Sodium Nitrite Injection and Sodium Thiosulfate Injection Drug Products Labeled for the Treatment of Cyanide Poisoning; Enforcement Action Dates, 71006-71008 [2012-28773]
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Federal Register / Vol. 77, No. 229 / Wednesday, November 28, 2012 / Notices
FOR FURTHER INFORMATION CONTACT:
Daniel Gittleson, Office of Information
Management, Food and Drug
Administration, 1350 Piccard Dr., PI50–
400B, Rockville, MD 20850, 301–796–
5156, Daniel.Gittleson@fda.hhs.gov.
SUPPLEMENTARY INFORMATION: On August
9, 2012, the Agency submitted a
proposed collection of information
entitled ‘‘Registration and Product
Listing for Owners and Operators of
Domestic Tobacco Product
Establishments and Listing of
Ingredients in Tobacco Products’’ to
OMB for review and clearance under 44
U.S.C. 3507. An Agency may not
conduct or sponsor, and a person is not
required to respond to, a collection of
information unless it displays a
currently valid OMB control number.
OMB has now approved the information
collection and has assigned OMB
control number 0910–0650. The
approval expires on October 31, 2015. A
copy of the supporting statement for this
information collection is available on
the Internet at https://www.reginfo.gov/
public/do/PRAMain.
Dated: November 21, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012–28774 Filed 11–27–12; 8:45 am]
BILLING CODE 4160–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2012–N–1134
Sodium Nitrite Injection and Sodium
Thiosulfate Injection Drug Products
Labeled for the Treatment of Cyanide
Poisoning; Enforcement Action Dates
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA) is announcing its
intention to take enforcement action
against unapproved injectable drug
products containing sodium nitrite
labeled for the treatment of cyanide
poisoning and unapproved injectable
drug products containing sodium
thiosulfate labeled for the treatment of
cyanide poisoning, and persons who
manufacture or cause the manufacture
or distribution of such products in
interstate commerce. Cyanide antidotes
carry serious risks and some
unapproved drug products may lack
Boxed Warnings and other warnings
required in the labeling of approved
cyanide antidotes. These unapproved
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SUMMARY:
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drug products compete with approved
products, and thus pose a direct
challenge to the drug approval system.
Injectable drug products containing
sodium nitrite or sodium thiosulfate
that are labeled for the treatment of
cyanide poisoning are new drugs that
require approved new drug applications
(NDAs) or abbreviated new drug
applications (ANDAs) in order to be
legally marketed.
DATES: This notice is effective
November 28, 2012. For information
about enforcement dates, see
SUPPLEMENTARY INFORMATION, section IV.
ADDRESSES: All communications in
response to this notice should be
identified with Docket No. FDA–2012–
N–1134 and directed to the appropriate
office listed in this document.
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, 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 (21 U.S.C. 355(j)): Office
of Generic Drugs, Center for Drug
Evaluation and Research, Food and
Drug Administration, 7519 Standish Pl.,
Rockville, MD 20855.
All other communications: Lori
Cantin, Office of Unapproved Drugs and
Labeling Compliance, Division of
Prescription Drugs, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5239,
Silver Spring, MD 20993–0002.
FOR FURTHER INFORMATION CONTACT: Lori
Cantin, Center for Drug Evaluation and
Research, Food and Drug
Administration, 10903 New Hampshire
Ave., Bldg. 51, Rm. 5239, Silver Spring,
MD 20993–0002, 301–796–1212, email:
lori.cantin@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
Cyanide is highly toxic in humans
and can be fatal if not immediately
treated with an effective antidote. On
January 14, 2011, FDA approved NDA
201444 for Nithiodote, a co-packaged
Sodium Nitrite Injection and Sodium
Thiosulfate Injection drug product,
labeled for treatment of acute cyanide
poisoning that is judged to be lifethreatening. On February 14, 2012, FDA
approved NDA 203922 for Sodium
Nitrite Injection for sequential use with
sodium thiosulfate for treatment of
acute cyanide poisoning that is judged
PO 00000
Frm 00016
Fmt 4703
Sfmt 4703
to be life-threatening, and NDA 203923
for Sodium Thiosulfate Injection for
sequential use with sodium nitrite for
treatment of acute cyanide poisoning
that is judged to be life-threatening.
