Additions and Modifications to the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness, 69668-69677 [2016-24333]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 81, Number 195 (Friday, October 7, 2016)]
[Rules and Regulations]
[Pages 69668-69677]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-24333]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 216

[Docket No. FDA-1999-N-0194 (Formerly 99N-4490)]
RIN 0910-AH08


Additions and Modifications 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Have Been Withdrawn or Removed From the Market for Reasons of Safety or 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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
amending its regulations to revise the list of drug products that have 
been withdrawn or removed from the market because the drug products or 
components of such drug products have been found to be unsafe or not 
effective. Drugs 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 (the FD&C Act). Specifically, the rule adds 24 
entries to this list of drug products, modifies the description of one 
entry on this list, and revises the list's title and introductory 
language. These revisions are necessary because information has come to 
the Agency's attention since March 8, 1999, when FDA published the 
original list as a final rule.

DATES: This rule is effective November 7, 2016.

FOR FURTHER INFORMATION CONTACT: Edisa Gozun, Center for Drug 
Evaluation and Research (HFD-310), Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 51, Rm. 5199, Silver Spring, MD 20993-0002, 
301-796-3110.

[[Page 69669]]


SUPPLEMENTARY INFORMATION:

`Table of Contents
Executive Summary
    Purpose of the Regulatory Action
    Summary of the Major Provisions of the Regulatory Action in 
Question
    Costs and Benefits
I. Background: The Provisions of 503A and 503B Pertaining to the 
Withdrawn or Removed List
II. Proposed Rule and Final Rule
    A. The Proposed Rule
    B. Presentation to the Advisory Committee
    C. The Final Rule
III. Comments on the Proposed Rule and FDA's Responses
    A. Comments on Proposed Entries for Inclusion on the List
    B. Comments on Other Issues
    C. Comments on Updating the List
    D. Miscellaneous Comments
IV. Legal Authority
V. Analysis of Environmental Impact
VI. Economic Analysis of Impacts
VII. Paperwork Reduction Act of 1995
VIII. Federalism
IX. References

Executive Summary

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 the 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)). Drugs 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. In this 
final rulemaking, 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 July 2, 2014 (79 FR 37687).
    Section 503A of the FD&C Act (21 U.S.C. 353a) refers to a list 
published by the Secretary of Health and Human Services 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. Furthermore, section 
503A(c)(1) of the FD&C Act 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.
    In addition, section 503B of the FD&C Act (21 U.S.C. 353b) refers 
to a list published by the Secretary 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.
    After soliciting public comments and consulting with the Pharmacy 
Compounding Advisory Committee (Advisory Committee), FDA is issuing 
this final rule revising and updating the list in Sec.  216.24 for 
purposes of both sections 503A and 503B of the FD&C Act. FDA may update 
this list in the future as necessary when information comes to the 
Agency's attention indicating that changes to the list are needed.

Summary of the Major Provisions of the Regulatory Action in Question

    The final rule: (1) Adds 24 entries to the list of drug products in 
Sec.  216.24 that cannot be compounded for human use under the 
exemptions provided by either section 503A or 503B of the FD&C Act 
because they 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, (2) modifies one entry already on the 
list to add an exception that allows a drug product to be compounded 
under certain circumstances, and (3) modifies the title of part 216 and 
the introductory text of Sec.  216.24.

Costs and Benefits

    The Agency is not aware of any routine compounding for human use of 
the drug products that are the subject of this rule, and therefore does 
not estimate any compliance costs or loss of sales as a result of 
finalizing regulations making these drugs ineligible for exemptions 
under sections 503A and 503B of the FD&C Act. The Agency has determined 
that this rule is not a significant regulatory action as defined by 
Executive Order 12866.

I. Background: The Provisions of 503A and 503B Pertaining to the 
Withdrawn or Removed List

    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 drugs under new drug applications (NDAs) or abbreviated 
new drug applications (ANDAs)).
    Section 503B of the FD&C Act created a new category of 
``outsourcing facilities.'' Outsourcing facilities, as defined in 
section 503B of the FD&C Act, are facilities that meet certain 
conditions described in section 503B, including registering with FDA as 
an outsourcing facility. If these conditions are satisfied, a drug 
compounded for human use by or under the direct supervision of a 
licensed pharmacist in an outsourcing facility is 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), but not from section 501(a)(2)(B).
    One of the conditions that must be satisfied to qualify for the 
exemptions under both sections 503A and 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 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 
(withdrawn or removed list) (see sections 503A(b)(1)(C) and 503B(a)(4) 
of the FD&C Act).

II. Proposed Rule and Final Rule

A. The Proposed Rule

    In the Federal Register of July 2, 2014, FDA proposed to revise the 
list of drug products that have been withdrawn or removed from the 
market because the drug products or components of such drug products 
have been found to be unsafe or not effective (the July 2014 proposed 
rule). Drugs appearing on this list may not be compounded under the 
exemptions provided by sections 503A and 503B of the FD&C Act. 
Specifically, FDA proposed to add 25 entries to this list of drug 
products and to modify the description of one entry on this list to add 
an exception for products compounded under certain circumstances. The 
preamble of the proposed rule explained that these revisions are 
necessary to ensure the list of drug products in Sec.  216.24 reflects 
information that has come to the Agency's attention since FDA published 
the original list in the 1999 final rule. Given that nearly identical 
criteria apply for a drug product 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, FDA proposed revising and updating the list 
at Sec.  216.24 for purposes of both sections 503A and 503B.

