Oral Dosage Form New Animal Drugs; Tetracycline Hydrochloride Soluble Powder

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 520

Oral Dosage Form New Animal Drugs; Tetracycline Hydrochloride

Soluble Powder

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the animal

drug regulations to reflect approval of two supplemental new animal

drug applications (NADA's) for safe and effective use of tetracycline

hydrochloride soluble powder. One supplemental NADA was filed by Wade

Jones Co., Inc., and covers the use of the drug product in the drinking

water of calves and swine for the control and treatment of certain

bacterial diseases and in the drinking water of poultry for the control

of certain bacterial diseases susceptible to the drug. The other

supplemental NADA was filed by Pfizer, Inc., and also covers use of the

drug in the drinking water of poultry for the control of certain

susceptible bacterial diseases. Both approvals reflect compliance with

the results of the National Academy of Sciences/National Research

Council (NAS/NRC), Drug Efficacy Study Group's (DESI) evaluation of the

drug's effectiveness and FDA's conclusions concerning that evaluation.

Additionally, the agency is technically amending the regulations to

make other needed corrections.

EFFECTIVE DATE: April 14, 1994.

FOR FURTHER INFORMATION CONTACT: Dianne T. McRae, Center for Veterinary

Medicine (HFV-102), Food and Drug Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301-594-1623.

SUPPLEMENTARY INFORMATION:

I. Background

Wade Jones Co., Inc., 409 North Bloomington, Lowell, AR 72745 (Wade

Jones), filed a supplement to approved NADA 65-140 for a soluble powder

containing 324 grams (g) of tetracycline hydrochloride (TC HCl)

activity per pound (lb). The drug is available in several product

container sizes, 2 and 5 lb tubs and 2.53, 5, and 10 ounce (oz)

packets. The drug is indicated for use in chickens at 200 to 400

milligrams per gallon (mg/gal) for control of infectious synovitis

caused by Mycoplasma synoviae and at 400 to 800 mg/gal for control of

chronic respiratory disease caused by M. gallisepticum and E. coli. The

drug is indicated for use in turkeys at 400 mg/gal for control of

infectious synovitis caused by M. synoviae and at 25 mg/lb of body

weight for control of complicating bacterial organisms associated with

bluecomb. It is also indicated for use in swine and calves at 10 mg/lb

of body weight for control and treatment of bacterial enteritis

(scours) and bacterial pneumonia. The NADA was originally approved July

5, 1966.

Pfizer, Inc., 235 East 42d St., New York, NY 10017 (Pfizer), filed

supplemental NADA 65-123 for TC HCl soluble powder (6.4 ounce (oz)

packet) to provide for use in chickens and turkeys under the same

conditions of use expressed above for the Wade Jones application. The

NADA was originally approved April 27, 1955.

II. The NAS/NRC DESI Evaluation

The drug products were subject to a NAS/NRC DESI evaluation of

effectiveness (DESI 0012NV). The findings were published in the Federal

Register of July 8, 1970 (35 FR 10966). NAS/NRC evaluated the products

as ``probably effective'' for oral treatment of animal diseases when

such diseases are caused by pathogenic microorganisms sensitive to

tetracycline hydrochloride, diseases such as: (1) Enteric and

respiratory diseases in poultry; (2) gastrointestinal and respiratory

diseases in swine; (3) infected wounds, gastrointestinal and

respiratory diseases in calves, sheep, and goats; (4) digestive system

and respiratory diseases, pyelonephritis, peritonitis, infected wounds,

abscesses, ulcers, and secondary bacterial invaders in dogs and cats;

(5) coccidiosis in dogs; and (6) hexamitiasis in turkeys.

NAS/NRC reached the following conclusions applicable to the subject

TC HCl drug products:

(1) Most of the dosage directions provide for a less than effective

dose, and the recommended minimum oral dose for large animals is 10 mg/

lb of body weight daily in divided doses and for small animals 25 mg/lb

body weight daily in divided doses;

(2) claims for the treatment of viral diseases must be limited to

microorganisms belonging to the psittacosis-lymphogranuloma group;

(3) each disease claim should be properly qualified as

``appropriate for use in (name of disease) caused by pathogens

sensitive to (name of drug),'' and if the disease cannot be so

qualified the claim must be dropped;

(4) claims made ``for prevention of'' or ``to prevent'' should be

replaced with ``as an aid in the control of'' or ``to aid in the

control of'';

(5) as applicable, the manufacturer's label should warn that

treated animals must consume enough medicated water or medicated feed

to provide a therapeutic dose under the conditions that prevail--as a

precaution, the label should state the desired oral dose per unit of

animal weight per day for each species as a guide to effective use of

the preparation in drinking water or feed.

