[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]


-----------------------------------------------------------------------

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: [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.
---------------------------------------------------------------------------

    \1\ The term person includes individuals, partnerships, 
corporations, and associations (21 U.S.C. 321(e)).
---------------------------------------------------------------------------

    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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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\
---------------------------------------------------------------------------

    \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'')).
---------------------------------------------------------------------------

    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