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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 046-592 BMD® - supplemental approval (April 29, 1991)

I. GENERAL INFORMATION:

NADA046-592
Sponsor:A. L. Laboratories, Inc.
One Executive Drive
P. O. Box 1399
Fort Lee, NJ 07024
Generic Name:bacitracin methylene disalicylate
Trade Name:BMD ®
Marketing Status:Over the Counter (OTC)
Effect of Supplement:This supplement adds the claim for the control of clostridial enteritis caused by C. perfringens in suckling piglets born to sows medicated with BMD.

II. INDICATIONS FOR USE

For control of clostridial enteritis caused by C. perfringens in suckling piglets when fed to sows from 14 days before through 21 days after farrowing on premises with a history of clostridial scours.

III. DOSAGE:

A.DOSAGE FORMBMD Type A Medicated Articles
Concentrations: 25, 30, 40, 50, 60 and 75 grams/lb.
B.ROUTE OF ADMINISTRATIONFeed at a level of 250 grams/ton of feed from 14 days before through 21 days after farrowing.
C.RECOMMENDED DOSAGES:Orally in the feed.

IV. EFFECTIVENESS:

Well-controlled range finding studies using pregnant sows in an environment infected with Clostridium perfringens were conducted under investigational new animal drug regulations to establish an optimal dose/duration of administration profile. Sows (with controls) were fed BMD at levels of 0, 50, 150 and 250 grams/ton of feed to determine an optimal dose as measured by control of clostridial enteritis in piglets and increased rate of weight gain in said piglets. Results from these studies showed that the 250 g/ton dose level was better than the 150 g/ton dose level in the primary efficacy parameters of scour scores and mortality due to clostridium, and these parameters were near maximum efficacy at the 250 g/ton dose.

Four well-controlled replicated studies were conducted in Illinois, Minnesota, Missouri and Nebraska to confirm the efficacy of BMD for control of clostridial enteritis in neonatal pigs. These trials, conducted among natural outbreaks of the disease, entailed feeding pregnant sows of varying parity BMD at 250 grams/ton of feed for a minimum of 14 days and a maximum of 18 days before through 21 days after farrowing. Since the sow was the experimental unit, piglet mortality due to clostridial enteritis was expressed as a percent of pigs born alive and average daily gain and scouring score were expressed as a litter average. Scour score ranged from 1 (normal) to 4 (severe diarrhea). Details and results of the individual trials follow:

Pivotal Study No. 1 - Trial MO-S-32-88

A. Investigator:

Dr. James Lucas
605 State Street
Bedford, IA 50833

B. Location of Trial: Hopkins, MO

C. General Design of the Trial:

Purpose of Study: To establish that suckling piglets born to sows fed BMD at 250 grams/ton of feed for 14 days prior to and 21 days after farrowing experienced less morbidity and mortality and increased rate of weight gain compared to offspring of unmedicated sows under conditions where clostridial enteritis due to C. perfringens is present.

Test Animals: Pregnant sows of locally popular crossbreed at least 2-1/2 weeks before farrowing were used. Animals were ranked by farrowing date and paired off, each pair treated and control were assigned randomly to a block. Treatments were assigned randomly to the pen with the restriction that there was one pen per block for each of the two treatments. Health status of the piglets was the criterion of efficacy as measured by percent mortality, degree of diarrhea observed and rate of weight gain.

Treatment: Pregnant sows were given feed medicated with BMD at a level of 0 and 250 grams/ton of feed - 13 animals per treatment.

Results:

The medicated group of sows (250 grams/ton) lost fewer pigs from all causes than the controls, (7 vs 31), and fewer from Clostridium perfringens, (2 vs 24), even though there were more sows in the treatment group (13 vs 10). There was a higher incidence of scours in the control groups. The pigs in the medicated group weighed more at weaning. Results are summarized in the table below.

Effect of Feeding BMD to Pregnant Sows on Mortality Due to C. perfringens,
the Average Daily Gain and the Scouring of Newborn Piglets

Piglet Performance(a)

BMD,g/tonNo.SowsMortality,%ADG,lb/dayScour Scores
010 (b)27.30.4201.90
250132.00.4681.06

(a) The sow is the experimental unit. Percent mortality due to C. perfringens, ADG and scour score are per litter data for piglets.

(b) Three control (0 g/ton) sows did not farrow within the required time period.

Pivotal Study No. 2 - Trial IL-S-33-89

A. Investigator:

Dr. Dennis Mefford
P. O. Box 371
Oneida, IL 61467

B. Location of Trial: Woodhull, IL

C. General Design of the Trial:

Purpose of Study: To establish that suckling piglets born to sows fed BMD at 250 grams/ton of feed for 14 days prior to through 21 days after farrowing experienced less morbidity and mortality and increased rate of weight gain compared to offspring of unmedicated sows under conditions where clostridial enteritis due to C. perfringens is present.