Sodium thiosulfate and sodium nitrite
pose the risk of hypotension (low blood
pressure), and sodium nitrite also poses
the risk of methemoglobinemia, a
disorder characterized by the presence
of a higher than normal level of
methemoglobin in the blood.
Methemoglobin is an oxidized form of
hemoglobin that has a decreased affinity
for oxygen, resulting in a reduced ability
to release oxygen to body tissue.
Methemoglobinemia can lead to
neurological and cardiac symptoms due
to lack of adequate oxygen in body
tissues. The approved Sodium Nitrite
Injection and Nithiodote carry Boxed
Warnings for these serious adverse
reactions.
FDA is aware of several unapproved
drug products containing sodium nitrite
or sodium thiosulfate labeled to treat
cyanide poisoning. These unapproved
drug products containing sodium nitrite
or sodium thiosulfate are sold
individually, as well as in cyanide
antidote kits. Unapproved cyanide
antidote kits may also contain other
unapproved drugs (e.g., amyl nitrite) or
medical products (e.g., syringes) that are
intended for potential use with sodium
nitrite and sodium thiosulfate. This
notice is issued under sections 502 (21
U.S.C. 352) and 505 of the FD&C Act
and applies to unapproved injectable
drug products containing sodium nitrite
or sodium thiosulfate labeled to treat
cyanide poisoning that are currently
being manufactured or distributed.
II. Safety Concerns With Unapproved
New Drugs
Because marketed unapproved new
drug products have not been through
FDA’s approval process, there are safety
risks associated with them. Some
unapproved drug product labeling omits
safety warnings, such as the Boxed
Warnings required on Sodium Nitrite
Injection and Nithiodote, which are
important for safe use of the drug
products. Without these warnings, the
unapproved drug products may be used
in inappropriate circumstances or
without appropriate monitoring, posing
an increased risk to public health.
Patients being treated for cyanide
poisoning require close monitoring and
may require repeat doses of antidote,
supplemental oxygen, and ventilatory
support. Cyanide antidotes containing
sodium nitrite or amyl nitrite may
induce methemoglobinemia, which may
require additional treatment.
E:\FR\FM\28NON1.SGM
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Federal Register / Vol. 77, No. 229 / Wednesday, November 28, 2012 / Notices
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The expected risks associated with
use of sodium nitrite or sodium
thiosulfate drug products are also
potentially greater for unapproved drug
products because the quality, safety, and
efficacy of unapproved formulations
have not been demonstrated to FDA. For
example, information on the ingredients
and data on the bioavailability of
unapproved drug products have not
been submitted for FDA review, nor has
FDA had the opportunity to assess the
adequacy of their chemistry,
manufacturing, and control
specifications. Also, unapproved drug
products have unapproved labeling that
may not contain appropriate dosing
information. For example, the sodium
thiosulfate component of Nithiodote is
dosed for children based on body
weight or body surface area, whereas
FDA is aware of unapproved sodium
thiosulfate products labeled for use in
children at a lower dose based only on
body surface area. Such discrepancies in
dosing may lead to underdosing of
sodium thiosulfate in children.
III. Legal Status of Products Identified
in This Notice
FDA has reviewed the publicly
available scientific literature for
unapproved injectable sodium nitrite
and sodium thiosulfate products labeled
for treatment of cyanide poisoning. In
no case did FDA find literature
sufficient to support a determination
that any of these drug products are
generally recognized as safe and
effective. Therefore, these 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 NDAs or ANDAs in order to
be legally marketed.
Also, 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 their toxicity or
other potentiality for harmful effect, are
not safe to use except under the
supervision of a practitioner licensed by
law to administer such drugs. Because
any drug product covered by this notice
meets the definition of ‘‘prescription
drug’’ in 503(b)(1)(A), 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 in that
it fails to bear adequate directions for
use. An approved prescription drug is
exempt from the requirement in section
502(f)(1) that it bear adequate direction
for use if, among other things, it bears
the NDA-approved labeling (21 CFR
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201.100(c)(2) and 21 CFR 201.115).
Because the unapproved 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 they are misbranded under
section 502(f)(1).
