[Federal Register Volume 79, Number 127 (Wednesday, July 2, 2014)]
[Proposed Rules]
[Pages 37687-37696]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-15371]


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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-AH10


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Have Been Withdrawn or Removed From the Market for Reasons of Safety or 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: Proposed rule; withdrawal of previous proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
proposing to amend its regulations to revise the list of drug products 
that may not be compounded under the exemptions provided by the Federal 
Food, Drug, and Cosmetic Act (the FD&C Act) because the drug products 
have been withdrawn or removed from the market after the drug products 
or components of such drug products were found to be unsafe or not 
effective. Specifically, the proposed rule would add 25 drug products 
to this list of drug products and modify the description of one drug 
product on this list to add an exception. These revisions are necessary 
because new information has come to the Agency's attention since March 
8, 1999, when FDA published the original list as a final rule. FDA is 
also withdrawing the previous proposed rule regarding additions to this 
list (see the Federal Register of January 4, 2000).

DATES: Submit either electronic or written comments on the proposed 
rule by September 2, 2014. The January 4, 2000, proposed rule (65 FR 
256) is withdrawn as of July 2, 2014.

ADDRESSES: You may submit comments, identified by Agency name and 
Docket No. FDA-1999-N-0194 and/or Regulatory Information Number (RIN) 
number 0910-AH10, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper submissions): 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency 
name, Docket No. FDA-1999-N-0194, and RIN 0910-AH10 for this 
rulemaking. All comments received may be posted without change to 
http://www.regulations.gov, including any personal information 
provided. For additional information on submitting comments, see the 
``Request for Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

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.

SUPPLEMENTARY INFORMATION: 

I. Background

    Section 503A of the FD&C Act (21 U.S.C. 353a) 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)).
    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).

A. Court Decisions Regarding the Pharmacy Compounding Provisions of the 
FD&C Act

    As originally enacted, section 503A of the FD&C Act included 
prohibitions on the advertising and solicitation of prescriptions for 
any particular compounded drug, class of drug, or type of drug. Seven 
compounding pharmacies challenged the advertising and solicitation 
provisions of section 503A of the FD&C Act as an impermissible 
regulation of commercial speech. In February 2001, the U.S. Court of 
Appeals for the Ninth Circuit held that the prohibition on advertising 
and promotion in section 503A(c) and the provision of section 503A(a) 
of the FD&C Act that requires that the prescription be ``unsolicited,'' 
were unconstitutional restrictions on commercial speech. (See Western 
States Med. Ctr. v. Shalala, 238 F.3d 1090 (9th Cir. 2001).) 
Furthermore, the Ninth Circuit held that the advertising and 
solicitation provisions could not be severed from the rest of section 
503A and, as a result, found section 503A of the FD&C Act to be invalid 
in its

[[Page 37688]]

entirety. In April 2002, the U.S. Supreme Court affirmed the Ninth 
Circuit's decision that the advertising and solicitation provisions 
were unconstitutional; it did not, however, rule on the severability of 
section 503A of the FD&C Act. (See Thompson v. Western States Med. 
Ctr., 535 U.S. 357 (2002).)
    In light of these decisions, FDA issued a Compliance Policy Guide 
in 2002 to provide guidance on FDA's approach concerning the regulation 
of pharmacy compounding. (See the Federal Register of June 7, 2002 (67 
FR 39409).)
    In September 2004, 10 pharmacies brought suit in the U.S. District 
Court for the Western District of Texas challenging FDA's authority to 
regulate compounded drugs. In August 2006, the District Court held, in 
part, that compounded human drugs are implicitly exempt from the ``new 
drug'' definition in section 201(p) of the FD&C Act and, as a result, 
are not subject to the FD&C Act's new drug approval requirements. (See 
Medical Ctr. Pharm. v. Gonzales, 451 F. Supp. 2d 854 (W.D. Tex. 2006).) 
The District Court also held that the advertising and solicitation 
provisions in section 503A of the FD&C Act that the Supreme Court had 
found to be unconstitutional were severable from the rest of that 
section.
    The Federal Government appealed the decision of the U.S. District 
Court for the Western District of Texas. In July 2008, the U.S. Court 
of Appeals for the Fifth Circuit reversed the District Court's finding 
of an implicit exemption for compounded drugs from the new drug 
approval requirements in the FD&C Act, holding, instead, that 
compounded drugs fall within the definition of ``new drug'' in the FD&C 
Act and, therefore, are subject to regulation by FDA. (See Medical Ctr. 
Pharm. v. Mukasey, 536 F.3d 383 (5th Cir. 2008).) The Fifth Circuit 
also held that the advertising and solicitation provisions are 
severable from the rest of section 503A of the FD&C Act, and as a 
result, the other provisions of section 503A remain in effect.
    The Fifth Circuit's severability ruling conflicted with the earlier 
Ninth Circuit decision, which held that the advertising and 
solicitation provisions cannot be severed from section 503A of the FD&C 
Act, and rendered all of section 503A void. Following a fungal 
meningitis outbreak in September 2012, FDA sought legislation to, among 
other things, resolve the split in the Circuits to clarify that section 
503A of the FD&C Act was valid nationwide.

B. 2013 Drug Quality and Security Act

    On November 27, 2013, President Obama signed the Drug Quality and 
Security Act (Pub. L. 113-54) (DQSA) that contains important provisions 
relating to the oversight of compounding of human drugs. This new law 
removes from section 503A of the FD&C Act the provisions that had been 
held unconstitutional by the U.S. Supreme Court in 2002. By removing 
these provisions, the new law clarifies that section 503A of the FD&C 
Act applies nationwide. In addition, the DQSA adds a new section 503B 
of the FD&C Act (21 U.S.C. 353b) that creates 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); but not section 501(a)(2)(B). 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)).
    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 proposing to 
revise and update the list at Sec.  216.24 (21 CFR 216.24) for purposes 
of both sections 503A and 503B. Accordingly, the proposed rule that 
published in the Federal Register of January 4, 2000, which would have 
amended the list in Sec.  216.24, is withdrawn (see DATES).

