[Federal Register Volume 80, Number 127 (Thursday, July 2, 2015)]
[Notices]
[Pages 38212-38216]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-16360]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2015-N-2008]
Unapproved and Misbranded Otic Prescription Drug Products;
Enforcement Action Dates
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
its intention to take enforcement action against unapproved and
misbranded otic drug products labeled for prescription use and
containing benzocaine; benzocaine and antipyrine; benzocaine,
antipyrine, and zinc acetate; benzocaine, chloroxylenol, and
hydrocortisone; chloroxylenol and pramoxine; or chloroxylenol,
pramoxine, and hydrocortisone; and against persons who manufacture or
cause the manufacture or distribution of such products in interstate
commerce. These unapproved and misbranded prescription drug products
are marketed without evidence of safety and effectiveness; may present
safety concerns; and pose a direct challenge to the new drug approval
system and, in some cases, the over-the-counter (OTC) drug monograph
system.
DATES: This notice is effective July 2, 2015. For information about
enforcement dates, see SUPPLEMENTARY INFORMATION, section IV.
ADDRESSES: For all communications in response to this notice, identify
with Docket No. FDA-2015-N-2008 and direct to the appropriate office
listed in this ADDRESSES section as follows:
Applications under section 505(b) of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. 355(b)): Division of Anesthesia,
Analgesia, and Addiction Products (for drug products with analgesic and
anti-inflammatory indications), or Division of Anti-Infective Drug
Products (for drug products with anti-infective indications), Office of
New Drugs, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD
20993-0002.
Applications under section 505(j) of the FD&C Act: Office of
Generic Drugs, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 75, Silver Spring, MD
20993-0002.
All other communications about this action should be directed to:
Kathleen Joyce, Division of Prescription Drugs, Office of Unapproved
Drugs and Labeling Compliance, Center for Drug Evaluation and Research,
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm.
5236, Silver Spring, MD 20993-0002; 301-796-3329 or email:
[email protected].
FOR FURTHER INFORMATION CONTACT: Kathleen Joyce, Division of
Prescription Drugs, Office of Unapproved Drugs and Labeling Compliance,
Center for Drug Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 51, rm. 5236, Silver Spring, MD 20993-
0002; 301-796-3329 or email: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing its intention to take enforcement action against
certain unapproved and misbranded otic drug products labeled for
prescription use. These marketed unapproved and misbranded otic drug
products are labeled for, among other things, the temporary relief of
pain associated with ear infections or inflammation, including acute
otitis media (middle ear infection), otitis media with effusion (fluid
in the ear, but without infection), and acute otitis externa (infection
in the outer ear or ``swimmer's ear''). Other indications for these
unapproved drug products include anti-infective and anti-inflammatory
claims, as well as claims for the removal of cerumen (earwax).
This notice covers the following marketed unapproved prescription
otic drug products: (1) Single-ingredient otic drug products containing
benzocaine; (2) fixed-dose combination otic drug products containing
benzocaine and antipyrine; (3) fixed-dose combination otic drug
products containing benzocaine, antipyrine, and zinc
[[Page 38213]]
acetate; (4) fixed-dose combination otic drug products containing
benzocaine, chloroxylenol, and hydrocortisone; (5) fixed-dose
combination otic drug products containing chloroxylenol and pramoxine;
and (6) fixed-dose combination otic drug products containing
chloroxylenol, pramoxine, and hydrocortisone. These drug products are
marketed without evidence of safety and effectiveness, present safety
concerns, and pose a direct challenge to the new drug approval system
and, in some cases, the OTC drug monograph system.
For example, FDA is aware of many unapproved and misbranded
prescription fixed-dose combination drug products containing benzocaine
and antipyrine that are labeled for use for the prompt relief of pain
and reduction of inflammation in the congestive and serous stages of
acute otitis media and for adjuvant therapy during systemic antibiotic
administration for resolution of acute otitis media. These products
have also been labeled to facilitate the removal of excessive or
impacted cerumen. FDA has received at least five adverse event reports
of allergic reactions to these drug products, including angioedema of
the ear, eye, face, neck, and/or mouth. We are also aware of at least
one case of methemoglobinemia associated with the administration of an
otic product containing benzocaine in an infant, which resulted in
death (Ref. 1). Methemoglobinemia is a serious blood disorder in which
an abnormal amount of methemoglobin (a form of hemoglobin) is produced
(Ref. 2). Other less serious adverse reactions associated with these
products include contact hypersensitivity, pruritus, stinging, burning,
and irritation.
