Approval Date: July 7, 1994
Freedom of Information Summary
NADA 139-472
I. GENERAL INFORMATION:
NADA 139-472 Sponsor: Fermenta Animal Health Company
Generic Name: tiamulin hydrogen fumarate Trade Name: DENAGARD; Antibiotic Premix, DENAGARD; 5 Medicated Premix, DENAGARD; 10 Medicated Premix (Type A Medicated Articles) Marketing Status: Over the Counter (OTC) Effect of Supplement: To add the label claim for treatment of swine dysentery at 200 g/ton for 14 days. II. INDICATIONS FOR USE
For treatment of swine dysentery associated with Serpulina(formerly Treponema) hyodysenteriae susceptible to tiamulin; for control of swine dysentery associated with Serpulina(formerly Treponema) hyodysenteriaesusceptible to tiamulin; for increased weight gain and improved feed efficiency from weaning to market.
III. DOSAGE
A. DOSAGE FORM premix B. ROUTE OF ADMINISTRATION oral, via feed C. RECOMMENDED DOSAGES: 200 g/ton for treatment of swine dysentery; 35 g/ton for control of swine dysentery; 10 g/ton for increased weight gain and feed efficiency from weaning to market weight.
IV. EFFECTIVENESS
Pivotal studies conducted to establish effectiveness of tiamulin for treatment of swine dysentery are summarized below.
a. Dose Determination Study
Investigators:
Beverly George, Ph.D. and Diane Fagerberg, Ph.D.
Colorado Animal Research Enterprises
6200 East County Road 56
Fort Collins, Colorado 80524
This controlled dose titration study with randomized block arrangement of treatments utilized 64 six-week old crossbred pigs (33 barrows, 31 gilts) which were allotted four per pen on the basis of weight and gender to 16 pens. Infection was accomplished by administering a growth culture of Serpulina(formerly Treponema) hyodysenteriae(strain B 204) via stomach tube to all pigs. When clinical signs of dysentery (diarrhea, blood feces) subsequently appeared, medication was begun. Average weight at the start of test medication was 39.6 pounds.
The test treatments were tiamulin hydrogen fumarate in feed at 100, 200 and 300 g/ton. Control pigs were not medicated. Medication continued for 14 days and was followed by a 21-day post-medication observation period.
The major criteria of effectiveness are listed in Table 4. 1 which presents treatment mean values over the 35-day test.
(Eds. note: The following table consists of 5 columns.)
Table 4.1. Decision variables in dose determination study MDA 062788 tiamulin (g/ton) Criteria (Days 1-35) 0 100 200 300 Deaths due to swine dysentery 2 2 0 1 Average daily gain, lb 0.94 1.30 1.54 1.54 Average daily feed, lb 2.65 3.27 3.71 3.69 Gain/lb of feed .353 .398 .417 .417 Pig days with diarrhea, % 33.7 12.4 14.8 6.6 Pig days with bloody feces, % 17.4 5.6 2.1 1.1No signs of toxicity or of adverse reaction to tiamulin were observed.b. Dose Determination Study
Investigator:
Gerald Duhamel, D.V.M., Ph.D.
Department of Veterinary Science
University of Nebraska, East Campus
Lincoln, Nebraska 68583
Eighty crossbred pigs (48 barrows, 32 gilts) were used in this controlled dose titration study of randomized block design. The pigs were infected by administering via stomach tube a homogenate of cecal and colon tissues taken from donor pigs with clinical signs of the disease. When clinical signs appeared among test pigs, they were allotted to pens on the basis of disease severity, weight and gender. There were 16 pens of five pigs each with the overall average weight at the start of medication 50.7 pounds.
The test treatments were tiamulin hydrogen fumarate at 0 (nonmedicated control), 100, 200 and 300 g/ton for 14 days followed by a 3-week post-medication observation period. Major criteria of effectiveness are listed in Table 4.2 which shows treatment mean values for the total 35-day test period.
(Eds. note: The following table consists of 5 columns.)
Table 4.2. Decision variables in dose determination study MDA 121288 tiamulin, g/ton Criteria (Days 1-35) 0 100 200 300 Deaths due to swine dysentery 3 3 2 2 Average dally gain, lb 1.15 1.71 1.90 1.72 Average dally feed, lb 3.33 3.92 4.05 3.52 Gain/feed .346 .436 .470 .479 Pig days with diarrhea, % 60.2 21.1 10.7 10.8 Pig days with bloody feces, % 13.6 4.2 2.4 4.6No signs of toxicity or adverse reaction to tiamulin were observed in this trial.c. Analysis of Dose Determination Studies
The Colorado and Nebraska studies were combined and an analysis of variance was done on the percent pig days with diarrhea by pens for test Days 1 to 14 using an arcsin square root transformation. For Days 1 to 14 all three dose levels were significantly different from the control (p<.01). Linear plateau modeling was done for Days 1 to 14. Two models appeared to be almost equal with both having significant coefficients and high sq R (.98). The F-value for residuals were not significant. Thus, the model with fewer parameters was chosen. This was the linear plateau model III(2) having a plateau at 200 g/ton.
