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Compliance), those steps must be done to FD&C Act) because the drug products and Research (HFD–310), Food and comply with this AD; any steps that are not have been withdrawn or removed from Drug Administration, 10903 New labeled as RC are recommended. Those steps the market after the drug products or Hampshire Ave., Bldg. 51, Rm. 5199, that are not labeled as RC may be deviated components of such drug products were Silver Spring, MD 20993–0002, 301– from, done as part of other actions, or done found to be unsafe or not effective. 796–3110. using accepted methods different from those identified in the specified service Specifically, the proposed rule would SUPPLEMENTARY INFORMATION: add 25 drug products to this list of drug information without obtaining approval of an I. Background AMOC, provided the steps labeled as RC can products and modify the description of be done and the airplane can be put back in one drug product on this list to add an Section 503A of the FD&C Act (21 a serviceable condition. Any substitutions or exception. These revisions are necessary U.S.C. 353a) describes the conditions changes to steps labeled as RC require because new information has come to that must be satisfied for human drug approval of an AMOC. the Agency’s attention since March 8, products compounded by a licensed (k) Related Information 1999, when FDA published the original pharmacist or licensed physician to be list as a final rule. FDA is also exempt from the following three (1) For more information about this AD, contact Marie Hogestad, Aerospace Engineer, withdrawing the previous proposed rule sections of the FD&C Act: (1) Section Systems and Equipment Branch, ANM–130S, regarding additions to this list (see the 501(a)(2)(B) (21 U.S.C. 351(a)(2)(B)) Seattle Aircraft Certification Office (ACO), Federal Register of January 4, 2000). (concerning current good manufacturing FAA, 1601 Lind Avenue SW., Renton, WA DATES: Submit either electronic or practice); (2) section 502(f)(1) (21 U.S.C. 98057–3356; phone: 425–917–6418; fax: 425– written comments on the proposed rule 352(f)(1)) (concerning the labeling of 917–6590; email: [email protected]. by September 2, 2014. The January 4, drugs with adequate directions for use); (2) For service information identified in 2000, proposed rule (65 FR 256) is and (3) section 505 (21 U.S.C. 355) this AD, contact Boeing Commercial withdrawn as of July 2, 2014. (concerning the approval of drugs under Airplanes, Attention: Data & Services ADDRESSES: You may submit comments, new drug applications (NDAs) or Management, P. O. Box 3707, MC 2H–65, abbreviated new drug applications Seattle, WA 98124–2207; telephone 206– identified by Agency name and Docket 544–5000, extension 1; fax 206–766–5680; No. FDA–1999–N–0194 and/or (ANDAs)). Internet https://www.myboeingfleet.com. You Regulatory Information Number (RIN) One of the conditions that must be may view this referenced service information number 0910–AH10, by any of the satisfied to qualify for the exemptions at the FAA, Transport Airplane Directorate, following methods: under section 503A of the FD&C Act is 1601 Lind Avenue SW., Renton, WA. For that the licensed pharmacist or licensed information on the availability of this Electronic Submissions physician does not compound a drug material at the FAA, call 425–227–1221. Submit electronic comments in the product that appears on a list published Issued in Renton, Washington, on June 24, following way: by the Secretary in the Federal Register 2014. • Federal eRulemaking Portal: http:// of drug products that have been Jeffrey E. Duven, www.regulations.gov. Follow the withdrawn or removed from the market Manager, Transport Airplane Directorate, instructions for submitting comments. because such drug products or components of such drug products have Aircraft Certification Service. Written Submissions [FR Doc. 2014–15505 Filed 7–1–14; 8:45 am] been found to be unsafe or not effective Submit written submissions in the (see section 503A(b)(1)(C) of the FD&C BILLING CODE 4910–13–P following ways: Act). • Mail/Hand delivery/Courier (for paper submissions): Division of Dockets A. Court Decisions Regarding the DEPARTMENT OF HEALTH AND Management (HFA–305), Food and Drug Pharmacy Compounding Provisions of HUMAN SERVICES Administration, 5630 Fishers Lane, Rm. the FD&C Act 1061, Rockville, MD 20852. As originally enacted, section 503A of Food and Drug Administration Instructions: All submissions received the FD&C Act included prohibitions on must include the Agency name, Docket the advertising and solicitation of 21 CFR Part 216 No. FDA–1999–N–0194, and RIN 0910– prescriptions for any particular [Docket No. FDA–1999–N–0194 (Formerly AH10 for this rulemaking. All compounded drug, class of drug, or type 99N–4490)] comments received may be posted of drug. Seven compounding without change to http:// pharmacies