FDA is also aware of at least one unapproved and misbranded
prescription single-ingredient otic drug product containing benzocaine
that is labeled for use as a topical anesthetic in the external
auditory canal to relieve ear pain, and for the treatment of acute
otitis media, acute swimmer's ear, and other forms of otitis externa.
Potential adverse reactions include methemoglobinemia, local burning,
stinging, tenderness or edema, and hypersensitivity reactions.
FDA is aware of an unapproved and misbranded prescription fixed-
dose combination drug product containing benzocaine, antipyrine, and
zinc acetate that is labeled with an indication to relieve pain,
congestion, and swelling caused by middle ear inflammation (acute
otitis media), and to help remove earwax. Potential adverse reactions
include methemoglobinemia and contact hypersensitivity, pruritus,
stinging, burning, and irritation.
FDA is also aware of an unapproved and misbranded prescription
fixed-dose combination drug product containing benzocaine,
chloroxylenol, and hydrocortisone that is labeled for the treatment of
superficial infections of the external auditory canal complicated by
inflammation caused by organisms susceptible to the action of the
antimicrobial, and to control itching in the auditory canal. Unapproved
and misbranded prescription fixed-dose combination products containing
chloroxylenol and pramoxine are also on the market and labeled for
treating superficial external ear infections and the associated
itching. Potential adverse reactions for these fixed-dose combination
products include contact hypersensitivity, pruritus, stinging, burning,
and irritation.
In addition, FDA is aware of various unapproved and misbranded
prescription fixed-dose combination drug products containing
chloroxylenol, pramoxine, and hydrocortisone that are labeled with
analgesic, anti-inflammatory and anti-infective indications. The
chloroxylenol, pramoxine, and hydrocortisone drug products are labeled
for the treatment of superficial infections of the outer ear,
inflammation, and itching. Potential adverse reactions include
pruritus, stinging, burning, and irritation.
In addition to the safety concerns listed previously, these drugs
present direct challenges to the FDA drug approval system and, in some
cases, the OTC monograph system. These drugs directly challenge the new
drug approval system by competing with approved otic drug products
appropriately labeled for anti-inflammatory uses and the treatment of
otitis externa. The unapproved and misbranded drug products covered by
this notice also pose a direct challenge to the OTC drug monograph
system because they compete with legally marketed OTC products labeled
for cerumen removal and ear drying aid indications under an OTC drug
monograph (part 344 (21 CFR part 344)).
For the reasons described in sections II and III, among others,
FDA's drug approval process is critical to protecting the public
health. Drugs are evaluated by FDA before being marketed to ensure that
they are safe and effective for their intended uses and are only
approved for marketing after a careful risk-benefit analysis. The drug
approval process is designed to avoid the risks associated with
potentially unsafe, ineffective, and fraudulent drugs.\1\
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\1\ See ``Marketed Unapproved Drugs--Compliance Policy Guide''
(Marketed Unapproved Drugs CPG) at 5, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf.
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II. Safety and Effectiveness Concerns With Unapproved New Drugs
The new drug approval process affords FDA the opportunity to review
and evaluate a drug before it is marketed to ensure safety, efficacy,
and quality. This includes reviewing the processes used to manufacture
the active pharmaceutical ingredient(s) and the finished drug product,
and the labeling of the drug product. Because marketed unapproved new
drug products have not undergone FDA's rigorous premarket review and
approval process, they may present safety risks. This is particularly
true because FDA has not reviewed and approved the label for unapproved
new drugs, so some unapproved drug labeling omits or modifies safety
warnings or other information that is important to ensure safe use,
such as drug interactions or potential adverse experiences.