Test Animals: The test system was pregnant sows in individual test pens on a practical swine farm where the disease is prevalent. The sows were on test from approximately 2.5 weeks pre-farrowing to 3 weeks post- farrowing. Animals were ranked by farrowing date and paired off, each pair treated and control were assigned randomly to a block. Treatments were assigned randomly to the pen with the restriction that there was one pen per block for each of the two treatments. Health status of the piglets was the criterion of efficacy as measured by percent mortality, degree of diarrhea observed and rate of weight gain.

Treatment: Pregnant sows were given feed medicated with BMD at a level of 0 and 250 grams/ton of feed - 12 animals per treatment.

Results:

The BMD treated sows weaned 8.83 pigs per litter. The control sows weaned 6.77 pigs per litter. This 2.06 pig increase in weaning average was primarily due to a 1.66 pig per litter reduction in death loss due to clostridial diarrhea. The pigs from the BMD treated sows had only slightly higher 21-day weights per pig. The reduced weaning average of over two pigs per litter in the control sows probably reduced the competition for available milk allowing each pig more nutrition. However, litter weaning weights were higher for the BMD treated sows due to the increase in the average number of pigs weaned.

The improved average number of pigs weaned and weaning weights in conjunction with a reduction in pigs requiring treatment for clostridial scours as evidenced by the improvement in fecal consistency scores, shows that BMD treatment of the sows is an effective method of controlling clostridial enteritis. Results are summarized in the table below.

Effect of Feeding BMD to Pregnant Sows on Mortality Due to C. perfringens,
the Average Daily Gain and the Scouring of Newborn Piglets

Piglet Performance(a)

BMD,g/tonNo.SowsMortality,%ADG,lb/dayScour Scores
013 (b)21.10.4511.95
250127.20.4551.35

(a) The sow is the experimental unit. Percent mortality due to C. perfringens, ADG and scour score are per litter data for piglets.

(b) One extra control sow included.

Pivotal Study No. 3 - Trial MN-S-34-89

A. Investigator:

Dr. James Cecil
101 19th Street
Spirit Lake, IA 51360

B. Location of Trial: Lakefield, MN

C. General Design of the Trial:

Purpose of Study: To establish that suckling piglets born to sows fed BMD at 250 grams/ton of feed for 14 days prior to through 21 days after farrowing experienced less morbidity and mortality and increased rate of weight gain compared to offspring of unmedicated sows under conditions where clostridial enteritis due C. perfringens is present.

Test Animals: The test system was pregnant sows in individual test pens on a practical swine farm where the disease is prevalent. The sows were on test from approximately 2.5 weeks pre-farrowing to 3 weeks post- farrowing. Treatments were assigned randomly to the pen with the restriction that there was one pen per block for each of the two treatments. Health status of the piglets was the criterion of efficacy as measured by percent mortality, degree of diarrhea observed and rate of weight gain.

Treatment: Pregnant sows were given feed medicated with BMD at a level of 0 and 250 grams/ton of feed - 11 animals per treatment.

Results:

The results of feeding BMD to pregnant sows on the mortality due to clostridial enteritis, average daily gain and scouring of newborn piglets are summarized in the table below. Mortality declined from 25.4% in controls to 0% in piglets from sows fed BMD. Scour score was also improved from 1.46 in piglets from control sows to 1.00 in piglets from sows fed BMD. (Scour score 1 = no diarrhea, 4 = greatest degree of diarrhea.) Average daily gain was improved from 0.429 lb/day in controls to 0.525 lb/day in piglets from sows fed BMD.

Effect of Feeding BMD to Pregnant Sows on Mortality Due to C. perfringens,
the Average Daily Gain and the Scouring of Newborn Piglets

 

Piglet Performance(a)

BMD,g/tonNo.SowsMortality,%ADG,lb/dayScour Scores
011(10) (b)25.40.4291.46
250110.00.5251.00

(a) The sow is the experimental unit. Percent mortality due to C. perfringens, ADG and scour score are per litter data for piglets.

(b) Average daily gain and scour score data were not available for one control litter due to 100% mortality.

Pivotal Study No. 4 - Trial NE-S-35-89

A. Investigator:

Dr. Roy Schultz
RR 1, Box 46
Avoca, IA 51521

B. Location of Trial: Herman, NE

C. General Design of the Trial:

Purpose of Study: To establish that suckling piglets born to sows fed BMD at 250 grams/ton of feed for 14 days prior to through 21 days after farrowing experienced less morbidity and mortality and increased rate of weight gain compared to offspring of unmedicated sows under conditions where clostridial enteritis due to C. perfringens is present.

Test Animals: The test system was pregnant sows in individual test pens on a practical swine farm where the disease is prevalent. The sows were on test from approximately 2.5 weeks pre-farrowing to 3 weeks post- farrowing. Treatments were assigned randomly to the pen with the restriction that there was one pen per block for each of the two treatments. Health status of the piglets was the criterion of efficacy as measured by percent mortality, degree of diarrhea observed and rate of weight gain.