C. Regulatory History of the List

1. Original List
    In the Federal Register of October 8, 1998 (63 FR 54082), FDA 
proposed a rule to establish the original list of drug products that 
have been withdrawn or removed from the market because the drug 
products or the components of such drug products were found to be 
unsafe or not effective (1998 proposed rule). The 1998 proposed rule 
was presented to the Pharmacy Compounding Advisory Committee (Advisory 
Committee) at a meeting held on October 14 and 15, 1998 (63 FR 47301, 
September 4, 1998). The Advisory Committee did not have any adverse 
comments on the 1998 proposed rule and did not suggest any changes. A 
transcript of the October 1998 Advisory Committee meeting may be found 
at the Division of Dockets Management (see ADDRESSES) and at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm290713.htm.
    In the Federal Register of March 8, 1999 (64 FR 10944), FDA 
published a final rule that codified the original list in Sec.  216.24 
(1999 final rule).
2. 2000 Proposed Rule and Additional Drug Products for the List in 
Sec.  216.24
    In the Federal Register of January 4, 2000 (65 FR 256), FDA 
proposed a rule to amend Sec.  216.24 (2000 proposed rule). 
Specifically, FDA proposed to add all drug products containing 
aminopyrine and all drug products containing astemizole to the original 
list of drug products withdrawn or removed from the market because they 
have been found to be unsafe or not effective. After the 2000 proposed 
rule published, three additional drug products (cisapride, 
grepafloxacin, and troglitazone) were identified as candidates for 
addition to the list. These five drug products were presented to the 
Advisory Committee at a meeting held on July 13 and 14, 2000 (65 FR 
40104, June 29, 2000). The Advisory Committee voted to include 
aminopyrine, astemizole, cisapride, grepafloxacin, and troglitazone to 
the list of drug products that have been withdrawn or removed from the 
market because they were found to be unsafe or not effective. A 
transcript of the July 2000 Advisory Committee meeting may be found at 
the Division of Dockets Management (see ADDRESSES) and at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm290713.htm.
3. New Proposed Rule To Amend the List in Sec.  216.24
    This proposed rule would add to Sec.  216.24 the five drug products 
identified in section I.C.2 and additional drug products that have been 
withdrawn or removed from the market since the publication of the 1999 
final rule because the drug products or components of such drug 
products were found to be unsafe or not effective. FDA also proposes to 
modify the description of one drug product contained in the original 
list to add an exception that would allow the product to be compounded 
under certain

[[Page 37689]]

circumstances. These revisions are necessary to ensure the list of 
drugs in Sec.  216.24 reflects new information that has come to the 
Agency's attention since FDA published the original list in the 1999 
final rule. As with the original list, the primary focus of this 
proposed rule is on drug products that have been withdrawn or removed 
from the market because they were 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 were found to be not 
effective, or to update the list as new information becomes available 
to the Agency regarding products that were removed from the market 
because they were found to be unsafe.
    This proposed rule would replace the 2000 proposed rule. The list 
set forth in this proposed rule would apply to compounders and 
outsourcing facilities seeking to qualify for the exemptions under 
either section 503A or section 503B of the FD&C Act. Accordingly, the 
2000 proposed rule to amend Sec.  216.24 is withdrawn. In preparing 
this proposed rule, FDA has taken into consideration the discussions 
held by the July 2000 Advisory Committee and that Advisory Committee's 
vote to include aminopyrine, astemizole, cisapride, grepafloxacin, and 
troglitazone on the list of drug products that have been withdrawn or 
removed from the market because they were found to be unsafe or not 
effective.
    Additional nominations for this list can be submitted to FDA for 
consideration in comments to this proposed rule.

II. Procedural Issue for Comment

    Section 503A of the FD&C Act describes the list in section 
503A(b)(1)(C) as 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. This suggests that FDA 
can develop the 503A(b)(1)(C) list by publishing it in the Federal 
Register and does not need to go through notice and comment rulemaking. 
Section 503A(c)(1) of the FD&C Act, however, 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. In 1998 and 
1999, FDA used rulemaking to develop the original list of drug products 
that had been withdrawn or removed from the market, and consulted the 
Pharmacy Compounding Advisory Committee about the list. In 2000, FDA 
also proposed to amend the list through rulemaking after consultation 
with the Advisory Committee.
    Meanwhile, new section 503B of the FD&C Act describes the list in 
section 503B(a)(4) as 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. 
Section 503B(c) of the FD&C Act requires that the Secretary implement 
through regulations, following consultation with an advisory committee, 
a list of drugs or categories of drugs that present demonstrable 
difficulties for compounding that are reasonably likely to lead to an 
adverse effect on the safety or effectiveness of the drug or category 
of drugs and therefore may not be compounded under section 503B. (See 
section 503B(a)(6) of the FD&C Act.) Section 503B does not, however, 
include any similar requirement for rulemaking or consultation with an 
advisory committee to establish the list of drugs that may not be 
compounded under section 503B of the FD&C Act because they 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.
    As noted, FDA plans to publish a single list of drug products 
(referred to as ``the withdrawn or removed list'' or ``the list'') 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. FDA invites comments on the appropriate procedure to update 
the list in the future. The Agency believes that the timely sharing of 
information about safety concerns relating to compounding drugs for 
human use without undue delay is essential to the protection of public 
health. FDA 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 is seeking an alternative procedure to 
update the withdrawn or removed list in the future. Although FDA is 
publishing a proposed rule today to add 25 drugs to the list, FDA is 
also soliciting public input through this Federal Register notice on 
alternative procedures for updating the list and requests that this 
input be submitted to FDA for consideration in comments to this 
proposed rule. FDA will specify in the final rule the procedure it will 
use to update the list in the future.

III. Description of This Proposed Rule

A. Amendments to Introductory Text

    FDA is proposing to add the phrase ``or section 503B(a)'' to the 
introductory text of Sec.  216.24 to clarify that drug products 
included in the list in Sec.  216.24 will not qualify for the 
exemptions under either section 503A(a) or section 503B(a) of the FD&C 
Act when compounded.