[[Page 69670]]

    As with the original list, the primary focus of the July 2014 
proposed rule and this final rule is on drug products that have been 
withdrawn or removed from the market because they have been found to be 
unsafe. FDA may propose at a later date to add other drug products to 
the list that have been withdrawn or removed from the market because 
they have been found to be not effective, or to update the list as 
information becomes available to the Agency regarding products that 
were withdrawn or removed from the market because they have been found 
to be unsafe.
    In the preamble of the July 2014 proposed rule, FDA also invited 
comments on the appropriate procedure to update the list in the future. 
FDA described the provisions of sections 503A and 503B of the FD&C Act 
regarding how the Agency is to create and update the list, and noted 
the differences between the procedures set forth in sections 503A and 
503B. The Agency explained that it believes that the timely sharing of 
information about safety concerns relating to compounding drugs for 
human use is essential to the protection of public health. FDA also 
explained that it is concerned that consulting with the Advisory 
Committee and completing the rulemaking process are likely to 
contribute to substantial delay in updating the list to reflect current 
safety information. FDA therefore announced that the Agency was seeking 
an alternative procedure to update the withdrawn or removed list in the 
future and solicited public comment. FDA also stated that it would 
specify in the final rule the procedure it will use to update the list 
in the future.

B. Presentation to the Advisory Committee

    At a meeting held on February 23 and 24, 2015 (see the Federal 
Register of January 26, 2015 (80 FR 3967)), FDA presented to the 
Advisory Committee the 25 entries it proposed to include on the list 
and the proposed modification to the listing for one entry. The 
Advisory Committee voted in favor of including each drug product entry 
on the list as proposed by FDA. In addition, because FDA had received a 
comment on the July 2014 proposed rule requesting that FDA clarify the 
entry for adenosine phosphate, FDA presented a potential modification 
to the Advisory Committee and the Committee voted in favor of the 
modification.

C. The Final Rule

1. List of Drug Products
    The Agency has considered the record of the February 2015 Advisory 
Committee deliberations, that Advisory Committee's votes, and the 
comments submitted on the July 2014 proposed rule (see section III). 
Based on the information before FDA and its own knowledge and 
expertise, FDA is:
     Adding 24 entries to the withdrawn or removed list in 
Sec.  216.24 as written in the proposed rule; and
     Modifying the description of one drug product entry 
already on this list, bromfenac sodium, to add an exception when the 
product is compounded under certain circumstances as written in the 
proposed rule.

At this time, FDA is not finalizing the entry in the proposed rule for 
all extended-release drug products containing oxycodone hydrochloride 
that have not been determined by FDA to have abuse-deterrent 
properties. The addition of an entry to the withdrawn or removed list 
for oxycodone hydrochloride remains under consideration by FDA.
2. A Single Withdrawn or Removed List Will Apply for the Purposes of 
Both Sections 503A and 503B
    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, FDA is revising and 
updating the list at Sec.  216.24 for purposes of both sections 503A 
and 503B. The list in Sec.  216.24 applies to compounders seeking to 
qualify for the exemptions under section 503A and outsourcing 
facilities seeking to qualify for the exemptions under section 503B. 
Drug products that appear on this list have been withdrawn or removed 
from the market because they have been found to be unsafe or not 
effective and may not be compounded for human use under the exemptions 
provided by either section 503A or 503B of the FD&C Act.
3. Procedure for Updating the List Going Forward
    After consideration of the comments submitted on the July 2014 
proposed rule (see section III of this document), at this time FDA 
intends to continue updating the list through notice and comment 
rulemaking, and we are therefore not proposing or adopting an 
alternative process with the publication of this final rule. We 
recognize that adding drug products to the list may limit their 
availability, and the notice and comment process informs interested 
members of the public of how the Agency proposes to revise the list and 
gives them an opportunity to contribute to the process. Additionally, 
we intend to create a Web page, described in more detail in the 
paragraphs that follow, that contains information about any drugs that 
we are considering proposing or that we have proposed for addition to 
the withdrawn or removed list. We believe that the Web page will be a 
valuable source of timely information for patients, prescribers, and 
compounders.
    In the following paragraphs, FDA discusses its current thinking 
about the procedures we intend to use to revise the withdrawn or 
removed list as needed. This discussion does not create rights or 
impose binding obligations on the Agency. In section III, we respond 
further to specific comments about whether the Agency should adopt 
alternative procedures.
    We intend to propose regulations to revise the withdrawn or removed 
list periodically, as appropriate, as we identify drugs that we 
tentatively determine should be listed. We would also propose 
regulations when we tentatively determine that changes to the status of 
drug products already on the list should result in a revision to their 
listing, for example, if some version of a drug on the list has been 
approved for marketing. As FDA identifies drugs that it is considering 
for a future rule proposal, we intend to collect and post together on a 
single page of the Agency's Web site relevant information about those 
drugs. The information may include, for example, Federal Register 
notices announcing withdrawal of approval of a drug application and 
accompanying safety communications or information, Federal Register 
notices announcing an Agency determination that a drug product was 
removed from sale for reasons of safety or effectiveness, or other 
relevant FDA Alerts, FDA Drug Safety Communications, FDA News Releases, 
Public Health Advisories, Dear Healthcare Practitioner Letters, Citizen 
Petitions, and Sponsor Letters.
    If FDA determines that issuing proposed and then final regulations 
to add a drug product to the withdrawn or removed list before 
consulting the Advisory Committee is necessary to protect the public 
health, then it will do so as permitted under section 503A(c)(1) of the 
FD&C Act. Based on the Agency's experience to date, we expect that this 
will rarely be necessary, and that we will instead generally consult 
the Advisory Committee before adding a drug product to the withdrawn or 
removed list.

