Extralabel Animal Drug Use; Fluoroquinolones and Glycopeptides; Order of Prohibition

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 530

[Docket No. 97N-0172]

Extralabel Animal Drug Use; Fluoroquinolones and Glycopeptides;

Order of Prohibition

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule; order of prohibition.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is issuing an order

prohibiting the extralabel use of fluoroquinolones and glycopeptides.

The agency is issuing this order because it believes that some

extralabel uses of fluoroquinolones and glycopeptides in food-producing

animals are capable of increasing the level of drug resistant zoonotic

pathogens (pathogens that are infective to humans) in treated animals

at the time of slaughter. FDA finds that some extralabel uses of

fluoroquinolone and glycopeptide drugs in food-producing animals likely

will cause an adverse event, which constitutes a finding under the

Animal Medicinal

[[Page 27945]]

Drug Use Clarification Act of 1994 (the AMDUCA) that extralabel use of

these drugs in food animals presents a risk to the public health.

Therefore, the agency is issuing this order of prohibition.

DATES: The order of prohibition is effective August 20, 1997. Submit

written comments by July 21, 1997.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Richard L. Arkin, Center for

Veterinary Medicine (HFV-238), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-1737.

SUPPLEMENTARY INFORMATION:

I. Background

On October 22, 1994, the President signed the AMDUCA into law (Pub.

L. 103-396). The AMDUCA which amended the Federal Food, Drug, and

Cosmetic Act (the act) (21 U.S.C. 301 et seq.) to allow licensed

veterinarians to prescribe extralabel uses of approved animal drugs and

human drugs in animals. Section 2(a)(4)(D) of the AMDUCA (21 U.S.C.

360b(a)(4)(D)) provides that the agency may prohibit an extralabel drug

use in animals if, after affording an opportunity for public comment,

the agency finds that such use presents a risk to the public health.

In the Federal Register of November 7, 1996 (61 FR 57732), FDA

published the implementing regulations for the AMDUCA. The regulations

will be codified in part 530 (21 CFR part 530). Sections 530.21 and

530.25 describe the basis for issuing an order prohibiting an

extralabel drug use in food-producing animals. The procedure to be

followed in issuing an order of prohibition is set out in Sec. 530.25.

The list of drugs prohibited from extralabel use is set forth in

Sec. 530.41.

The AMDUCA requires that opportunity be given for public comment

before a prohibition becomes effective. The regulation provides, at

Sec. 530.25, for a public comment period of not less than 60 days. It

also provides that the order of prohibition will become effective 90

days after the date of publication, unless FDA revokes the order,

modifies it or extends the period of public comment. The regulation

also states that reasons for the prohibition will be specified.

In the November 7, 1996 final rule, FDA responded to comments from

the public on the proposed rule to implement the AMDUCA (61 FR 25106,

May 17, 1996) that expressed concerns about the implications of

extralabel use for the development and transfer of antimicrobial

resistance. FDA's response to these comments noted that the agency

believes that the selection of resistant human pathogens could be a

basis for restricting extralabel drug use provided that the statutory

standards for restriction can be met for particular drugs or classes of

drugs (61 FR 57732 at 57736 and 57737). The agency is aware that an

association between use of antimicrobial drugs and antimicrobial

resistance has been documented (Refs. 1, 2, 3, 4, and 5). Antimicrobial

resistant zoonotic enteric microorganisms can be transmitted to humans

through consumption of animal products, and certain resistant

microorganisms can be transmitted through contact with farm animals and

through the environment.

In response to comments suggesting that the agency prohibit

extralabel use of approved fluoroquinolones and glycopeptides in food-

producing animals, the agency stated that it had decided to initiate

the process specified by the AMDUCA to implement such prohibition (61

FR 57732 at 57737). The agency's Center for Veterinary Medicine (CVM)

has, since the time it first approved a fluoroquinolone for use in food

animals (August 1995), informally asked veterinarians to voluntarily

refrain from extralabel use of these drugs in food animals.

Veterinarians' professional associations have actively encouraged their

members to refrain from indiscriminate extralabel use of

fluoroquinolones.