B. Amendments To Add Drug Products to the List

    FDA is proposing to amend Sec.  216.24 to include the 25 drug 
products described in the following paragraphs that have been withdrawn 
or removed from the market since the 1999 final rule was published 
(March 1999) because such drug products or components of such drug 
products have been found to be unsafe or not effective.
    A drug product that is included in the list codified at Sec.  
216.24 is not entitled to the exemptions provided in section 503A(a) of 
the FD&C Act, and is subject to sections 501(a)(2)(B), 502(f)(1), and 
505 of the FD&C Act, in addition to other applicable provisions. In 
addition, a drug that is included in the list codified at Sec.  216.24 
is not entitled to the exemptions provided in section 503B(a) of the 
FD&C Act, and is subject to sections 502(f)(1) and 505 of the FD&C Act, 
in addition to other applicable provisions.
    The listed drugs are ineligible for the exemptions set forth in 
sections 503A and 503B of the FD&C Act because they have been withdrawn 
or removed from the market because they were found to be unsafe or not 
effective. 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. 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

[[Page 37690]]

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. For drugs that are listed with 
these types of limitations, any compounding of the drug will be closely 
scrutinized to ensure that the compounding of the drug does not create 
a product that is unsafe or not effective. If it appears to do so, FDA 
may determine that the drug is not entitled to the exemptions provided 
in sections 503A and 503B of the FD&C Act. Those compounding these 
particular drugs should take note of the reasons FDA has cited for 
including a drug on this list, and carefully consider these reasons 
when considering whether or not to compound a drug that is so listed.
    The following drug products are arranged alphabetically by the 
established names of the active ingredients contained in the drug 
products and are proposed for inclusion in Sec.  216.24. For many of 
the drugs, the proprietary or trade name of some or all of the drug 
products that contained the active ingredient are also given in the 
preamble paragraphs describing the withdrawn or removed drug products. 
In several cases, the withdrawn or removed drug products are identified 
according to the established name of the active ingredient, listed as a 
particular salt or ester of the active moiety. The following list 
includes a brief summary of the reasons why each drug product is being 
proposed for inclusion.
    Alatrofloxacin mesylate: All drug products containing 
alatrofloxacin mesylate. Alatrofloxacin mesylate, formerly marketed as 
TROVAN Injection, was associated with serious liver injury. On June 9, 
1999, FDA announced in a Public Health Advisory that the NDA holder 
agreed to a limited distribution of TROVAN (alatrofloxacin mesylate) 
Injection and TROVAN (trovafloxacin mesylate) tablets, 100 milligrams 
(mg) and 200 mg, to in-patient healthcare facilities (Ref. 1). 
Subsequently, in the Federal Register of June 16, 2006 (71 FR 34940), 
FDA announced that it was withdrawing the approval of the NDA for 
TROVAN Injection after the NDA holder notified the Agency that the drug 
product was no longer marketed and requested that the approval of the 
NDA be withdrawn.
    Aminopyrine: All drug products containing aminopyrine. Aminopyrine 
was associated with agranulocytosis, a condition characterized by a 
decrease in the number of certain blood cells and lesions on the mucous 
membrane and skin. Some cases of agranulocytosis were fatal. In 1964, 
FDA declared drug products containing aminopyrine to be new drugs and 
invited NDAs for these drug products, but only for use as an 
antipyretic in serious situations where other, safer drugs could not be 
used. FDA received no NDAs for drug products containing aminopyrine, 
and those unapproved drug products were removed from the market (see 
the Federal Register of October 4, 1977 (42 FR 53954), and January 4, 
2000 (65 FR 256)). Aminopyrine was presented to the Advisory Committee 
at the July 2000 meeting, and the Advisory Committee voted to include 
aminopyrine on the withdrawn or removed list (see the Federal Register 
of June 29, 2000 (65 FR 40104)).
    Astemizole: All drug products containing astemizole. Astemizole, 
formerly marketed as HISMANAL 10-mg tablets, was associated with life-
threatening heart arrhythmias. Patients with liver dysfunction or who 
were taking other drugs that interfered with the metabolism of 
astemizole were also found to be at risk of serious cardiac adverse 
events while taking astemizole. On June 18, 1999, the NDA holder 
withdrew HISMANAL (astemizole) 10-mg tablets from the market. In the 
Federal Register of August 23, 1999 (64 FR 45973), FDA announced its 
determination that HISMANAL (astemizole) 10-mg tablets were removed 
from the market for safety reasons. (See also the Federal Register of 
January 4, 2000 (65 FR 256).) Astemizole was presented to the Advisory 
Committee at the July 2000 meeting, and the Advisory Committee voted to 
include astemizole on the withdrawn or removed list (see the Federal 
Register of June 29, 2000 (65 FR 40104)).
    Cerivastatin sodium: All drug products containing cerivastatin 
sodium. Cerivastatin sodium, formerly marketed as BAYCOL tablets, was 
associated with increased risk of rhabdomyolysis. Fatal rhabdomyolysis 
was reported most frequently when used at higher doses, when used in 
elderly patients, and particularly, with concomitant use of gemfibrozil 
(LOPID). In an August 8, 2001, ``Dear Healthcare Professional Letter,'' 
the NDA holder stated that it discontinued the marketing and 
distribution of all dosage strengths of BAYCOL (Ref. 2).
    Chloramphenicol: All oral drug products containing chloramphenicol. 
Chloramphenicol was formerly marketed as CHLOROMYCETIN 
(chloramphenicol) Capsules. In a letter dated October 9, 2007, the 
application holder requested withdrawal of the ANDA for CHLOROMYCETIN 
(chloramphenicol) Capsules, 50 mg, 100 mg, and 250 mg. In the Federal 
Register of February 11, 2009 (74 FR 6896), FDA announced that it was 
withdrawing approval of the ANDA, 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 
chloramphenicol may be higher than the risk associated with the 
intravenous formulation (see the Federal Register of July 13, 2012 (77 
FR 41412)). FDA is not aware of any oral drug products containing 
chloramphenicol currently being marketed.
    Cisapride: All drug products containing cisapride. Cisapride, 
formerly marketed as PROPULSID tablets and suspension, was associated 
with serious cardiac arrhythmias and death. In an April 12, 2000 ``Dear 
Healthcare Professional Letter,'' the NDA holder stated that it would 
discontinue marketing the drug as of July 14, 2000, and make the 
product available only through an investigational limited access 
program

[[Page 37691]]