[[Page 69671]]

    When FDA consults the Advisory Committee in the ordinary course, 
FDA may issue a proposed rule announcing proposed updates to the list 
prior to convening the Advisory Committee, or it may convene the 
Advisory Committee first to discuss potential updates and then publish 
a proposed rule. The order will depend on the timing of the Advisory 
Committee meetings, the priority of matters that may be brought before 
the Advisory Committee, and the status of other compounding-related 
rulemakings. There are numerous steps that must be completed before 
holding an FDA advisory committee meeting, which make it difficult to 
schedule a meeting on short notice. For instance: (1) Meeting 
participants must be contacted to determine their availability, and 
travel and lodging arrangements must be made; (2) conflict of interest 
screening and review must be completed before an advisory committee 
member can participate in a particular matter; (3) a Federal Register 
notice must be published for each meeting to announce to the public 
that a meeting will be held, and it must generally be published no 
later than 15 days prior to the meeting; (4) a meeting location must be 
secured; (5) meeting materials for the committee must be compiled for 
committee members, and a redacted version must be created for posting 
on the FDA Web site; numerous other logistical steps must be completed.
    Regardless of the order in which FDA holds the Advisory Committee 
meeting and issues a proposed rule, and with the exception noted 
previously of the likely to be rare instances where FDA determines that 
it is necessary to revise the list in Sec.  216.24 prior to 
consultation with the Advisory Committee to protect the public health, 
FDA will only finalize any additions or modifications to the list after 
consulting the Advisory Committee about the relevant drug or drugs, and 
after FDA has provided an opportunity for public comments to be 
submitted on the proposed rule. In addition to having an opportunity to 
submit comments on any specific proposals to the docket of the proposed 
rule, members of the public will also have an opportunity to comment on 
any potential updates to the list at the Advisory Committee meetings as 
well. An open public hearing session will be scheduled at each of these 
meetings, during which interested persons will have an opportunity to 
submit their views.
    In instances where FDA first consults the Advisory Committee about 
a drug product and subsequently proposes regulations to update the list 
with a new or modified entry for the drug product, FDA generally does 
not expect to convene the Advisory Committee a second time before 
deciding whether to finalize the entry. The Agency may bring the entry 
back to the Advisory Committee if that is warranted. We do not expect 
this will occur very often given the opportunity to submit views to the 
Advisory Committee before the rule is proposed and as evidenced by the 
fact that we received no comments on 25 of the 26 entries that were 
proposed for addition or modification to the list in the July 2014 
proposed rule.

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

    Seven comments were submitted on the July 2014 proposed rule. 
Comments were received from two pharmacists; two health professionals; 
an organization representing health care practitioners, as well as food 
and dietary supplement companies and consumer advocates; and two 
organizations representing pharmacists. FDA has summarized and 
responded to these comments in the following paragraphs.
    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. General
    (Comment 1) One comment supported the list in the proposed rule and 
recommended that FDA finalize the list as soon as possible.
    (Response) FDA agrees with the comment.
2. Specific Drug Entries for Inclusion on the List
    a. Oral Chloramphenicol (Comment 2). FDA received one comment on 
the proposal to include all oral drug products containing 
chloramphenicol on the withdrawn or removed list. The comment requested 
that FDA ``reconsider and reclassify Chloramphenicol 250 mg tablets 
labeling for tropical [sic] medical use and packaging changes; rather 
than withdraw from the marketplace for developing nations [World Health 
Organization,] WHO list of drug use.'' The comment stated that 
chloramphenicol 250 milligrams (mg) is used to control hemorrhagic 
fever-like illnesses (e.g., Lassa Fever, Ebola) and also stated that 
control and survival benefits outweigh the risks of thrombocytopenia 
and aplastic anemia in the already anemic patient when used in the 
short term appropriately.
    (Response) FDA disagrees with the suggested revisions. For the 
reasons that follow, FDA will add all oral drug products containing 
chloramphenicol to the list in Sec.  216.24.
    In the Federal Register of February 11, 2009 (74 FR 6896), FDA 
announced that it was withdrawing approval of ANDA 60-591 for 
Chloromycetin (chloramphenicol) Capsules 50 mg, 100 mg, and 250 mg, 
effective March 13, 2009. Armenpharm, Ltd., submitted a citizen 
petition dated February 7, 2011 (Docket No. FDA-2011-P-0081), under 
Sec.  10.30 (21 CFR 10.30), requesting that the Agency determine 
whether Chloromycetin (chloramphenicol) Capsules, 250 mg, were 
withdrawn from sale for reasons of safety or effectiveness. After 
considering the citizen petition, FDA determined that the drug product 
was withdrawn for reasons of safety or effectiveness. With the approval 
of additional therapies with less severe adverse drug effects, FDA 
determined that the risks associated with Chloromycetin 
(chloramphenicol) Capsules, 250 mg, as then labeled, outweighed the 
benefits. Furthermore, Chloromycetin (chloramphenicol) Capsules, 250 
mg, may cause a number of adverse reactions, the most serious being 
bone marrow depression (anemia, thrombocytopenia, and granulocytopenia 
temporally associated with treatment). Additionally, prior to the 
removal of the capsule drug product from the market, a boxed warning in 
the prescribing information for both chloramphenicol sodium succinate 
injection and chloramphenicol capsules stated that serious hypoplastic 
anemia, thrombocytopenia, and granulocytopenia are known to occur after 
administration of chloramphenicol. The boxed warning also described 
fatal aplastic anemia associated with administration of the drug and 
aplastic anemia attributed to chloramphenicol that later terminated in 
leukemia. There is published literature that suggests that the risk of 
fatal aplastic anemia associated with the oral formulation of

