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71006 Federal Register / Vol. 77, No. 229 / Wednesday, November 28, 2012 / Notices

FOR FURTHER INFORMATION CONTACT: drug products compete with approved to be life-threatening, and NDA 203923 Daniel Gittleson, Office of Information products, and thus pose a direct for Injection for Management, and Drug challenge to the drug approval system. sequential use with sodium for Administration, 1350 Piccard Dr., PI50– Injectable drug products containing treatment of acute poisoning 400B, Rockville, MD 20850, 301–796– or that is judged to be life-threatening. 5156, [email protected]. that are labeled for the treatment of Sodium thiosulfate and sodium nitrite SUPPLEMENTARY INFORMATION: On August are new drugs that pose the risk of hypotension (low blood 9, 2012, the Agency submitted a require approved new drug applications pressure), and sodium nitrite also poses proposed collection of information (NDAs) or abbreviated new drug the risk of , a entitled ‘‘Registration and Product applications (ANDAs) in order to be disorder characterized by the presence Listing for Owners and Operators of legally marketed. of a higher than normal level of Domestic Tobacco Product DATES: This notice is effective methemoglobin in the blood. Establishments and Listing of November 28, 2012. For information Methemoglobin is an oxidized form of Ingredients in Tobacco Products’’ to about enforcement dates, see hemoglobin that has a decreased affinity OMB for review and clearance under 44 SUPPLEMENTARY INFORMATION, section IV. for oxygen, resulting in a reduced ability U.S.C. 3507. An Agency may not ADDRESSES: All communications in to release oxygen to body tissue. conduct or sponsor, and a person is not response to this notice should be Methemoglobinemia can to required to respond to, a collection of identified with Docket No. FDA–2012– neurological and cardiac symptoms due information unless it displays a N–1134 and directed to the appropriate to lack of adequate oxygen in body currently valid OMB control number. office listed in this document. tissues. The approved Sodium Nitrite OMB has now approved the information Applications under section 505(b) of Injection and Nithiodote carry Boxed collection and has assigned OMB the Federal Food, Drug, and Cosmetic Warnings for these serious adverse control number 0910–0650. The Act (the FD&C Act) (21 U.S.C. 355(b)): reactions. approval expires on October 31, 2015. A Division of Anesthesia, Analgesia, and FDA is aware of several unapproved copy of the supporting statement for this Addiction Products, Office of New drug products containing sodium nitrite information collection is available on Drugs, Center for Drug Evaluation and or sodium thiosulfate labeled to treat the Internet at http://www.reginfo.gov/ Research, Food and Drug cyanide poisoning. These unapproved public/do/PRAMain. Administration, 10903 New Hampshire drug products containing sodium nitrite Dated: November 21, 2012. Ave., Bldg. 22, Spring, MD or sodium thiosulfate are sold Leslie Kux, 20993–0002. individually, as well as in cyanide Applications under section 505(j) of kits. Unapproved cyanide Assistant Commissioner for Policy. the FD&C Act (21 U.S.C. 355(j)): Office antidote kits may also contain other [FR Doc. 2012–28774 Filed 11–27–12; 8:45 am] of Generic Drugs, Center for Drug unapproved drugs (e.g., ) or BILLING CODE 4160–01–P Evaluation and Research, Food and medical products (e.g., syringes) that are Drug Administration, 7519 Standish Pl., intended for potential use with sodium Rockville, MD 20855. nitrite and sodium thiosulfate. This DEPARTMENT OF HEALTH AND All other communications: Lori notice is issued under sections 502 (21 HUMAN SERVICES Cantin, Office of Unapproved Drugs and U.S.C. 352) and 505 of the FD&C Act Food and Drug Administration Labeling Compliance, Division of and applies to unapproved injectable Prescription Drugs, Center for Drug drug products containing sodium nitrite [Docket No. FDA–2012–N–1134 Evaluation and Research, Food and or sodium thiosulfate labeled to treat Drug Administration, 10903 New cyanide poisoning that are currently Sodium Nitrite Injection and Sodium Hampshire Ave., Bldg. 51, Rm. 5239, being manufactured or distributed. Thiosulfate Injection Drug Products Silver Spring, MD 20993–0002. Labeled for the Treatment of Cyanide II. Safety Concerns With Unapproved FOR FURTHER INFORMATION CONTACT: Lori Poisoning; Enforcement Action Dates New Drugs Cantin, Center for Drug Evaluation and AGENCY: Food and Drug Administration, Research, Food and Drug Because marketed unapproved new HHS. Administration, 10903 New Hampshire drug products have not been through ACTION: Notice. Ave., Bldg. 51, Rm. 5239, Silver Spring, FDA’s approval process, there are safety MD 20993–0002, 301–796–1212, email: risks associated with them. Some SUMMARY: The Food and Drug [email protected]. unapproved drug product labeling omits Administration (FDA) is announcing its SUPPLEMENTARY INFORMATION: safety warnings, such as the Boxed intention to take enforcement action Warnings required on Sodium Nitrite against unapproved injectable drug I. Background Injection and Nithiodote, which are products containing sodium nitrite Cyanide is highly toxic in humans important for safe use of the drug labeled for the treatment of cyanide and can be fatal if not immediately products. Without these