Document ID: FDA-2016-N-2462-0020
Agency: fda
Document Type: Rule
Title: List of Drug Products That Have Been Withdrawn or Removed From the
Market for Reasons of Safety or Effectiveness
Posted Date: 2018-12-11T05:00Z

[Federal Register Volume 83, Number 237 (Tuesday, December 11, 2018)]
[Rules and Regulations]
[Pages 63569-63574]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-26712]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 216

[Docket No. FDA-2016-N-2462]
RIN 0910-AH35

List of Drug Products That Have Been Withdrawn or Removed From 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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
amending its regulations to revise the list 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been withdrawn or removed from the market because such drug products or 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. Drug products appearing on this list may not be compounded 
under the exemptions provided by sections 503A and 503B of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act). Specifically, the final rule 
adds two entries to this list of drug products.

DATES: This rule is effective January 10, 2019.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule into 
the ``Search'' box and follow the prompts, and/or go to the Dockets 
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Alexandria Fujisaki, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5169, Silver Spring, MD 20993-0002, 301-
796-3110.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Regulatory Action
    B. Summary of the Major Provisions of the Regulatory Action
    C. Legal Authority
    D. Costs and Benefits
II. Background
    A. Relevant Provisions of the Statute
    B. The List of Drug Products in Sec.  216.24
    C. Regulatory History of the List
III. Proposed Rule and Final Rule
    A. Presentation to the Advisory Committee
    B. The Proposed Rule
    C. The Final Rule
IV. Comments on the Proposed Rule and FDA's Responses
    A. Comments on Proposed Entries for Inclusion on the List
    B. Miscellaneous Comments
V. Legal Authority
VI. Analysis of Environmental Impact
VII. Economic Analysis of Impacts
VIII. Paperwork Reduction Act of 1995
IX. Consultation and Coordination With Indian Tribal Governments
X. Federalism
XI. References

I. Executive Summary

A. Purpose of the Regulatory Action

    FDA is amending its regulations to revise the list 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 (referred to as ``the withdrawn or removed 
list'' or ``the list'') (Sec.  216.24 (21 CFR 216.24)). Drug products 
appearing on the withdrawn or removed list may not be compounded under 
the exemptions provided by sections 503A and 503B of the FD&C Act (21 
U.S.C. 353a and 353b). In this final rule, the Agency is finalizing in 
part the proposed amendments to Sec.  216.24 set forth in the proposed 
rule published in the Federal Register of October 18, 2016 (81 FR 
71648).

B. Summary of the Major Provisions of the Regulatory Action

    After soliciting public comments and consulting with the FDA 
Pharmacy Compounding Advisory Committee (the Committee), we are adding 
the following entries to the list in Sec.  216.24 of drug products that 
have been withdrawn or removed from the market because such drug 
products or

[[Page 63570]]

components of such drug products have been found to be unsafe or not 
effective:
    Bromocriptine mesylate: All drug products containing bromocriptine 
mesylate for prevention of physiological lactation.
    Ondansetron hydrochloride: All intravenous drug products containing 
greater than a 16 milligram (mg) single dose of ondansetron 
hydrochloride.

C. Legal Authority

    Sections 503A, 503B, and 701(a) of the FD&C Act (21 U.S.C. 353a, 
353b, and 371(a)) provide the principal legal authority for this final 
rule.

D. Costs and Benefits

    The Agency is not aware of routine compounding of the drug products 
that are the subject of this final rule. Therefore, we do not estimate 
any compliance costs or loss of sales as a result of the prohibition 
against compounding these drug products for human use. The Agency has 
determined that this rulemaking is not a significant regulatory action 
as defined by Executive Order 12866.