[[Page 69672]]

chloramphenicol may be higher than the risk associated with the 
intravenous formulation (see the Federal Register of July 13, 2012 (77 
FR 41412)).
    In December 2015, FDA initiated the process to suspend 
chloramphenicol ANDA 60-851, which was held by Armenpharm. FDA sent a 
letter to Armenpharm notifying the company of the Agency's initial 
determination that Chloromycetin (chloramphenicol) Capsules, 250 mg 
were withdrawn for reasons of safety or effectiveness and of the 
Agency's initial decision to suspend approval of ANDA 60-851 (See 
Docket No. FDA-2011-P-0081). Under Sec.  314.153(b)(2) (21 CFR 
314.153(b)(2)), Armenpharm had 30 days from that notification in which 
to present written comments or information bearing on the initial 
decision. On December 17, 2016, Armenpharm submitted comments 
requesting an oral hearing under Sec.  314.153(b)(4). On March 17, 
2016, however, Armenpharm withdrew its oral hearing request.
    FDA issued a notice in the Federal Register announcing the 
suspension of ANDA 60-851 (see 81 FR 64914, September 21, 2016). In the 
same notice, FDA announced the following drug products were withdrawn 
from sale for reasons of safety or effectiveness: Chloromycetin 
(chloramphenicol) Capsules, 50 mg and 100 mg; Amphicol 
(chloramphenicol) Capsules, 100 mg; and Chloromycetin Palmitate 
(chloramphenicol palmitate), oral suspension 150 mg/5 mL as currently 
labeled.
    After reviewing the comment regarding the proposed oral 
chloramphenicol entry, FDA reassessed whether to include oral 
chloramphenicol on the list, and if so, how to describe the entry. 
FDA's January 2015 review on oral chloramphenicol (available as Tab 8 
of Ref. 1 of the briefing document for the February 2015 Advisory 
Committee meeting) determined that oral chloramphenicol formulations, 
regardless of the specific oral forms and strengths, are expected to 
have a safety profile similar to that of chloramphenicol capsules, 250 
mg. Furthermore, FDA's January 2015 review on oral chloramphenicol 
noted that the Agency was not aware of any evidence that 
chloramphenicol has antiviral activity against causative agents of 
viral hemorrhagic fever, including Ebola. Chloramphenicol's mechanism 
of antibacterial action is by binding to the 50S subunit of the 
bacterial ribosome, a structure not found in viruses. Therefore, there 
is no putative mechanism to expect antiviral activity.
    This FDA review on oral chloramphenicol was presented to the 
Advisory Committee on February 23, 2015, and the Advisory Committee 
voted in favor of the Agency's proposal to include all oral drug 
products containing chloramphenicol on the list.
    b. Adenosine Phosphate (Comment 3). FDA received one comment asking 
that FDA clarify whether the entry for adenosine phosphate that was 
part of the original list finalized in 1999 is intended to include all 
three forms of adenosine phosphate (mono-, di-, and triphosphate).
    (Response) For the reasons that follow, FDA declines to modify the 
entry for adenosine phosphate on the list in Sec.  216.24 at this time.
    The preamble of the 1998 proposed rule to establish the original 
list (see 63 FR 54082, October 8, 1998) stated that adenosine 
phosphate, formerly marketed as a component of Adeno for injection, 
Adco for injection, and other drug products, was determined to be 
neither safe nor effective for its intended uses as a vasodilator and 
an anti-inflammatory. FDA directed the removal of these drug products 
from the market in 1973.
    After reviewing the comment to the docket of the July 2014 proposed 
rule regarding the adenosine phosphate entry, FDA began to assess 
whether to modify the adenosine phosphate entry and, if so, how.
    FDA prepared a review on adenosine phosphate (available as Tab 7 of 
Ref. 1 of the briefing document for the February 2015 Advisory 
Committee meeting) and consulted with the Advisory Committee on 
February 23, 2015 on the comment, as discussed in section II.B.
    Ultimately, FDA determined that it is unnecessary to modify the 
entry for adenosine phosphate on the list in Sec.  216.24 at this time. 
None of the substances raised in the comment (adenosine 5'-
monophosphate (AMP), adenosine 5'-diphosphate (ADP), and adenosine 5'-
triphosphate (ATP)) satisfy the requirements for a bulk drug substance 
that may be used in compounding under either section 503A or section 
503B.\1\ Consequently, at this time, a drug product compounded with 
AMP, ADP, or ATP would be ineligible for the exemptions provided under 
either section 503A or section 503B.
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    \1\ These substances are not the subject of an applicable United 
States Pharmacopeia or National Formulary monograph, a component of 
an FDA-approved drug, on a list of bulk drug substances established 
by FDA that may be used in compounding, or on a drug shortage list 
in effect under section 506E of the FD&C Act (21 U.S.C. 356e). See 
section 503A(b)(A)(i) and section 503B(a)(2)(A) of the FD&C Act.
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    c. Propoxyphene. No comments were submitted regarding propoxyphene. 
Since the time the proposed rule was published, however, FDA announced 
in the Federal Register of September 12, 2014 (79 FR 54729) that it was 
withdrawing approval of three propoxyphene products. The holders of the 
applications for the three products had been given notice of 
opportunity for a hearing in the Federal Register of March 10, 2014 (79 
FR 13308) (the March 10, 2014, notice), and no timely request for a 
hearing on the matter was received. In addition, FDA announced in the 
Federal Register of April 15, 2016 (81 FR 22283), that it was 
correcting a notice that appeared in the Federal Register of March 10, 
2014 (79 FR 13308). The March 10, 2014, notice announced the withdrawal 
of approval of 54 propoxyphene products with agreement from holders of 
the affected applications. The April 15, 2016, notice added one 
additional propoxyphene product, NDA 017507, held by Xanodyne 
Pharmaceuticals, to the table of products for which approval was 
withdrawn with agreement from the holders of the affected applications.