warnings, the poisoning and unapproved injectable treated with an effective antidote. On unapproved drug products may be used drug products containing sodium January 14, 2011, FDA approved NDA in inappropriate circumstances or thiosulfate labeled for the treatment of 201444 for Nithiodote, a co-packaged without appropriate monitoring, posing cyanide poisoning, and persons who Sodium Nitrite Injection and Sodium an increased risk to public health. manufacture or cause the manufacture Thiosulfate Injection drug product, Patients being treated for cyanide or distribution of such products in labeled for treatment of acute cyanide poisoning require close monitoring and interstate commerce. Cyanide poisoning that is judged to be life- may require repeat doses of antidote, carry serious risks and some threatening. On February 14, 2012, FDA supplemental oxygen, and ventilatory unapproved drug products may lack approved NDA 203922 for Sodium support. Cyanide antidotes containing Boxed Warnings and other warnings Nitrite Injection for sequential use with sodium nitrite or amyl nitrite may required in the labeling of approved sodium thiosulfate for treatment of induce methemoglobinemia, which may cyanide antidotes. These unapproved acute cyanide poisoning that is judged require additional treatment.

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The expected risks associated with 201.100(c)(2) and 21 CFR 201.115). Unapproved Drugs CPG, the Agency use of sodium nitrite or sodium Because the unapproved prescription may, at its discretion, identify a period thiosulfate drug products are also drug products subject to this notice do of time during which the Agency does potentially greater for unapproved drug not have approved applications with not intend to initiate an enforcement products because the quality, safety, and approved labeling, they fail to qualify action against a currently marketed efficacy of unapproved formulations for the exemptions to the requirement unapproved drug solely on the grounds have not been demonstrated to FDA. For that they bear ‘‘adequate directions for that it lacks an approved application example, information on the ingredients use,’’ and they are misbranded under under section 505 of the FD&C Act. and data on the bioavailability of section 502(f)(1). With respect to drug products covered unapproved drug products have not IV. Notice of Intent To Take by this notice, the Agency intends to been submitted for FDA review, nor has Enforcement Action exercise its enforcement discretion for FDA had the opportunity to assess the only a limited period of time because adequacy of their chemistry, Although not required to do so by the there are safety risks with respect to the manufacturing, and control Administrative Procedure Act, the products covered by this notice, and specifications. Also, unapproved drug FD&C Act (or any rules issued under its there are FDA-approved drug products products have unapproved labeling that authority), or for any other legal reason, to meet patient needs. Therefore, the may not contain appropriate dosing FDA is providing this notice to persons 1 Agency intends to implement this information. For example, the sodium who are marketing unapproved and notice as follows. thiosulfate component of Nithiodote is misbranded drug products containing For the effective date of this notice, dosed for children based on body sodium nitrite and sodium thiosulfate see the DATES section of this document. weight or body surface area, whereas labeled to treat cyanide poisoning, Any drug product covered by this notice FDA is aware of unapproved sodium either sold individually or as part of a that a company (including a thiosulfate products labeled for use in kit. The Agency intends to take manufacturer or distributor) began children at a lower dose based only on enforcement action against such marketing after September 19, 2011, is body surface area. Such discrepancies in products and those who manufacture subject to immediate enforcement dosing may lead to underdosing of them or cause them to be manufactured action. For products covered by this sodium thiosulfate in children. or shipped in interstate commerce. In notice that a company (including a the event that unapproved sodium III. Legal Status of Products Identified manufacturer or distributor) began nitrite and sodium thiosulfate are in This Notice marketing in the United States on or packaged in a kit with other unapproved before September 19, 2011, FDA intends FDA has reviewed the publicly drugs (e.g., amyl nitrite) or medical to take enforcement action against any available scientific literature for products (e.g., syringes) and labeled for such product that is not listed with the unapproved injectable sodium nitrite treatment of cyanide poisoning, FDA Agency in full compliance with section and sodium thiosulfate products labeled intends to take action against the entire 510 of the FD&C Act (21 U.S.C. 360) for treatment of cyanide poisoning. In kit based on the unapproved sodium before November 27, 2012, and is no case did FDA find literature thiosulfate and sodium nitrite manufactured, shipped, or otherwise sufficient to support a determination components. introduced or delivered for introduction that any of these drug products are Manufacturing or shipping the drug into interstate commerce by any person generally recognized as safe and