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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 106-964 APRALAN® Soluble Powder - original approval

Approval Date: November 20, 1981

I. GENERAL INFORMATION

NADA106-964
Sponsor:Elanco Products Company
A Division of Eli Lilly and Company
740 South Alabama Street
Indianapolis, Indiana 46285
Generic Name:apramycin sulfate
Trade Name:APRALAN® Soluble Powder
Marketing Status: 

 

II. INDICATIONS FOR USE

APRALAN® Soluble Powder is indicated for the oral treatment of porcine colibacillosis (weanling pig scours) caused by strains of E. coli sensitive to apramycin.

 

III. DOSAGE

A. DOSAGE FORM: Soluble Powder

B. ROUTE OF ADMINISTRATION: Oral administration via swine drinking water at the rate of 25 mg/kg of body weight (11.4 mg/lb/day) daily for 7 days

C. RECOMMENDED DOSAGES: Add to the drinking water at the rate of 750 mg/gallon and monitor water consumption to determine that the recommended dosage is being consumed. The drug concentration should be adjusted according to water consumption.

 

IV. EFFECTIVENESS

All studies were well-controlled apramycin treatment versus nonmedicated controls experiments. A total of 528 pigs with colibacillosis in Iowa, Indiana and Washington State were evaluated for rate of weight gain, feed efficiency and diarrhea. Colibacillosis was diagnosed based upon demonstration of hemolytic Escherichia coli in the pigs.

A. Oral Administration of Apramycin for the Treatment of Colibacillosis in Weanling Pigs

Location:

Iowa State University
Swine Nutrition
Ames, Iowa

Investigator:

Vaughn Speer, Ph.D.
Professor, Animal Science Department
Iowa State University

Monitor:

Paul Gorham, D.V.M
Lilly Research Laboratories
Greenfield, Indiana

Summary:

One hundred twenty weaned pigs with diarrhea were allotted, based upon weight and litter source, to 20 pens of six pigs, in each of three experiments. Four treatment groups, each composed of five pens, were evaluated in each experiment. Apramycin was administered in the drinking water at levels of 0.1, 0.5, 1.0, 1.25 and 1.5 g/gal for seven days. Body weight, feed consumed and the incidence of diarrhea were evaluated for three weeks.

TreatmentPensGain (lbs) Per Pig*Feed/Gain*Diarrhea Index *,**
No apramycin154.932.4530.7
Apramycin, 0.1 g/gal53.92.6624.0
Apramycin, 0.5 g/gal106.252.1223.0
Apramycin. 0.75 g/gal58.21.9517.8
Apramycin, 1.0 g/gal157.61.9918.5
Apramycin. 1.25 g/gal57.82.0214.0
Apramycin, 1.5 g/gal58.31.8815.8

* 0-21 day data
** Higher index number indicates more severe diarrhea

Pigs with colibacillosis and treated with apramycin in the drinking water for seven days at levels of 0.5 g/gal or higher had improved weight gain and feed efficiency and a reduction in diarrhea. For all varibles, the responses were semilar between 750 and 1500 mg/gal. It was concluded that 750 mg/gal was the optimum dosage.

B. Oral Administration of Apramycin for the Treatment of Colibacillosis in Weanling Pigs

Location:

Commercial Pig Producer
Decatur, Indiana

Investigator:

Jim A. Miyat, D.V.M.
Lilly Research Laboratories
Greenfield, Indiana

Summary:

Sixty-eight weaned pigs with diarrhea were allotted, based upon weight, litter source and diarrhea index, to four groups of 17 pigs each. Two randomly assigned groups received nonmedicated drinking water and two, 0.75 g/gal apramycin in the drinking water for seven days. Body weight, feed consumed and the incidence of diarrhea were evaluated for three weeks.

TreatmentPensGain (kg)*Feed/Gain*Diarrhea Index**
No apramycin22.931.745.07
Apramycin, 0.75 g/gal23.81.643.13

* 0-21 day data
** 0-14 day data, higher index number indicates more severe diarrhea.

