[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Have Been Withdrawn or Removed From the Market for Reasons of Safety or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have been withdrawn or removed from the market after the drug products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256) is withdrawn as of July 2, 2014.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.
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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.
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\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.
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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).
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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