[Federal Register Volume 68, Number 40 (Friday, February 28, 2003)]
[Rules and Regulations]
[Pages 9528-9530]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-4741]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 530

[Docket No. 03N-0024]


New Animal Drugs; Phenylbutazone; Extralabel Animal Drug Use; 
Order of Prohibition

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (we) is issuing an order 
prohibiting the extralabel use of phenylbutazone animal and human drugs 
in female dairy cattle 20 months of age or older. We are issuing this 
order based on evidence that extralabel use of phenylbutazone in female 
dairy cattle 20 months of age or older will likely cause an adverse 
event in humans. We find that such extralabel use presents a risk to 
the public health for the purposes of the Animal Medicinal Drug Use 
Clarification Act of 1994 (AMDUCA).

DATES: This rule is effective May 29, 2003. We invite your written or 
electronic comments. We will consider all comments that we receive by 
April 29, 2003.

ADDRESSES: Submit your written comments to the Dockets Management 
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Gloria J. Dunnavan, Center for 
Veterinary Medicine (HFV-230), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-827-1168, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. AMDUCA

    AMDUCA (Public Law 103-396) was signed into law on October 22, 
1994. It amended the Federal Food, Drug, and Cosmetic Act (the act) to 
permit licensed veterinarians to prescribe extralabel uses of approved 
animal and human drugs in animals. However,

[[Page 9529]]

section 512(a)(4)(D) of the act (21 U.S.C. 360b(a)(4)(D)) gives us 
authority to prohibit an extralabel drug use in animals if, after 
affording an opportunity for public comment, we find that such use 
presents a risk to the public health.
    In the Federal Register of November 7, 1996 (61 FR 57732), we 
published the implementing regulations (codified at part 530 (21 CFR 
part 530)) for AMDUCA. The sections regarding prohibition of extralabel 
use of drugs in food-producing animals are found at Sec. Sec.  530.21 
and 530.25. These sections describe the basis for issuing an order 
prohibiting an extralabel drug use in food-producing animals and the 
procedure to be followed in issuing an order of prohibition.
    We may issue a prohibition order if we find that extralabel use in 
animals presents a risk to the public health. Under Sec.  530.3(e), 
this means that we have evidence that demonstrates that the use of the 
drug has caused or likely will cause an adverse event.
    Section 530.25 provides 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 we 
revoke the order, modify it, or extend the period of public comment. 
The list of drugs prohibited from extralabel use is found in Sec.  
530.41.

II. Phenylbutazone

    Phenylbutazone became available for use in humans for the treatment 
of rheumatoid arthritis and gout in 1949 (Ref. 1), but is no longer 
approved, and thus not marketed, for any human use in the United 
States. This is because some patients treated with phenylbutazone have 
experienced severe toxic reactions, and other effective, less toxic 
drugs are available to treat the same conditions (Refs. 1 and 2).
    Phenylbutazone is known for its ulcerogenic, nephrotoxic, and 
hemotoxic effects in horses, dogs, rats, and humans (Refs. 2, 4, 5, 6, 
7, and 8). It is known to induce blood dyscrasias, including aplastic 
anemia, leukopenia, agranulocytosis, thrombocytopenia, and deaths 
(Refs. 7 and 8). The reported adverse reactions were associated with 
the human clinical use of 200 to 800 milligrams phenylbutazone per day 
(Refs. 7 and 8). Hypersensitivity reactions of the serum-sickness type 
have also been reported in patients with phenylbutazone. The threshold 
for this effect has not been defined. Therefore, it is unclear what 
level of exposure would be required to trigger such reactions in 
sensitive people. Moreover, phenylbutazone is a carcinogen, as 
determined by the National Toxicology Program (NTP) based on positive 
results in genotoxicity tests and some evidence of carcinogenicity seen 
in the rat and mouse in carcinogenicity bioassays NTP conducted (Ref. 
3).
    For animals, phenylbutazone is currently approved only for oral and 
injectable use in dogs and horses. Use in horses is limited to use in 
horses not intended for food. There are currently no approved uses of 
phenylbutazone in food-producing animals.
    Investigation by FDA and state regulatory counterparts has recently 
found phenylbutazone on farms and identified tissue residues in culled 
dairy cattle. In addition, the U.S. Department of Agriculture's 
(USDA's) Food Safety Inspection Service has reported phenylbutazone 
residues in culled cattle presented for slaughter for human food 
throughout the United States in the past 2 calendar years. This 
evidence indicates that the extralabel use of phenylbutazone in female 
dairy cattle 20 months of age or older will likely result in the 
presence, at slaughter, of residues that are toxic to humans, including 
being carcinogenic, at levels that have not been shown to be safe. 
Because of the likelihood of this adverse event, we are issuing an 
order prohibiting the extralabel use of phenylbutazone drugs in female 
dairy cattle 20 months of age or older.
    We will continue to monitor the extralabel use of phenylbutazone 
and will adjust the scope of this prohibition should we find that 
extralabel use in other species or classes of animals presents a risk 
to public health.