FDA intends to prohibit by order the extralabel use of

fluoroquinolones and glycopeptides in food-producing animals because,

as discussed in sections II and III of this document, the agency has

determined that use of these drugs other than for the approved label

indications in food-producing animals meets the criteria for

prohibition in the AMDUCA. These drugs are added to the list of drugs

prohibited for extralabel use at Sec. 530.41.

Sixty days from the date of this publication are provided for

comment. The order will become effective 90 days from the date of this

publication, unless the agency before that time revokes or modifies the

order, or extends the period for public comment.

In passing the AMDUCA, Congress granted FDA broad authority to

protect the public health by allowing the agency to restrict or

prohibit extralabel uses. A prohibition may be based on a finding that

an extralabel use ``presents a risk to the public health,'' which FDA

has defined in Sec. 530.3(e) as ``likely will cause an adverse event.''

The statutory scheme clearly establishes that prohibiting an extralabel

use does not jeopardize an underlying approval or the future

approvability of the same active ingredient or class of drug. A total

prohibition against extralabel use is an action by the agency which

restricts use of the drug to conditions of use established through

approval of a new animal drug application. A finding of ``likely will

cause an adverse event'' is not a determination regarding the safety of

the drug for its approved uses. That determination is made in the

approval process, i.e., an approved drug has been determined to be safe

for use under labeled conditions.

II. Fluoroquinolones

FDA has approved sarafloxacin and enrofloxacin, both of which are

fluoroquinolones, for therapeutic use in poultry. The approvals, the

first of which was granted in August 1995, are for sarafloxacin

hydrochloride for use in drinking water and sarafloxacin and

enrofloxacin injectable products. The agency had previously approved

enrofloxacin for use in nonfood animals.

All of these approvals are conditioned on use under a

veterinarian's supervision. This restriction for the food-producing

animal approvals was established, among other reasons, to reduce the

rate of emergence of sarafloxacin-resistant organisms. Public health

concerns associated with potential increases in antimicrobial

resistance were satisfactorily addressed in the poultry approvals by

establishing conditions of use intended to minimize inappropriate use

of the products and to minimize excretion of the drug and drug-

resistant zoonotic pathogens into the environment. Essentially, the

agency was assured that under the conditions of use stated in the

approval, any increase in the level of resistant zoonotic pathogens

present in the animals at time of slaughter would be insignificant. The

sponsors agreed to provide baseline susceptibility information on

target animal pathogens and to conduct ongoing monitoring of the target

animal pathogens as a postmarketing surveillance program. Also, FDA

implemented with the Centers for Disease Control and Prevention and the

U.S. Department of Agriculture a national antibiotic resistance

monitoring program in zoonotic enteric pathogens in order to detect

emerging resistance to these pathogens and contain their development.

Thus, the agency concluded that resistance development under the

conditions of approval could be monitored and adequately contained.

Before granting the food animal approvals for fluoroquinolones, CVM

[[Page 27946]]

sought advice from its Veterinary Medicine Advisory Committee, and the

Center for Drug Evaluation and Research's Anti-Infective Drugs Advisory

Committee (the joint committee), in a joint meeting held May 11 and 12,

1994. The joint committee agreed that there is a need for

fluoroquinolones in food animal medicine and did not object to the

approval of fluoroquinolones for such use. However, the joint committee

members generally supported restrictions on the use of the drugs in

order to maximize benefits and minimize risks related to the

development of resistant organisms. Use restrictions that were

suggested included prohibiting extralabel use, as well as requiring a

veterinarian's supervision and monitoring resistance levels.