II. Background

A. Relevant Provisions of the Statute

    Section 503A of the FD&C Act describes the conditions that must be 
satisfied for human drug products compounded by a licensed pharmacist 
or licensed physician to be exempt from the following three sections of 
the FD&C Act: (1) Section 501(a)(2)(B) (21 U.S.C. 351(a)(2)(B)) 
(concerning current good manufacturing practice); (2) section 502(f)(1) 
(21 U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate 
directions for use); and (3) section 505 (21 U.S.C. 355) (concerning 
the approval of new drugs under new drug applications (NDAs) or 
abbreviated new drug applications (ANDAs)).
    In addition, section 503B of the FD&C Act describes the conditions 
that must be satisfied for a drug compounded for human use by or under 
the direct supervision of a licensed pharmacist in an outsourcing 
facility to be exempt from three sections of the FD&C Act: (1) Section 
502(f)(1), (2) section 505, and (3) section 582 (21 U.S.C. 360eee-1) 
(concerning drug supply chain security).
    One of the conditions that must be satisfied for a drug product to 
qualify for the exemptions under sections 503A or 503B of the FD&C Act 
is that the compounder does not compound a drug product that appears on 
a list published by the Secretary of Health and Human Services (the 
Secretary) (delegated to FDA) 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 (the 
withdrawn or removed list) (see sections 503A(b)(1)(C), 503B(a)(4), and 
503B(a)(11) of the FD&C Act).

B. The List of Drug Products in Sec.  216.24

    The drug products listed in the withdrawn or removed list codified 
at Sec.  216.24 have been withdrawn or removed from the market because 
they have been found to be unsafe or not effective. A drug product that 
is included in the withdrawn or removed list is not eligible for the 
exemptions provided in section 503A(a) from sections 501(a)(2)(B), 
502(f)(1), and 505 of the FD&C Act. In addition, a drug that is 
included in the withdrawn or removed list is not eligible for the 
exemptions provided in section 503B(a) from sections 502(f)(1), 505, 
and 582 of the FD&C Act.

C. Regulatory History of the List

    The Food and Drug Modernization Act of 1997 (Pub. L. 105-115) added 
section 503A to the FD&C Act. On October 8, 1998, FDA proposed a rule 
in the Federal Register (63 FR 54082) to establish the original 
withdrawn or removed list. On March 8, 1999, FDA finalized this rule 
(64 FR 10944), prohibiting the products described on the original list 
from being compounded under the exemptions provided by section 503A(a) 
of the FD&C Act.
    Following the addition of section 503B to the FD&C Act on November 
27, 2013, through the enactment of the Drug Quality and Security Act 
(Pub. L. 113-54), FDA published a proposed rule to revise and update 
the list in Sec.  216.24 on July 2, 2014 (79 FR 37687); FDA published 
the final rule to amend Sec.  216.24 in the Federal Register of October 
7, 2016 (81 FR 69668) (2016 final rule). Given that nearly identical 
criteria apply for a drug to be included on the list referred to in 
section 503A(b)(1)(C) and the list referred to in section 503B(a)(4) of 
the FD&C Act, the 2016 final rule added language to Sec.  216.24 
clarifying that it applies for purposes of both sections 503A and 503B.

III. Proposed Rule and Final Rule

A. Presentation to the Advisory Committee

    At a meeting held on June 17 and 18, 2015 (see the Federal Register 
of May 22, 2015 (80 FR 29717)), FDA presented to the Committee FDA's 
proposal to add to the withdrawn or removed list all drug products 
containing more than 325 mg of acetaminophen per dosage unit, all drug 
products containing aprotinin, all drug products containing 
bromocriptine mesylate for the prevention of physiological lactation, 
and all intravenous drug products containing greater than a 16 mg 
single dose of ondansetron hydrochloride. The Committee voted in favor 
of including each drug product entry on the list as proposed by FDA.\1\
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    \1\ A transcript of the June 2015 Committee meeting (Ref. 1) and 
briefing information that includes reviews and background on the 
proposed entries (Ref. 2) may be found at the Dockets Management 
Staff (see ADDRESSES) and at https://wayback.archive-it.org/7993/20170111202622/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm431285.htm.
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B. The Proposed Rule

    In the Federal Register of October 18, 2016, FDA proposed to revise 
the withdrawn or removed list to add all drug products containing 
aprotinin, all drug products containing bromocriptine mesylate for the 
prevention of physiological lactation, and all intravenous drug 
products containing greater than a 16 mg single dose of ondansetron 
hydrochloride (October 2016 proposed rule). The addition of all drug 
products containing more than 325 mg of acetaminophen per dosage unit 
to the list was not included in the October 2016 proposed rule and 
remains under consideration by the Agency.