With respect to the otic drug products subject to this notice, FDA
is particularly concerned about pediatric labeling because these drug
products are often prescribed for young children, a population most
susceptible to ear infections (Ref 3). FDA has not assessed the
scientific support, if any, for the use of these drug products in
pediatric populations. In other words, none of these products have been
shown to be safe for use in any population, including children or
infants. In fact, as described in section I, FDA has received at least
five adverse events reports associated with unapproved prescription
otic products. There is also the potential for rare, but serious
adverse events to occur, including methemoglobinemia, a dangerous blood
disorder. Not all of these adverse events are included in the labeling
for these unapproved drug products.
FDA also has concerns regarding the manufacturing processes for
unapproved new drugs. When new drugs are marketed without FDA approval,
FDA does not have an opportunity, prior to product marketing, to
determine whether the manufacturing processes for the drugs are
adequate to ensure that they are of suitable quality.
For example, the Agency scrutinizes the chemistry, manufacturing,
and controls involved in producing the active pharmaceutical ingredient
(API or drug substance) and finished dosage
[[Page 38214]]
form or drug product.\2\ With respect to the drug substance, FDA's
examination includes the following: (1) Physical and chemical
characteristics and stability of the drug substance; (2) the process
controls used in manufacturing and packaging; and (3) specifications
necessary to ensure the identity, strength, quality, and purity of the
drug substance. For the drug product, FDA's review includes the
following: (1) The specifications for the components used in the
manufacture of the drug product; (2) manufacturing and packaging
procedures and process controls; and (3) the specifications necessary
to ensure the identity, strength, quality, and purity of the drug
product. Unapproved drug products do not undergo this review process,
and therefore the quality of the finished drug product is uncertain.
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\2\ See, generally, Sec. 314.50(d) (21 CFR 314.50(d)). See also
section 505(d)(3) of the FD&C Act requiring FDA to determine whether
the methods used in, and the facilities and controls used for, the
manufacture, processing, and packing of such a drug are adequate to
preserve its identity, strength, quality, and purity.
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Because unapproved new drugs have not been subject to FDA's
premarket review and approval process, FDA cannot be sure that
unapproved drugs are effective. Section 505(d) of the FD&C Act requires
``substantial evidence'' of safety and effectiveness. ``Substantial
evidence'' is evidence consisting of adequate and well-controlled
investigations, including clinical investigations, by experts qualified
by scientific training and experience to evaluate the effectiveness of
the drug involved, on the basis of which it could fairly and
responsibly be concluded by such experts that the drug will have the
effect it purports or is represented to have under the conditions of
use prescribed, recommended, or suggested in the labeling or proposed
labeling thereof (section 505(d)(7) of the FD&C Act).
Among other characteristics, an adequate and well-controlled study
must use a design that permits a valid comparison with a control to
provide a quantitative assessment of the pertinent drug effects (Sec.
314.126(b)(2)) (21 CFR 314.126(b)(2)). The method of selection of
subjects must assure that those subjects have the disease or condition
being studied (Sec. 314.126(b)(3)) .
A review of the current literature suggests that the efficacy of
unapproved prescription otic drugs in managing pain associated with ear
infections is uncertain (Ref. 4). Use of unapproved products of
uncertain efficacy may delay treatment with products that have been
proven to be effective, leading to undue prolonged pain and discomfort.
In conclusion, these drug products are marketed without evidence of
safety and effectiveness; present actual and potential safety concerns;
and pose a direct challenge to the new drug approval system. In some
cases, they may directly challenge the OTC drug monograph system.
III. Legal Status of Products Identified in This Notice
FDA has reviewed the publicly available scientific literature for
the following unapproved prescription drug products: (1) Single-
ingredient otic drug products containing benzocaine; (2) fixed-dose
combination otic drug products containing benzocaine and antipyrine;
(3) fixed-dose combination otic drug products containing benzocaine,
antipyrine, and zinc acetate; (4) fixed-dose combination otic drug
products containing benzocaine, chloroxylenol, and hydrocortisone; (5)
fixed-dose combination otic drug products containing chloroxylenol and
pramoxine; and (6) fixed-dose combination otic drug products containing
chloroxylenol, pramoxine, and hydrocortisone. In no case did FDA find
literature sufficient to support a determination that any of these
prescription products are generally recognized as safe and effective.
