80_FR_38339 80 FR 38212 - Unapproved and Misbranded Otic Prescription Drug Products; Enforcement Action Dates

80 FR 38212 - Unapproved and Misbranded Otic Prescription Drug Products; Enforcement Action Dates

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 80, Issue 127 (July 2, 2015)

Page Range38212-38216
FR Document2015-16360

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.

Federal Register, Volume 80 Issue 127 (Thursday, July 2, 2015)
[Federal Register Volume 80, Number 127 (Thursday, July 2, 2015)]
[Notices]
[Pages 38212-38216]
From the Federal Register Online  [www.thefederalregister.org]
[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



                                                    38212                            Federal Register / Vol. 80, No. 127 / Thursday, July 2, 2015 / Notices

                                                    total of 1,020 inquiries (1,020 ÷ 217 =                    assessment for a specific proposed                     the request, and submit the request to
                                                    4.7). Information submitted with each                      generic drug product. As a result, these               FDA. As a result, we estimate that it will
                                                    inquiry varies widely in content,                          inquiries can vary between 1 to 10                     take an average of 5,100 total hours
                                                    depending on the complexity of the                         burden hours, respectively.                            annually for industry to prepare and
                                                    request. Inquiries that are defined as                       Because the content of inquiries                     submit inquiries considered controlled
                                                    controlled correspondence (i.e.,                           considered controlled correspondence is                correspondence.
                                                    inquiries that request information on a                    widely varied, we are providing an
                                                    specific element of generic drug product                   average burden hour for each inquiry.                    Description of Respondents:
                                                    development) may range from a simple                       We estimate that it will take an average               Respondents are human generic drug
                                                    inquiry on generic drug labeling to a                      of 5 hours per inquiry for industry to                 manufacturers and related industry.
                                                    more complex inquiry for a formulation                     gather necessary information, prepare

                                                                                                        TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1
                                                                                                                                                   Number of                             Average
                                                                                                                                 Number of                           Total annual
                                                              Submission of controlled correspondence                                            responses per                         burden per   Total hours
                                                                                                                                respondents                           responses
                                                                                                                                                   respondent                           response

                                                    Manufacturers, Related Industry, and Representatives ......                     217                 4.7             1,020              5          5,100
                                                       1 There   are no capital costs or operating and maintenance costs associated with this collection of information.


                                                    References                                                 pramoxine, and hydrocortisone; and                     Labeling Compliance, Center for Drug
                                                    1. ‘‘Generic Drug User Fee Act Program                     against persons who manufacture or                     Evaluation and Research, Food and
                                                         Performance Goals and Procedures’’                    cause the manufacture or distribution of               Drug Administration, 10903 New
                                                         (GDUFA Commitment Letter) for                         such products in interstate commerce.                  Hampshire Ave., Bldg. 51, Rm. 5236,
                                                         fiscal years 2013 through 2017,                       These unapproved and misbranded                        Silver Spring, MD 20993–0002; 301–
                                                         available at http://www.fda.gov/                      prescription drug products are marketed                796–3329 or email: Kathleen.Joyce@
                                                         downloads/ForIndustry/UserFees/                       without evidence of safety and                         fda.hhs.gov.
                                                         GenericDrugUserFees/                                  effectiveness; may present safety                      FOR FURTHER INFORMATION CONTACT:
                                                         UCM282505.pdf).                                       concerns; and pose a direct challenge to               Kathleen Joyce, Division of Prescription
                                                    2. Id. at p. 15. The Web page quoted in                    the new drug approval system and, in                   Drugs, Office of Unapproved Drugs and
                                                         the controlled correspondence                         some cases, the over-the-counter (OTC)                 Labeling Compliance, Center for Drug
                                                         definition has been updated as the                    drug monograph system.                                 Evaluation and Research, Food and
                                                         link provided in the GDUFA                            DATES: This notice is effective July 2,                Drug Administration, 10903 New
                                                         Commitment Letter is no longer                        2015. For information about                            Hampshire Ave., Bldg. 51, rm. 5236,
                                                         accessible.                                           enforcement dates, see SUPPLEMENTARY                   Silver Spring, MD 20993–0002; 301–
                                                                                                               INFORMATION, section IV.                               796–3329 or email: Kathleen.Joyce@
                                                      Dated: June 26, 2015.
                                                    Leslie Kux,                                                ADDRESSES: For all communications in                   fda.hhs.gov.
                                                    Associate Commissioner for Policy.
                                                                                                               response to this notice, identify with                 SUPPLEMENTARY INFORMATION:
                                                                                                               Docket No. FDA–2015–N–2008 and
                                                    [FR Doc. 2015–16358 Filed 7–1–15; 8:45 am]                                                                        I. Background
                                                                                                               direct to the appropriate office listed in
                                                    BILLING CODE 4164–01–P
                                                                                                               this ADDRESSES section as follows:                        FDA is announcing its intention to
                                                                                                                 Applications under section 505(b) of                 take enforcement action against certain
                                                                                                               the Federal Food, Drug, and Cosmetic                   unapproved and misbranded otic drug
                                                    DEPARTMENT OF HEALTH AND
                                                                                                               Act (the FD&C Act) (21 U.S.C. 355(b)):                 products labeled for prescription use.
                                                    HUMAN SERVICES
                                                                                                               Division of Anesthesia, Analgesia, and                 These marketed unapproved and
                                                    Food and Drug Administration                               Addiction Products (for drug products                  misbranded otic drug products are
                                                                                                               with analgesic and anti-inflammatory                   labeled for, among other things, the
                                                    [Docket No. FDA–2015–N–2008]                               indications), or Division of Anti-                     temporary relief of pain associated with
                                                                                                               Infective Drug Products (for drug                      ear infections or inflammation,
                                                    Unapproved and Misbranded Otic                             products with anti-infective                           including acute otitis media (middle ear
                                                    Prescription Drug Products;                                indications), Office of New Drugs,                     infection), otitis media with effusion
                                                    Enforcement Action Dates                                   Center for Drug Evaluation and                         (fluid in the ear, but without infection),
                                                    AGENCY:      Food and Drug Administration,                 Research, Food and Drug                                and acute otitis externa (infection in the
                                                    HHS.                                                       Administration, 10903 New Hampshire                    outer ear or ‘‘swimmer’s ear’’). Other
                                                    ACTION:   Notice.                                          Ave., Bldg. 22, Silver Spring, MD                      indications for these unapproved drug
                                                                                                               20993–0002.                                            products include anti-infective and anti-
                                                    SUMMARY:   The Food and Drug                                 Applications under section 505(j) of                 inflammatory claims, as well as claims
                                                    Administration (FDA or Agency) is                          the FD&C Act: Office of Generic Drugs,                 for the removal of cerumen (earwax).
                                                    announcing its intention to take                           Center for Drug Evaluation and                            This notice covers the following
asabaliauskas on DSK5VPTVN1PROD with NOTICES