(Ref. 3). Cisapride was presented to the Advisory Committee at the July 
2000 meeting, and the Advisory Committee voted to include cisapride on 
the withdrawn or removed list (see the Federal Register of June 29, 
2000 (65 FR 40104)).
    Esmolol hydrochloride: All parenteral drug products containing 
esmolol HCl that supply 250 mg/milliliter (mL) of concentrated esmolol 
per 10-mL ampule. Esmolol hydrochloride (HCl), 250 mg/mL per 10-mL 
ampule, formerly marketed as BREVIBLOC Injection 250 mg/mL per 10-mL 
ampule, was associated with increased risk of medication errors 
resulting in serious adverse events, including deaths. The NDA holder 
sent a letter to FDA on June 28, 2007, notifying the Agency that the 
company had decided to cease the manufacture and distribution of 
BREVIBLOC (esmolol HCl) Injection, 250 mg/mL, 10-mL ampule. In a 
citizen petition dated March 27, 2008 (Docket No. FDA-2008-P-0284), 
submitted under Sec.  10.30 and in accordance with 21 CFR 314.122 and 
314.161, Bedford Laboratories (Bedford) requested that the Agency 
determine whether BREVIBLOC (esmolol HCl) Injection, 250 mg/mL, 10-mL 
ampule, was withdrawn from sale for reasons of safety or effectiveness. 
In the Federal Register of May 5, 2010 (75 FR 24710), FDA announced its 
determination that BREVIBLOC (esmolol HCl) Injection 250 mg/mL, 10-mL 
ampule, was withdrawn from the market for safety reasons.
    Etretinate: All drug products containing etretinate. Etretinate was 
formerly marketed as TEGISON Capsules. In a letter dated September 23, 
1999, the NDA holder requested that FDA withdraw the approval of the 
NDA for TEGISON (etretinate) Capsules because it had discontinued 
marketing the product. The letter also stated that the drug was not 
withdrawn for safety reasons. However, in an acknowledgement letter 
dated December 30, 2002, FDA informed the NDA holder that TEGISON 
(etretinate) Capsules was removed from the market because it posed a 
greater risk of birth defects than SORIATANE (acitretin), the product 
that replaced TEGISON (etretinate) Capsules (see the Federal Register 
of September 10, 2003 (68 FR 53384)). Subsequently, in the Federal 
Register of September 10, 2003, FDA announced it was withdrawing 
approval of the NDA.
    Gatifloxacin: All drug products containing gatifloxacin (except 
ophthalmic solutions). Gatifloxacin was formerly marketed as TEQUIN 
tablets, injection, and oral suspension. In January 2003, FDA received 
revised product labeling relating to several approved supplements for 
TEQUIN (gatifloxacin). This revised labeling deleted references to 
TEQUIN injection, 10 mg/mL (200 mg), indicating that this product was 
no longer being marketed; therefore, the product was moved from the 
prescription drug product list to the ``Discontinued Drug Product 
List'' section of the ``Approved Drug Products With Therapeutic 
Equivalence Evaluations'' (the Orange Book). In response to a citizen 
petition from Apotex Corp. (Docket No. FDA-2005-P-0369),\1\ FDA 
determined, as set forth in the Federal Register of February 3, 2006 
(71 FR 5858), that TEQUIN injection, 10 mg/mL (200 mg), was not 
withdrawn for reasons of safety and effectiveness. On May 1, 2006, 
Public Citizen Research Group submitted a citizen petition (Docket No. 
FDA-2006-P-0081),\2\ under Sec.  10.30, requesting that FDA immediately 
ban TEQUIN because of the increased risk of dysglycemia (hypoglycemia, 
low blood sugar, and hyperglycemia, high blood sugar) in humans. In 
June 2006, the NDA holder announced that it would no longer market 
TEQUIN. In the Federal Register of September 9, 2008 (73 FR 52357), FDA 
announced its determination that all dosage forms and strengths of 
TEQUIN (gatifloxacin) were withdrawn from the market for safety 
reasons. There are currently approved gatifloxacin ophthalmic solutions 
on the market. Thus, FDA is proposing to include all drug products 
containing gatifloxacin, except ophthalmic solutions, on the withdrawn 
or removed list.
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    \1\ This citizen petition was originally assigned docket number 
2005P-0023/CP1. The number was changed to FDA-2005-P-0369 as a 
result of FDA's transition to its new docketing system (http://www.regulations.gov) in January 2008.
    \2\ This citizen petition was originally assigned docket number 
2006P-0178. The number was changed to FDA-2006-P-0081 as a result of 
FDA's transition to its new docketing system (http://www.regulations.gov) in January 2008.
---------------------------------------------------------------------------

    Grepafloxacin: All drug products containing grepafloxacin. 
Grepafloxacin, formerly marketed as RAXAR tablets, was associated with 
cardiac repolarization, manifested as QTc interval prolongation on the 
electrocardiogram, which could put patients at risk of Torsade de 
Pointes. The NDA holder sent a letter to FDA on March 5, 2003, 
requesting that FDA withdraw the approval of the NDA for RAXAR tablets, 
stating that the product was no longer being marketed. In an 
acknowledgment letter dated June 20, 2003, FDA stated that RAXAR 
(grepafloxacin) tablets had been removed from the market because of 
safety concerns. In a followup letter dated January 12, 2007, FDA 
informed the NDA holder that the RAXAR NDA should be withdrawn because 
of the cardiovascular risks stated previously. The NDA holder sent a 
letter to FDA on March 20, 2007, agreeing with FDA's determination to 
initiate the withdrawal of the RAXAR NDA, and FDA subsequently 
announced that approval of the NDA was withdrawn (see the Federal 
Register of June 14, 2007 (72 FR 32852), and July 9, 2007 (72 FR 
37244)). Grepafloxacin was presented to the Advisory Committee at the 
July 2000 meeting, and the Advisory Committee voted to include 
grepafloxacin on the withdrawn or removed list (see the Federal 
Register of June 29, 2000 (65 FR 40104)).
    Methoxyflurane: All drug products containing methoxyflurane. 
Methoxyflurane, formerly marketed as PENTHRANE Inhalation Liquid, 99.9 
percent, was associated with serious, irreversible, and even fatal 
nephrotoxicity and hepatotoxicity in humans. In the Federal Register of 
August 16, 2001 (66 FR 43017), FDA announced that it was withdrawing 
the approval of the NDA after the NDA holder notified the Agency that 
PENTHRANE (methoxyflurane) Inhalation Liquid was no longer being 
marketed under the NDA and requested withdrawal of the application. In 
a citizen petition dated August 25, 2004 (Docket No. FDA-2004-P-
0337),\3\ submitted under Sec.  10.30, and in accordance with Sec.  
314.161, AAC Consulting Group requested that the Agency determine 
whether PENTHRANE (methoxyflurane) Inhalation Liquid, 99.9 percent, was 
withdrawn from sale for reasons of safety or effectiveness. In the 
Federal Register of September 6, 2005 (70 FR 53019), FDA announced its 
determination that PENTHRANE Inhalation Liquid, 99.9 percent, was 
withdrawn from the market for safety reasons.
---------------------------------------------------------------------------