Therefore, these prescription drug products are ``new drugs'' within
the meaning of section 201(p) of the FD&C Act (21 U.S.C. 321(p)), and
they require approved new drug applications (NDAs) or abbreviated new
drug applications (ANDAs) to be legally marketed.
The unapproved drug products covered by this notice are labeled for
prescription use. Prescription drugs are defined under section
503(b)(1)(A) of the FD&C Act (21 U.S.C. 353(b)(1)(A)) as drugs that,
because of toxicity or other potentially harmful effect, are not safe
to use except under the supervision of a practitioner licensed by law
to administer such drugs. If an unapproved drug product covered by this
notice meets the definition of ``prescription drug'' in section
503(b)(1)(A) of the FD&C Act, adequate directions cannot be written for
it so that a layman can use the product safely for its intended uses
(21 CFR 201.5). Consequently, it is misbranded under section 502(f)(1)
of the FD&C Act (21 U.S.C. 352(f)(1)) in that it fails to bear adequate
directions for use. A prescription drug is exempt from the requirement
in section 502(f)(1) of the FD&C Act that it bear adequate directions
for use if, among other things, it bears the FDA-approved labeling (21
CFR 201.100(c)(2) and 201.115). Because the prescription drug products
subject to this notice do not have approved applications with approved
labeling, they fail to qualify for the exemptions to the requirement
that they bear ``adequate directions for use,'' and are misbranded
under section 502(f)(1) of the FD&C Act.
If a drug covered by this notice is labeled as a prescription drug
but does not meet the definition of ``prescription drug'' under section
503(b)(1)(A) of the FD&C Act, the drug is misbranded under section
503(b)(4)(B).
The final OTC drug monograph in part 344, ``Topical Otic Drug
Products for Over-the Counter Human Use'' (Topical Otic Drug
monograph), permits the use of carbamide peroxide 6.5 percent
formulated in an anhydrous glycerin vehicle as an active ingredient for
earwax removal, in the amounts and under the conditions specified in
the final Topical Otic Drug monograph (see Sec. 344.10). The final OTC
drug monograph also permits the use of isopropyl alcohol 95 percent in
an anhydrous glycerin 5 percent base as an ear drying aid in the
amounts and under the conditions specified in the final Topical Otic
Drug monograph (see Sec. 344.12).
The final Topical Otic Drug monograph is the only monograph that
specifies the requirements for marketing an OTC drug for cerumen
removal. Unless a product included in this notice was reformulated and
labeled to meet all the requirements of the final Topical Otic Drug
monograph, the product would require an approved NDA or ANDA to be
legally marketed.\3\
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\3\ In addition to any other applicable requirements, firms that
manufacture OTC drugs must comply with the labeling requirements in
21 CFR 201.66.
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IV. Notice of Intent To Take Enforcement Action
Although not required to do so by the Administrative Procedure Act,
by the FD&C Act (or any rules issued under its authority), or for any
other legal reason, FDA is providing this notice to persons \4\ who are
marketing the following unapproved and misbranded drugs labeled for
prescription use: (1) Single-ingredient otic drug products containing
benzocaine; (2) fixed-dose combination otic drug products containing
benzocaine and antipyrine; (3) fixed-dose combination otic drug
products containing benzocaine, antipyrine, and zinc acetate; (4)
fixed-dose combination otic drug products containing benzocaine,
chloroxylenol, and
[[Page 38215]]
hydrocortisone; (5) fixed-dose combination otic drug products
containing chloroxylenol and pramoxine; and (6) fixed-dose combination
otic drug products containing chloroxylenol, pramoxine, and
hydrocortisone. The Agency intends to take enforcement action against
such products and those who manufacture them or cause them to be
manufactured or shipped in interstate commerce.
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\4\ The term ``person'' includes individuals, partnerships,
corporations, and associations (21 U.S.C. 321(e)).