                                                    enforcement action against unapproved                      Research, Food and Drug                                marketed unapproved prescription otic
                                                    and misbranded otic drug products                          Administration, 10903 New Hampshire                    drug products: (1) Single-ingredient otic
                                                    labeled for prescription use and                           Ave., Bldg. 75, Silver Spring, MD                      drug products containing benzocaine;
                                                    containing benzocaine; benzocaine and                      20993–0002.                                            (2) fixed-dose combination otic drug
                                                    antipyrine; benzocaine, antipyrine, and                      All other communications about this                  products containing benzocaine and
                                                    zinc acetate; benzocaine, chloroxylenol,                   action should be directed to: Kathleen                 antipyrine; (3) fixed-dose combination
                                                    and hydrocortisone; chloroxylenol and                      Joyce, Division of Prescription Drugs,                 otic drug products containing
                                                    pramoxine; or chloroxylenol,                               Office of Unapproved Drugs and                         benzocaine, antipyrine, and zinc


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                                                                                    Federal Register / Vol. 80, No. 127 / Thursday, July 2, 2015 / Notices                                                38213

                                                    acetate; (4) fixed-dose combination otic                 contact hypersensitivity, pruritus,                   with potentially unsafe, ineffective, and
                                                    drug products containing benzocaine,                     stinging, burning, and irritation.                    fraudulent drugs.1
                                                    chloroxylenol, and hydrocortisone; (5)                      FDA is also aware of an unapproved                 II. Safety and Effectiveness Concerns
                                                    fixed-dose combination otic drug                         and misbranded prescription fixed-dose                With Unapproved New Drugs
                                                    products containing chloroxylenol and                    combination drug product containing
                                                    pramoxine; and (6) fixed-dose                                                                                     The new drug approval process
                                                                                                             benzocaine, chloroxylenol, and
                                                    combination otic drug products                                                                                 affords FDA the opportunity to review
                                                                                                             hydrocortisone that is labeled for the
                                                    containing chloroxylenol, pramoxine,                                                                           and evaluate a drug before it is marketed
                                                                                                             treatment of superficial infections of the
                                                    and hydrocortisone. These drug                                                                                 to ensure safety, efficacy, and quality.
                                                                                                             external auditory canal complicated by                This includes reviewing the processes
                                                    products are marketed without evidence
                                                    of safety and effectiveness, present                     inflammation caused by organisms                      used to manufacture the active
                                                    safety concerns, and pose a direct                       susceptible to the action of the                      pharmaceutical ingredient(s) and the
                                                    challenge to the new drug approval                       antimicrobial, and to control itching in              finished drug product, and the labeling
                                                    system and, in some cases, the OTC                       the auditory canal. Unapproved and                    of the drug product. Because marketed
                                                    drug monograph system.                                   misbranded prescription fixed-dose                    unapproved new drug products have
                                                       For example, FDA is aware of many                     combination products containing                       not undergone FDA’s rigorous
                                                    unapproved and misbranded                                chloroxylenol and pramoxine are also                  premarket review and approval process,
                                                    prescription fixed-dose combination                      on the market and labeled for treating                they may present safety risks. This is
                                                    drug products containing benzocaine                      superficial external ear infections and               particularly true because FDA has not
                                                    and antipyrine that are labeled for use                  the associated itching. Potential adverse             reviewed and approved the label for
                                                    for the prompt relief of pain and                        reactions for these fixed-dose                        unapproved new drugs, so some
                                                    reduction of inflammation in the                         combination products include contact                  unapproved drug labeling omits or
                                                    congestive and serous stages of acute                    hypersensitivity, pruritus, stinging,                 modifies safety warnings or other
                                                    otitis media and for adjuvant therapy                    burning, and irritation.                              information that is important to ensure
                                                    during systemic antibiotic                                  In addition, FDA is aware of various               safe use, such as drug interactions or
                                                    administration for resolution of acute                   unapproved and misbranded                             potential adverse experiences.
                                                    otitis media. These products have also                   prescription fixed-dose combination                      With respect to the otic drug products
                                                    been labeled to facilitate the removal of                drug products containing chloroxylenol,               subject to this notice, FDA is
                                                    excessive or impacted cerumen. FDA                       pramoxine, and hydrocortisone that are                particularly concerned about pediatric
                                                    has received at least five adverse event                 labeled with analgesic, anti-                         labeling because these drug products are
                                                    reports of allergic reactions to these                   inflammatory and anti-infective                       often prescribed for young children, a
                                                    drug products, including angioedema of                   indications. The chloroxylenol,                       population most susceptible to ear
                                                    the ear, eye, face, neck, and/or mouth.                  pramoxine, and hydrocortisone drug                    infections (Ref 3). FDA has not assessed