The data and information presented to the joint committee, and

otherwise available to the agency, support the agency's conclusion that

some extralabel uses of fluoroquinolones in food animals meet the

AMDUCA regulation's standard of ``likely will cause an adverse event''

(Ref. 6). Recent reports from the United Kingdom (U.K.) of the

occurrence of human cases and epizootic spread of a multiple-drug

resistant strain of Salmonella typhimurium, Definitive Type 104 (DT

104) are also of concern, (Refs. 7, 8, and 9). Epidemiological surveys

have found an increase in the percentage of DT 104 isolates in the U.K.

to be resistant to ciprofloxacin, a fluoroquinolone which is used for

the treatment of invasive salmonellosis in humans including

salmonellosis caused by DT 104. The spread of DT 104 in the U.K. from

animals to man has been associated with exposure via food and direct

contact is supported by data from the U.K. An association between

veterinary use of enrofloxacin and the development of fluoroquinolone

resistance in DT 104 has been suggested by several scientists (Ref. 7).

Additionally, studies in the U.K. and Europe document the development

of Campylobacter and Salmonella resistant to fluoroquinolones following

introduction of fluoroquinolone use in both humans and food animals

(Refs. 10, 11, 12, 13, 14, and 15).

Expert opinion expressed during the joint committee meeting and

opinions in comments to the proposed AMDUCA implementing regulations

support the view that increased selective pressure on bacteria

resulting from some of the many potential extralabel uses of

fluoroquinolones likely will lead to resistance development and to the

maintenance of the resistance levels until slaughter, thereby

increasing the risk of transfer of resistant organisms to humans and

the compromise of human therapy. The data and information necessary to

determine, in particular situations, whether the resistance level at

time of slaughter would be increased above normal as a result of

extralabel use is not generally available to practicing veterinarians,

who must make the extralabel use decisions. Thus, while the agency

cannot know the effect of each and every potential extralabel use on

the development of resistant pathogens and on their presence on or in

animals at the time of slaughter, it can reasonably conclude, based on

available information, that such development likely will occur, and

that such resistant pathogens likely will be present at slaughter as a

result of some extralabel uses. Because some extralabel uses likely

would cause an adverse public health event, the agency is acting in the

interest of the public health by prohibiting extralabel use of

fluoroquinolones in food-producing animals. The agency is thereby

restricting such drugs to conditions of use that are established

through the new animal drug approval process.

As explained previously, this conclusion does not undermine the new

animal drug approvals that have been granted for fluoroquinolones

because the necessary assurances of safety to the public were provided

for the approved conditions of use during the approval process.

The AMDUCA does not require the agency to prohibit an extralabel

use when the use meets the statutory standard for prohibition. The act

states that the agency ``may'' do so. The agency believes that this is

an appropriate case for the use of the prohibition authority Congress

provided. In addition to the reasons previously stated, the agency

notes that fluoroquinolones are used extensively in human medicine to

treat many infectious diseases, and they are the only antimicrobial

agents that are effective for treatment of certain diseases. Also,

extralabel use of fluoroquinolones in food-producing animals would

interfere with CVM's ability to interpret the monitoring and

surveillance data that will be obtained through the National

Antimicrobial Susceptibility Monitoring Program (see 61 FR 57732 at

57736 and 57737) and the postapproval monitoring program for the

approved fluoroquinolones. These data are critical because early

detection of emerging resistance, identified through the monitoring

program, will allow the agency to contain any resistance that does

occur, thereby limiting its spread.

III. Glycopeptides

One glycopeptide, vancomycin, is approved for use in human

medicine. No glycopeptides are approved for animal use. Thus, as a

practical matter, the agency's prohibition against extralabel use in

animals of glycopeptides applies only to this one human drug product.

However, the prohibition will apply to any future animal drug approvals

of glycopeptides unless the circumstances at the time of such approval

cause the agency to reevaluate any part of the prohibition.

A number of scientific organizations and individual experts who

commented on the proposed AMDUCA regulations recommended that the

agency prohibit extralabel use of glycopeptides (Ref. 16). Those

comments are supported by the following data and information.

Glycopeptide-resistant Enterococci have become a very serious concern

in human medicine, because a lack of effective alternative drugs for

treatment have resulted in increased morbidity and mortality (Ref. 4).

Vancomycin is a major agent used for treating serious methicillin-

resistant Staphylococcus aureus infections.