Pigs with colibacillosis and treated with apramycin in the drinking water for seven days at a level of 0.75 g/gal had improved weight gain and feed efficiency and a reduction in diarrhea.

C. Apramycin Soluble for the Treatment of Colibacillosis in Weanling Pigs

Location:

Washington Stale University
Swine Nutrition
Pullman, Washington

Investigator:

0. A. Froseth, Ph.D.
Avian Science Department
Washington State University

Monitor:

Dean C. Young, D.V.M.
Lilly. Research Laboratories
Greenfield, Indiana

Summary:

One hundred weaned pigs with diarrhea were divided into 10 pens of 10 pigs each. Five pens, randomly selected, received nonmedicated drinking water and five pens, 0.75 g/gal apramycin in the drinking water for seven days. Body weight, feed consumed and the incidence of diarrhea were evaluated for three weeks.

TreatmentPensAvg. Daily Gain (kg)Feed/Gain*Diarrhea Index**
No apramycin5.35l.895.4
Apramycin,-0.75 g/gal5.382l.723.8

* 0-21 day data
** Mean diarrhea score on day 7, higher index number indicates more severe diarrhea.

Pigs with colibacillosis and treated with apramycin in the drinking water for seven days at a level of 0.75 g/gal had improved weight gain and feed efficiency and a reduction in diarrhea.

 

V. ANIMAL SAFETY

Extensive studies were conducted to establish the safety of apramycin in swine. These included acute and subacute toxicity studies in which the drug was shown to have a five-times margin of safety when administered as labeled.

In acute oral toxicity studies single doses of 500 mg/kg, 800 mg/kg, and 1250 mg/kg were administered to pigs by gavage. There were no treatment-related deaths, therefore, the LD1 is greater than 1250 mg/kg (50 x use level) of body weight.no treatment-related deaths, therefore, the LD1 is greater than 1250 mg/kg (50 x use level) of body weight.

Intramuscular administration of 1000 mg/kg body weight to pigs resulted only in transient pain and lameness of 48 hour duration.

Twenty-eight-day subacute toxicity studies at 1, 3, and 5 x the recommended dosage produced no signs of adverse effects. There were no treatment-related changes in organ weights, hematology, serum chemistry and urinalysis nor were any gross or histopathological lesions observed.

Swine fed 100 grams apramycin per ton of feed for 5 weeks showed no more signs of gastrointestinal irritation than control pigs receiving an apramycin-free ration.

Pigs were fed apramycin at 100 grams per ton of feed for eight weeks. A conditioned avoidance response test system (sound-shock) was used to determine auditory responses. It was found that apramycin treated swine responded as well as unmedicated controls.

Studies were conducted to determine the effect of oral doses of apramycin sulfate upon the fecal consistency of baby pigs. Dosages of 50 mg to 200 mg resulted in less firm stools for a day or two following treatment but caused no adverse effect upon the gain or survival of the pigs. This was the only sign of possible toxicity detected in swine.

The administration of apramycin (2 g of activity per gallon, 0.53 g/liter) via drinking water to sows of proven parity for seven-day periods at breeding, early gestation (days 21-28 after breeding), and early lactation (parturition to 7 days), was without adverse effect on conception rate, litter size, litter gain during nursing, and survival rate of pigs to weaning. Likewise, the administration of the same concentration of apramycin to the boar prior to and during breeding was without adverse effect on conception rate and litter size.

 

VI. HUMAN SAFETY

Fifteen in vivo toxicity studies were conducted involving mice, rats, rabbits, guinea pigs, chickens, and dogs treated with graded levels of apramycin.

Acute toxicity tests were conducted in mice, rats, dogs, rabbits, guinea pigs, and chickens.