    \3\ This citizen petition was originally assigned docket number 
2004P-0379. The number was changed to FDA-2004-P-0337 as a result of 
FDA's transition to its new docketing system (http://www.regulations.gov) in January 2008.
---------------------------------------------------------------------------

    Novobiocin sodium: All drug products containing novobiocin sodium. 
Novobiocin sodium, formerly marketed as ALBAMYCIN capsule, 250 mg, was 
associated with adverse reactions that included relatively common skin 
reactions, jaundice, hepatic failure, and blood dyscrasias 
(neutropenia, anemia, and thrombocytopenia). Literature also revealed 
concerns about the development of novobiocin-resistant Staphylococci 
during treatment and a potential for drug interactions. On June

[[Page 37692]]

9, 1999, the NDA holder sent an annual report to FDA that indicated 
that ALBAMYCIN (novobiocin sodium) capsule, 250 mg, was no longer being 
manufactured, and on June 27, 2007, the NDA holder sent a letter to FDA 
notifying the Agency that ALBAMYCIN (novobiocin sodium) capsule, 250 
mg, had been discontinued. In the Federal Register of February 11, 2009 
(74 FR 6896), FDA announced that it was withdrawing approval of the NDA 
in response to the NDA holder's withdrawal request. Crixmore LLC 
submitted a citizen petition dated July 9, 2008 (Docket No. FDA-2008-P-
0431), under Sec.  10.30, requesting that the Agency determine whether 
ALBAMYCIN (novobiocin sodium) capsule, 250 mg, was withdrawn from sale 
for reasons of safety or effectiveness. In the Federal Register of 
January 19, 2011 (76 FR 3143), FDA announced its determination that 
ALBAMYCIN (novobiocin sodium) capsule, 250 mg, was withdrawn from the 
market for reasons of safety or effectiveness.
    Oxycodone hydrochloride: All extended-release drug products 
containing oxycodone hydrochloride that have not been determined by FDA 
to have abuse-deterrent properties. OXYCONTIN (oxycodone hydrochloride) 
extended-release tablets were approved in multiple strengths under NDA 
20-553 in 1995. The formulation was often abused by manipulating the 
product to defeat its extended-release mechanism, causing the oxycodone 
to be released more rapidly. This product was voluntarily withdrawn 
from sale following introduction of a reformulated version, also 
marketed as OXYCONTIN (oxycodone hydrochloride) extended-release 
tablets, which was developed with physicochemical properties intended 
to make the tablets more difficult to manipulate for purposes of abuse 
or misuse and was approved in multiple strengths under NDA 22-272 in 
2010. Several parties submitted citizen petitions under Sec.  10.30, 
requesting that the Agency determine whether original OXYCONTIN 
(oxycodone HCl) extended-release tablets were voluntarily withdrawn 
from sale for reasons other than safety or effectiveness.\4\ In a 
letter to FDA dated March 19, 2013, the NDA holder requested withdrawal 
of approval of NDA 20-553 for original OXYCONTIN. In the Federal 
Register of April 18, 2013 (78 FR 23273), FDA published notice of its 
determination that original OXYCONTIN, NDA 20-553, was withdrawn from 
sale for reasons of safety or effectiveness. The notice concluded that 
``[o]riginal OXYCONTIN . . . poses an increased potential for abuse by 
certain routes of administration, when compared to reformulated 
OXYCONTIN. Based on the totality of the data and information available 
to the Agency at this time, FDA concludes that the benefits of original 
OXYCONTIN no longer outweigh its risks.'' In the Federal Register of 
August 7, 2013 (78 FR 48177), FDA announced that it was withdrawing the 
approval of NDA 20-553. In addition, because the drug approval process 
is the most appropriate way for FDA to evaluate the effect and labeling 
of products with potentially abuse-deterrent properties, compounding of 
opioid products with potentially abuse-deterrent properties will be 
closely scrutinized.
---------------------------------------------------------------------------

    \4\ Varam, Inc., Docket No. FDA-2011-P-0473 (June 9, 2011) (10, 
15, 20, 30, 40, 50, 80, and 160 mg); Sheppard, Mullin, Richter & 
Hampton LLP, Docket No. FDA-2010-P-0540 (October 8, 2010) (10, 15, 
20, 30, 40, 60, and 80 mg); Lachman Consultant Services, Inc., 
Docket No. FDA-2010-P-0526 (September 30, 2010) (10, 15, 20, 30, 40, 
60, 80, and 160 mg). Lachman also submitted a petition in 2001 
concerning just Purdue Pharma LP's 2001 withdrawal of the 160 mg 
strength, Docket No. FDA-2001-P-0473 (formerly Docket No. 2001P-
0426) (September 18, 2001).
---------------------------------------------------------------------------