B. Comments on Other Issues

1. Ripeness of Proposed Rule
    (Comment 4) FDA received two comments suggesting that the issuance 
of the July 2014 proposed rule was premature. The comments expressed 
concern that FDA had proposed adding drug products to the previously 
existing list of drug products withdrawn from the market for safety and 
efficacy reasons without first obtaining input from the Advisory 
Committee. One of the comments further suggested that the proposed rule 
be withdrawn until such time as the drug products, proposed to be 
added, could be reviewed by the Advisory Committee.
    (Response) FDA notes that the July 2014 Federal Register notice was 
a notice of proposed rulemaking, not a final rule. Section 503A(c)(1) 
of the FD&C Act states that before issuing regulations to implement 
section 503A(b)(1)(C) pertaining to the withdrawn or removed rule 
(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. The changes in a proposed rule are not 
effective or implemented unless and until a proposed rule is finalized. 
Because the Agency convened and

[[Page 69673]]

consulted the Advisory Committee on February 23, 2015, regarding each 
of the amendments to the list we are finalizing in the present rule, 
the Agency has satisfied the statutory requirements of section 
503A(c)(1) of the FD&C Act.
2. Single List
    (Comment 5) One comment suggested that the Agency should finalize 
its proposal to publish one list for both section 503A and section 503B 
of the FD&C Act.
    (Response) FDA agrees with this comment.

C. Comments on Updating the List

    FDA received comments from five different submitters on the 
procedure for updating the list.
    (Comment 6) FDA received two comments regarding a specific 
alternative approach to the current process of issuing first a proposed 
rule followed by a final rule before adopting any additions or 
modifications to the list. One comment recommended use of an interim 
final rule or final rule with comment to allow for the flexibility to 
review public input, yet incorporate the latest safety information into 
the practice of compounding. Another comment recommended that in 
instances where public health may be of significant concern, the Agency 
convene an emergency meeting of the Advisory Committee within 5 
business days to obtain specific input and recommendations to the 
Secretary for immediate inclusion of a drug product on the list.
    (Response) As noted previously in section II.C.3, there are 
numerous steps that must be completed before holding an FDA advisory 
committee meeting, which make it difficult to schedule a meeting on 
short notice. In the likely to be rare instances where FDA determines 
that it is necessary to revise the list in Sec.  216.24 prior to 
consultation with the Advisory Committee to protect the public health, 
FDA will add the drug to the list prior to consultation with the 
Advisory Committee under section 503A(c)(1) of the FD&C Act.
    With respect to issuing interim final rules or final rules with 
comment, the Agency's current thinking is that the process described in 
section II.C.3 will allow the Agency to provide timely public notice of 
emerging safety information and appropriate opportunity for interested 
persons to comment before FDA revises the withdrawn or removed list.
    (Comment 7) FDA received a comment suggesting that upon receipt of 
a notice to withdraw a product from the market for safety and efficacy 
reasons by the NDA or ANDA holder, FDA inform the Advisory Committee 
and include a review of that request on the Committee's next scheduled 
meeting agenda.
    (Response) FDA does not agree that it should inform the Advisory 
Committee when it is advised by an NDA or ANDA holder that the NDA or 
ANDA holder has removed a drug from the market for safety or efficacy 
reasons, or that such a drug should necessarily be included on the 
Advisory Committee's next scheduled meeting agenda. FDA considers but 
does not rely solely on an NDA or ANDA holder's assertions or 
representations to determine whether a drug has been withdrawn or 
removed from the market because it has been found to be unsafe or not 
effective. Rather, the Agency considers a range of information before 
the Agency, such as information provided by the NDA or ANDA holder, 
information contained in the Agency's files, and the Agency's 
independent evaluation of relevant literature and data on possible 
postmarketing adverse events. When the Agency decides to propose a 
change, it will proceed as described previously in section II.C. The 
timing of any consultation with the Advisory Committee will also depend 
on, among other things, the timing of the Advisory Committee meetings 
and the relative priority of matters that may be brought before the 
Advisory Committee.
    (Comment 8) Another comment recommended soliciting public input 
specifically on how to incorporate the ``do not compound'' list when 
publishing intent to withdraw a drug.
    (Response) FDA does not believe it is necessary or that it would be 
efficient to separately solicit public input every time the Agency 
publishes a notice in the Federal Register of its intent to withdraw 
approval of a drug.
    When the Agency publishes a notice in the Federal Register of its 
intent to withdraw approval of a drug, it does so to give a particular 
party or parties notice and an opportunity for a hearing on the 
proposed withdrawal. This process may or may not result in a withdrawal 
of approval of the application, and even if the application is 
withdrawn the reasons may not relate to the safety or efficacy of the 
drug. Whether or how a drug should be included on the withdrawn or 
removed list under sections 503A and 503B of the FD&C Act is a separate 
question. In general, as discussed previously in this document in 
section II.C.3, interested members of the public will have the 
opportunity to review and comment on any proposals to add a drug to or 
revise an entry for a drug already on the withdrawn or removed list.
    (Comment 9) FDA received several comments opposing any approach to 
updating the withdrawn or removed list that would eliminate public 
review from the process. One comment stated that FDA already has the 
ability to remove from the market any drug that is dangerous and 
claimed that this does not justify completely eliminating public 
involvement in the process of making additions to the withdrawn or 
removed list. Another suggested that additions and changes to the 
withdrawn or removed list be made through notice and comment 
rulemaking, observing that such a notice and comment period will allow 
stakeholders to review FDA's safety and efficacy concerns for a 
particular drug product prior to addition to the withdrawn or removed 
list. One comment recommended incorporating public discussion about how 
to address a drug on the list when convening a drug advisory committee. 
One suggested all additions to the list go through an advisory 
committee that is open to public comment. One suggested that no 
revisions to the list occur without the input and review of the 
Advisory Committee.
    (Response) We appreciate these comments, and as explained in 
section II.C.3., at this time we have decided not to adopt or propose 
an alternative process to notice and comment rulemaking for revising 
the withdrawn or removed list. Additionally, FDA intends to consult the 
Advisory Committee prior to placing a drug on the withdrawn or removed 
list unless we determine that the issuance of such regulations before 
consultation is necessary to protect the public health. These 
procedures provide ample opportunity for public input regarding 
additions or modifications to the list, including: (1) An opportunity 
to present relevant information at an open public hearing held when the 
Advisory Committee meets to consider proposed revisions to the list and 
(2) an opportunity to submit comments on each proposed rule before it 
is finalized.
    (Comment 10) One comment recommended that all drug products 
currently on the list be reviewed by the Advisory Committee on an 
annual basis to determine whether any change in therapy or use of those 
drugs necessitates either removal or the clarification of certain 
salts, dosage forms, or other clinical application to assure 
accessibility of medications for patients.
    (Response) FDA has considered this comment and does not believe it 
is necessary to require an annual review