challenged the advertising RIN 0910–AH10 www.regulations.gov, including any and solicitation provisions of section Additions and Modifications to the List personal information provided. For 503A of the FD&C Act as an of Drug Products That Have Been additional information on submitting impermissible regulation of commercial comments, see the ‘‘Request for Withdrawn or Removed From the speech. In February 2001, the U.S. Court Comments’’ heading of the Market for Reasons of Safety or of Appeals for the Ninth Circuit held SUPPLEMENTARY INFORMATION section of Effectiveness that the prohibition on advertising and this document. promotion in section 503A(c) and the AGENCY: Food and Drug Administration, Docket: For access to the docket to provision of section 503A(a) of the HHS. read background documents or FD&C Act that requires that the ACTION: Proposed rule; withdrawal of comments received, go to http:// prescription be ‘‘unsolicited,’’ were previous proposed rule. www.regulations.gov and insert the unconstitutional restrictions on docket number, found in brackets in the commercial speech. (See Western States SUMMARY: The Food and Drug heading of this document, into the Med. Ctr. v. Shalala, 238 F.3d 1090 (9th Administration (FDA or the Agency) is ‘‘Search’’ box and follow the prompts Cir. 2001).) Furthermore, the Ninth proposing to amend its regulations to and/or go to the Division of Dockets Circuit held that the advertising and revise the list of drug products that may Management, 5630 Fishers Lane, Rm. solicitation provisions could not be not be compounded under the 1061, Rockville, MD 20852. severed from the rest of section 503A exemptions provided by the Federal FOR FURTHER INFORMATION CONTACT: and, as a result, found section 503A of Food, Drug, and Cosmetic Act (the Edisa Gozun, Center for Drug Evaluation the FD&C Act to be invalid in its

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entirety. In April 2002, the U.S. B. 2013 Drug Quality and Security Act on October 14 and 15, 1998 (63 FR Supreme Court affirmed the Ninth On November 27, 2013, President 47301, September 4, 1998). The Circuit’s decision that the advertising Obama signed the Drug Quality and Advisory Committee did not have any and solicitation provisions were Security Act (Pub. L. 113–54) (DQSA) adverse comments on the 1998 unconstitutional; it did not, however, that contains important provisions proposed rule and did not suggest any rule on the severability of section 503A relating to the oversight of changes. A transcript of the October of the FD&C Act. (See Thompson v. compounding of human drugs. This 1998 Advisory Committee meeting may Western States Med. Ctr., 535 U.S. 357 new law removes from section 503A of be found at the Division of Dockets (2002).) the FD&C Act the provisions that had Management (see ADDRESSES) and at been held unconstitutional by the U.S. http://www.fda.gov/Drugs/Guidance In light of these decisions, FDA issued ComplianceRegulatoryInformation/ a Compliance Policy Guide in 2002 to Supreme Court in 2002. By removing these provisions, the new law clarifies PharmacyCompounding/ provide guidance on FDA’s approach ucm290713.htm. concerning the regulation of pharmacy that section 503A of the FD&C Act applies nationwide. In addition, the In the Federal Register of March 8, compounding. (See the Federal Register 1999 (64 FR 10944), FDA published a of June 7, 2002 (67 FR 39409).) DQSA adds a new section 503B of the FD&C Act (21 U.S.C. 353b) that creates final rule that codified the original list In September 2004, 10 pharmacies a new category of ‘‘outsourcing in § 216.24 (1999 final rule). brought suit in the U.S. District Court facilities.’’ Outsourcing facilities, as 2. 2000 Proposed Rule and Additional for the Western District of Texas defined in section 503B of the FD&C Drug Products for the List in § 216.24 challenging FDA’s authority to regulate Act, are facilities that meet certain In the Federal Register of January 4, compounded drugs. In August 2006, the conditions described in section 503B, District Court held, in part, that 2000 (65 FR 256), FDA proposed a rule including registering with FDA as an to amend § 216.24 (2000 proposed rule). compounded human drugs are outsourcing facility. If these conditions Specifically, FDA proposed to add all implicitly exempt from the ‘‘new drug’’ are satisfied, a drug compounded for drug products containing aminopyrine definition in section 201(p) of the FD&C human use by or under the direct and all drug products containing Act and, as a result, are not subject to supervision of a licensed pharmacist in astemizole to the original list of drug the FD&C Act’s new drug approval an outsourcing facility is exempt from products withdrawn or removed from requirements. (See Medical Ctr. Pharm. three sections of the FD&C Act: (1) the market because they have been v. Gonzales, 451 F. Supp. 2d 854 (W.D. Section 502(f)(1), (2) section 