                                                    We are also aware of at least one case                   products are labeled for the treatment of             the scientific support, if any, for the use
                                                    of methemoglobinemia associated with                                                                           of these drug products in pediatric
                                                                                                             superficial infections of the outer ear,
                                                    the administration of an otic product                                                                          populations. In other words, none of
                                                                                                             inflammation, and itching. Potential
                                                    containing benzocaine in an infant,                                                                            these products have been shown to be
                                                                                                             adverse reactions include pruritus,
                                                    which resulted in death (Ref. 1).                                                                              safe for use in any population, including
                                                                                                             stinging, burning, and irritation.
                                                    Methemoglobinemia is a serious blood                                                                           children or infants. In fact, as described
                                                    disorder in which an abnormal amount                        In addition to the safety concerns
                                                                                                                                                                   in section I, FDA has received at least
                                                    of methemoglobin (a form of                              listed previously, these drugs present
                                                                                                                                                                   five adverse events reports associated
                                                    hemoglobin) is produced (Ref. 2). Other                  direct challenges to the FDA drug
                                                                                                                                                                   with unapproved prescription otic
                                                    less serious adverse reactions associated                approval system and, in some cases, the
                                                                                                                                                                   products. There is also the potential for
                                                    with these products include contact                      OTC monograph system. These drugs
                                                                                                                                                                   rare, but serious adverse events to occur,
                                                    hypersensitivity, pruritus, stinging,                    directly challenge the new drug                       including methemoglobinemia, a
                                                    burning, and irritation.                                 approval system by competing with                     dangerous blood disorder. Not all of
                                                       FDA is also aware of at least one                     approved otic drug products                           these adverse events are included in the
                                                    unapproved and misbranded                                appropriately labeled for anti-                       labeling for these unapproved drug
                                                    prescription single-ingredient otic drug                 inflammatory uses and the treatment of                products.
                                                    product containing benzocaine that is                    otitis externa. The unapproved and                       FDA also has concerns regarding the
                                                    labeled for use as a topical anesthetic in               misbranded drug products covered by                   manufacturing processes for
                                                    the external auditory canal to relieve ear               this notice also pose a direct challenge
                                                    pain, and for the treatment of acute                                                                           unapproved new drugs. When new
                                                                                                             to the OTC drug monograph system                      drugs are marketed without FDA
                                                    otitis media, acute swimmer’s ear, and                   because they compete with legally
                                                    other forms of otitis externa. Potential                                                                       approval, FDA does not have an
                                                                                                             marketed OTC products labeled for                     opportunity, prior to product marketing,
                                                    adverse reactions include                                cerumen removal and ear drying aid
                                                    methemoglobinemia, local burning,                                                                              to determine whether the manufacturing
                                                                                                             indications under an OTC drug                         processes for the drugs are adequate to
                                                    stinging, tenderness or edema, and                       monograph (part 344 (21 CFR part 344)).
                                                    hypersensitivity reactions.                                                                                    ensure that they are of suitable quality.
                                                       FDA is aware of an unapproved and                        For the reasons described in sections                 For example, the Agency scrutinizes
                                                    misbranded prescription fixed-dose                       II and III, among others, FDA’s drug                  the chemistry, manufacturing, and
asabaliauskas on DSK5VPTVN1PROD with NOTICES




                                                    combination drug product containing                      approval process is critical to protecting            controls involved in producing the
                                                    benzocaine, antipyrine, and zinc acetate                 the public health. Drugs are evaluated                active pharmaceutical ingredient (API or
                                                    that is labeled with an indication to                    by FDA before being marketed to ensure                drug substance) and finished dosage
                                                    relieve pain, congestion, and swelling                   that they are safe and effective for their
                                                    caused by middle ear inflammation                        intended uses and are only approved for                  1 See ‘‘Marketed Unapproved Drugs—Compliance

                                                                                                             marketing after a careful risk-benefit                Policy Guide’’ (Marketed Unapproved Drugs CPG)
                                                    (acute otitis media), and to help remove                                                                       at 5, available at http://www.fda.gov/downloads/
                                                    earwax. Potential adverse reactions                      analysis. The drug approval process is                Drugs/GuidanceComplianceRegulatoryInformation/
                                                    include methemoglobinemia and                            designed to avoid the risks associated                Guidances/UCM070290.pdf.