IV. Notice of Intent To Take
Enforcement Action
Although not required to do so by the
Administrative Procedure Act, the
FD&C Act (or any rules issued under its
authority), or for any other legal reason,
FDA is providing this notice to persons 1
who are marketing unapproved and
misbranded drug products containing
sodium nitrite and sodium thiosulfate
labeled to treat cyanide poisoning,
either sold individually or as part of a
kit. 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. In
the event that unapproved sodium
nitrite and sodium thiosulfate are
packaged in a kit with other unapproved
drugs (e.g., amyl nitrite) or medical
products (e.g., syringes) and labeled for
treatment of cyanide poisoning, FDA
intends to take action against the entire
kit based on the unapproved sodium
thiosulfate and sodium nitrite
components.
Manufacturing or shipping the drug
products covered by this notice can
result in enforcement action, including
seizure, injunction, or other judicial or
administrative proceeding. Consistent
with policies described in the Agency’s
guidance entitled ‘‘Marketed
Unapproved Drugs—Compliance Policy
Guide’’ (the Marketed Unapproved
Drugs CPG) (https://www.fda.gov/down
loads/Drugs/GuidanceCompliance
RegulatoryInformation/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.
As described in the Marketed
1 The
term person includes individuals,
partnerships, corporations, and associations (21
U.S.C. 321(e)).
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Fmt 4703
Sfmt 4703
71007
Unapproved Drugs CPG, the Agency
may, at its discretion, identify a period
of time during which the Agency does
not intend to initiate an enforcement
action against a currently marketed
unapproved drug solely on the grounds
that it lacks an approved application
under section 505 of the FD&C Act.
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 safety risks with respect to the
products covered by this notice, and
there are FDA-approved drug products
to meet patient needs. 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 in the United States 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 November 27, 2012, and is
manufactured, shipped, or otherwise
introduced or delivered for introduction
into interstate commerce by any person
on or after November 27, 2012. 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 2 in the United States before
November 27, 2012 and that is
manufactured, shipped, or otherwise
introduced or delivered for introduction
into interstate commerce by any person
on or after November 28, 2012.
However, for drug products covered
by this notice that a company (including
a manufacturer or distributor) began
marketing in the United States on or
before September 19, 2011, are listed
with FDA in full compliance with
section 510 of the FD&C Act before
November 27, 2012 (‘‘currently
marketed and listed’’), and are
manufactured, shipped, or otherwise
introduced or delivered for introduction
into interstate commerce by any person
on or after November 28, 2012 the
Agency intends to exercise its
2 For purposes 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.
E:\FR\FM\28NON1.SGM
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71008
Federal Register / Vol. 77, No. 229 / Wednesday, November 28, 2012 / Notices
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enforcement discretion as follows: FDA
intends to initiate enforcement action
against any such currently marketed and
listed product that is manufactured on
or after February 26, 2013, or that is
shipped on or after May 28, 2013.
Further, FDA intends to take
enforcement action against any person
who manufactures or ships such
products after these dates. 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 the
following apply: (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 practice,
adverse 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.3
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 number listed with the Agency in
full compliance with section 510 of the
3 If FDA finds it necessary to take enforcement
action against a product covered by this notice, the
Agency may take action relating to all of the
defendant’s other violations of the FD&C Act at the
same time. For example, if a firm continues to
manufacture or market a product covered by this
notice after the applicable enforcement date has
passed, to preserve limited Agency resources, FDA
may take enforcement action relating to all of the
firm’s unapproved drugs that require applications at
the same time (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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FD&C Act before November 27, 2012. 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 the manufacturing or
distribution of products covered by this
notice without removing them from the
listing of their products under section
510(j) of the FD&C Act. Other firms may
discontinue manufacturing or
distributing listed products in response
to this notice. Firms that wish to notify
the Agency of product discontinuation
should send a letter, signed by the firm’s
chief executive officer, fully identifying
the discontinued product(s), including
NDC number(s), and stating that the
manufacturing and/or distribution of the
products has (have) been discontinued.
The letter should be sent electronically
to Lori Cantin (see ADDRESSES). Firms
should also electronically update the
listing of their products under section
510(j) of the FD&C Act to reflect
discontinuation of products covered by
this notice. Questions on electronic drug
listing updates should be sent to:
eDRLS@fda.hhs.gov. FDA plans to rely
on its existing records, including its
drug listing records, the results of any
subsequent inspections, or other
available information, when it targets
violations for enforcement action.
Dated: November 20, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012–28773 Filed 11–27–12; 8:45 am]
BILLING CODE 4160–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2012–D–0276]
Guidance for Industry: Enforcement
Policy Concerning Rotational Warning
Plans for Smokeless Tobacco
Products; Withdrawal of Guidance
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice; withdrawal.