505, and (3) found to be unsafe or not effective. After Tex. 2006).) The District Court also held section 582 (21 U.S.C. 360eee); but not the 2000 proposed rule published, three that the advertising and solicitation section 501(a)(2)(B). One of the additional drug products (cisapride, provisions in section 503A of the FD&C conditions in section 503B of the FD&C grepafloxacin, and troglitazone) were Act that the Supreme Court had found Act that must be satisfied to qualify for identified as candidates for addition to to be unconstitutional were severable the exemptions is that the drug does not the list. These five drug products were from the rest of that section. appear on a list published by the presented to the Advisory Committee at Secretary of drugs that have been a meeting held on July 13 and 14, 2000 The Federal Government appealed the withdrawn or removed from the market decision of the U.S. District Court for (65 FR 40104, June 29, 2000). The because such drugs or components of Advisory Committee voted to include the Western District of Texas. In July such drugs have been found to be unsafe 2008, the U.S. Court of Appeals for the aminopyrine, astemizole, cisapride, or not effective (see section 503B(a)(4)). grepafloxacin, and troglitazone to the Fifth Circuit reversed the District Given that nearly identical criteria list of drug products that have been Court’s finding of an implicit exemption apply for a drug to be included on the withdrawn or removed from the market for compounded drugs from the new list referred to in section 503A(b)(1)(C) because they were found to be unsafe or drug approval requirements in the FD&C and the list referred to in section not effective. A transcript of the July Act, holding, instead, that compounded 503B(a)(4) of the FD&C Act, FDA is 2000 Advisory Committee meeting may drugs fall within the definition of ‘‘new proposing to revise and update the list be found at the Division of Dockets drug’’ in the FD&C Act and, therefore, at § 216.24 (21 CFR 216.24) for purposes Management (see ADDRESSES) and at are subject to regulation by FDA. (See of both sections 503A and 503B. http://www.fda.gov/Drugs/Guidance Medical Ctr. Pharm. v. Mukasey, 536 Accordingly, the proposed rule that ComplianceRegulatoryInformation/ F.3d 383 (5th Cir. 2008).) The Fifth published in the Federal Register of PharmacyCompounding/ Circuit also held that the advertising January 4, 2000, which would have ucm290713.htm. and solicitation provisions are severable amended the list in § 216.24, is from the rest of section 503A of the withdrawn (see DATES). 3. New Proposed Rule To Amend the FD&C Act, and as a result, the other List in § 216.24 provisions of section 503A remain in C. Regulatory History of the List This proposed rule would add to effect. 1. Original List § 216.24 the five drug products The Fifth Circuit’s severability ruling In the Federal Register of October 8, identified in section I.C.2 and additional conflicted with the earlier Ninth Circuit 1998 (63 FR 54082), FDA proposed a drug products that have been decision, which held that the rule to establish the original list of drug withdrawn or removed from the market advertising and solicitation provisions products that have been withdrawn or since the publication of the 1999 final cannot be severed from section 503A of removed from the market because the rule because the drug products or the FD&C Act, and rendered all of drug products or the components of components of such drug products were section 503A void. Following a fungal such drug products were found to be found to be unsafe or not effective. FDA meningitis outbreak in September 2012, unsafe or not effective (1998 proposed also proposes to modify the description FDA sought legislation to, among other rule). The 1998 proposed rule was of one drug product contained in the things, resolve the split in the Circuits presented to the Pharmacy original list to add an exception that to clarify that section 503A of the FD&C Compounding Advisory Committee would allow the product to be Act was valid nationwide. (Advisory Committee) at a meeting held compounded under certain

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circumstances. These revisions are is necessary to protect the public health. soliciting public input through this necessary to ensure the list of drugs in In 1998 and 1999, FDA used rulemaking Federal Register notice on alternative § 216.24 reflects new information that to develop the original list of drug procedures for updating the list and has come to the Agency’s attention since products that had been withdrawn or requests that this input be submitted to FDA published the original list in the removed from the market, and consulted FDA for consideration in comments to 1999 final rule. As with the original list, the Pharmacy Compounding Advisory this proposed rule. FDA will specify in the primary focus of this