C. The Final Rule

    The Agency has considered the public discussion and the advice 
provided by the Committee regarding these matters at the June 2015 
meeting, as well as the October 2016 proposed rule, including the 
comments submitted on the proposed rule (see section IV). Based on the 
information before FDA and its own knowledge and expertise, FDA is 
adding two entries from the proposed rule to the withdrawn or removed 
list in Sec.  216.24.
    The two entries FDA is adding to Sec.  216.24 are as follows:
    Bromocriptine mesylate: All drug products containing bromocriptine 
mesylate for prevention of physiological lactation.
    Ondansetron hydrochloride: All intravenous drug products containing 
greater than a 16 mg single dose of ondansetron hydrochloride.
    At this time, FDA is not finalizing the entry in the proposed rule 
for all drug products containing aprotinin. The addition of an entry to 
the withdrawn or removed list for drug products containing aprotinin 
remains under consideration by FDA.

[[Page 63571]]

IV. Comments on the Proposed Rule and FDA's Responses

    Four comments, all from individuals, were submitted on the October 
2016 proposed rule. FDA has summarized and responded to the relevant 
comments in the following paragraphs. A comment about ``hernia repair 
with mesh and plug'' has not been answered because it was not relevant 
to this rulemaking. Comments regarding the proposed addition of an 
entry to the withdrawn or removed list for aprotinin will not be 
answered at this time because the entry remains under consideration by 
FDA.
    To make it easier to identify the comments and FDA's responses, the 
word ``Comment,'' in parentheses, appears before the comment's 
description, and the word ``Response,'' in parentheses, appears before 
the Agency's response. We have numbered each comment to help 
distinguish between different comments. Similar comments are grouped 
together under the same number, and, in some cases, different subjects 
discussed in the same comment are separated and designated as distinct 
comments for purposes of FDA's response. The number assigned to each 
comment or comment topic is purely for organizational purposes and does 
not signify the comment's value or importance or the order in which the 
comments were received.