    Pemoline: All drug products containing pemoline. Pemoline, formerly 
marketed as CYLERT tablets and chewable tablets, was associated with 
liver failure. FDA determined that the overall risk of liver toxicity 
from CYLERT and generic pemoline outweighed the benefits of the drug. 
On October 24, 2005, FDA announced in an FDA Alert that the NDA and 
ANDA holders chose to stop sales and marketing of CYLERT and generic 
pemoline in May 2005 (Ref. 4).
    Pergolide mesylate: All drug products containing pergolide 
mesylate. Pergolide mesylate, formerly marketed as PERMAX tablets, was 
associated with increased risk of heart valve damage. On March 29, 
2007, FDA announced in a Public Health Advisory that the NDA and ANDA 
holders agreed to withdraw PERMAX and generic pergolide mesylate from 
the market (Ref. 5).
    Phenylpropanolamine (PPA): All drug products containing PPA. A 
study demonstrated that PPA was associated with increased risk of 
hemorrhagic stroke. On November 6, 2000, FDA announced in a Public 
Health Advisory that it was taking steps to remove PPA from all drug 
products and requested that all drug companies discontinue marketing 
products containing PPA (Ref. 6). In response to FDA's request, 
companies reformulated their products to exclude PPA. In a notice 
published in the Federal Register on August 14, 2001 (66 FR 42665), FDA 
offered an opportunity for a hearing on a proposal to issue an order, 
under section 505(e) of the FD&C Act, withdrawing approval of 13 NDAs 
and 8 ANDAs for products containing phenylpropanolamine. (Although the 
August 14, 2001, notice stated that FDA proposed to withdraw approval 
of 16 NDAs and 8 ANDAs, the notice listed only 13 NDAs and 8 ANDAs.) 
FDA withdrew approval of ANDA 71-099 for BROMATAPP Extended-Release 
Tablets in a notice published in the Federal Register of February 20, 
2002 (67 FR 7702) after the application holder informed FDA that the 
product was no longer being marketed and requested withdrawal. In the 
Federal Register of February 20, 2014 (79 FR 9744), FDA announced that 
the NDA and ANDA products containing PPA were no longer shown to be 
safe for use under the conditions that formed the basis upon which the 
applications were approved, and thus the Agency was withdrawing 
approval of 20 products containing PPA.
    Polyethylene glycol (PEG) 3350, sodium chloride, sodium 
bicarbonate, potassium chloride, and bisacodyl: All drug products 
containing PEG 3350, sodium chloride, sodium bicarbonate, and potassium 
chloride for oral solution, and 10 mg or more of bisacodyl delayed-
release tablets. PEG 3350, sodium chloride, sodium bicarbonate, and 
potassium chloride for oral solution, and four bisacodyl delayed-
release tablets, 5 mg (20-mg bisacodyl), formerly marketed as 
HALFLYTELY AND BISACODYL TABLETS BOWEL PREP KIT (20-mg bisacodyl), was 
associated with ischemic colitis. The NDA holder informed FDA that it 
ceased to manufacture and market HALFLYTELY AND BISACODYL TABLETS BOWEL 
PREP KIT (20-mg bisacodyl) as of September 25, 2007. On July 15, 2008, 
FDA received a citizen petition (Docket No. FDA-2008-P-0412), submitted 
under Sec.  10.30, from Foley & Lardner LLP. The petition requested 
that the Agency determine whether HALFLYTELY AND BISACODYL TABLETS 
BOWEL PREP KIT (PEG-3350, sodium chloride, sodium bicarbonate, and 
potassium chloride for oral solution and four bisacodyl delayed release 
tablets, 5 mg) (HALFLYTELY AND BISACODYL TABLETS BOWEL PREP KIT (20-mg 
bisacodyl)), manufactured by Braintree Laboratories, Inc. (Braintree), 
was withdrawn from sale for reasons of safety or effectiveness. In the 
Federal Register of

[[Page 37693]]