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                                                    38214                           Federal Register / Vol. 80, No. 127 / Thursday, July 2, 2015 / Notices

                                                    form or drug product.2 With respect to                   been proven to be effective, leading to               201.115). Because the prescription drug
                                                    the drug substance, FDA’s examination                    undue prolonged pain and discomfort.                  products subject to this notice do not
                                                    includes the following: (1) Physical and                    In conclusion, these drug products are             have approved applications with
                                                    chemical characteristics and stability of                marketed without evidence of safety and               approved labeling, they fail to qualify
                                                    the drug substance; (2) the process                      effectiveness; present actual and                     for the exemptions to the requirement
                                                    controls used in manufacturing and                       potential safety concerns; and pose a                 that they bear ‘‘adequate directions for
                                                    packaging; and (3) specifications                        direct challenge to the new drug                      use,’’ and are misbranded under section
                                                    necessary to ensure the identity,                        approval system. In some cases, they                  502(f)(1) of the FD&C Act.
                                                    strength, quality, and purity of the drug                may directly challenge the OTC drug                      If a drug covered by this notice is
                                                    substance. For the drug product, FDA’s                   monograph system.                                     labeled as a prescription drug but does
                                                    review includes the following: (1) The                                                                         not meet the definition of ‘‘prescription
                                                                                                             III. Legal Status of Products Identified
                                                    specifications for the components used                                                                         drug’’ under section 503(b)(1)(A) of the
                                                                                                             in This Notice
                                                    in the manufacture of the drug product;                                                                        FD&C Act, the drug is misbranded
                                                    (2) manufacturing and packaging                             FDA has reviewed the publicly                      under section 503(b)(4)(B).
                                                    procedures and process controls; and (3)                 available scientific literature for the                  The final OTC drug monograph in
                                                    the specifications necessary to ensure                   following unapproved prescription drug                part 344, ‘‘Topical Otic Drug Products
                                                    the identity, strength, quality, and                     products: (1) Single-ingredient otic drug             for Over-the Counter Human Use’’
                                                    purity of the drug product. Unapproved                   products containing benzocaine; (2)                   (Topical Otic Drug monograph), permits
                                                    drug products do not undergo this                        fixed-dose combination otic drug                      the use of carbamide peroxide 6.5
                                                    review process, and therefore the                        products containing benzocaine and                    percent formulated in an anhydrous
                                                    quality of the finished drug product is                  antipyrine; (3) fixed-dose combination                glycerin vehicle as an active ingredient
                                                                                                             otic drug products containing                         for earwax removal, in the amounts and
                                                    uncertain.
                                                                                                             benzocaine, antipyrine, and zinc                      under the conditions specified in the
                                                       Because unapproved new drugs have                     acetate; (4) fixed-dose combination otic              final Topical Otic Drug monograph (see
                                                    not been subject to FDA’s premarket                      drug products containing benzocaine,                  § 344.10). The final OTC drug
                                                    review and approval process, FDA                         chloroxylenol, and hydrocortisone; (5)                monograph also permits the use of
                                                    cannot be sure that unapproved drugs                     fixed-dose combination otic drug                      isopropyl alcohol 95 percent in an
                                                    are effective. Section 505(d) of the FD&C                products containing chloroxylenol and                 anhydrous glycerin 5 percent base as an
                                                    Act requires ‘‘substantial evidence’’ of                 pramoxine; and (6) fixed-dose                         ear drying aid in the amounts and under
                                                    safety and effectiveness. ‘‘Substantial                  combination otic drug products                        the conditions specified in the final
                                                    evidence’’ is evidence consisting of                     containing chloroxylenol, pramoxine,                  Topical Otic Drug monograph (see
                                                    adequate and well-controlled                             and hydrocortisone. In no case did FDA                § 344.12).
                                                    investigations, including clinical                       find literature sufficient to support a                  The final Topical Otic Drug
                                                    investigations, by experts qualified by                  determination that any of these                       monograph is the only monograph that
                                                    scientific training and experience to                    prescription products are generally                   specifies the requirements for marketing
                                                    evaluate the effectiveness of the drug                   recognized as safe and effective.                     an OTC drug for cerumen removal.
                                                    involved, on the basis of which it could                 Therefore, these prescription drug                    Unless a product included in this notice
                                                    fairly and responsibly be concluded by                   products are ‘‘new drugs’’ within the                 was reformulated and labeled to meet
                                                    such experts that the drug will have the                 meaning of section 201(p) of the FD&C                 all the requirements of the final Topical
                                                    effect it purports or is represented to                  Act (21 U.S.C. 321(p)), and they require              Otic Drug monograph, the product
                                                    have under the conditions of use                         approved new drug applications (NDAs)                 would require an approved NDA or
                                                    prescribed, recommended, or suggested                    or abbreviated new drug applications                  ANDA to be legally marketed.3
                                                    in the labeling or proposed labeling                     (ANDAs) to be legally marketed.
                                                    thereof (section 505(d)(7) of the FD&C                      The unapproved drug products                       IV. Notice of Intent To Take
                                                    Act).                                                    covered by this notice are labeled for                Enforcement Action
                                                       Among other characteristics, an                       prescription use. Prescription drugs are                Although not required to do so by the
                                                    adequate and well-controlled study                       defined under section 503(b)(1)(A) of                 Administrative Procedure Act, by the
                                                    must use a design that permits a valid                   the FD&C Act (21 U.S.C. 353(b)(1)(A)) as              FD&C Act (or any rules issued under its
                                                    comparison with a control to provide a                   drugs that, because of toxicity or other              authority), or for any other legal reason,
                                                    quantitative assessment of the pertinent                 potentially harmful effect, are not safe to           FDA is providing this notice to persons 4
                                                    drug effects (§ 314.126(b)(2)) (21 CFR                   use except under the supervision of a                 who are marketing the following
                                                    314.126(b)(2)). The method of selection                  practitioner licensed by law to                       unapproved and misbranded drugs
                                                    of subjects must assure that those                       administer such drugs. If an unapproved               labeled for prescription use: (1) Single-
                                                    subjects have the disease or condition                   drug product covered by this notice                   ingredient otic drug products containing
                                                    being studied (§ 314.126(b)(3)) .                        meets the definition of ‘‘prescription                benzocaine; (2) fixed-dose combination
                                                       A review of the current literature                    drug’’ in section 503(b)(1)(A) of the                 otic drug products containing
                                                    suggests that the efficacy of unapproved                 FD&C Act, adequate directions cannot                  benzocaine and antipyrine; (3) fixed-
                                                    prescription otic drugs in managing                      be written for it so that a layman can use            dose combination otic drug products
                                                    pain associated with ear infections is                   the product safely for its intended uses              containing benzocaine, antipyrine, and
                                                    uncertain (Ref. 4). Use of unapproved                    (21 CFR 201.5). Consequently, it is                   zinc acetate; (4) fixed-dose combination
                                                                                                             misbranded under section 502(f)(1) of
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                                                    products of uncertain efficacy may                                                                             otic drug products containing
                                                    delay treatment with products that have                  the FD&C Act (21 U.S.C. 352(f)(1)) in                 benzocaine, chloroxylenol, and
                                                                                                             that it fails to bear adequate directions
                                                      2 See, generally, § 314.50(d) (21 CFR 314.50(d)).      for use. A prescription drug is exempt                  3 In addition to any other applicable