III. Request for Comments

    We are providing 60 days from the date of this publication for you 
to comment. The order will become effective May 29, 2003, unless we 
revoke or modify the order, or extend the comment period. You may send 
written or electronic comments to the Dockets Management Branch (see 
ADDRESSES) by April 29, 2003. Submit a single copy of electronic 
comments to http://www.fda.gov/dockets/ecomments or two hard copies of 
any written comments, except that individuals may submit one hard copy. 
Please identify your comments with the docket number found in brackets 
in the heading of this document. You may read any comments that we 
receive at our Dockets Management Branch reading room (see ADDRESSES). 
The reading room is open from 9 a.m. to 4 p.m., Monday through Friday, 
except for Federal holidays.

IV. Order of Prohibition

    Therefore, I hereby issue the following order under section 
512(a)(4)(D) of the act and 21 CFR 530.21 and 530.25. We find that 
extralabel use of phenylbutazone animal drugs and human drugs in female 
dairy cattle 20 months of age or older likely will cause an adverse 
event which constitutes a finding under section 512(a)(4)(D) of the act 
that extralabel use of this drug presents a risk to the public health. 
Therefore, we are prohibiting the extralabel use of this drug in female 
dairy cattle 20 months of age or older.

V. References

    The following references have been placed on display in the Dockets 
Management Branch (see ADDRESSES). You may view them between 9 a.m. and 
4 p.m., Monday through Friday.
    1. Insel, P. A., ``Analgesic-Antipyretics and Anti-inflammatory 
Agents, and Drugs Employed in the Treatment of Gout,'' Goodman and 
Gilman, The Pharmacological Basis of Therapeutics, 9th ed., edited by 
J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon, and A. G. 
Gilman, McGraw-Hill, pp. 642-643, 1996.
    2. McEvoy, G. K., ``American Hospital Formulary Service B Drug 
Information 93,'' American Society of Hospital Pharmacists, Inc., 
Bethesda, MD, p. 1194, 1993.
    3. National Toxicology Program, ``Toxicology and Carcinogenesis 
Studies of Phenylbutazone in F344/N rats and B6C3F1 Mice (gavage 
studies)'' National Toxicology Program Technical Report number 367, NIH 
publication number 90-2822, 1990.
    4. Edited by R. J Anderson, J. G. Gambertoglio, and R. W. Schrier, 
``Clinical Use of Drugs in Renal Failure,'' Charles C. Thomas, 
Springfield, IL, p. 6, 1976.
    5. Carpenter, S. L., and W. M. McDonnell, ``Misuses of Veterinary 
Phenylbutazone,'' Archives of Internal Medicine, vol. 155, pp. 1229-
1231, 1995.
    6. Council on Drugs, ``Registry on Blood Dyscrasias,'' Report to 
the Council, Journal of the American Medical Association, vol. 179(11), 
pp. 888-890, 1962.
    7. Hazardous Substances Data Bank, 2000. http://www.csi.micromedex.com/DATA/HS/HS3159F.htm
    8. Humphreys, D. J., Veterinary Toxicology, Bailli[eacute]re 
Tindall, p. 92, 1988.

List of Subjects in 21 CFR Part 530

    Administrative practice and procedure, Advertising, Animal drugs,

[[Page 9530]]

Labeling, Reporting and recordkeeping requirements.

    Accordingly, under the Federal Food, Drug, and Cosmetic Act and 
under authority delegated to the Commissioner of Food and Drugs and 
redelegated to the Director of the Center for Veterinary Medicine, 21 
CFR part 530 is amended as follows:

PART 530--EXTRALABEL DRUG USE IN ANIMALS

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

    Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 351, 
352, 353, 355, 357, 360b, 371, 379e.


Sec.  530.41  [Amended]

    2. Section 530.41 is amended by adding paragraph (a)(12) to read as 
follows:


Sec.  530.41  Drugs prohibited for extralabel use in animals.

    (a) * * *
    (12) Phenylbutazone.
* * * * *

    Dated: February 13, 2003.
Stephen F. Sundlof,
Director, Center for Veterinary Medicine.
[FR Doc. 03-4741 Filed 2-27-03; 8:45 am]
BILLING CODE 4160-01-S