A. Comments on Proposed Entries for Inclusion on the List

1. Bromocriptine Mesylate
    (Comment 1) One comment supported the proposal to include all drug 
products containing bromocriptine mesylate for prevention of 
physiological lactation on the withdrawn or removed list.
    (Response 1) FDA agrees with the comment.
    (Comment 2) FDA received one comment opposing the proposal to 
include all drug products containing bromocriptine mesylate for 
prevention of physiological lactation on the withdrawn or removed list. 
The comment asserts that bromocriptine mesylate offers ``significant 
improvements in the quantity and quality of life,'' and, although it 
has ``serious adverse effects,'' the benefits of bromocriptine mesylate 
compared to its risks ``should warrant continuous approvability.''
    (Response 2) FDA disagrees with the comment. For the reasons that 
follow, FDA will add all drug products containing bromocriptine 
mesylate for prevention of physiological lactation to the list in Sec.  
216.24.
    As a preliminary matter, the issue in this rulemaking is whether 
all drug products containing bromocriptine mesylate for the indication 
of prevention of physiological lactation were withdrawn or removed from 
the market because they were found to be unsafe or not effective for 
this indication. The criteria that must be met to place a drug product 
on the withdrawn or removed list are laid out in the FD&C Act. Under 
sections 503A and 503B of the FD&C Act, to be placed on the withdrawn 
or removed list, drug products must 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.
    As FDA previously explained in the October 2016 proposed rule, FDA 
withdrew approval of PARLODEL (bromocriptine mesylate, NDA 17962) for 
the indication of prevention of physiological lactation in a document 
published in the Federal Register of January 17, 1995 (60 FR 3404). At 
the time, PARLODEL was the only marketed drug product containing 
bromocriptine mesylate labeled with this indication. FDA's 2015 
``Review of Bromocriptine Mesylate for the Withdrawn or Removed List'' 
indicates that the 1995 withdrawal of PARLODEL for prevention of 
physiological lactation was based on the unfavorable benefit-risk 
balance of this product for this indication. See ``Review of 
Bromocriptine Mesylate for the Withdrawn or Removed List'' in the FDA 
Briefing Document for the June 17 and 18, 2015 Pharmacy Compounding 
Advisory Committee Meeting, available at https://wayback.archive-it.org/7993/20170113060809/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm449533.htm. In particular, in a notice published in the Federal 
Register on August 23, 1994 (59 FR 43347), FDA concluded that 
bromocriptine mesylate's risks of hypertension, seizures, and 
cardiovascular accidents outweighed the product's marginal benefit in 
preventing postpartum lactation, which can be suppressed without risk 
by using more conservative, nonpharmacological treatments. Withdrawal 
of PARLODEL's indication for the prevention of physiological lactation 
became effective on February 16, 1995 (60 FR 3404). FDA has determined 
that all drug products containing bromocriptine mesylate for prevention 
of physiological lactation were withdrawn or removed from the market 
because such products have been found to be unsafe or not effective. We 
note that FDA-approved drug products containing bromocriptine mesylate 
for other indications, such as treatment of Parkinson's disease, 
acromegaly, and prolactin-secreting adenomas, remain marketed.
    FDA's 2015 review, which included a discussion of the withdrawal of 
PARLODEL's indication for the prevention of physiological lactation, 
was presented to the Committee at the meeting held on June 17 and 18, 
2015, and the Committee voted in favor of the Agency's proposal to 
include all drug products containing bromocriptine mesylate for the 
prevention of physiological lactation on the list. For these reasons, 
FDA proposed in the October 2016 proposed rule to include all drug 
products containing bromocriptine mesylate for the prevention of 
physiological lactation on the withdrawn or removed list.
    The comment offered no scientific rationale or support for its 
position that this drug product should not be on the list; therefore, 
FDA is including bromocriptine mesylate for prevention of physiological 
lactation on the withdrawn or removed list.
2. Ondansetron Hydrochloride
    (Comment 3) One comment supported the proposal to include all 
intravenous drug products containing greater than a 16 mg single dose 
of ondansetron hydrochloride on the withdrawn or removed list.
    (Response 3) FDA agrees with the comment.
    (Comment 4) FDA received one comment on the proposal to include all 
intravenous drug products containing greater than a 16 mg single dose 
of ondansetron hydrochloride suggesting ``perhaps there is more to 
investigate and stricter regulation of the administration of IV 
ondansetron hydrochloride is warranted in the future.''
    (Response 4) FDA intends to monitor future approvals, withdrawals, 
or removals of drugs, to consider other relevant information that may 
suggest the need to revise the withdrawn or removed list, and to 
propose modifications as appropriate. In addition, members of the 
public can submit a citizen petition at any time under 21 CFR 10.25 and 
10.30 requesting that FDA add, modify, or remove an entry on the list 
(with data to support their request), and FDA will consider and respond 
to the petition.
    (Comment 5) FDA received one comment opposing the proposal to 
include all intravenous drug products containing greater than a 16 mg 
single dose of ondansetron hydrochloride on

[[Page 63572]]