                                                    See also section 505(d)(3) of the FD&C Act requiring     from the requirement in section                       requirements, firms that manufacture OTC drugs
                                                    FDA to determine whether the methods used in,            502(f)(1) of the FD&C Act that it bear                must comply with the labeling requirements in 21
                                                    and the facilities and controls used for, the                                                                  CFR 201.66.
                                                    manufacture, processing, and packing of such a
                                                                                                             adequate directions for use if, among                   4 The term ‘‘person’’ includes individuals,

                                                    drug are adequate to preserve its identity, strength,    other things, it bears the FDA-approved               partnerships, corporations, and associations (21
                                                    quality, and purity.                                     labeling (21 CFR 201.100(c)(2) and                    U.S.C. 321(e)).



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                                                                                    Federal Register / Vol. 80, No. 127 / Thursday, July 2, 2015 / Notices                                                    38215

                                                    hydrocortisone; (5) fixed-dose                           Any drug product covered by this notice                either of the following applies: (1) A
                                                    combination otic drug products                           that a company (including a                            manufacturer or distributor of drug
                                                    containing chloroxylenol and                             manufacturer or distributor) began                     products covered by this notice is
                                                    pramoxine; and (6) fixed-dose                            marketing after September 19, 2011, is                 violating other provisions of the FD&C
                                                    combination otic drug products                           subject to immediate enforcement                       Act, including, but not limited to,
                                                    containing chloroxylenol, pramoxine,                     action. For products covered by this                   violations related to FDA’s current good
                                                    and hydrocortisone. The Agency                           notice that a company (including a                     manufacturing practices, adverse drug
                                                    intends to take enforcement action                       manufacturer or distributor) began                     event reporting, labeling, or
                                                    against such products and those who                      marketing on or before September 19,                   misbranding requirements other than
                                                    manufacture them or cause them to be                     2011, FDA intends to take enforcement                  those identified in this notice or (2) it
                                                    manufactured or shipped in interstate                    action against any such product that is                appears that a firm, in response to this
                                                    commerce.                                                not listed with the Agency in full                     notice, increases its manufacture or
                                                       Manufacturing or shipping the drug                    compliance with section 510 of the                     interstate shipment of drug products
                                                    products covered by this notice can                      FD&C Act (21 U.S.C. 360) before July 1,                covered by this notice above its usual
                                                    result in enforcement action, including                  2015, and is manufactured, shipped, or                 volume during these periods.7
                                                    seizure, injunction, or other judicial or                otherwise introduced or delivered for                     Nothing in this notice, including
                                                    administrative proceeding.5 Consistent                   introduction into interstate commerce                  FDA’s intent to exercise its enforcement
                                                    with policies described in the Agency’s                  by any person on or after July 1, 2015.                discretion, alters any person’s liability
                                                    Marketed Unapproved Drugs CPG                            FDA also intends to take enforcement                   or obligations in any other enforcement
                                                    (available at http://www.fda.gov/                        action against any drug product covered                action, or precludes the Agency from
                                                    downloads/Drugs/GuidanceCompliance                       by this notice that is listed with FDA in              initiating or proceeding with
                                                    RegulatoryInformation/Guidances/                         full compliance with section 510 of the                enforcement action in connection with
                                                    UCM070290.pdf), the Agency does not                      FD&C Act but is not being commercially                 any other alleged violation of the FD&C
                                                    expect to issue a warning letter or any                  used or sold 6 in the United States before             Act, whether or not related to a drug
                                                    other further warning to firms marketing                 July 1, 2015, and that is manufactured,                product covered by this notice.
                                                    drug products covered by this notice                     shipped, or otherwise introduced or                    Similarly, a person who is or becomes
                                                    before taking enforcement action. The                    delivered for introduction into interstate             enjoined from marketing unapproved or
                                                    Agency also reminds firms that, as                       commerce by any person on or after July                misbranded drugs may not resume
                                                    stated in the Marketed Unapproved                        2, 2015.                                               marketing of such products based on
                                                    Drugs CPG, any unapproved drug                              However, for drug products covered                  FDA’s exercise of enforcement
                                                    marketed without a required approved                     by this notice that a company (including               discretion as described in this notice.
                                                    application is subject to Agency                         a manufacturer or distributor): (1) Began                 Drug manufacturers and distributors
                                                    enforcement action at any time. The                      marketing in the United States on or                   should be aware that the Agency is
                                                    issuance of this notice does not in any                  before September 19, 2011; (2) are listed              exercising its enforcement discretion as
                                                    way obligate the Agency to issue similar                 with FDA in full compliance with                       described previously only in regard to
                                                    notices (or any notice) in the future                    section 510 of the FD&C Act before July                drug products covered by this notice
                                                    regarding marketed unapproved drugs                      1, 2015 (‘‘currently marketed and                      that are marketed under a National Drug
                                                    (see Marketed Unapproved Drugs CPG                       listed’’); and (3) are manufactured,                   Code (NDC) number listed with the
                                                    at 5).                                                   shipped, or otherwise introduced or                    Agency in full compliance with section
                                                       As described in the Marketed                          delivered for introduction into interstate             510 of the FD&C Act before July 1, 2015.
                                                    Unapproved Drugs CPG, the Agency                                                                                As previously stated, drug products
                                                                                                             commerce by any person on or after July
                                                    may, at its discretion, identify a period                                                                       covered by this notice that are currently
                                                                                                             2, 2015, the Agency intends to exercise
                                                    of time (i.e., a grace period) during                                                                           marketed but not listed with the Agency
                                                                                                             its enforcement discretion as follows:
                                                    which the Agency does not intend to                                                                             on the date of this notice must, as of the
                                                                                                             FDA intends to initiate enforcement
                                                    initiate an enforcement action against a                                                                        effective date of this notice, have
                                                                                                             action regarding any such currently
                                                    currently marketed unapproved drug                                                                              approved applications before their
                                                                                                             marketed and listed product that is
                                                    solely on the grounds that the drug lacks                                                                       shipment in interstate commerce.
                                                                                                             manufactured on or after August 17,
                                                    an approved application under section                                                                           Moreover, any person or firm that has
                                                                                                             2015, or that is shipped on or after
                                                    505 of the FD&C Act. In deciding                                                                                submitted or submits an application but
                                                                                                             September 30, 2015. Furthermore, FDA
                                                    whether to allow such a grace period,                                                                           has yet to receive approval for such
                                                    the Agency considers several factors,                    intends to take enforcement action                     products is still responsible for full
                                                    which are described in the Marketed                      against any person who manufactures or                 compliance with this notice.
                                                    Unapproved Drugs CPG. With respect to                    ships such products after these dates.
                                                                                                             The purpose of these enforcement                       V. Discontinued Products
                                                    drug products covered by this notice,
                                                    the Agency intends to exercise its                       timeframes is to allow manufacturers                     Some firms may have previously
                                                    enforcement discretion for only a                        and distributors to deplete their current              discontinued manufacturing or
                                                    limited period of time, because there are                inventory and ensure a smooth                          distributing products covered by this
                                                    readily available legally marketed                       transition for consumers. Any person                   notice without discontinuing the listing
                                                    alternatives. Therefore, the Agency                      who has submitted or submits an                        as required under section 510(j) of the
                                                    intends to implement this notice as                      application for a drug product covered                 FD&C Act. Other firms may discontinue
                                                                                                             by this notice but has not received
asabaliauskas on DSK5VPTVN1PROD with NOTICES