FDA concurred with the NAS/NRC findings, interpreting the phrase

``cannot be so qualified'' in item (3) of the paragraph immediately

above to mean ``is not supported by adequate data.'' FDA proceeded to

review all available data relating to the effectiveness of similar

products to determine which label claims were supported by the

requisite proof of effectiveness. The review resulted in the agency

concluding that the data supported effectiveness only for the control

and treatment of certain bacterial diseases susceptible to TC HCl in

calves, swine, chickens, and turkeys.

Subsequently, Wade Jones and Pfizer complied with the NAS/NRC

evaluation and FDA's conclusions by filing supplemental NADA's which

revised the drug products' labeling as follows: (1) Adopting the dosage

recommended by NAS/NRC; (2) dropping all claims for viral diseases; (3)

properly qualifying disease claims; (4) revising prevention claims to

read ``Control of''; and (5) adding to the manufacturer's label the

warning statement concerning factors influencing adequate consumption

of medicated water.

The NAS/NRC evaluation is concerned only with the drugs'

effectiveness and safety to the treated animal. It does not take into

account the safety for human food use of food derived from drug-treated

animals.

Wade Jones' supplemental NADA is approved as of September 15, 1993,

and Pfizer's supplemental NADA is approved as of March 18, 1994. The

regulations are amended by revising Sec. 520.2345d (21 CFR 520.2345d)

to reflect the approvals.

FDA's approval of the supplemental NADA's does not involve a

reevaluation or reaffirmation of the human food safety data in the

parent applications. Tolerances for residues of the drug and its

metabolites in chickens, turkeys, swine, and calves of 0.25 part per

million are currently codified in 21 CFR 556.720.

III. Environmental Impact

The agency has carefully considered the potential environmental

effects of approving the Wade Jones Supplement. FDA has concluded that

the action will not have a significant impact on the human environment,

and that an environmental impact statement is not required. The

agency's finding of no significant impact and the evidence supporting

that finding, contained in an environmental assessment, may be seen in

the Dockets Management Branch (HFA-305), Food and Drug Administration,

rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857, between 9 a.m. and 4

p.m., Monday through Friday.

With regard to approving the Pfizer supplement, the agency has

determined under 21 CFR 25.24(d)(1)(i) that this action is of a type

that does not individually or cumulatively have a significant effect on

the human environment. Therefore, neither an environmental assessment

nor an environmental impact statement is required.

Under section 512(c)(2)(F)(iii) of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 360b(c)(2)(F)(iii)), these approvals do not

qualify for exclusivity periods because their applications do not

contain reports of new clinical or field investigations (other than

bioequivalence or residue studies) and, in the case of food-producing

animals, human food safety studies (other than bioequivalence or

residue studies) essential to approval of the supplements and conducted

or sponsored by the applicants.

In accordance with the freedom of information provisions of part 20

(21 CFR part 20) and Sec. 514.11(e)(2)(ii) (21 CFR 514.11(e)(2)(ii)),

summaries of safety and effectiveness data and information submitted to

support approval of these applications may be seen in the Dockets

Management Branch (address above) between 9 a.m. and 4 p.m., Monday

through Friday.

IV. The Technical Amendments

In conjunction with amending Sec. 520.2345d to codify the NAS/NRC

DESI finalization of Wade Jones' and Pfizer's NADA's the agency is

using this occasion to rewrite Sec. 520.2345d to clarify the

regulations. Section 520.2345d is the recodified version of section

546.180d(c). This latter section was one of many antibiotic drug

sections affected by the final rule that published in the Federal

Register of August 18, 1992 (57 FR 37318) for the purpose of: (1)

Removing the technical regulations that included the requirements for

certification and tests and methods of assay and (2) recodifying, based

on route of administration, the remaining provisions concerning

conditions of marketing. However, when Sec. 546.180d was recodified,

the agency did not include other technical changes to update changes in

the approved conditions of marketing. Accordingly, FDA is revising

Sec. 520.2345d to codify the currently approved conditions of marketing

and to make the following needed corrections: (1) The section heading

is revised to fully identify the drug as the hydrochloride; (2) the

``Specifications'' paragraph is removed and information concerning drug

concentrations is incorporated into the ``Sponsors'' paragraph; (3) the

second sentence of the NAS/NRC status paragraph is removed because it

has been superseded by enactment of the Generic Animal Drug and Patent

Term Restoration Act of 1988; (4) the drug labeler code for Upjohn Co.