One study in the U.K. has shown that vancomycin resistant bacteria

may be acquired from animals (Ref. 17). Another study, done in Denmark,

has established a connection between feed use of avoparcin, a

glycopeptide, and vancomycin-resistant Enterococcus faecium (E.

Faecium) (Ref. 18). The resistant organisms were found in food products

from both poultry and swine that had been fed avoparcin. Further,

vancomycin-resistant E. faecium of the same type were found in both

pigs and humans, leading the authors to conclude that vancomycin

resistant E. faecium can be transmitted to humans through food.

The ``adverse event'' associated with extralabel use of

glycopeptides in food-producing animals is therefore the same as that

discussed earlier with regard to extralabel use of fluoroquinolones.

The agency's basis for prohibiting extralabel uses in food-producing

animals of glycopeptides is also the same as that for fluoroquinolones.

That is, the extralabel use of glycopeptides in food-producing animals

likely will lead to increased risk of transfer of resistant organisms

to humans and compromise human therapy. Therefore, the agency is acting

in the interest of the public health and prohibiting the extralabel use

of glycopeptides in food-producing animals.

[[Page 27947]]

IV. References

The following information has been placed on display in the Dockets

Management Branch (address above) and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday through Friday.

1. Report of the ASM Task Force on Antibiotic Resistance, The

American Society for Microbiology Public and Scientific Affairs

Board, Washington, March 16, 1995.

2. Lederberg, J., R. E. Shope, and S. C. Oaks, eds., Emerging

Infections; Microbial Threats to Health in the United States,

Institute of Medicine Committee on Emerging Microbial Threats to

Health, pp. 159-160, National Academy Press, 15, Washington, 1992.

3. Letter from Kenneth I. Berns and Gail Cassell, American

Society of Microbiology, p. 1, to Dockets Management Branch (HFA-

305), Food and Drug Administration, dated July 31, 1996.

4. U.S. Congress, Office of Technology Assessment, Impacts of

Antibiotic-Resistant Bacteria, OTA-H-629 p. 72, U.S. Government

Printing Office, Washington, DC, September 1995.

5. Piddock, L. J. V., ``Does the Use of Antimicrobial Agents in

16 Veterinary Medicine and Animal Husbandry Select Antibiotic-

Resistant Bacteria That Infect Man and Compromise Antimicrobial

Chemotherapy?'' Journal of Antimicrobial Chemotherapy, Vol. 38, pp.

1-3, 1996.

6. Joint Meeting of the Veterinary Medicine Advisory Committee

and Anti-Infective Drugs Advisory Committee, Food and Drug

Administration, Gaithersburg, MD, Associated Reporters of

Washington, pp. 144-195 (transcript), Washington, May 12, 1994.

7. Threlfall, E. J., et al., ``Increasing Spectrum of Resistance

in Multiresistant Salmonella typhimurium,'' Lancet, Vol. 327, pp.

1053-1054, 1996.

8. Threlfall, E. J., et al., ``Epidemic in Cattle of Salmonella

Typhimurium DT104 with Chromosomally Integrated Multiple Drug

Resistance,'' Veterinary Record, Vol. 134, p. 577, 1994.

9. Wall, P. G., et al., ``A Case Control Study of Infection with

an Epidemic Strain of Multi-resistant Salmonella Typhimurium DT104

in England and Wales,'' Communicable Disease Report, Vol. 4, pp.

R130-135, 1995.

10. Endtz, et al., ``Quinolone Resistance in Campylobacter

Isolated from Man and Poultry Following the Introduction of

Fluoroquinolones in Veterinary Medicine,'' Journal of Antimicrobial

Chemotherapy, Vol. 27, pp. 199-208, 1991.

11. Endtz, H. P., et al., ``Fluoroquinolone Resistance in

Campylobacter Spp. Isolated from Human Stools and Poultry

Products,'' Lancet, Vol. 335, p. 787, 1990.

12. Piddock, L. J. V., et al., ``Quinolone Resistance in

Salmonella Spp: Veterinary Pointers,'' Lancet, Vol. 336, p. 125,

1990.