products covered by this notice can on or after November 27, 2012. FDA also effective. Therefore, these products are result in enforcement action, including intends to take enforcement action ‘‘new drugs’’ within the meaning of seizure, injunction, or other judicial or against any drug product covered by section 201(p) of the FD&C Act (21 administrative proceeding. Consistent this notice that is listed with FDA in full U.S.C. 321(p)), and they require with policies described in the Agency’s compliance with section 510 of the approved NDAs or ANDAs in order to guidance entitled ‘‘Marketed FD&C Act but is not being commercially be legally marketed. Unapproved Drugs—Compliance Policy 2 Also, the unapproved drug products used or sold in the United States before Guide’’ (the Marketed Unapproved November 27, 2012 and that is covered by this notice are labeled for Drugs CPG) (http://www.fda.gov/down prescription use. Prescription drugs are manufactured, shipped, or otherwise loads/Drugs/GuidanceCompliance introduced or delivered for introduction defined under section 503(b)(1)(A) of RegulatoryInformation/Guidances/ the FD&C Act (21 U.S.C. 353(b)(1)(A)) as into interstate commerce by any person UCM070290.pdf), the Agency does not on or after November 28, 2012. drugs that, because of their toxicity or expect to issue a warning letter or any other potentiality for harmful effect, are However, for drug products covered other further warning to firms marketing by this notice that a company (including not safe to use except under the drug products covered by this notice supervision of a practitioner licensed by a manufacturer or distributor) began before taking enforcement action. The marketing in the United States on or law to administer such drugs. Because Agency also reminds firms that, as any drug product covered by this notice before September 19, 2011, are listed stated in the Marketed Unapproved with FDA in full compliance with meets the definition of ‘‘prescription Drugs CPG, any unapproved drug drug’’ in 503(b)(1)(A), adequate section 510 of the FD&C Act before marketed without a required approved November 27, 2012 (‘‘currently directions cannot be written for it so application is subject to Agency that a layman can use the product safely marketed and listed’’), and are enforcement action at any time. The manufactured, shipped, or otherwise for its intended uses (21 CFR 201.5). issuance of this notice does not in any Consequently, it is misbranded under introduced or delivered for introduction way obligate the Agency to issue similar into interstate commerce by any person section 502(f)(1) of the FD&C Act in that notices (or any notice) in the future it fails to bear adequate directions for on or after November 28, 2012 the regarding marketed unapproved drugs. Agency intends to exercise its use. An approved prescription drug is As described in the Marketed exempt from the requirement in section 2 For purposes of this notice, the phrase 502(f)(1) that it bear adequate direction 1 The term person includes individuals, ‘‘commercially used or sold’’ means that the for use if, among other things, it bears partnerships, corporations, and associations (21 product has been used in a business or activity the NDA-approved labeling (21 CFR U.S.C. 321(e)). involving retail or wholesale marketing and/or sale.

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enforcement discretion as follows: FDA FD&C Act before November 27, 2012. As withdrawal of a guidance entitled intends to initiate enforcement action previously stated, drug products ‘‘Enforcement Policy Concerning against any such currently marketed and covered by this notice that are currently Rotational Warning Plans for Smokeless listed product that is manufactured on marketed but not listed with the Agency Tobacco Products,’’ that was announced or after February 26, 2013, or that is on the date of this notice must, as of the in the Federal Register on June 8, 2010. shipped on or after May 28, 2013. effective date of this notice, have DATES: The withdrawal is effective Further, FDA intends to take approved applications before their November 28, 2012. enforcement action against any person shipment in interstate commerce. FOR FURTHER INFORMATION CONTACT: Ele who manufactures or ships such Moreover, any person or firm that has Ibarra-Pratt, Center for Tobacco products after these dates. Any person submitted or submits an application but Products, Office of Compliance and who has submitted or submits an has yet to receive approval for such Enforcement, Food and Drug application for a drug product covered products is still responsible for full Administration, 9200 Corporate Blvd., by this notice but has not received compliance with this notice. Rockville, MD 20850–3229, 1–877–287– approval must comply with this notice. 