the withdrawn or removed list. The comment asserts that ondansetron 
hydrochloride offers ``significant improvements in the quantity and 
quality of life,'' and, although it has ``serious adverse effects,'' 
the benefits of ondansetron hydrochloride compared to its risks 
``should warrant continuous approvability.''
    (Response 5) FDA disagrees with the comment. For the reasons that 
follow, FDA will add all intravenous drug products containing greater 
than a 16 mg single dose of ondansetron hydrochloride to the list in 
Sec.  216.24.
    As noted earlier, the issue in this rulemaking is whether drug 
products containing greater than a 16 mg single dose of ondansetron 
hydrochloride were withdrawn or removed from the market because they 
were found to be unsafe or not effective.
    As FDA previously explained in the October 2016 proposed rule, in 
the Federal Register of June 10, 2015 (80 FR 32962), FDA announced its 
determination under 21 CFR 314.161 and 314.162(a)(2) that the NDA for 
Ondansetron (ondansetron hydrochloride) Injection, USP, 32 mg/50 mL, 
single IV dose was withdrawn from sale for reasons of safety. In 
particular, this product was associated with a specific type of 
irregular heart rhythm called QT interval prolongation, and the data 
suggest that any dose above the maximum recommendation of 16 mg per 
dose intravenously has the potential for increased risk of QT 
prolongation. FDA made this determination after holders of one NDA and 
four ANDAs voluntarily removed such products from the market and 
requested that FDA withdraw approval of their respective applications 
under 21 CFR 314.150(d). Thus, all drug products containing greater 
than a 16 mg single dose of ondansetron hydrochloride have been 
withdrawn or removed from the market because such drug products have 
been found to be unsafe or not effective. We note that FDA-approved 
drug products containing lower single doses of ondansetron 
hydrochloride remain marketed.
    FDA's review of intravenous drug products containing greater than a 
16 mg single dose of ondansetron hydrochloride was presented to the 
Committee at the meeting held on June 17 and 18, 2015, and the 
Committee voted in favor of the Agency's proposal to include all 
intravenous drug products containing greater than a 16 mg single dose 
of ondansetron hydrochloride on the list. For these reasons, FDA 
proposed in the October 2016 proposed rule to include all intravenous 
drug products containing greater than a 16 mg single dose of 
ondansetron hydrochloride on the withdrawn or removed list.
    (Comment 6) FDA received one comment asserting that ondansetron 
hydrochloride should not be recommended for use by pregnant women 
because it was not approved by FDA for pregnant women.
    (Response 6) This comment is outside the scope of this rulemaking. 
Compounded drugs are not FDA approved and this rulemaking addresses the 
placement of certain drug products on the withdrawn or removed list, 
including all intravenous drug products containing greater than a 16 mg 
single dose of ondansetron hydrochloride. As previously noted, drugs 
appearing on this list may not be compounded under the exemptions 
provided by sections 503A and 503B of the FD&C Act. Therefore, to the 
extent the commenter believes that intravenous drug products containing 
greater than a 16 mg single dose of ondansetron hydrochloride should 
not be compounded for pregnant women under the exemptions provided by 
sections 503A and 503B of the FD&C Act, we agree. The addition of the 
entry FDA is finalizing regarding ondansetron hydrochloride through 
this rulemaking for the list in Sec.  216.24 will prohibit compounding 
of intravenous drug products containing greater than a 16 mg single 
dose of ondansetron hydrochloride under the exemptions provided by 
sections 503A and 503B of the FD&C Act for all patients, including 
pregnant women.

V. Legal Authority

    Sections 503A and 503B of the FD&C Act provide the principal legal 
authority for this final rule. As described previously in section II, 
section 503A of the FD&C Act describes the conditions that must be 
satisfied for human drug products compounded by a licensed pharmacist 
or licensed physician to be exempt from three sections of the FD&C Act 
(sections 501(a)(2)(B), 502(f)(1), and 505). One of the conditions that 
must be satisfied to qualify for the exemptions under section 503A of 
the FD&C Act is that the licensed pharmacist or licensed physician does 
not compound a drug product that appears on a list published by FDA 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 (see 
section 503A(b)(1)(C) of the FD&C Act). Section 503A(c)(1) of the FD&C 
Act also states that the Secretary shall issue regulations to implement 
section 503A, and that before issuing regulations to implement section 
503A(b)(1)(C) pertaining to the withdrawn or removed list, among other 
sections, the Secretary shall convene and consult an advisory committee 
on compounding unless the Secretary determines that the issuance of 
such regulations before consultation is necessary to protect the public 
health.\2\
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    \2\ Note: The functions of the Secretary described herein have 
been delegated to FDA.
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    Section 503B of the FD&C Act describes the conditions that must be 
satisfied for a drug compounded for human use by or under the direct 
supervision of a licensed pharmacist in an outsourcing facility to be 
exempt from three sections of the FD&C Act (sections 502(f)(1), 505, 
and 582). One of the conditions in section 503B of the FD&C Act that 
must be satisfied to qualify for the exemptions is that the drug does 
not appear on a list published by FDA of drugs that have been withdrawn 
or removed from the market because such drugs or components of such 
drugs have been found to be unsafe or not effective (see section 
503B(a)(4)). To be eligible for the exemptions in section 503B, a drug 
must be compounded in an outsourcing facility in which the compounding 
of drugs occurs only in accordance with section 503B, including as 
provided in section 503B(a)(4) of the FD&C Act.
    Thus, sections 503A and 503B of the FD&C Act, in conjunction with 
our general rulemaking authority in section 701(a) of the FD&C Act (21 
U.S.C. 371(a)), serve as our principal legal authority for this final 
rule revising FDA's regulation on the list of drug products 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 in 
Sec.  216.24.

VI. Analysis of Environmental Impact

    We have 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.