                                                    follows.
                                                       For the effective date of this notice,                approval must comply with this notice.                   7 If FDA decides to take enforcement action


                                                    see the DATES section of this document.                     The Agency, however, does not                       against a product covered by this notice, the Agency
                                                                                                             intend to exercise its enforcement                     may simultaneously take action relating to
                                                                                                                                                                    defendant’s other violations of the FD&C Act. See,
                                                      5 In fact, U.S. Marshals seized $16.5 million of       discretion as outlined previously if                   e.g., United States v. Sage Pharmaceuticals, 210 F.
                                                    Auralgan Otic Solution (which contains antipyrine                                                               3d 475, 479–480 (5th Cir. 2000) (permitting the
                                                    and benzocaine) after Deston continued to market            6 For the purpose of this notice, the phrase        Agency to combine all violations of the FD&C Act
                                                    the unapproved new drug following an FDA                 ‘‘commercially used or sold’’ means that the           in one proceeding, rather than taking action against
                                                    warning letter. See http://www.fda.gov/NewsEvents/       product has been used in a business or activity        multiple violations of the FD&C Act in ‘‘piecemeal
                                                    Newsroom/PressAnnouncements/ucm243638.htm.               involving retail or wholesale marketing and/or sale.   fashion’’).



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                                                    38216                           Federal Register / Vol. 80, No. 127 / Thursday, July 2, 2015 / Notices