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Manufacturing or shipping the drug products covered by this notice
can result in enforcement action, including seizure, injunction, or
other judicial or administrative proceeding.\5\ Consistent with
policies described in the Agency's Marketed Unapproved Drugs CPG
(available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf), the
Agency does not expect to issue a warning letter or any other further
warning to firms marketing drug products covered by this notice before
taking enforcement action. The Agency also reminds firms that, as
stated in the Marketed Unapproved Drugs CPG, any unapproved drug
marketed without a required approved application is subject to Agency
enforcement action at any time. The issuance of this notice does not in
any way obligate the Agency to issue similar notices (or any notice) in
the future regarding marketed unapproved drugs (see Marketed Unapproved
Drugs CPG at 5).
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\5\ In fact, U.S. Marshals seized $16.5 million of Auralgan Otic
Solution (which contains antipyrine and benzocaine) after Deston
continued to market the unapproved new drug following an FDA warning
letter. See http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm243638.htm.
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As described in the Marketed Unapproved Drugs CPG, the Agency may,
at its discretion, identify a period of time (i.e., a grace period)
during which the Agency does not intend to initiate an enforcement
action against a currently marketed unapproved drug solely on the
grounds that the drug lacks an approved application under section 505
of the FD&C Act. In deciding whether to allow such a grace period, the
Agency considers several factors, which are described in the Marketed
Unapproved Drugs CPG. With respect to drug products covered by this
notice, the Agency intends to exercise its enforcement discretion for
only a limited period of time, because there are readily available
legally marketed alternatives. Therefore, the Agency intends to
implement this notice as follows.
For the effective date of this notice, see the DATES section of
this document. Any drug product covered by this notice that a company
(including a manufacturer or distributor) began marketing after
September 19, 2011, is subject to immediate enforcement action. For
products covered by this notice that a company (including a
manufacturer or distributor) began marketing on or before September 19,
2011, FDA intends to take enforcement action against any such product
that is not listed with the Agency in full compliance with section 510
of the FD&C Act (21 U.S.C. 360) before July 1, 2015, and is
manufactured, shipped, or otherwise introduced or delivered for
introduction into interstate commerce by any person on or after July 1,
2015. FDA also intends to take enforcement action against any drug
product covered by this notice that is listed with FDA in full
compliance with section 510 of the FD&C Act but is not being
commercially used or sold \6\ in the United States before July 1, 2015,
and that is manufactured, shipped, or otherwise introduced or delivered
for introduction into interstate commerce by any person on or after
July 2, 2015.
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\6\ For the purpose of this notice, the phrase ``commercially
used or sold'' means that the product has been used in a business or
activity involving retail or wholesale marketing and/or sale.
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However, for drug products covered by this notice that a company
(including a manufacturer or distributor): (1) Began marketing in the
United States on or before September 19, 2011; (2) are listed with FDA
in full compliance with section 510 of the FD&C Act before July 1, 2015
(``currently marketed and listed''); and (3) are manufactured, shipped,
or otherwise introduced or delivered for introduction into interstate
commerce by any person on or after July 2, 2015, the Agency intends to
exercise its enforcement discretion as follows: FDA intends to initiate
enforcement action regarding any such currently marketed and listed
product that is manufactured on or after August 17, 2015, or that is
shipped on or after September 30, 2015. Furthermore, FDA intends to
take enforcement action against any person who manufactures or ships
such products after these dates. The purpose of these enforcement
timeframes is to allow manufacturers and distributors to deplete their
current inventory and ensure a smooth transition for consumers. Any
person who has submitted or submits an application for a drug product
covered by this notice but has not received approval must comply with
this notice.
The Agency, however, does not intend to exercise its enforcement
discretion as outlined previously if either of the following applies:
(1) A manufacturer or distributor of drug products covered by this
notice is violating other provisions of the FD&C Act, including, but
not limited to, violations related to FDA's current good manufacturing
practices, adverse drug event reporting, labeling, or misbranding
requirements other than those identified in this notice or (2) it
appears that a firm, in response to this notice, increases its
manufacture or interstate shipment of drug products covered by this
notice above its usual volume during these periods.\7\
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\7\ If FDA decides to take enforcement action against a product
covered by this notice, the Agency may simultaneously take action
relating to defendant's other violations of the FD&C Act. See, e.g.,
United States v. Sage Pharmaceuticals, 210 F. 3d 475, 479-480 (5th
Cir. 2000) (permitting the Agency to combine all violations of the
FD&C Act in one proceeding, rather than taking action against
multiple violations of the FD&C Act in ``piecemeal fashion'').