VII. Economic Analysis of Impacts

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, Executive Order 13771, the 
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded 
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 
13563 direct us to assess all costs and benefits of available 
regulatory alternatives and, when regulation is

[[Page 63573]]

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 13771 requires that the costs associated with significant new 
regulations ``shall, to the extent permitted by law, be offset by the 
elimination of existing costs associated with at least two prior 
regulations.'' This final rule is not a significant regulatory action 
as defined by Executive Order 12866 and is not subject to Executive 
Order 13771.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because small businesses are not expected to incur any 
compliance costs or loss of sales due to this regulation, we certify 
that the final rule will not have a significant economic impact on a 
substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before issuing ``any rule that includes 
any Federal mandate that may result in the expenditure by State, local, 
and tribal governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any one 
year.'' The current threshold after adjustment for inflation is $150 
million, using the most current (2017) Implicit Price Deflator for the 
Gross Domestic Product. This final rule is not expected to result in an 
expenditure in any year that would meet or exceed this amount.
    This final rule amends Sec.  216.24 concerning human drug 
compounding. Specifically, the final rule adds to the list of drug 
products that may not be compounded under the exemptions provided by 
sections 503A and 503B of the FD&C Act because the drug products 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 (see section II). We are adding two entries to the list: Drug 
products containing bromocriptine mesylate for prevention of 
physiological lactation and intravenous drug products containing 
greater than a 16 mg single dose of ondansetron hydrochloride. The 
Agency is not aware of routine compounding of these drug products; 
therefore, we do not estimate any compliance costs or loss of sales as 
a result of the prohibition against compounding these drugs for human 
use.
    Unless we certify that a rule will not have a significant economic 
impact on a substantial number of small entities, the Regulatory 
Flexibility Act requires us to analyze regulatory options to minimize 
any significant economic impact of a regulation on small entities. Most 
pharmacies meet the Small Business Administration definition of a small 
entity, which is defined as having annual sales less than $27.5 million 
for this industry. We are not aware of any routine compounding of the 
drug products that are the subject of this final rule and do not 
estimate any compliance costs or loss of sales to small businesses as a 
result of the prohibition against compounding these drug products. 
Therefore, we certify that this final rule will not have a significant 
economic impact on a substantial number of small entities.

VIII. Paperwork Reduction Act of 1995

    This final 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.

IX. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this rule in accordance with the principles set 
forth in Executive Order 13175. We have determined that the rule does 
not contain policies that have substantial direct effects on one or 
more Indian Tribes, on the relationship between the Federal Government 
and Indian Tribes, or on the distribution of power and responsibilities 
between the Federal Government and Indian Tribes. Accordingly, we 
conclude that the rule does not contain policies that have tribal 
implications as defined in the Executive Order and, consequently, a 
tribal summary impact statement is not required.

X. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the final 
rule does not contain policies that have substantial direct effects on 
the States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the Agency concludes that 
the rule does not contain policies that have federalism implications as 
defined in the Executive order and, consequently, a federalism summary 
impact statement is not required.

XI. References

    The following references are on display in the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

    1. Transcript for the June 17-18, 2015, Meeting of the Pharmacy 
Compounding Advisory Committee, available at https://wayback.archive-it.org/7993/20170111202622/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm431285.htm.
    2. Briefing Information for the June 17-18, 2015, Meeting of the 
Pharmacy Compounding Advisory Committee, available at https://wayback.archive-it.org/7993/20170111202622/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm431285.htm.

List of Subjects in 21 CFR Part 216

    Drugs, Prescription drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
216 is amended as follows:

PART 216--HUMAN DRUG COMPOUNDING

0
1. The authority citation for part 216 continues to read as follows:

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

0
2. Amend Sec.  216.24 by adding, in alphabetical order, to the list of 
drugs ``Bromocriptine mesylate'' and ``Ondansetron hydrochloride'' to 
read as follows:

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

* * * * *
    Bromocriptine mesylate: All drug products containing bromocriptine 
mesylate for prevention of physiological lactation.
* * * * *
    Ondansetron hydrochloride: All intravenous drug products containing 
greater than a 16 milligram single dose of ondansetron hydrochloride.
* * * * *

[[Page 63574]]

    Dated: December 4, 2018.
Scott Gottlieb,
Commissioner of Food and Drugs.
[FR Doc. 2018-26712 Filed 12-10-18; 8:45 am]
 BILLING CODE 4164-01-P