March 19, 2010 (75 FR 13292), FDA announced its determination that 
HALFLYTELY AND BISACODYL TABLETS BOWEL PREP KIT (20-mg bisacodyl) was 
withdrawn from the market for reasons of safety or effectiveness. 
Similarly, PEG 3350, sodium chloride, sodium bicarbonate, and potassium 
chloride for oral solution, and two bisacodyl delayed-release tablets, 
5 mg (10-mg bisacodyl), formerly marketed as HALFLYTELY AND BISACODYL 
TABLETS BOWEL PREP KIT (10-mg bisacodyl), was associated with ischemic 
colitis. The NDA holder informed FDA that it ceased to manufacture and 
market HALFLYTELY AND BISACODYL TABLETS BOWEL PREP KIT (10-mg 
bisacodyl) as of July 17, 2010. On September 23, 2010, FDA received a 
citizen petition (Docket No. FDA-2010-P-0507), submitted under Sec.  
10.30, from Perrigo Company (Perrigo) requesting that the Agency 
determine whether HALFLYTELY AND BISACODYL TABLETS BOWEL PREP KIT (PEG-
3350, sodium chloride, sodium bicarbonate, and potassium chloride for 
oral solution and two bisacodyl delayed release tablets, 5 mg) 
(HALFLYTELY AND BISACODYL TABLETS BOWEL PREP KIT (10-mg bisacodyl)), 
manufactured by Braintree, was withdrawn from sale for reasons of 
safety or effectiveness. In the Federal Register of August 17, 2011 (76 
FR 51037), FDA announced its determination that HALFLYTELY AND 
BISACODYL TABLETS BOWEL PREP KIT (10-mg bisacodyl) was withdrawn from 
the market for reasons of safety or effectiveness.
    Propoxyphene: All drug products containing propoxyphene. 
Propoxyphene, formerly marketed under various names such as DARVON and 
DARVOCET, was associated with serious toxicity to the heart. In a drug 
safety communication dated November 19, 2010, FDA announced it had 
requested that companies voluntarily withdraw propoxyphene from the 
U.S. market and that FDA was recommending against the continued use and 
prescribing of the pain reliever propoxyphene because new data showed 
that the drug can cause serious toxicity to the heart, even when used 
at therapeutic doses. FDA concluded that the safety risks of 
propoxyphene outweighed its limited benefits for pain relief at 
recommended doses. The Agency's recommendation was based on all 
available data including data from a then-new study that evaluated the 
effects that increasing doses of propoxyphene have on the heart. The 
results of the study showed that when propoxyphene was taken at 
therapeutic doses, there were significant changes to the electrical 
activity of the heart which can increase the risk for serious abnormal 
heart rhythms (Ref. 7). In the Federal Register of March 10, 2014 (79 
FR 13308), FDA announced that due to this safety risk, the Agency was 
withdrawing approval of 54 propoxyphene products with agreement from 
holders of the affected applications. On that date, FDA also published 
a notice of opportunity for a hearing on its proposal to withdraw 
approval of three additional propoxyphene products for which FDA had 
not received correspondence from the application holders requesting 
that FDA withdraw approval (see the Federal Register of March 10, 2014 
(79 FR 13310)).
    Rapacuronium bromide: All drug products containing rapacuronium 
bromide. Rapacuronium bromide, formerly marketed as RAPLON for 
Injection, was associated with the occurrence of bronchospasm. In a 
letter dated March 27, 2001, the NDA holder announced that it 
voluntarily withdrew all batches of RAPLON for Injection from the 
market (Ref. 8). FDA subsequently announced in the Federal Register of 
March 19, 2012 (77 FR 16039) that it was withdrawing the approval of 
the NDA.
    Rofecoxib: All drug products containing rofecoxib. Rofecoxib, 
formerly marketed as VIOXX, was associated with increased risk of 
serious cardiovascular events, including heart attack and stroke. On 
September 30, 2004, FDA announced in a Public Health Advisory that the 
NDA holder voluntarily withdrew VIOXX from the market (Ref. 9).
    Sibutramine hydrochloride: All drug products containing sibutramine 
hydrochloride. Sibutramine hydrochloride (HCl), formerly marketed as 
MERIDIA oral capsules, was associated with increased risk of heart 
attack and stroke. In a letter dated October 12, 2010, the NDA holder 
requested that FDA withdraw the approval of the NDA for MERIDIA. In an 
acknowledgment letter dated November 1, 2010, FDA stated that the 
benefits of MERIDIA (sibutramine HCl) oral capsules no longer 
outweighed the risks in any identifiable population. FDA subsequently 
announced in the Federal Register of December 21, 2010 (75 FR 80061) 
that it was withdrawing approval of the NDA.
    Tegaserod maleate: All drug products containing tegaserod maleate. 
Tegaserod maleate, formerly marketed as ZELNORM, was associated with a 
higher chance of heart attack, stroke, and worsening heart chest pain 
that can become a heart attack, compared to a placebo. On March 30, 
2007, FDA announced in a Public Health Advisory that the NDA holder 
agreed to stop selling ZELNORM (Ref. 10). On July 27, 2007, FDA 
announced that it was permitting the restricted use of ZELNORM 
(tegaserod maleate) under a treatment investigational new drug (IND) 
protocol to treat irritable bowel syndrome with constipation (IBS-C) 
and chronic idiopathic constipation (CIC) in women younger than 55 who 
meet specific guidelines (Ref. 11). On April 2, 2008, FDA announced 
that the sponsor of ZELNORM notified FDA that it would no longer 
provide ZELNORM (tegaserod maleate) under a treatment IND protocol to 
treat IBS-C and CIC in women younger than 55; however, the sponsor 
agreed to continue to supply ZELNORM for use in emergency situations 
(Ref. 12).
    Troglitazone: All drug products containing troglitazone. 
Troglitazone, formerly marketed as REZULIN and PRELAY Tablets, a 
treatment for type 2 diabetes, was shown to be more toxic to the liver 
than two other more recently approved drugs that offered a similar 
benefit. In a letter dated May 1, 2002, the holder of the NDA for 
REZULIN (troglitazone) Tablets requested that FDA withdraw the NDA for 
REZULIN (troglitazone) Tablets because it had discontinued marketing 
the product in March 2000. FDA subsequently announced in the Federal 
Register of January 10, 2003 (68 FR 1469) that it was withdrawing the 
approval of the NDA for REZULIN. In a letter dated December 31, 2002, 
the holder of the NDA for PRELAY (troglitazone) Tablets requested that 
FDA withdraw the approval of the NDA for PRELAY (troglitazone) Tablets 
because it never marketed the drug and had no plans to market the drug 
in the future. In the Federal Register of August 11, 2003 (68 FR 
47581), FDA concluded that PRELAY was voluntarily withdrawn after 
review of safety data showed that REZULIN was more toxic to the liver 
than two other more recently approved drugs that offered a similar 
benefit, and FDA announced that it was withdrawing approval of the NDA 
for PRELAY. Troglitazone was presented to the Advisory Committee at the 
July 2000 meeting, and the Advisory Committee voted to include 
troglitazone on the withdrawn or removed list (see the Federal Register 
of June 29, 2000 (65 FR 40104)).
    Trovafloxacin mesylate: All drug products containing trovafloxacin 
mesylate. Trovafloxacin mesylate,

[[Page 37694]]

formerly marketed as TROVAN tablets, 100 mg and 200 mg, was associated 
with serious liver injury. On June 9, 1999, FDA announced in a Public 
Health Advisory that the NDA holder agreed to a limited distribution of 
TROVAN (alatrofloxacin mesylate) Injection and TROVAN (trovafloxacin 
mesylate) tablets, 100 mg and 200 mg, to in-patient healthcare 
facilities (Ref. 1). The holders of the NDAs for TROVAN (trovafloxacin 
mesylate) tablets, 100 mg and 200 mg, and TROVAN/ZITHROMAX COMPLIANCE 
PAK (trovafloxacin mesylate/azithromycin for oral suspension) notified 
the Agency that the drug products were no longer marketed and requested 
that the approval of the NDAs be withdrawn (see the Federal Register of 
September 22, 1999 (64 FR 51325), and June 16, 2006 (71 FR 34940)). FDA 
announced it was withdrawing approval of the NDAs in the Federal 
Register of September 22, 1999 (64 FR 51325), and June 16, 2006 (71 FR 
34940).
    Valdecoxib: All drug products containing valdecoxib. Valdecoxib, 
formerly marketed as BEXTRA, was associated with increased risk of 
serious cardiovascular events and an increased risk of serious skin 
reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, 
erythema multiforme) compared to other nonsteroidal anti-inflammatory 
drugs. On April 7, 2005, FDA announced in an FDA Alert that it had 
concluded that the overall risk versus benefit profile of BEXTRA 
(valdecoxib) was unfavorable and that the NDA holder had voluntarily 
removed BEXTRA from the market (Ref. 13). In letters dated May 27, 
2011, August 8, 2011, and October 31, 2011, the holder of the NDA for 
BEXTRA (valdexoxib) Tablets requested that FDA withdraw the NDA for 
BEXTRA (valdexoxib) Tablets. FDA subsequently announced in the Federal 
Register of August 2, 2013 (78 FR 46984) that it was withdrawing 
approval of the NDA.