The Food and Drug
Administration (FDA) is announcing the
SUMMARY:
PO 00000
Frm 00018
Fmt 4703
Sfmt 4703
withdrawal of a guidance entitled
‘‘Enforcement Policy Concerning
Rotational Warning Plans for Smokeless
Tobacco Products,’’ that was announced
in the Federal Register on June 8, 2010.
DATES: The withdrawal is effective
November 28, 2012.
FOR FURTHER INFORMATION CONTACT: Ele
Ibarra-Pratt, Center for Tobacco
Products, Office of Compliance and
Enforcement, Food and Drug
Administration, 9200 Corporate Blvd.,
Rockville, MD 20850–3229, 1–877–287–
1373, CTPCompliance@fda.hhs.gov.
SUPPLEMENTARY INFORMATION: On June
22, 2009, the President signed the
Family Smoking Prevention and
Tobacco Control Act (Pub. L. 111–31)
(Tobacco Control Act) into law. Section
204 of the Tobacco Control Act
amended section 3 of the
Comprehensive Smokeless Tobacco
Health Education Act of 1986
(Smokeless Tobacco Act), 15 U.S.C.
4402, to prescribe revised requirements
for health warning statements that must
appear on smokeless tobacco product
packages and advertisements, and to
require the submission of warning plans
for smokeless tobacco product packages
and advertisements to FDA for review
and approval, rather than to the Federal
Trade Commission (FTC). Section
3(b)(3) of the Smokeless Tobacco Act
requires the equal distribution and
display of warning statements on
packaging, and the quarterly rotation of
warning statements in advertising, for
each brand of smokeless tobacco
product ‘‘in accordance with a plan
submitted by the tobacco product
manufacturer, importer, distributor, or
retailer’’ to, and approved by, FDA.
These requirements took effect on June
22, 2010.
In a notice published in the Federal
Register of June 8, 2010 (75 FR 32481),
FDA announced the availability of a
guidance entitled ‘‘Enforcement Policy
Concerning Rotational Warning Plans
for Smokeless Tobacco Products.’’ This
guidance provided information to
industry and the public, including that
‘‘[a]t this time, as an exercise of
enforcement discretion, FDA does not
intend to commence or recommend
enforcement of the requirement that a
smokeless tobacco manufacturer,
distributor, importer, or retailer must
have an FDA-approved rotational
warning plan, so long as a rotational
warning plan has been submitted to
FDA by July 22, 2010.’’ FDA believed
that allowing additional time for the
review of warning plans would permit
an orderly transition of regulatory
authority from the FTC to FDA to
review and approve warning plans.
E:\FR\FM\28NON1.SGM
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]]>Agencies
[Federal Register Volume 77, Number 229 (Wednesday, November 28, 2012)]
[Notices]
[Pages 71006-71008]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-28773]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2012-N-1134
Sodium Nitrite Injection and Sodium Thiosulfate Injection Drug
Products Labeled for the Treatment of Cyanide Poisoning; Enforcement
Action Dates
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing its
intention to take enforcement action against unapproved injectable drug
products containing sodium nitrite labeled for the treatment of cyanide
poisoning and unapproved injectable drug products containing sodium
thiosulfate labeled for the treatment of cyanide poisoning, and persons
who manufacture or cause the manufacture or distribution of such
products in interstate commerce. Cyanide antidotes carry serious risks
and some unapproved drug products may lack Boxed Warnings and other
warnings required in the labeling of approved cyanide antidotes. These
unapproved drug products compete with approved products, and thus pose
a direct challenge to the drug approval system. Injectable drug
products containing sodium nitrite or sodium thiosulfate that are
labeled for the treatment of cyanide poisoning are new drugs that
require approved new drug applications (NDAs) or abbreviated new drug
applications (ANDAs) in order to be legally marketed.
DATES: This notice is effective November 28, 2012. For information
about enforcement dates, see SUPPLEMENTARY INFORMATION, section IV.
ADDRESSES: All communications in response to this notice should be
identified with Docket No. FDA-2012-N-1134 and directed to the
appropriate office listed in this document.
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, 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 (21 U.S.C.
355(j)): Office of Generic Drugs, Center for Drug Evaluation and
Research, Food and Drug Administration, 7519 Standish Pl., Rockville,
MD 20855.
All other communications: Lori Cantin, Office of Unapproved Drugs
and Labeling Compliance, Division of Prescription Drugs, Center for
Drug Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5239, Silver Spring, MD 20993-0002.
FOR FURTHER INFORMATION CONTACT: Lori Cantin, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5239, Silver Spring, MD 20993-0002, 301-
796-1212, email: lori.cantin@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
Cyanide is highly toxic in humans and can be fatal if not
immediately treated with an effective antidote. On January 14, 2011,
FDA approved NDA 201444 for Nithiodote, a co-packaged Sodium Nitrite
Injection and Sodium Thiosulfate Injection drug product, labeled for
treatment of acute cyanide poisoning that is judged to be life-
threatening. On February 14, 2012, FDA approved NDA 203922 for Sodium
Nitrite Injection for sequential use with sodium thiosulfate for
treatment of acute cyanide poisoning that is judged to be life-
threatening, and NDA 203923 for Sodium Thiosulfate Injection for
sequential use with sodium nitrite for treatment of acute cyanide
poisoning that is judged to be life-threatening. Sodium thiosulfate and
sodium nitrite pose the risk of hypotension (low blood pressure), and
sodium nitrite also poses the risk of methemoglobinemia, a disorder
characterized by the presence of a higher than normal level of
methemoglobin in the blood. Methemoglobin is an oxidized form of
hemoglobin that has a decreased affinity for oxygen, resulting in a
reduced ability to release oxygen to body tissue. Methemoglobinemia can
lead to neurological and cardiac symptoms due to lack of adequate
oxygen in body tissues. The approved Sodium Nitrite Injection and
Nithiodote carry Boxed Warnings for these serious adverse reactions.
FDA is aware of several unapproved drug products containing sodium
nitrite or sodium thiosulfate labeled to treat cyanide poisoning. These
unapproved drug products containing sodium nitrite or sodium
thiosulfate are sold individually, as well as in cyanide antidote kits.
Unapproved cyanide antidote kits may also contain other unapproved
drugs (e.g., amyl nitrite) or medical products (e.g., syringes) that
are intended for potential use with sodium nitrite and sodium
thiosulfate. This notice is issued under sections 502 (21 U.S.C. 352)
and 505 of the FD&C Act and applies to unapproved injectable drug
products containing sodium nitrite or sodium thiosulfate labeled to
treat cyanide poisoning that are currently being manufactured or
distributed.
II. Safety Concerns With Unapproved New Drugs
Because marketed unapproved new drug products have not been through
FDA's approval process, there are safety risks associated with them.
Some unapproved drug product labeling omits safety warnings, such as
the Boxed Warnings required on Sodium Nitrite Injection and Nithiodote,
which are important for safe use of the drug products. Without these
warnings, the unapproved drug products may be used in inappropriate
circumstances or without appropriate monitoring, posing an increased
risk to public health. Patients being treated for cyanide poisoning
require close monitoring and may require repeat doses of antidote,
supplemental oxygen, and ventilatory support. Cyanide antidotes
containing sodium nitrite or amyl nitrite may induce methemoglobinemia,
which may require additional treatment.
[[Page 71007]]
The expected risks associated with use of sodium nitrite or sodium
thiosulfate drug products are also potentially greater for unapproved
drug products because the quality, safety, and efficacy of unapproved
formulations have not been demonstrated to FDA. For example,
information on the ingredients and data on the bioavailability of
unapproved drug products have not been submitted for FDA review, nor
has FDA had the opportunity to assess the adequacy of their chemistry,
manufacturing, and control specifications. Also, unapproved drug
products have unapproved labeling that may not contain appropriate
dosing information. For example, the sodium thiosulfate component of
Nithiodote is dosed for children based on body weight or body surface
area, whereas FDA is aware of unapproved sodium thiosulfate products
labeled for use in children at a lower dose based only on body surface
area. Such discrepancies in dosing may lead to underdosing of sodium
thiosulfate in children.
III. Legal Status of Products Identified in This Notice
FDA has reviewed the publicly available scientific literature for
unapproved injectable sodium nitrite and sodium thiosulfate products
labeled for treatment of cyanide poisoning. In no case did FDA find
literature sufficient to support a determination that any of these drug
products are generally recognized as safe and effective. Therefore,
these 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 NDAs or
ANDAs in order to be legally marketed.