It was concluded that 200 g/ton is an acceptable dose level of tiamulin hydrogen fumarate in feed for the treatment of swine dysentery based on the parameter pig days with diarrhea.
d. Dose Confirmation Study
Investigator:
Camille Moore, D.V.M., M.S.
2505 Place Guilbault, C.P. 1313
Saint-Cesaire, Quebec, CANADA J0L 1T0
Sixty crossbred pigs, 30 gilts and 30 barrows, were allotted to replicate pen groups of five on the basis of gender and weight. Barrows and gilts were penned separately in this test of randomized block design. Six pens were infected nonmedicated controls and six pens were treated with tiamulin hydrogen fumarate at 220 ppm (200 g/ton) in feed for 14 days beginning when clinical signs of swine dysentery appeared subsequent to deliberate infection by feeding colon tissues from donor pigs from a herd with a natural outbreak of the disease. Average initial weight at the start of test feeding was 47.1 pounds (21.4 kg).
Major criteria of effectiveness are listed in Table 4.3 which presents treatment average values determined over the 14-day test medication period plus a 14-day post-medication observation period.
(Eds. note: The following table consists of 3 columns.)
Table 4.3. Decision variables in dose confirmation trial MDA 021390-C-1 tiamulin (g/ton) Criteria (Days 1-28) 0 200 Deaths due to swine dysentary 6 1 Average daily gain, lb -.27 1.43 Average daily feed, lb 1.19 3.28 Gain/feed (lb) -.305 .436 Pig days with diarrhea, % 93.0 16.1 Pig days with bloody feces, % 44.0 0.5Mortality was 20% in the controls and 3.3% in the treated group. This mortality was moderate for swine dysentery. When mortality was combined across pens by treatment, a Fisher's Exact test showed that the death rate between the two groups was significant (p=.05). Percent pig days diarrhea for test Days 8-14 showed that the treatments were significantly different (p<.01) with treatment means of 13.0% for treated and 94.3% for controls. Bloody feces for the same period also showed significant treatment differences (p<.01) with means 0.0% for treated and 47.1% for controls.No signs of toxicity or adverse reactions to tiamulin were observed in this trial.
It was concluded that feeding tiamulin hydrogen fumarate at 200 g/ton was effective for treatment of swine dysentery based on the parameters of mortality, pig days with diarrhea, and pig days with bloody feces.
e. Pivotal Field Trial
Investigator:
Kent Schwartz, D.V.M., M.S.
TEAM Associates
R.R. #2, Box #92
Story City, Iowa 50248
Eighty crossbred pigs (32 barrows, 48 gilts) from a herd experiencing a natural outbreak of swine dysentery were used. Swine dysentery associated with Serpulina(formerly Treponema) hyodysenteriaewas confirmed present on the basis of clinical signs and on the basis of gross lesions and the presence of Serpulinain colon tissues at necropsy of four contemporary pigs.
The pigs were allotted five per pen to 16 pens on the basis of clinical signs, weight and gender. There were two test treatments, tiamulin hydrogen fumarate at 0 (nonmedicated controls) and 200 g/ton for 14 days followed by a 21-day post-medication observation period, in this controlled test of randomized block design. Average initial weight was 65.2 pounds.
Major criteria of effectiveness are listed in Table 4.4 together with treatment mean values over the total 35-day test period. Data were evaluated by analyses of variance with the pen as the experimental unit.
(Eds. note: The following table consists of 3 columns.)
Table 4.4. Decision variables in clinical trial MDA 092189 tiamulin (g/ton) Criteria (Days 1-35) 0 200 Deaths due to swine dysentery 9 0 Average dally gain, lb .93 1.64 Average dally feed, lb 3.95 4.86 Gain/feed .231 .339 Pig days with diarrhea, % 34.1 11.8 Pig days with bloody feces, % 13.9 1.5Mortality due to swine dysentery was 22.5% in the controls and 0.0% in the treated group. This mortality was moderate for swine dysentery. When mortality was combined across pens by treatment, a Fisher's Exact test showed that the death rate between the two groups was significant (p<.01). An analysis of variance was done on the percent pig days with diarrhea by pens for test Days 1 to 14 using an arcsin square root transformation. For Days 1 to 14 the dose levels were significantly different (p<.01). The average percent pig days with diarrhea for Days 1 to 14 was 52.2% for the controls and 23.8% for the 200 g/ton dose level.No signs of toxicity or adverse reaction to tiamulin were observed in this trial.