Treatment: Pregnant sows were given feed medicated with BMD at a level of 0 and 250 grams/ton of feed - 11 animals per treatment.

Results: The results of feeding BMD to pregnant sows on the mortality due to clostridial enteritis, average daily gain and scouring of newborn piglets are summarized in the table below. Mortality declined from 22.2% in controls to 1.5% in piglets from sows fed BMD. Scour score was also improved from 1.92 in piglets from control sows to 1.08 in piglets from sows fed BMD. (Scour score 1 = no diarrhea, 4 = greatest degree of diarrhea.) Average daily gain was improved from 0.380 lb/day in controls to 0.494 lb/day in piglets from sows fed BMD.

Effect of Feeding BMD to Pregnant Sows on Mortality Due to C. perfringens,
the Average Daily Gain and the Scouring of Newborn Piglets

Piglet Performance(a)

BMD,g/tonNo.SowsMortality,%ADG,lb/dayScour Scores
01122.20.3801.92
250111.50.4941.08

(a) The sow is the experimental unit. Percent mortality due to C. perfringens, ADG and scour score are per litter data for piglets.

V. ANIMAL SAFETY:

Target animal safety studies conducted for the swine dysentery claim, codified into 21 CFR 558.76 (47 FR 18591), FOI Summary dated April 30, 1982, determined the effect of 500 g/ton of BMD fed continuously to sows from 30 days before breeding through mid-gestation. Abortions, stillbirths, litter size, birth weights, agalactia, and maternal weight and health status were evaluated and found not to be affected by the drug product. Field trial data submitted for this claim showed no adverse effect in abortions, stillbirths, litter size, birth weights, agalactia, and maternal weight and health status for sows fed 250 g/ton of BMD from late gestation to weaning. These studies, together with reproductive safety studies in rats and metabolic studies comparing the pharmacokinetics of bacitracin in the rat and the pig, adequately demonstrate the safety of this product for use in pregnant sows and gilts.</>

VI. HUMAN FOOD SAFETY:

An FOI Summary was prepared with the supplemental application to NADA 046-592 approved April 30, 1982 (47 FR 18591) providing for the use of BMD in swine feeds at a level of 250 grams/ton as set forth in 21 CFR 558.76.

This supplemental application is for an identical intake for treatment of a different condition and for a shorter period of time. Therefore, the human food safety data summarized in the previous FOI, which discusses the toxicity, safe concentration of residues, total residues, and regulatory method for the use of BMD in swine feeds at 250 g/ton of feed, are applicable and show that the use of BMD in swine feeds at a level of 250 g/ton is safe from the standpoint of human food safety.

VII. AGENCY CONCLUSIONS:

The data submitted in support of this supplemental NADA satisfy the requirements of 512 of the Act and demonstrate that BMD 50 premix, when used under its proposed conditions of use, is safe and effective for its labeled indications.

Four well controlled, replicated studies were conducted to establish the effectiveness of BMD for the control of clostridial enteritis caused by C. perfringens in suckling piglets born to sows medicated with BMD in the feed for the period 14 days before parturition and through 21 days after farrowing on premises with a history of clostridial scours. Based upon data provided showing a decrease in mortality (21%) and a decrease in the prevalence of diarrhea in the treated over the controls, the agency concludes that BMD at a level of 250 g/ton is an effective dose for control of clostridial enteritis. Reproductive safety studies in rats, metabolic studies comparing the pharmacokinetics of bacitracin in the rat and pig, reproductive safety studies in swine conducted for the swine dysentery claim, and the field trial results submitted for this claim, adequately demonstrate the safety of this product for pregnant sows.

Bacitracin products for use in food-producing animals are over-the-counter products. Accurate diagnosis can be made with a reasonable degree of certainty by the layman. Adequate directions for use have been written for the layman and the conditions of use prescribed on the labeling are likely to be carried out in practice. Therefore, the agency has concluded that this claim for bacitracin product be granted the over-the-counter marketing status.

Under CVM's supplemental approval policy (55 FR 46052; November 1, 1990), this is a category II approval because this supplemental NADA requests approval of an additional claim. A review of the underlying human safety data supporting approval of the original application was not required, because the supplement did not request a change in dose level or class of animal, and thus approval does not pose an increased human risk from exposure to residues.

As provided under the Generic Animal Drug and Patent Term Restoration Act of 1988 and section 512(c)(2)(F)(iii) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b(c)(2)(F)(iii), this supplemental approval qualifies for three years of marketing exclusivity because new clinical or field investigations conducted or sponsored by A.L. Laboratories Inc. were essential to the approval.

VIII. LABELING (Attached)

1. BLUE BIRD SWINE GESTATION (OR LACTATION) RATION (TYPE C)

Copies of applicable 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.

IV. SUMMARY OF EFFICACY DATA: