[Federal Register Volume 65, Number 2 (Tuesday, January 4, 2000)]
[Proposed Rules]
[Pages 256-258]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-76]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 216

[Docket No. 99N-4490]


Additions to the List of Drug Products That Have Been Withdrawn 
or Removed From the Market for Reasons of Safety or Effectiveness

AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its regulations to add two drug products to the list of drug products 
that may not be used for pharmacy compounding under the exemptions 
provided by the Federal Food, Drug, and Cosmetic Act (the act) because 
they have had their approval withdrawn or were removed from the market 
because the drug product or its components have been found to be unsafe 
or not effective.

DATES: Written comments must be received on or before March 20, 2000.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    President Clinton signed the Food and Drug Administration 
Modernization Act (Public Law 105-115) into law on November 21, 1997. 
One of the issues addressed in the legislation is the applicability of 
the act to the practice of pharmacy compounding. Compounding involves a 
process whereby a pharmacist or physician combines, mixes, or alters 
ingredients to create a customized medication for an individual 
patient. Section 127 of the Modernization Act, which adds section 503A 
to the act (21 U.S.C. 353a), describes the circumstances under which 
compounded drugs qualify for exemptions from certain adulteration, 
misbranding, and new drug provisions of the act (i.e., sections 
501(a)(2)(B), 502(f)(1), and 505 of the act (21 U.S.C. 351(a)(2)(B), 
352(f)(1), and 355)).
    Section 503A of the act contains several conditions that must be 
satisfied for pharmacy compounding to qualify for the exemptions. One 
of the conditions is that the licensed pharmacist or licensed physician 
does not ``compound a drug product that appears on a list published by 
the Secretary in the Federal Register of drug products that have been 
withdrawn or removed from the market because such drug products or 
components of such drug products have been found to be unsafe or not 
effective.''

II. Rulemaking to Establish the List

    In the Federal Register of October 8, 1998 (63 FR 54082), we 
proposed the original list of drug products that have had their 
approval withdrawn or were removed from the market because the drug 
product or its components have been found to be unsafe or not 
effective. We published the original list as a final rule in the 
Federal Register of March 8, 1999 (64 FR 10944). You may wish to read 
these documents for additional information about the list. The two 
Federal Register documents may be found on the Center for Drug 
Evaluation and Research's website at http://www.fda.gov/cder/pharmcomp/
default.htm or the Government Printing Office's website at http://
www.access.gpo.gov/su__docs/aces/aces140.html.
    The list was codified as Sec. 216.24 of Title 21 in the Code of 
Federal Regulations (CFR) (21 CFR 216.24). This is the first time we 
have proposed to amend the list.

III. Description of this Proposed Rule

    We are proposing that the drug products described below be added to

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the list of drug products that have had their approval withdrawn or 
were removed from the market because the drug product or its components 
have been found to be unsafe or not effective. Compounding a drug 
product that appears on the list is not covered by the exemption 
provided in section 503A(a) of the act, and it may be subject to 
enforcement action under sections 501(a)(2)(B), 502(f)(1), and 505 
(among other applicable provisions) of the act.
    Aminopyrine: All drug products containing aminopyrine. Drug 
products containing aminopyrine were used as an analgesic and an 
antipyretic. Aminopyrine caused agranulocytosis, a condition 
characterized by a decrease in the number of certain white blood cells 
and lesions on the mucous membrane and skin. Some of the cases of 
agranulocytosis were fatal. In 1964, we declared drug products 
containing aminopyrine to be new drugs. We invited new drug 
applications (NDA's) for these drug products, but only for use as an 
antipyretic in serious situations where other safer drugs could not be 
used (see 21 CFR 201.311 (42 FR 53954, October 4, 1977)). We received 
no NDA's for drug products containing aminopyrine, and those unapproved 
drug products were removed from the market by their manufacturers (see 
42 FR 53954).
    Astemizole: All drug products containing astemizole. Astemizole 
tablets were marketed under the trade name Hismanal and were indicated 
for the relief of symptoms associated with seasonal allergic rhinitis 
and chronic idiopathic urticaria. We approved the NDA for astemizole 
tablets in December 1988. Within a few years of the approval, it was 
learned that low-level overdosages of astemizole were resulting in 
life-threatening heart arrhythmias. Patients with liver dysfunction or 
who were taking other drugs that interfered with the metabolization of 
astemizole were also found to be at risk of serious cardiac adverse 
events while taking astemizole. The manufacturer of astemizole tablets, 
the only astemizole drug product, removed the product from the market 
on June 18, 1999. We published a notice in the Federal Register of 
August 23, 1999 (64 FR 45973), announcing our determination that 
astemizole tablets were withdrawn from the market for safety reasons.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) 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.

V. Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Executive Order 12866 
classifies a rule as significant if it meets any one of a number of 
specified conditions, including having an annual effect on the economy 
of $100 million or adversely affecting in a material way a sector of 
the economy, competition, or jobs, or if it raises novel legal or 
policy issues. As discussed below, the agency believes that this 
proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.
    The agency has not estimated any compliance costs or loss of sales 
due to this proposed rule because it prohibits pharmacy compounding of 
only those drug products that have already been withdrawn or removed 
from the market. Although the agency is not aware of any routine use of 
these drug products in pharmacy compounding, the agency invites the 
submission of comments on this issue and solicits current compounding 
usage data for these drug products.
    Unless an agency certifies that a rule will not have a significant 
economic impact on a substantial number of small entities, the 
Regulatory Flexibility Act requires agencies to analyze regulatory 
options to minimize any significant economic impact of a regulation on 
small entities. The agency is taking this action to comply with section 
503A of the act. This provision specifically directs us to develop a 
list of drug products that have been withdrawn or removed from the 
market because such products or components have been found to be unsafe 
or not effective. Any drug product on this list will not qualify for 
the pharmacy compounding exemptions under section 503A of the act.
    The drug products that are proposed to be added to the this list 
were manufactured by several different pharmaceutical firms, some of 
which may have qualified under the Small Business Administration (SBA) 
regulations (those with less than 750 employees) as small businesses. 
However, since the list only includes drug products that have already 
been withdrawn or removed from the market for safety or efficacy 
concerns, this proposal will not negatively impact these small 
businesses. Moreover, no compliance costs are estimated for any of 
these small pharmaceutical firms because they are not the subject of 
this rule and are not expected to realize any further loss of sales due 
to this proposal. Further, the SBA guidelines limit the definition of 
small drug stores or pharmacies to those that have less than $5.0 
million in sales. Again, the pharmacies that qualify as small 
businesses are not expected to incur any compliance costs or loss of 
sales due to this regulation because the products have already been 
withdrawn or removed from the market, and the agency believes that 
these drugs would be compounded only very rarely, if ever. Therefore, 
we certify that this rule will not have a significant economic impact 
on a substantial number of small entities.
    Section 202 of the Unfunded Mandates Reform Act requires that 
agencies prepare an assessment of anticipated costs and benefits before 
proposing any expenditure by State, local, and tribal governments, in 
the aggregate, or by the private sector of $100 million (adjusted 
annually for inflation) in any one year. The publication of the list of 
products withdrawn or removed from the market because they were found 
to be unsafe or ineffective will not result in expenditures of funds by 
State, local, and tribal governments or the private sector in excess of 
$100 million annually. Because the agency does not estimate any annual 
expenditures due to the proposed rule, we are not required to perform a 
cost/benefit analysis according to the Unfunded Mandates Reform Act.

VI. Paperwork Reduction Act of 1995

    We tentatively conclude that this proposed rule contains no 
collections of information. Therefore, clearance by the Office of 
Management and Budget under the Paperwork Reduction Act of 1995 is not 
required.

VII. Request for Comments

    Interested persons may, on or before March 20, 2000, submit to the 
Dockets

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Management Branch (address above) written comments regarding this 
proposal. 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 above between 9 a.m. and 4 
p.m., Monday through Friday.

List of Subjects in 21 CFR Part 216

    Drugs, Pharmacy compounding, Prescription drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 216 be amended as follows:

PART 216--PHARMACY COMPOUNDING

    1. The authority citation for 21 CFR part 216 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 352, 353a, 355, and 371.

    2. Amend Sec. 216.24 by adding alphabetically to the list of drug 
products ``Aminopyrine'' and ``Astemizole'' to read as follows:


Sec. 216.24  Drug products withdrawn or removed from the market for 
reasons of safety or effectiveness.

* * * * *
    Aminopyrine: All drug products containing aminopyrine.
    Astemizole: All drug products containing astemizole.
* * * * *

    Dated: December 10, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-76 Filed 1-3-00; 8:45 am]
BILLING CODE 4160-01-F