It was concluded that feeding tiamulin hydrogen fumarate at 200 g/ton for 14 days was effective in treating a natural outbreak of swine dysentery based on the parameters of mortality and pig days with diarrhea.
f. Corroborative Effectiveness Studies
Investigator:
Robert Friendship, D.V.M., M.S.
Clinical Research Building
University of Guelph
Guelph, Ontario, CANADA NIH 6H8
Clinical trial: Forty-eight crossbred pigs, 25 barrows and 23 gilts, were allotted 6 per pen based on weight and gender. Following a 24-hour fast the pigs were fed ground colon tissue and contents taken from pigs with clinical signs of the disease in commercial herds with histories of recent confirmed outbreaks of swine dysentery. When the majority of pigs subsequently exhibited clinical signs they were weighed and the test was initiated. There were four pens of six pigs as nonmedicated controls and four pens of six pigs fed tiamulin hydrogen fumarate in feed at 220 ppm (200 g/ton) for 14 days followed by an additional 14 days post-medication observation period. Average weight at the start of the test period was 30.8 pounds (14 kg).
The major criteria of effectiveness are listed in Table 4.5. Treatment average values shown in Table 4.5 are for the total 28-day test period. Data were analyzed by analyses of variance for a completely random test using the pen as the experimental unit.
(Eds. note: The following table consists of 3 columns.)
Table 4.5. Decision variables in dose confirmation trial MDA 021390-C-2 tiamulin (g/ton) Criteria (Days 1-28) 0 200 Deaths due to swine dysentery 14 1 Average daily gain, lb .12 .90 Average daily feed, lb 1.80 2.20 Gain/feed -.131 .405 Pigs with diarrhea, % 47.5 4.6 Pig days with bloody feces, % 10.7 0.6Mortality was 58.3% in the controls and 4.2% in the treated group. This mortality was severe for swine dysentery. When mortality was combined across pens by treatment, a Fisher's Exact Test showed that the death rate between the two groups was significant (p<.01).This study supports the effectiveness of tiamulin hydrogen fumarate at 200 g/ton in treating pigs with swine dysentery based on the parameter of mortality.
No signs of toxicity or adverse reactions to tiamulin were observed in this trial.
V. ANIMAL SAFETY
a. Pivotal Safety Study for Target Species (1X, 3X, 5X)
A subacute toxicity study was conducted at the Fermenta Animal Health Company Research Center, 1512 Webster Court, Fort Collins, CO 80524 by S. Rogers and S. L. Stroh, D.V.M. The purpose of the study was to investigate the margin of safety of feeding tiamulin at 200 g/ton to pigs for 14 days. The study was conducted in accordance with Good Laboratory Practices (GLP, 21 CFR Part 58).
Thirty-six male and female crossbred pigs averaging 96.5 lb were used in the trial. Four males and four female pigs were fed tiamulin at 200 g/ton (1X), 600 g/ton (3X) and 1000 g/ton (5X) for 42 days or 3 times the recommended duration. Twelve nonmedicated control pigs (7 males, 5 females) were included in the trial.
Clinical observations for signs of toxicity and rectal temperature determinations were made twice daily from test Days -2 to 41. Blood, urine and fecal samples were collected for examination from each pig on test Days 0, 14, 28 and 42.
Hematology examinations included red blood cell count, total white blood cell count and differential white cell count, platelet count, packed cell volume, mean corpuscular volume, hemoglobin concentration and partial prothrombin time. Blood serum chemistry examinations included the determination of calcium, phosphorus, sodium, potassium, chlorine, blood urea nitrogen, total protein, total and direct bilirubin, albumin, globulin, glucose, amylase, aspartate amino transferase and creatinine concentrations.
Urinalysis included determination of pH, specific gravity, protein, glucose, ketone, bilirubin and urobilinogen and examination for sediment and an evaluation of color and consistency. Fecal analyses included evaluation of color and consistency, test for occult blood and microscopic examination.
After 42 days on test the pigs were killed and thoroughly examined for gross lesions. The spleen, heart, liver, kidneys, thyroid and adrenals were weighed. A total of 36 tissues were collected and placed in fixative for possible microscopic examination.