The results of oral toxicity tests are shown in the following table:

ACUTE ORAL TOXICITY STUDIES OF APRAMYCIN

SpeciesLD 50 (mg/kg)
Mice>10,000
Rat> 8,000
Dog> 1,000
Rabbit> 1,600
Chicken> 1,000
Guinea Pig> 1,250

No sex differences were noted in any of the acute oral toxicity studies. The only sign of toxicity in dogs given an oral dose of 1,000 mg/kg was mild diarrhea and vomiting in two (2) of four (4) males and one (1) of four (4) females.

In the rabbit, signs of toxicity during the first week of observation included anorexia, weight loss, and some hypoactivity. The rabbits appeared normal during the second week.

Signs of toxicity in guinea pigs included anorexia in both sexes; alopecia and distended abdomens in females. A reduction in weight gain was evident for both male and female animals given high doses of apramycin. Delayed deaths occurred in one (1) of five (5) male and one (1) of five (5) female guinea pigs given 1250 mg activity/kg. Of the remaining eight (8) animals in this dose group, five (5) were found to have mild renal injury at necropsy.

No signs of toxicity were seen in chickens.

The results of acute intravenous toxicity studies are as follows:

ACUTE INTRAVENOUS TOXICITY OF APRAMYCIN

 LD50 (mg/kg)
SpeciesMaleFemale
Mice570573
Rats15961640

All mortalities occurred within 30 minutes in mice and with one exception, within one hour in the rat. The deaths appeared to be due to CNS toxicity.

Two (2) of ten (10) mice surviving an intravenous dose of 620 mg/kg showed enlarged kidneys upon gross examination. Microscopic examination of kidneys from rats surviving an intravenous dose of 1800 mg/kg revealed varying degrees of nephrosis in four (4) animals.

Dermal application of 2000 mg/kg (1040 mg activity/kg) of apramycin to either intact or abraded rabbit skin caused no mortality during a 14-day observation period. Instillation of 36 mg (19 mg activity) of apramycin into the rabbit eye caused slight reversible conjunctival. redness in two (2) of six (6) animals. Attempts to sensitize the guinea pig by applying 29.2 mg apramycin activity 3 times a week for 3 weeks and challenging 2 weeks later were negative.

In pilot toxicity studies all rats maintained on diets containing 0.05, 0.1, or 0.2% apramycin activity, equivalent to doses up to 191 mg activity/kg body weight/day for males and 193 mg activity/kg/day for females, survived a 14-day study. No significant changes in growth, efficiency of food utilization or clinical chemical parameters were observed. No treatment related histopathological changes were observed in the kidney.

Apramycin was administered orally to dogs at 250, 1250 or 1600 mg activity/kg/day for 14 days without mortality. Anorexia accompanied by weight loss was observed in all dogs, and vomiting and dark feces occurred in animals given the highest doses. Nephrosis was found in all animals with the severity varying from very mild at 250 mg/kg to moderate or severe for the highest dose groups.

In order to test ototoxicity potential, apramycin was-administered subcutaneously to cats at a dose of 100 mg/kg/day for 30 days. Only one (1) of four (4) cats completed the study. Anorexia and weight loss were apparent in all animals. Righting reflex and post-rotatory nystagmus time were unaffected by apramycin treatment in three (3) of four (4) cats. In the other cat, righting reflex was normal but post-rotatory nystagmus time declined slowly (from 23 to 17 seconds) during the first 22 days and rapidly to 9 seconds on day 25, the day the animal was killed. Extreme elevations in clinical chemistry parameters were noted in this same animal. Severe nephrosis-was found at necropsy in three(3) of three (3) cats.

