supported by the absence of any adverse effects in this parallel bioequivalency study and during the treatment period for the tissue residue study.

 

VI. HUMAN SAFETY

Safe Concentration of Residues: The tolerance established by publication in the Code of Federal Regulations (CFR) for residue of tetracycline in edible tissues of chickens under 21 CFR 556.720 is 0.25 part per million (ppm).

Tissue Residue Study

1. A tissue residue depletion study was performed by Colorado Animal Research Enterprises Inc., Fort Collins, CO.

2. General:

a. Purpose:

To determine the appropriate withdrawal time for SOLU-TET 324 by studying TCH depletion in edible broiler tissues after administration of the product to broiler chickens for the maximum labeled treatment duration of 14 days at the NAS/NRC DESI recommended level of 25 mg TCH/lb. body weight per day.

b. Test Animals: A total of 60 Peterson X Acre strain broilers were used as follows:

  Group 1 (SOLU-TET): 27 male birds
  Group 2 (SOLU-TET): 27 female birds
  Group 3 (Control): 3 male birds (Nonmedicated)
  Group 4 (Control): 3 female birds (Nonmedicated)

Each group was housed in adjacent pens on wood shavings over concrete flooring in one room of a building. Randomization within sex was done according to weight stratification so that each treatment group had approximately the same total body weight.

Of the 60 birds used, six (3 males and 3 females) were nonmedicated negative controls and 54 (27 males and 27 females) were treated with SOLU-TET 324.

c. Treatment Schedule:

Treatments were administered continuously for 14 consecutive days. Sampling was performed on birds at 0, 6, 12, 24, 36, 48, 60, 72 and 96 hours after treatment withdrawal.

d. Parameters Measured:

The following parameters were measured: individual body weights, feed and water consumption, feed efficiency, drug consumption and TCH residue levels in skin with adhering fat, breast and thigh muscle, abdominal fat and liver.

3. Results:

Mean assayed TCH tissue residues of SOLU-TET treated birds are summarized in Table 4. Laboratory detection limits of TCH in the tissues ranged from 0.116-0.185 ppm. As a point of reference, the tolerance for TCH in tissues is 0.25 ppm (21 CFR 556.720).

Only at the 0 hour withdrawal sampling did the average drug in any tissue exceed the 0.25 ppm tolerance limit; liver tissue averaged 0.584 ppm and muscle tissue averaged <0.265 ppm at this sampling. No drug was detected in any of the fat specimens from this sampling and the average level in skin tissue was < 0.133 ppm.

Table 4. Mean (male and female combined) tissue residue levels of tetracycline hydrochloride (TCH) from SOLU-TET medicated broilers at various periods of withdrawal from medication.

Mean Assayed TCH Residue (ppm)

Hours Skin w/ White Withdrawn Fat Liver Muscle Fat

0 <0.153 0.584 <0.265 a ±0.354 6 <0.126 <0.170 a a 12 <0.129 <0.178 a a 24 a <0.171 a NA 36 <0.125 <0.178 a NA 48 a <0.185 NA NA 60 a <0.199 NA NA 72 a a NA NA 96 a a NA NA

a All samples at the indicated collection interval were below lower limit of measurement. NA = Not assayed since all tissues at two more previous samplings were below lower limit of measurement. Lower Limits of Measurement (ppm): Skin w/Fat = 0.116-0.128; Liver = 0.146-0.185; White Muscle = 0.132-0.154; Fat = 0.116.

At 6 hours withdrawal and beyond, only two tissue specimens contained more than 0.25 ppm tetracycline: 0.260 ppm in the liver specimen from a single male at 6 hours withdrawal and 0.269 ppm in liver tissue from a single male at 60 hours withdrawal. Abdominal fat tissue was assayed only at the 0, 6 and 12 hour withdrawal intervals. Since none of the fat samples tested at those three successive intervals contained quantifiable levels of tetracycline, that tissue was not assayed at subsequent samplings in accordance with protocol provisions. For the same reason, muscle tissue was only assayed through the 36 hour withdrawal interval. All skin tissue specimens contained less than 0.25 ppm tetracycline and all skin specimens at 48 hour withdrawal and beyond did not contain quantifiable levels of the drug.

The above data are adequate to support a 4-day withdrawal period.

Regulatory Methods:

The regulatory analytical method used for detection of residues of tetracycline hydrochloride is a microbiological test using Bacillus cereus suspension. The method is a modification of the official method published by the Food and Drug Administration, "Antibiotic Residues in Milk, Dairy Products, and Animal Tissues: Methods, Reports, and Protocols", revised October 1968, reprinted December 1974.

The method was demonstrated to be comparable to the official method by the research laboratory. The detection limits developed by the laboratory were well below the published tolerance level of 0.25 part per million.

 

VII. Agency Conclusions:

The data submitted in support of this original NADA satisfy the requirements of section 512 of the Act and demonstrate that Solu-Tet 324 (tetracycline hydrochloride soluble powder), when used under its proposed conditions of use, is safe and effective for the labeled indications. The approval provides for the use of tetracycline hydrochloride soluble powder in chickens for the control of chronic respiratory disease (CRD) and air sac infection caused by Mycoplasma gallisepticum and Esherichia coli, and infectious synovitis caused by Mycoplasma synoviae susceptible to tetracycline.

The firm submitted a bioequivalency study and a tissue residue depletion study in support of the approval and has shown its product to be bioequivalent to the pioneer product which was reviewed by NAS/NRC/DESI.

The tolerance for tetracycline is codified in section 21 CFR 556.720 and is established at 0.25 ppm for negligible residues in uncooked edible tissues of chickens. A four-day withdrawal period has been granted.

Tetracycline hydrochloride soluble powders for use in food-producing animals are currently on the market as over-the-counter products. Accurate diagnosis can be made with a reasonable degree of certainty by the layman, and the conditions for use prescribed on the labeling are likely to be followed in practice. Therefore, the Center for Veterinary Medicine has concluded that this product should remain under over-the-counter marketing status.

Under the Generic Animal Drug and Patent Term Restoration Act of 1988, this approval does not qualify for an exclusivity period. The reports supporting the approval do not qualify as "new clinical or field investigations" under that section due to earlier approvals for the product based upon similar investigations.