Tissues from all pigs fed tiamulin at 1000 g/ton and their corresponding nonmedicated controls were examined microscopically.
During the 42 day feeding period pigs fed tiamulin at 200, 600 and 1000 g/ton gained 33%, 25% and 22% more weight; ate 19%, 13% and 35% more feed daily; and were 10%, 7% and 10% more efficient, respectively, than nontreatment control groups. No signs of toxicity or adverse reaction to the drug were observed clinically.
Overall group mean values for hematology and for blood serum chemistry values were generally well within published normal values or not significantly different from control pig values. No distinct trends with dose level or with time were found. Urinalysis and fecal analysis found a small number of pigs in both the nonmedicated and the medicated groups with blood in urine or in feces periodically. Differences in organ weights between treatments were not large and no test article-related findings were observed in gross examination of tissues of all pigs at necropsy or in microscopic examination of the tissues of pigs fed tiamulin at 1000 g/ton (5X level).
It was concluded that feeding tiamulin at 200 g/ton to pigs for 14 days is safe.
b. Corroborative Safety Studies
1) Additional results of the studies of the safety of administering tiamulin hydrogen fumarate orally to pigs at various dose levels and for varied durations are described in FOI summaries to NADA 134-644 and to NADA 139-472 incorporated by reference. In particular, the FOI summary to NADA 139-472 describes the results of a safety trial in which pigs were fed tiamulin at levels to 200 g/ton for 99 days with no adverse drug related effects detected.
2)A preliminary (pilot) subacute study was conducted by S. Rogers at the Fermenta Animal Health Company Research Center, 1512 Webster Court, Fort Collins, Colorado 80524 to determine if pigs would consume feed containing tiamulin hydrogen fumarate at levels up to 1000 g/ton and if any signs of toxicity would appear within four weeks.
Twelve crossbred pigs averaging 92.6 pounds were allotted to three pens of four on the basis of weight and gender. Treatments, randomly assigned to pens, were (1) nonmedicated control, (2) tiamulin at 600 g/ton and (3) tiamulin at 1000 g/ton. The pigs were observed daily for signs of toxicity, adverse reactions and illness. Individual body weights and the feed consumption of pen groups were determined weekly for four weeks when the test ended.
Pigs fed tiamulin at 600 g/ton and at 1000 g/ton gained 32% and 21% more weight, consumed 26% and 15% more feed and were 4% and 5% more efficient, respectively, than nonmedicated control pigs over the total 28-day test. No signs of toxicity or adverse reactions were observed.
It was concluded that feeding tiamulin hydrogen fumarate at levels up to 1000 g/ton for 28 days did not depress feed consumption and did not result in any signs of toxicity.
VI. HUMAN FOOD SAFETY
a. Toxicity Tests
Short-term toxicity studies in mice, rats, dogs, pigs, chickens and turkeys as well as a one-year feeding study in dogs, a lifetime feeding study in mice, a lifetime feeding study in rats, a three-generation reproduction and teratology study in rats, fertility studies in male and female rats and a teratology study in rabbits are discussed in detail in the FOI Summary for NADA 134-644
b. Safe Concentration of Total Residues
The safe concentration of total residues of tiamulin is established at 3.6 ppm in muscle, 10.8 ppm in liver and 14.4 ppm in kidney and fat as published in 21 CFR 556.738. The FOI Summary for NADA 134-644 includes a discussion of the calculations of these values.
c. Total Residue Depletion and Metabolism Studies
Results of metabolism studies of tiamulin in rats and the target species (swine) are found in the FOI summary for NADA 134-644 as well as a discussion of the major metabolites, selection of the marker residue (8-alpha-hydroxymutilin) and regulatory (GC) and confirmatory (GC-MS) methods for the detection of the marker substance in the target tissue, swine liver.
d. Tolerance for the Marker Residue
The established tolerance for the marker residue, 8-alpha-hydroxymutilin, is 0.4 ppm in swine liver. The basis for selecting this marker and the tolerance in liver is discussed in the FOI Summary for NADA 134-644.
e. Study Establishing the Withdrawal Period
A study was conducted by S. Rogers and S. Stroh, D.V.M., at Fermenta Animal Health Company Research Center, 1512 Webster Court, Fort Collins, Colorado 80524. The purpose of the study was to determine the depletion of tiamulin in swine following administration of the antibiotic in feed at 200 g/ton for 14 days to establish a withdrawal time.
