[Federal Register Volume 77, Number 229 (Wednesday, November 28, 2012)]
[Notices]
[Pages 71006-71008]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-28773]
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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.
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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: [email protected].
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)
(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. 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: [email protected]. 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