Also, 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 their toxicity or other potentiality for harmful
effect, are not safe to use except under the supervision of a
practitioner licensed by law to administer such drugs. Because any drug
product covered by this notice meets the definition of ``prescription
drug'' in 503(b)(1)(A), 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 in that it fails to bear adequate directions for use. An
approved prescription drug is exempt from the requirement in section
502(f)(1) that it bear adequate direction for use if, among other
things, it bears the NDA-approved labeling (21 CFR 201.100(c)(2) and 21
CFR 201.115). Because the unapproved 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 they are misbranded
under section 502(f)(1).
IV. Notice of Intent To Take Enforcement Action
Although not required to do so by the Administrative Procedure Act,
the FD&C Act (or any rules issued under its authority), or for any
other legal reason, FDA is providing this notice to persons \1\ who are
marketing unapproved and misbranded drug products containing sodium
nitrite and sodium thiosulfate labeled to treat cyanide poisoning,
either sold individually or as part of a kit. 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. In the event that unapproved sodium nitrite and sodium
thiosulfate are packaged in a kit with other unapproved drugs (e.g.,
amyl nitrite) or medical products (e.g., syringes) and labeled for
treatment of cyanide poisoning, FDA intends to take action against the
entire kit based on the unapproved sodium thiosulfate and sodium
nitrite components.
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\1\ 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. Consistent with policies
described in the Agency's guidance entitled ``Marketed Unapproved
Drugs--Compliance Policy Guide'' (the Marketed Unapproved Drugs CPG)
(https://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. As described in the
Marketed Unapproved Drugs CPG, the Agency may, at its discretion,
identify a period of time during which the Agency does not intend to
initiate an enforcement action against a currently marketed unapproved
drug solely on the grounds that it lacks an approved application under
section 505 of the FD&C Act. 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 safety risks with
respect to the products covered by this notice, and there are FDA-
approved drug products to meet patient needs. 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 in the United States 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
November 27, 2012, and is manufactured, shipped, or otherwise
introduced or delivered for introduction into interstate commerce by
any person on or after November 27, 2012. 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 \2\ in the United States
before November 27, 2012 and that is manufactured, shipped, or
otherwise introduced or delivered for introduction into interstate
commerce by any person on or after November 28, 2012.
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\2\ For purposes 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) began marketing in the United
States on or before September 19, 2011, are listed with FDA in full
compliance with section 510 of the FD&C Act before November 27, 2012
(``currently marketed and listed''), and are manufactured, shipped, or
otherwise introduced or delivered for introduction into interstate
commerce by any person on or after November 28, 2012 the Agency intends
to exercise its
[[Page 71008]]
enforcement discretion as follows: FDA intends to initiate enforcement
action against any such currently marketed and listed product that is
manufactured on or after February 26, 2013, or that is shipped on or
after May 28, 2013. Further, FDA intends to take enforcement action
against any person who manufactures or ships such products after these
dates. 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 the following apply: (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 practice,
adverse 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.\3\
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\3\ If FDA finds it necessary to take enforcement action against
a product covered by this notice, the Agency may take action
relating to all of the defendant's other violations of the FD&C Act
at the same time. For example, if a firm continues to manufacture or
market a product covered by this notice after the applicable
enforcement date has passed, to preserve limited Agency resources,
FDA may take enforcement action relating to all of the firm's
unapproved drugs that require applications at the same time (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 number listed with the Agency in full
compliance with section 510 of the FD&C Act before November 27, 2012.
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 the manufacturing or
distribution of products covered by this notice without removing them
from the listing of their products under section 510(j) of the FD&C
Act. Other firms may discontinue manufacturing or distributing listed
products in response to this notice. Firms that wish to notify the
Agency of product discontinuation should send a letter, signed by the
firm's chief executive officer, fully identifying the discontinued
product(s), including NDC number(s), and stating that the manufacturing
and/or distribution of the products has (have) been discontinued. The
letter should be sent electronically to Lori Cantin (see ADDRESSES).
Firms should also electronically update the listing of their products
under section 510(j) of the FD&C Act to reflect discontinuation of
products covered by this notice. Questions on electronic drug listing
updates should be sent to: eDRLS@fda.hhs.gov. FDA plans to rely on its
existing records, including its drug listing records, the results of
any subsequent inspections, or other available information, when it
targets violations for enforcement action.
Dated: November 20, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-28773 Filed 11-27-12; 8:45 am]
BILLING CODE 4160-01-P