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Nothing in this notice, including FDA's intent to exercise its
enforcement discretion, alters any person's liability or obligations in
any other enforcement action, or precludes the Agency from initiating
or proceeding with enforcement action in connection with any other
alleged violation of the FD&C Act, whether or not related to a drug
product covered by this notice. Similarly, a person who is or becomes
enjoined from marketing unapproved or misbranded drugs may not resume
marketing of such products based on FDA's exercise of enforcement
discretion as described in this notice.
Drug manufacturers and distributors should be aware that the Agency
is exercising its enforcement discretion as described previously only
in regard to drug products covered by this notice that are marketed
under a National Drug Code (NDC) number listed with the Agency in full
compliance with section 510 of the FD&C Act before July 1, 2015. As
previously stated, drug products covered by this notice that are
currently marketed but not listed with the Agency on the date of this
notice must, as of the effective date of this notice, have approved
applications before their shipment in interstate commerce. Moreover,
any person or firm that has submitted or submits an application but has
yet to receive approval for such products is still responsible for full
compliance with this notice.
V. Discontinued Products
Some firms may have previously discontinued manufacturing or
distributing products covered by this notice without discontinuing the
listing as required under section 510(j) of the FD&C Act. Other firms
may discontinue
[[Page 38216]]
manufacturing or distributing listed products in response to this
notice. All firms are required to electronically update the listing of
their products under section 510(j) of the FD&C Act to reflect
discontinuation of unapproved products covered by this notice (21 CFR
207.21(b)). Questions on electronic drug listing updates should be sent
to [email protected]. In addition to the required update, firms can
also notify the Agency of product discontinuation by sending a letter,
signed by the firm's chief executive officer and fully identifying the
discontinued product(s), including the product NDC number(s), and
stating that the manufacturing and/or distribution of the product(s)
have been discontinued. The letter should be sent electronically to
Kathleen Joyce (see ADDRESSES). FDA plans to rely on its existing
records, including its drug listing records, the results of any
subsequent inspections, or other available information when considering
enforcement action.
VI. Reformulated Products
FDA cautions firms against reformulating their products into
unapproved new drugs without benzocaine; benzocaine and antipyrine;
benzocaine, antipyrine, and zinc acetate; benzocaine, chloroxylenol,
and hydrocortisone; chloroxylenol and pramoxine; or chloroxylenol,
pramoxine, and hydrocortisone and marketing them under the same name or
substantially the same name (including a new name that contains the old
name) in anticipation of an enforcement action based on this notice. As
stated in the Marketed Unapproved Drugs CPG, FDA intends to give higher
priority to enforcement actions involving unapproved drugs that are
reformulated to evade an anticipated FDA enforcement action but have
not been brought into compliance with the law. In addition,
reformulated products marketed under a name previously identified with
a different active ingredient have the potential to confuse healthcare
practitioners and harm patients.
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.
1. Logan, B. K. and A.M. Gordon, ``Case Report: Death of an Infant
Involving Benzocaine,'' Journal of Forensic Sciences, vol. 50, pp.
1486-1488, 2005.
2. Cortazzo, J. A. and A. D. Lichtman, ``Methemoglobinemia: A Review
and Recommendations for Management.'' Journal of Cardiothoracic and
Vascular Anesthesia, vol. 28(4), pp. 1055-1059. 2014.
3. Lieberthal, A. S., A. E. Carroll, T. Chonmaitree, et al., ``The
Diagnosis and Management of Acute Otitis Media,'' Pediatrics, vol.
131, pp. e964-e999, 2013.
4. Wood, D. N., N. Naas, and C. W. Gregory, ``Clinical Trials
Assessing Ototopical Agents in the Treatment of Pain Associated with
Acute Otitis Media in Children,'' International Journal of
Otorhinolaryngology, vol. 76, pp. 1229-1335, 2012.
Dated: June 26, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-16360 Filed 7-1-15; 8:45 am]
BILLING CODE 4164-01-P