[[Page 69674]]

by the Advisory Committee of all drug products on the list. Such a 
review is not necessary, practical, or feasible. Once a drug has been 
added to the list, FDA does not expect that there will frequently be a 
need to revise the entry for that drug. FDA intends to monitor future 
approvals, withdrawals, or removals of listed drugs, to consult other 
relevant information that may suggest a need for revisions to the list, 
and to propose modifications as appropriate. In addition, members of 
the public can submit a citizen petition at any time under Sec.  10.30 
requesting that FDA modify or remove an entry on the list (with 
adequate data to support their request), and FDA will consider and 
respond to the petition.
    (Comment 11) One comment recommended that FDA issue an annual 
request in the Federal Register for submissions by the public of drug 
products to be reviewed and considered for inclusion on the list, 
inform the Advisory Committee of any submitted drug products, and 
include a review of those submissions on the Advisory Committee's next 
scheduled meeting agenda.
    (Response) FDA disagrees with the suggestion to issue an annual 
request in the Federal Register for submissions by the public of drug 
products to be reviewed and considered for inclusion on the list. We 
welcome suggestions by the public of drug products to consider and 
review for inclusion on the list, or of a modification to an entry in 
the list, at any time through the citizen petition process (see 
response to comment 10). We do not wish to restrict the submissions of 
such suggestions to just once a year. FDA does intend to consult with 
Advisory Committee as described in section II.C.3.

D. Miscellaneous Comments

    (Comment 12) One comment stated that nowhere within the proposed 
rule is there a formal process for reviewing, updating, and informing 
the compounding community of changes or updates to the list of drugs 
withdrawn or removed from the market for safety and efficacy reasons. 
The comment contends this is of grave concern to the pharmacy community 
and one which must be addressed.
    (Response) FDA agrees that the compounding community should be 
informed of and have an opportunity to review and comment on proposed 
revisions to the list of drugs at Sec.  216.24, that have been 
withdrawn or removed from the market because they have been found to be 
unsafe or not effective. The process outlined in section II.C.3 
provides notice and an opportunity to comment to the compounding 
community and to the general public. Further, as noted elsewhere, 
members of the compounding community and other members of the public 
can submit a citizen petition at any time under Sec.  10.30, requesting 
that FDA modify or remove an entry on the list (with adequate data to 
support their request), and FDA will consider and respond to the 
petition.
    (Comment 13) One comment suggested that the Secretary establish 
minimum criteria that must be met before any drug product may be added 
to the withdrawn or removed list.
    (Response) FDA disagrees with this comment. The criteria that must 
be met to place a drug on the withdrawn or removed list are laid out in 
the statute. Under sections 503A and 503B of the FD&C Act, drug 
products on the withdrawn or removed list are those 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. At this time, FDA does not believe it would be helpful to 
issue guidance or regulations to further define or interpret this 
standard. Instead, FDA intends to discuss in any rulemaking the basis 
for the Agency's proposal to add a drug product to the list or to 
modify an entry on the list.
    (Comment 14) One comment observed that under both sections 503A and 
503B of the FD&C Act, drugs may be added to the list if they have been 
found to be not effective. The comment went on to note that without the 
crucial check in the rulemaking process afforded by public review, FDA 
would be able to ban from compounding any drug on the pretext of it 
being ``not effective.''
    (Response) As described in section II.C.3, FDA intends to revise 
the list by using notice-and-comment rulemaking and, generally, to 
consult the Advisory Committee. Interested members of the public will 
have the opportunity to submit their views through this process. In 
addition, in the preamble to the July 2014 proposed rule, FDA observed 
that as with the original list, the primary focus of the July 2014 
proposed rule was on drug products that have been withdrawn or removed 
from the market because they have been found to be unsafe. FDA further 
stated that FDA may propose at a later date to add to the list other 
drug products that have been withdrawn or removed from the market 
because they have been found to be not effective, or to update the list 
as information becomes available to the Agency regarding products that 
have been removed from the market because they have been found to be 
unsafe.
    (Comment 15) One comment suggested that when updating the list, a 
process be considered by which FDA will consider exemptions (for 
example, when a drug or drug component may be compounded for a specific 
formulation, strength, or route of administration).
    (Response) FDA agrees that sometimes it may be appropriate to 
except a specific formulation (including strength), dosage form, or 
route of administration of a drug on the list. Indeed, as discussed 
further in FDA's response to the following comment, FDA has already 
engaged in this practice when it deems such exceptions appropriate. 
Going forward, when FDA is considering an addition or modification to 
the list, FDA will continue to consider the appropriateness of such 
exceptions on a case-by-case basis.
    (Comment 16) One comment advised that ingredients should be banned 
completely and absolutely with great caution.
    (Response) With respect to whether drugs on the withdrawn or 
removed list may be used in compounding, as FDA indicated in the 
preamble to the July 2014 proposed rule, most drugs on the list may not 
be compounded in any form. There are, however, two categories of 
exceptions. In the first category, a particular formulation, 
indication, dosage form, or route of administration of a drug is 
explicitly excluded from an entry on the list because an approved drug 
containing the same active ingredient(s) has not been withdrawn or 
removed from the market because it has been found to be unsafe or not 
effective. For such drugs, the formulation, indication, dosage form, or 
route of administration expressly excluded from the list may be 
eligible for the exemptions provided in sections 503A and 503B of the 
FD&C Act. In the second category, some drugs are listed only with 
regard to certain formulations, concentrations, indications, routes of 
administration, or dosage forms because they have been found to be 
unsafe or not effective in those particular formulations, 
concentrations, indications, routes of administration, or dosage forms.
    In addition, FDA notes that just because a drug is on the withdrawn 
or removed list does not mean it is banned completely and absolutely 
from compounding. In certain circumstances, if warranted, drugs that 
have been withdrawn or removed from the market could be made available 
for use under FDA regulations on expanded access at 21 CFR part 312, 
subpart I. If conditions in the regulations are met, expanded access 
programs allow the use of a drug

