[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,
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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,
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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