                                                    manufacturing or distributing listed                     2. Cortazzo, J. A. and A. D. Lichtman,                ForIndustry/UserFees/
                                                    products in response to this notice. All                      ‘‘Methemoglobinemia: A Review and                PrescriptionDrugUserFee/
                                                    firms are required to electronically                          Recommendations for Management.’’                ucm326192.htm. Individual comments
                                                    update the listing of their products                          Journal of Cardiothoracic and Vascular           may be viewed at http://
                                                                                                                  Anesthesia, vol. 28(4), pp. 1055–1059.
                                                    under section 510(j) of the FD&C Act to                       2014.
                                                                                                                                                                   www.regulations.gov/
                                                    reflect discontinuation of unapproved                    3. Lieberthal, A. S., A. E. Carroll, T.               #!documentDetail;D=FDA-2012-N-0967-
                                                    products covered by this notice (21 CFR                       Chonmaitree, et al., ‘‘The Diagnosis and         0595 or by visiting the Division of
                                                    207.21(b)). Questions on electronic drug                      Management of Acute Otitis Media,’’              Dockets Management (HFA–305), Food
                                                    listing updates should be sent to                             Pediatrics, vol. 131, pp. e964–e999,             and Drug Administration, 5630 Fishers
                                                    eDRLS@fda.hhs.gov. In addition to the                         2013.                                            Lane, Rm. 1061, Rockville, MD 20852,
                                                    required update, firms can also notify                   4. Wood, D. N., N. Naas, and C. W. Gregory,           between 9 a.m. and 4 p.m., Monday
                                                    the Agency of product discontinuation                         ‘‘Clinical Trials Assessing Ototopical           through Friday.
                                                    by sending a letter, signed by the firm’s                     Agents in the Treatment of Pain
                                                                                                                  Associated with Acute Otitis Media in            FOR FURTHER INFORMATION CONTACT:
                                                    chief executive officer and fully                                                                              Graham Thompson, Center for Drug
                                                                                                                  Children,’’ International Journal of
                                                    identifying the discontinued product(s),                      Otorhinolaryngology, vol. 76, pp. 1229–          Evaluation and Research, Food and
                                                    including the product NDC number(s),                          1335, 2012.                                      Drug Administration, 10903 New
                                                    and stating that the manufacturing and/                                                                        Hampshire Ave., Bldg. 51, Rm. 1146,
                                                    or distribution of the product(s) have                     Dated: June 26, 2015.
                                                                                                             Leslie Kux,
                                                                                                                                                                   Silver Spring, MD 20993, 301–796–
                                                    been discontinued. The letter should be                                                                        5003, FAX: 301–847–8443, email:
                                                    sent electronically to Kathleen Joyce                    Associate Commissioner for Policy.
                                                                                                                                                                   PatientFocused@fda.hhs.gov, or Stephen
                                                    (see ADDRESSES). FDA plans to rely on                    [FR Doc. 2015–16360 Filed 7–1–15; 8:45 am]
                                                                                                                                                                   Ripley, Center for Biologics Evaluation
                                                    its existing records, including its drug                 BILLING CODE 4164–01–P                                and Research, Food and Drug
                                                    listing records, the results of any                                                                            Administration, 10903 New Hampshire
                                                    subsequent inspections, or other                                                                               Ave., Bldg. 71, Rm. 7301, Silver Spring,
                                                    available information when considering                   DEPARTMENT OF HEALTH AND                              MD 20993, 240–402–7911.
                                                    enforcement action.                                      HUMAN SERVICES
                                                                                                                                                                   SUPPLEMENTARY INFORMATION:
                                                    VI. Reformulated Products                                Food and Drug Administration                          I. Background
                                                      FDA cautions firms against                             [Docket No. FDA–2012–N–0967]
                                                    reformulating their products into                                                                                 On July 9, 2012, the President signed
                                                    unapproved new drugs without                                                                                   into law the Food and Drug
                                                                                                             Prescription Drug User Fee Act
                                                    benzocaine; benzocaine and antipyrine;                                                                         Administration Safety and Innovation
                                                                                                             Patient-Focused Drug Development;
                                                    benzocaine, antipyrine, and zinc                                                                               Act (FDASIA) (Pub. L. 112–144). Title I
                                                                                                             Announcement of Disease Areas for