C. Amendment To Modify the Description of a Drug Product on the List

    FDA is proposing to amend Sec.  216.24 to modify the description of 
bromfenac sodium on the list.
    Bromfenac sodium: All drug products containing bromfenac sodium 
(except ophthalmic solutions). The use of bromfenac sodium, formerly 
marketed as DURACT (bromfenac sodium) Capsules, was associated with 
fatal hepatic failure. The manufacturer of DURACT Capsules voluntarily 
withdrew the drug from the market on June 22, 1998 (see the Federal 
Register of October 8, 1998 (63 FR 54082)). On March 8, 1999, FDA 
included all drug products containing bromfenac sodium in the list 
codified at Sec.  216.24 when FDA published the 1999 final rule (64 FR 
10944). Since then, FDA has approved bromfenac ophthalmic solutions, 
and although one of these, XIBROM (bromfenac ophthalmic solution) 
0.09%, was discontinued by the NDA holder in 2011, FDA announced its 
determination in the Federal Register of May 13, 2011 (76 FR 28045) 
that it was not withdrawn for reasons of safety or effectiveness. (See 
also Docket No. FDA-2011-P-0128.) Approved bromfenac ophthalmic 
solutions are currently on the market. Thus, FDA is proposing to 
include all drug products containing bromfenac sodium on the list with 
an exception for ophthalmic solutions.
    For the convenience of the reader, the regulatory text of Sec.  
216.24 provided with this proposed rule includes the drug products 
proposed for addition and modification discussed in this document and 
the drug products codified by the 1999 final rule.

IV. 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.

V. Analysis of Impacts

    FDA has examined the impacts of the proposed 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 proposed 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 
propose to 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 proposing ``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 $141 million, using the most current (2013) Implicit 
Price Deflator for the Gross Domestic Product. We do not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    This rule proposes to amend Sec.  216.24 concerning pharmacy 
compounding. Specifically, the proposed rule would add to or modify 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 were withdrawn or removed from the market because such drug 
products or components of such drug products were found to be unsafe or 
not effective (see section III). The Agency is proposing to add 25 drug 
products to the list and to modify the description of 1 drug product on 
the list to add an exception. The Agency is not aware of any routine 
use of these drug products in pharmacy compounding 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. However, the 
Agency invites the submission of comments and solicits current 
compounding usage data for these drug products, if they are compounded 
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 proposes to certify that this proposed rule will not have a 
significant

[[Page 37695]]

economic impact on a substantial number of small entities.

VI. Paperwork Reduction Act of 1995

    The submission of comments on this proposed rule and the submission 
of additional nominations for the list that is the subject of this 
rulemaking would be submissions in response to a Federal Register 
notice, in the form of comments, which are excluded from the definition 
of ``information'' under 5 CFR 1320.3(h)(4) of OMB 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 proposed rule contains no other collection of 
information.

VII. Request for Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in the brackets in the heading of this document. Received 
comments may be seen in the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday, and will be posted to the 
docket at http://www.regulations.gov.

VIII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified the Web site addresses in this reference section, but FDA 
is not responsible for any subsequent changes to the Web sites after 
this document publishes in the Federal Register.)

1. FDA Public Health Advisory Letter from Murray M. Lumpkin, Deputy 
Center Director (Review Management), Center for Drug Evaluation and 
Research, FDA, Re: Food and Drug Administration TROVAN 
(Trovafloxacin/Alatrofloxacin Mesylate) Interim Recommendations 
(June 9, 1999), http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm053103.htm.
2. Letter from E. Paul Mac Carthy, Vice President, Head U.S. Medical 
Science, Bayer Corporation, to Healthcare Professional, Re: Market 
withdrawal of Baycol (cerivastatin) (August 8, 2001), http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM173692.pdf.
3. Letter from Jan Gheuens, Vice President, Medical Affairs, Janssen 
Pharmaceutica, to Healthcare Professional (April 12, 2000), 
PROPULSID (cisapride) Dear Healthcare Professional Letter (April 
2000), http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175000.htm.
4. FDA Alert--Information for Healthcare Professionals: Pemoline 
Tablets and Chewable Tablets (marketed as CYLERT) (October 2005), 
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126461.htm.
5. FDA Public Health Advisory--Pergolide (marketed as PERMAX) (March 
29, 2007), http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm051285.htm.
6. FDA Public Health Advisory--Safety of Phenylpropanolamine 
(November 6, 2000), http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm052236.htm.
7. FDA Drug Safety Communication--FDA Recommends Against the 
Continued Use of Propoxyphene (November 19, 2010), http://www.fda.gov/Drugs/DrugSafety/ucm234338.htm.
8. Letter from Deborah Shapse, Medical Director, Organon, Inc., Re: 
Voluntary Market Withdrawal of RAPLON (rapacuronium bromide) for 
Injection, All Batches (March 27, 2001), http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM173891.pdf.
9. FDA Public Health Advisory--Safety of VIOXX (September 30, 2004), 
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106274.htm.
10. FDA Public Health Advisory--Tegaserod maleate (marketed as 
ZELNORM) (March 30, 2007), http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm051284.htm.
11. FDA News Release, ``FDA Permits Restricted Use of Zelnorm for 
Qualifying Patients'' (July 27, 2007), http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108956.htm.
12. FDA--ZELNORM (tegaserod maleate) Information (April 2, 2008), 
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103223.htm.
13. FDA Alert--Information for Healthcare Professionals: Valdecoxib 
(marketed as Bextra) (April 7, 2005), http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124649.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, the proposed 
rule that published on January 4, 2000 (65 FR 256), is withdrawn and it 
is proposed that 21 CFR part 216 be amended as follows:

PART 216--HUMAN DRUG COMPOUNDING

0
1. The authority citation for 21 CFR 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 
were 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.

[[Page 37696]]

    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 entretinate.
    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.
    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 dermatalogic application).
    Nomifensine maleate: All drug products containing nomifensine 
maleate.
    Novobiocin sodium: All drug products containing novobiocin sodium.
    Oxycodone hydrochloride: All extended-release drug products 
containing oxycodone hydrochloride that have not been determined by FDA 
to have abuse-deterrent properties.
    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.
    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: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-15371 Filed 7-1-14; 8:45 am]
BILLING CODE 4164-01-P