(000009) is removed because the firm was incorrectly listed as the

sponsor of approvals for the use of TC HCl soluble powder in the

drinking water of calves, swine, chickens, and turkeys; (5) the drug

labeler code for Vetri-Tech, Inc. (058752), has been changed to that

for Arkansas Micro Specialties, Inc. (047863), since Vetri-Tech, Inc.,

has transferred ownership of its NADA (use of drug in chickens) to

Arkansas Micro Specialties, Inc., (57 FR 12711, April 13, 1992), and

(6) in the calf and swine claims, the name of the causative agent,

Hemophilus is changed to Actinobacillus pleuropneumoniae, the current

scientific name.

List of Subjects in 21 CFR Part 520

Animal drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs and

redelegated to the Center for Veterinary Medicine, 21 CFR part 520 is

amended as follows:

PART 520--ORAL DOSAGE FORM NEW ANIMAL DRUGS

1. The authority citation for 21 CFR part 520 continues to read as

follows:

Authority: Sec. 512 of the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 360b).

2. Section 520.2345d is revised to read as follows:

Sec. 520.2345d Tetracycline hydrochloride soluble powder.

(a) Sponsors. The following sponsors listed in Sec. 510.600(c) of

this chapter hold approvals for the drug concentrations (i.e., grams of

tetracycline hydrochloride per pound) and conditions of use indicated:

(1) 047864 and 054273, 102.4 and 324 grams per pound as in

paragraph (d) of this section.

(2) 000069, 25 grams per pound as in paragraphs (d)(3) and (d)(4)

of this section.

(3) 010042, 102.4 and 324 grams per pound as in paragraphs (d)(1)

and (d)(2) of this section.

(4) 047863, 102.4 and 324 grams per pound as in paragraph (d)(3) of

this section.

(b) Related tolerances. See Sec. 556.720 of this chapter.

(c) National Academy of Sciences/National Research Council (NAS/

NRC) status. The conditions of use specified in paragraph (d) of this

section were NAS/NRC reviewed and found effective.

(d) Conditions of use in drinking water--(1) Calves--(i) Amount. 10

milligrams per pound of body weight per day in divided doses.

(ii) Indications for use. Control and treatment of bacterial

enteritis (scours) caused by Escherichia coli and bacterial pneumonia

(shipping fever complex) associated with Pasteurella spp.,

Actinobacillus pleuropneumoniae (Hemophilus spp.), and Klebsiella spp.,

susceptible to tetracycline.

(iii) Limitations. Administer for 3 to 5 days; do not slaughter

animals for food within 4 days of treatment for sponsor 010042 and

within 5 days of treatment for sponsors 047864 and 054273; prepare a

fresh solution daily; use as the sole source of tetracycline.

(2) Swine--(i) Amount. 10 milligrams per pound of body weight per

day in divided doses.

(ii) Indications for use. Control and treatment of bacterial

enteritis (scours) caused by E. coli and bacterial pneumonia associated

with Pasteurella spp., A. pleuropneumoniae (Hemophilus spp.), and

Klebsiella spp., susceptible to tetracycline.

(iii) Limitations. Administer for 3 to 5 days; do not slaughter

animals for food within 7 days of treatment for sponsor 010042 and

within 4 days of treatment for sponsors 047864 and 054273; prepare a

fresh solution daily; use as the sole source of tetracycline.

(3) Chickens--(i) Amount. Chronic respiratory disease: 400 to 800

milligrams per gallon. Infectious synovitis: 200 to 400 milligrams per

gallon.

(ii) Indications for use. Control of chronic respiratory disease

(CRD or air-sac disease) caused by Mycoplasma gallisepticum and E.

coli; control of infectious synovitis caused by M. synoviae susceptible

to tetracycline.

(iii) Limitations. Administer for 7 to 14 days; do not slaughter

for food within 4 days of treatment; not for use in chickens producing

eggs for human consumption; prepare a fresh solution daily; use as the

sole source of tetracycline.

(4) Turkeys--(i) Amount. For infectious synovitis: 400 milligrams

per gallon. For complicating bacterial organisms associated with

bluecomb (transmissible enteritis or coronaviral enteritis): 25

milligrams per pound of body weight per day.

(ii) Indications for use. Control of infectious synovitis caused by

M. synoviae; control of bluecomb complicated by organisms sensitive to

tetracycline.

(iii) Limitations. Administer for 7 to 14 days; do not slaughter

for food within 4 days of treatment; not for use in turkeys producing

eggs for human consumption; prepare a fresh solution daily; use as the

sole source of tetracycline.

Dated: April 7, 1994.

Robert C. Livingston,

Director, Office of New Animal Drug Evaluation, Center for Veterinary

Medicine.

[FR Doc. 94-9044 Filed 4-13-94; 8:45 am]

BILLING CODE 4160-01-F