13. Piddock, L. J. V., ``Quinolone Resistance and Campylobacter

Spp.'' (review), Journal of Antimicrobial Chemotherapy, Vol. 36, pp.

891-898, 1995.

14. Griggs, D. J., et al., ``Quinolone Resistance in Veterinary

Isolates of Salmonella,'' Journal of Antimicrobial Chemotherapy,

Vol. 33, pp. 1173-1189, 1994.

15. Velazquez, J. B., et al., ``Incidence and Transmission of

Antibiotic Resistance in Campylobacter Jejuni and Campylobacter

Coli,'' Journal of Antimicrobial Chemotherapy, Vol. 35, pp. 173-178,

1995.

16. Letter from William A. Craig, Professor of Medicine and

Pharmaceutics, University of Wisconsin, to Dockets Management Branch

(HFA-305), Food and Drug Administration, July 31, 1996.

17. Bates, J., J. Z. Jordens, and D. T. Griffiths, ``Farm

Animals as a Putative Reservoir for Vancomycin-resistant

Enterococcal Infection in Man,'' Journal of Antimicrobial

Chemotherapy, Vol. 34, pp. 507-516, 1994.

18. ``Report from the Danish Veterinary Laboratory: The Effect

of Avoparcin Used as a Feed Additive on the Occurrence of Vancomycin

Resistant Enterococcus Faecium in Pig and Poultry Production,''

Danish Veterinary Laboratory, Copenhagen, July 1995.

V. Request for Comments

Interested persons may, on or before July 21, 1997, submit to the

Dockets Management Branch (address above) written comments regarding

this document. Two copies of any comments are to be submitted, except

that individuals may submit one copy. Comments are to be identified

with the docket number found in brackets in the heading of this

document. Received comments may be seen in the office between 9 a.m.

and 4 p.m., Monday through Friday.

VI. Order of Prohibition

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

under the authority delegated to the Commissioner of Food and Drugs, I

hereby issue the following order under section 2(a)(4)(D) of the

AMDUCA, Pub. L. 1-3-396 (21 U.S.C. 360b(a)(4)(D)) and Secs. 530.21 and

530.25. FDA finds that some extralabel uses of fluoroquinolone and

glycopeptide drugs in food-producing animals likely will cause an

adverse event, which constitutes a finding under the AMDUCA that

extralabel use of these drugs in food animals presents a risk to the

public health. Therefore, fluoroquinolone and glycopeptide drugs are

prohibited for extralabel use in food-producing animals.

List of Subjects in 21 CFR Part 530

Administrative practice and procedure, Advertising, Animal drugs,

Animal feeds, Drugs, Labeling, Prescription drugs, Reporting and

recordkeeping requirements.

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 530 is

amended to read as follows:

PART 530--EXTRALABEL DRUG USE IN ANIMALS

1. The authority citation for 21 CFR part 530 continues to read as

follows:

Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act

(15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 501, 502, 503, 505,

507, 512, 701, and 721 of the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b, 371, 379e).

2. Section 530.41 is revised to read as follows:

Sec. 530.41 Drugs prohibited for extralabel use in animals.

(a) The following drugs, families of drugs, and substances are

prohibited for extralabel animal and human drug uses in food-producing

animals.

(1) Chloramphenicol;

(2) Clenbuterol;

(3) Diethylstilbestrol (DES);

(4) Dimetridazole;

(5) Ipronidazole;

(6) Other nitroimidazoles;

(7) Furazolidone (except for approved topical use);

(8) Nitrofurazone (except for approved topical use);

(9) Sulfonamide drugs in lactating dairy cattle (except approved

use of sulfadimethoxine, sulfabromomethazine, and

sulfaethoxypyridazine);

(10) Fluoroquinolones; and

(11) Glycopeptides.

(b) The following drugs, families of drugs, and substances are

prohibited for extralabel animal and human drug uses in nonfood-

producing animals: [Reserved.]

Dated: May 19, 1997.

Stephen F. Sundlof,

Director, Center for Veterinary Medicine.

[FR Doc. 97-13677 Filed 5-20-97; 2:50 pm]

BILLING CODE 4160-01-F