In subacute toxicity studies, rats were maintained for 3 months on diets containing 200, 400 or 1000 ppm of apramycin sulfate (104, 208 or 520 ppm apramycin activity) or were allowed to consume a 1% w/v (0.52% w/v as activity) solution of apramycin sulfate as their only source of liquid. Average daily doses of 50.4 mg/kg (26.2 mg activity/kg) and 62.7 mg/kg (32.6 mg activity/kg) were consumed by the male and female rats maintained on the 1000 ppm diets. Male and female rats drinking the 1% solution consumed a daily average of 1040 mg/kg (547 mg activity/kg) and 1359 mg/kg (707 mg activity/kg), respectively. All rats survived with mild diarrhea as the only observable effect. No apramycin-related effects on body weight gain, efficiency of food utilization, hematology, clinical chemistry or relative organ weight parameters were noted in this study. Histopathologic examination. of tissues did not reveal any lesions related to apramycin treatment.

Daily oral doses of 5, 10, or 25 mg/kg for 3 months in dogs produced no changes in body weight, behavior and appearance, or hematology, urinalysis, and clinical chemistry parameters. Variations in relative organ weight data were not considered related to apramycin administration. No treatment-related gross or histopathologic lesions were observed.

Many other tests indicate apramycin has no adverse effect upon the environment.

Nitrogen fixing organisms, including Azotobacter chroococcum, Anabaena flos aquae , and Rhizobium species , were tested for their susceptibility to apramycin in broth culture. Generally the inhibitory concentration for A. chroococcum, A. flos aquae , and R. leguminosarum was 0.1 ppm. R. japonicum inhibition by the antibiotic varied with strains between 1 and 10 ppm.

When incorporated to depths of 4 and 9 inches in soil, apramycin at application rates of 480 lbs/A (160 ppm) and below, caused no statistically significant inhibition of nodulation or acetylene reduction (nitrogenase) activity in soybean fields. The high apramycin rate in the 9 inch incorporation study did show a 24.8% reduction in mean nodule weight. However, a wide range of plant to plant variation in nodule development and size is expected. In this case, one of the replicates from the high treatment produced 23% more nodules than the control average. The second highest rate, 120 lb/A (40 ppm) also showed a decrease from controls which was statistically insignificant. The coefficient of variation was above 40% in 5 of 6 treatments and above 60% in half the treatments.

Apramycin had little effect on sewage-digesting organisms as determined by standard methods for examining waste water. Using a laboratory scale, semicontinuous aerated sewage system, apramycin was tested at an initial concentration of 0.1 ppm and gradually increased to 102.4 ppm. In 26 days changes that occurred in the biochemical oxygen demand, bacterial populations, pH and solid's content of treated systems also occurred in the negative controls. Apramycin was not detrimental to the digestive process.

Tissue residue studies were adequate to demonstrate that residues of apramycin in edible tissues of treated animals will be below the corresponding tolerances following the 28-day withdrawal period provided in the labeling.

Tolerances of 0.1 part per million (ppm) are established for total residues of apramycin in uncooked swine muscle, 0.3 ppm for liver, and 0.4 ppm for kidney and fat. A drug residue assay measuring parent apramycin (the marker residue) in the target tissue, kidney, serves to monitor the total residue in edible tissues. A marker residue concentration of 0.1 ppm in kidney corresponds to 0.4 ppm total residue in this target tissue.

The regulatory analytical method for detection of residues of the drug is filed in the Food Additive's analytical manual on display in the Dockets Management Branch, Room 4-62, 5600 Fishers Lane, Rockville, Maryland 20852.

Based on toxicological studies including mutagenicity assays and because the structure of apramycin did not provide any reason for suspicion of carcinogenicity, apramycin has been assigned to category "A" (low-risk toxicity) under current Threshold Assessment procedures. Consequently, apramycin was not required to enter the stepwise data collection procedures of the "Chemical Compounds in Food Producing Animals" proposal (44 FR 17070-17114, March 20, 1979).

 

VII. AGENCY CONCLUSIONS

The data submitted in support of this NADA comply with the requirements of § 512 of the Act and demonstrate that APRALAN® Soluble Powder, when used under its proposed conditions of use, is safe and effective for the oral treatment of porcine colibacillosis (weanling pig scours) caused by strains of E. coli sensitive to apramycin.

 

VIII. LABELING (Attached)

  1. Apralan® product label

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.