Twenty-four crossbred pigs averaging 47 lb were used. Ten males and 10 females were self-fed feed containing tiamulin hydrogen fumarate at 200 g/ton for 14 days. Four pigs were fed nonmedicated feed. After 14 days of test drug feeding the medicated feed was withdrawn and replaced with nonmedicated control feed. At 12, 24, 48, 72 and 96 hours after the end of medication two males and two females were killed and their livers excised for analyses of the marker residue, 8-alpha-hydroxymutilin, using Fermenta's alternate determinative method. Both the original and alternate methods are gas chromatography procedures, and the alternate method differs from the original in only minor aspects (e.g. a megabore GC column was substituted for a packed column, using the same silicone liquid phase, and toluene was substituted for benzene). The alternate method was reviewed and accepted by FDA. The results of these analyses are summarized in Table 6.1.
(Eds. note: The following table consists of 3 columns.)
Table 6.1 Residues of 8-alpha-hydroxymutilin in livers of swine fed 200 g tiamulin hydrogen fumarate/ton for 14 days. Withdrawal Number of Mean ±SD Time (hours) Animals (ppb) 12 4 595±185 24 4 715±320 48 4 384±156 72 4 271±116 96 4 199±68The 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 7 days was assigned for swine fed 200 g tiamulin hydrogen fumarate/ton for 14 days.f. Regulatory Method
The regulatory assay method for determining 8-alpha-hydroxymutilin, the tiamulin marker in swine liver involves extraction, derivatization and then quantitation by gas chromatography (GC). A confirmatory method involves gas chromatography-mass spectrometry (GC-MS). In method validation conducted prior to test sample analyses in this residue depletion study, an overall recovery of 91±4% was obtained from control tissues spiked with 8-alpha-hydroxymutilin at 200, 400 and 800 ppb. The limit of quantitation was 50 ppb.
The regulatory analytical methods for determining 8-alpha-hydroxymutilin in swine liver are on file at the Center for Veterinary Medicine, Food and Drug Administration, HFV-199, 5600 Fishers Lane, RockviIIe, 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 (the Act) and 21 CFR Part 514 of the implementing regulations. The data demonstrate that tiamulin Type A medicated article is effective for the treatment of swine dysentery associated with Serpulina(formerly Treponema) hyodysenteriae when administered in feed for 14 days at a level of 200 grams tiamulin per ton.
A tolerance for the tiamulin marker residue, 8-alpha-hydroxymutilin, is established in swine at 0.4 ppm in liver, the target tissue (21 CFR 556.738) to ensure safe concentrations of total residues of tiamulin of 3.6, 10.8, 14.4 and 14.4 ppm in muscle, liver, kidney, and fat. For a discussion of the tolerance calculation see the FOI Summary for NADA 134-644.
A withdrawal period of 7 days was calculated from a rate depletion study of tiamulin residues in swine, following the administration of DENAGARD® Type A medicated article at a level of 200 g/ton for 14 consecutive days.
Labeling directions are adequate to enable laypersons to appropriately diagnose and subsequently use this product to treat swine dysentery associated with Serpulina(formerly Treponerna) hyodysenteriae.DENAGARD® Type A medicated article is currently approved for over-the-counter (OTC) use in swine as described in 21 CFR 558.600.
Under the Center's supplemental approval policy (21 CFR 514.106(b)(2)(iii, iv, v and x)), this is a Category II change. The approval of this change is not expected to have any adverse effect on the safety or effectiveness of this new animal drug. Accordingly, this approval did not require a reevaluation of the safety and effectiveness data in the parent application.
Under Section 512(c)(2)(F)(iii) of the Act, this approval for food-producing animals qualifies for THREE (3) years of marketing exclusivity beginning on the date of approval because the supplemental application contains reports of new clinical or field investigations (other than bioequivalence or residue studies) essential to the approval of the application and conducted or sponsored by the applicant. The THREE years of marketing exclusivity applies only to the claim for the treatment of swine dysentery, for which the supplemental application was approved.
VIII. LABELLING(Attached)
1. DENAGARD® 10 Medicated premix package label
2. DENAGARD® 5 Medicated premix package label
3. Bluebird Swine Feed (Type B) Medicated Cautions Statements, Preparation and Use Directions
4. Bluebird COMPLETE SWINE RATION (Type C) Medicated (10 g/ton) Package Label
5. Bluebird COMPLETE SWINE RATION (Type C) Medicated (35 g/ton) Package Label
6. Bluebird COMPLETE SWINE RATION (Type C) Medicated (200 g/ton) Package Label
Copies of these labels may be obtained by writing to the:
Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857
Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.