1373, [email protected]. The Agency, however, does not V. Discontinued Products SUPPLEMENTARY INFORMATION: On June intend to exercise its enforcement Some firms may have previously 22, 2009, the President signed the discretion as outlined previously if the discontinued the manufacturing or Family Smoking Prevention and following apply: (1) A manufacturer or distribution of products covered by this Tobacco Control Act (Pub. L. 111–31) distributor of drug products covered by notice without removing them from the (Tobacco Control Act) into law. Section this notice is violating other provisions listing of their products under section 204 of the Tobacco Control Act of the FD&C Act, including, but not 510(j) of the FD&C Act. Other firms may limited to, violations related to FDA’s discontinue manufacturing or amended section 3 of the current good manufacturing practice, distributing listed products in response Comprehensive Smokeless Tobacco adverse event reporting, labeling, or to this notice. Firms that wish to notify Health Education Act of 1986 misbranding requirements other than the Agency of product discontinuation (Smokeless Tobacco Act), 15 U.S.C. those identified in this notice, or (2) it should send a letter, signed by the firm’s 4402, to prescribe revised requirements appears that a firm, in response to this chief executive officer, fully identifying for health warning statements that must notice, increases its manufacture or the discontinued product(s), including appear on smokeless tobacco product interstate shipment of drug products NDC number(s), and stating that the packages and advertisements, and to covered by this notice above its usual manufacturing and/or distribution of the require the submission of warning plans volume during these periods.3 products has (have) been discontinued. for smokeless tobacco product packages Nothing in this notice, including The letter should be sent electronically and advertisements to FDA for review FDA’s intent to exercise its enforcement to Lori Cantin (see ADDRESSES). Firms and approval, rather than to the Federal discretion, alters any person’s liability should also electronically update the Trade Commission (FTC). Section or obligations in any other enforcement listing of their products under section 3(b)(3) of the Smokeless Tobacco Act action, or precludes the Agency from 510(j) of the FD&C Act to reflect requires the equal distribution and initiating or proceeding with discontinuation of products covered by display of warning statements on enforcement action in connection with this notice. Questions on electronic drug packaging, and the quarterly rotation of any other alleged violation of the FD&C listing updates should be sent to: warning statements in advertising, for Act, whether or not related to a drug [email protected]. FDA plans to rely each brand of smokeless tobacco product covered by this notice. on its existing records, including its product ‘‘in accordance with a plan Similarly, a person who is or becomes drug listing records, the results of any submitted by the tobacco product enjoined from marketing unapproved or subsequent inspections, or other manufacturer, importer, distributor, or misbranded drugs may not resume available information, when it targets retailer’’ to, and approved by, FDA. marketing of such products based on violations for enforcement action. These requirements took effect on June 22, 2010. FDA’s exercise of enforcement Dated: November 20, 2012. discretion as described in this notice. In a notice published in the Federal Drug manufacturers and distributors Leslie Kux, Register of June 8, 2010 (75 FR 32481), should be aware that the Agency is Assistant Commissioner for Policy. FDA announced the availability of a exercising its enforcement discretion as [FR Doc. 2012–28773 Filed 11–27–12; 8:45 am] guidance entitled ‘‘Enforcement Policy described previously only in regard to BILLING CODE 4160–01–P Concerning Rotational Warning Plans drug products covered by this notice for Smokeless Tobacco Products.’’ This that are marketed under a National Drug guidance provided information to Code number listed with the Agency in DEPARTMENT OF HEALTH AND industry and the public, including that full compliance with section 510 of the HUMAN SERVICES ‘‘[a]t this time, as an exercise of enforcement discretion, FDA does not Food and Drug Administration 3 If FDA finds it necessary to take enforcement intend to commence or recommend action against a product covered by this notice, the [Docket No. FDA–2012–D–0276] enforcement of the requirement that a Agency may take action relating to all of the smokeless tobacco manufacturer, defendant’s other violations of the FD&C Act at the Guidance for Industry: Enforcement same time. For example, if a firm continues to distributor, importer, or retailer must manufacture or market a product covered by this Policy Concerning Rotational Warning have an FDA-approved rotational notice after the applicable enforcement date has Plans for Smokeless Tobacco warning plan, so long as a rotational passed, to preserve limited Agency resources, FDA Products; Withdrawal of Guidance may take enforcement action relating to all of the warning plan has been submitted to firm’s unapproved drugs that require applications at AGENCY: Food and Drug Administration, FDA by July 22, 2010.’’ FDA believed the same time (see, e.g., United States v. Sage HHS. that allowing additional time for the Pharmaceuticals, 210 F.3d 475, 479–480 (5th Cir. review of warning plans would permit 2000) (permitting the Agency to combine all ACTION: Notice; withdrawal. violations of the FD&C Act in one proceeding, an orderly transition of regulatory rather than taking action against multiple violations SUMMARY: The Food and Drug authority from the FTC to FDA to of the FD&C Act in ‘‘piecemeal fashion’’)). Administration (FDA) is announcing the review and approve warning plans.

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