                                                    acetate; benzocaine, chloroxylenol, and                                                                        of FDASIA reauthorizes the Prescription
                                                                                                             Meetings Conducted in Fiscal Years
                                                    hydrocortisone; chloroxylenol and                                                                              Drug User Fee Act (PDUFA), which
                                                                                                             2016–2017
                                                    pramoxine; or chloroxylenol,                                                                                   provides FDA with the necessary user
                                                    pramoxine, and hydrocortisone and                        AGENCY:    Food and Drug Administration,              fee resources to maintain an efficient
                                                    marketing them under the same name or                    HHS.                                                  review process for human drug and
                                                    substantially the same name (including                   ACTION:   Notice of availability.                     biologic products. The reauthorization
                                                    a new name that contains the old name)                                                                         of PDUFA includes performance goals
                                                    in anticipation of an enforcement action                 SUMMARY:    The Food and Drug                         and procedures that represent FDA’s
                                                    based on this notice. As stated in the                   Administration (FDA or Agency) is                     commitments during FYs 2013–2017.
                                                    Marketed Unapproved Drugs CPG, FDA                       announcing the selection of disease                   These commitments are referred to in
                                                    intends to give higher priority to                       areas to be addressed during fiscal years             section 101 of FDASIA and are available
                                                    enforcement actions involving                            (FYs) 2016–2017of its Patient-Focused                 on the FDA Web site at http://
                                                    unapproved drugs that are reformulated                   Drug Development Initiative. This                     www.fda.gov/downloads/ForIndustry/
                                                    to evade an anticipated FDA                              initiative is being conducted to fulfill              UserFees/PrescriptionDrugUserFee/
                                                    enforcement action but have not been                     FDA’s performance commitments under                   UCM270412.pdf.
                                                    brought into compliance with the law.                    the fifth authorization of the                           Section X of these commitments
                                                    In addition, reformulated products                       Prescription Drug User Fee Act (PDUFA                 relates to enhancing benefit-risk
                                                    marketed under a name previously                         V). This effort provides a more                       assessments in regulatory decision
                                                    identified with a different active                       systematic approach under PDUFA V                     making. A key part of regulatory
                                                    ingredient have the potential to confuse                 for obtaining the patients’ perspective               decision making is establishing the
                                                    healthcare practitioners and harm                        on disease severity and currently                     context in which the particular decision
                                                    patients.                                                available treatments for a set of disease             is made. For purposes of drug marketing
                                                                                                             areas. FDA selected these disease areas               approval, this includes an
                                                    VIII. References                                         based on a careful consideration of the               understanding of the severity of the
                                                      The following references have been                     public comments received after                        treated condition and the adequacy of
                                                    placed on display in the Division of                     publication of a preliminary list of                  the available therapies. Patients who
                                                    Dockets Management (see ADDRESSES)                       disease areas in the Federal Register on              live with a disease have a direct stake
                                                    and may be seen by interested persons                    October 8, 2014.                                      in the outcome of FDA’s decisions and
asabaliauskas on DSK5VPTVN1PROD with NOTICES




                                                    between 9 a.m. and 4 p.m., Monday                        ADDRESSES: The general schedule of FYs                are in a unique position to contribute to
                                                    through Friday, and are available                        2016–2017 Patient-Focused Drug                        the Agency’s understanding of their
                                                    electronically at http://                                Development meetings, along with                      disease.
                                                    www.regulations.gov.                                     materials from past meetings (such as                    FDA has committed to obtaining the
                                                    1. Logan, B. K. and A.M. Gordon, ‘‘Case                  transcripts and webcast recordings)                   patient perspective on at least 20
                                                         Report: Death of an Infant Involving                from past meetings, can be found at the               disease areas during the course of
                                                         Benzocaine,’’ Journal of Forensic                   Web site for Patient-Focused Drug                     PDUFA V. For each disease area, the
                                                         Sciences, vol. 50, pp. 1486–1488, 2005.             Development, http://www.fda.gov/                      Agency will conduct a public meeting to


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Document Created: 2015-12-15 13:16:16
Document Modified: 2015-12-15 13:16:16
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionNotices
ActionNotice.
DatesThis notice is effective July 2, 2015. For information about enforcement dates, see SUPPLEMENTARY INFORMATION, section IV.
ContactKathleen 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]
FR Citation80 FR 38212 

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