[[Page 69675]]

in a clinical setting to treat patients with a serious or immediately 
life-threatening disease or a condition that has no comparable or 
satisfactory alternative therapies to diagnose, monitor, or treat the 
patient's disease or condition (see Guidance for Industry, Expanded 
Access to Investigational Drugs for Treatment Use--Questions and 
Answers (June 2016), available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf).
    FDA will apply the statutory standard for placing drugs on the 
withdrawn or removed list, and intends to follow the process described 
in section II.C.3 to consult with the Advisory Committee and provide 
the public with notice and opportunity for comment.

IV. Legal Authority

    Sections 503A and 503B of the FD&C Act provide the principal legal 
authority for this final rule. As described in section I of this 
document, 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 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 (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 rule, 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.
    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 the Secretary 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).
    Therefore, sections 503A and 503B of the FD&C Act and our general 
rulemaking authority in section 701(a) of the FD&C Act (21 U.S.C. 
371(a)) together serve as our principal legal authority for this final 
rule revising FDA's regulations on drug products withdrawn or removed 
from the market because the drug product or a component of the drug 
product have been found to be unsafe or not effective in Sec.  216.24.

V. Analysis of Environmental Impact

    FDA 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.

VI. Economic Analysis of Impacts

    FDA has examined the impacts of the rule under Executive Order 
12866, Executive Order 13563, 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 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). 
The Agency believes that this rule is not a significant regulatory 
action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies 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 this rule will not have a significant economic impact on a 
substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies 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 $146 million, using the most current (2015) Implicit 
Price Deflator for the Gross Domestic Product. We do not expect this 
rule to result in any 1-year expenditure that would meet or exceed this 
amount.
    This rule amends Sec.  216.24 concerning human drug compounding. 
Specifically, the rule adds to and modifies 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). The rule adds 24 entries to the list and 
modifies the description of one drug entry on the list. The Agency is 
not aware of any routine compounding of these drug products and, 
therefore, does not estimate any compliance costs or loss of sales as a 
result of the prohibition against compounding these drugs for human 
use.
    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. Most pharmacies meet the Small Business Administration 
definition of a small entity, which is defined as having annual sales 
less than $25.5 million for this industry. The Agency is not aware of 
any routine compounding of these drug products and does not estimate 
any compliance costs or loss of sales to small businesses as a result 
of the prohibition against compounding these drugs. Therefore, the 
Agency certifies that this rule will not have a significant economic 
impact on a substantial number of small entities.

VII. Paperwork Reduction Act of 1995

    The submission of comments on this rule were submissions in 
response to a Federal Register notice, in the form of comments, which 
are excluded from the definition of ``information'' under 5 CFR

[[Page 69676]]

1320.3(h)(4) of Office of Management and Budget regulations on the 
Paperwork Reduction Act (i.e., facts or opinions submitted in response 
to general solicitations of comments from the public, published in the 
Federal Register or other publications, regardless of the form or 
format thereof, provided that no person is required to supply specific 
information pertaining to the commenter, other than that necessary for 
self-identification, as a condition of the Agency's full consideration 
of the comment). The rule contains no other collection of information.

VIII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that this 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.

IX. References

    In addition to the references placed on display in the Division of 
Dockets Management for the proposed rule under Docket No. FDA-1999-N-
0194 (formerly 99N-4490), the following reference is on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852 under Docket No. FDA-
1999-N-0194 (formerly 99N-4490) and is available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; it 
is also available electronically at https://www.regulations.gov. (FDA 
has verified the Web site address in this reference section as of the 
date this document publishes in the Federal Register, but Web sites are 
subject to change over time.)

1. Briefing Information for the February 23-24, 2015, Meeting of the 
Pharmacy Compounding Advisory Committee (available at https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm433803.htm).

    For the convenience of the reader, the regulatory text of Sec.  
216.24 provided with this final rule includes the drug products 
described in this final rule and the drug products codified by the 1999 
final rule.

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 is revised to read as follows:

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


0
2. The heading for part 216 is revised to read as set forth above.

0
3. Section 216.24 is revised to read as follows:


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

    The following drug products were 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 following drug 
products may not be compounded under the exemptions provided by section 
503A(a) or section 503B(a) of the Federal Food, Drug, and Cosmetic Act:
    Adenosine phosphate: All drug products containing adenosine 
phosphate.
    Adrenal cortex: All drug products containing adrenal cortex.
    Alatrofloxacin mesylate: All drug products containing 
alatrofloxacin mesylate.
    Aminopyrine: All drug products containing aminopyrine.
    Astemizole: All drug products containing astemizole.
    Azaribine: All drug products containing azaribine.
    Benoxaprofen: All drug products containing benoxaprofen.
    Bithionol: All drug products containing bithionol.
    Bromfenac sodium: All drug products containing bromfenac sodium 
(except ophthalmic solutions).
    Butamben: All parenteral drug products containing butamben.
    Camphorated oil: All drug products containing camphorated oil.
    Carbetapentane citrate: All oral gel drug products containing 
carbetapentane citrate.
    Casein, iodinated: All drug products containing iodinated casein.
    Cerivastatin sodium: All drug products containing cerivastatin 
sodium.
    Chloramphenicol: All oral drug products containing chloramphenicol.
    Chlorhexidine gluconate: All tinctures of chlorhexidine gluconate 
formulated for use as a patient preoperative skin preparation.
    Chlormadinone acetate: All drug products containing chlormadinone 
acetate.
    Chloroform: All drug products containing chloroform.
    Cisapride: All drug products containing cisapride.
    Cobalt: All drug products containing cobalt salts (except 
radioactive forms of cobalt and its salts and cobalamin and its 
derivatives).
    Dexfenfluramine hydrochloride: All drug products containing 
dexfenfluramine hydrochloride.
    Diamthazole dihydrochloride: All drug products containing 
diamthazole dihydrochloride.
    Dibromsalan: All drug products containing dibromsalan.
    Diethylstilbestrol: All oral and parenteral drug products 
containing 25 milligrams or more of diethylstilbestrol per unit dose.
    Dihydrostreptomycin sulfate: All drug products containing 
dihydrostreptomycin sulfate.
    Dipyrone: All drug products containing dipyrone.
    Encainide hydrochloride: All drug products containing encainide 
hydrochloride.
    Esmolol hydrochloride: All parenteral dosage form drug products 
containing esmolol hydrochloride that supply 250 milligrams/milliliter 
of concentrated esmolol per 10-milliliter ampule.
    Etretinate: All drug products containing etretinate.
    Fenfluramine hydrochloride: All drug products containing 
fenfluramine hydrochloride.
    Flosequinan: All drug products containing flosequinan.
    Gatifloxacin: All drug products containing gatifloxacin (except 
ophthalmic solutions).
    Gelatin: All intravenous drug products containing gelatin.
    Glycerol, iodinated: All drug products containing iodinated 
glycerol.
    Gonadotropin, chorionic: All drug products containing chorionic 
gonadotropins of animal origin.
    Grepafloxacin: All drug products containing grepafloxacin.
    Mepazine: All drug products containing mepazine hydrochloride or 
mepazine acetate.
    Metabromsalan: All drug products containing metabromsalan.
    Methamphetamine hydrochloride: All parenteral drug products 
containing methamphetamine hydrochloride.

[[Page 69677]]

    Methapyrilene: All drug products containing methapyrilene.
    Methopholine: All drug products containing methopholine.
    Methoxyflurane: All drug products containing methoxyflurane.
    Mibefradil dihydrochloride: All drug products containing mibefradil 
dihydrochloride.
    Nitrofurazone: All drug products containing nitrofurazone (except 
topical drug products formulated for dermatologic application).
    Nomifensine maleate: All drug products containing nomifensine 
maleate.
    Novobiocin sodium: All drug products containing novobiocin sodium.
    Oxyphenisatin: All drug products containing oxyphenisatin.
    Oxyphenisatin acetate: All drug products containing oxyphenisatin 
acetate.
    Pemoline: All drug products containing pemoline.
    Pergolide mesylate: All drug products containing pergolide 
mesylate.
    Phenacetin: All drug products containing phenacetin.
    Phenformin hydrochloride: All drug products containing phenformin 
hydrochloride.
    Phenylpropanolamine: All drug products containing 
phenylpropanolamine.
    Pipamazine: All drug products containing pipamazine.
    Polyethylene glycol 3350, sodium chloride, sodium bicarbonate, 
potassium chloride, and bisacodyl: All drug products containing 
polyethylene glycol 3350, sodium chloride, sodium bicarbonate, and 
potassium chloride for oral solution, and 10 milligrams or more of 
bisacodyl delayed-release tablets.
    Potassium arsenite: All drug products containing potassium 
arsenite.
    Potassium chloride: All solid oral dosage form drug products 
containing potassium chloride that supply 100 milligrams or more of 
potassium per dosage unit (except for controlled-release dosage forms 
and those products formulated for preparation of solution prior to 
ingestion).
    Povidone: All intravenous drug products containing povidone.
    Propoxyphene: All drug products containing propoxyphene.
    Rapacuronium bromide: All drug products containing rapacuronium 
bromide.
    Reserpine: All oral dosage form drug products containing more than 
1 milligram of reserpine.
    Rofecoxib: All drug products containing rofecoxib.
    Sibutramine hydrochloride: All drug products containing sibutramine 
hydrochloride.
    Sparteine sulfate: All drug products containing sparteine sulfate.
    Sulfadimethoxine: All drug products containing sulfadimethoxine.
    Sulfathiazole: All drug products containing sulfathiazole (except 
for those formulated for vaginal use).
    Suprofen: All drug products containing suprofen (except ophthalmic 
solutions).
    Sweet spirits of nitre: All drug products containing sweet spirits 
of nitre.
    Tegaserod maleate: All drug products containing tegaserod maleate.
    Temafloxacin hydrochloride: All drug products containing 
temafloxacin hydrochloride.
    Terfenadine: All drug products containing terfenadine.
    3,3',4',5-tetrachlorosalicylanilide: All drug products containing 
3,3',4',5-tetrachlorosalicylanilide.
    Tetracycline: All liquid oral drug products formulated for 
pediatric use containing tetracycline in a concentration greater than 
25 milligrams/milliliter.
    Ticrynafen: All drug products containing ticrynafen.
    Tribromsalan: All drug products containing tribromsalan.
    Trichloroethane: All aerosol drug products intended for inhalation 
containing trichloroethane.
    Troglitazone: All drug products containing troglitazone.
    Trovafloxacin mesylate: All drug products containing trovafloxacin 
mesylate.
    Urethane: All drug products containing urethane.
    Valdecoxib: All drug products containing valdecoxib.
    Vinyl chloride: All aerosol drug products containing vinyl 
chloride.
    Zirconium: All aerosol drug products containing zirconium.
    Zomepirac sodium: All drug products containing zomepirac sodium.

    Dated: October 3, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-24333 Filed 10-6-16; 8:45 am]
 BILLING CODE 4164-01-P