proposed rule Committee about the list. In 2000, FDA the final rule the procedure it will use is on drug products that have been also proposed to amend the list through to update the list in the future. withdrawn or removed from the market rulemaking after consultation with the because they were found to be unsafe. Advisory Committee. III. Description of This Proposed Rule FDA may propose at a later date to add Meanwhile, new section 503B of the A. Amendments to Introductory Text other drug products to the list that have FD&C Act describes the list in section FDA is proposing to add the phrase been withdrawn or removed from the 503B(a)(4) as a list published by the ‘‘or section 503B(a)’’ to the introductory market because they were found to be Secretary of drugs that have been text of § 216.24 to clarify that drug not effective, or to update the list as new withdrawn or removed from the market products included in the list in § 216.24 information becomes available to the because such drugs or components of will not qualify for the exemptions Agency regarding products that were such drugs have been found to be unsafe under either section 503A(a) or section removed from the market because they or not effective. Section 503B(c) of the 503B(a) of the FD&C Act when were found to be unsafe. FD&C Act requires that the Secretary This proposed rule would replace the implement through regulations, compounded. 2000 proposed rule. The list set forth in following consultation with an advisory B. Amendments To Add Drug Products this proposed rule would apply to committee, a list of drugs or categories to the List compounders and outsourcing facilities of drugs that present demonstrable FDA is proposing to amend § 216.24 seeking to qualify for the exemptions difficulties for compounding that are to include the 25 drug products under either section 503A or section reasonably likely to lead to an adverse 503B of the FD&C Act. Accordingly, the effect on the safety or effectiveness of described in the following paragraphs 2000 proposed rule to amend § 216.24 is the drug or category of drugs and that have been withdrawn or removed withdrawn. In preparing this proposed therefore may not be compounded from the market since the 1999 final rule, FDA has taken into consideration under section 503B. (See section rule was published (March 1999) the discussions held by the July 2000 503B(a)(6) of the FD&C Act.) Section because such drug products or Advisory Committee and that Advisory 503B does not, however, include any components of such drug products have Committee’s vote to include similar requirement for rulemaking or been found to be unsafe or not effective. aminopyrine, astemizole, cisapride, consultation with an advisory A drug product that is included in the grepafloxacin, and troglitazone on the committee to establish the list of drugs list codified at § 216.24 is not entitled to list of drug products that have been that may not be compounded under the exemptions provided in section withdrawn or removed from the market section 503B of the FD&C Act because 503A(a) of the FD&C Act, and is subject because they were found to be unsafe or they have been withdrawn or removed to sections 501(a)(2)(B), 502(f)(1), and not effective. from the market because such drugs or 505 of the FD&C Act, in addition to Additional nominations for this list components of such drugs have been other applicable provisions. In addition, can be submitted to FDA for found to be unsafe or not effective. a drug that is included in the list consideration in comments to this As noted, FDA plans to publish a codified at § 216.24 is not entitled to the proposed rule. single list of drug products (referred to exemptions provided in section 503B(a) as ‘‘the withdrawn or removed list’’ or of the FD&C Act, and is subject to II. Procedural Issue for Comment ‘‘the list’’) that cannot be compounded sections 502(f)(1) and 505 of the FD&C Section 503A of the FD&C Act for human use under the exemptions Act, in addition to other applicable describes the list in section provided by either section 503A or 503B provisions. 503A(b)(1)(C) as a list published by the of the FD&C Act because they have been The listed drugs are ineligible for the Secretary in the Federal Register of drug withdrawn or removed from the market exemptions set forth in sections 503A products that have been withdrawn or because such drug products or and 503B of the FD&C Act because they removed from the market because such components of such drug products have have been withdrawn or removed from drug products or components of such been found to be unsafe or not effective. the market because they were found to drug products have been found to be FDA invites comments on the be unsafe or not effective. Most drugs on unsafe or not effective. This suggests appropriate procedure to update the list the list may not be compounded in any that FDA can develop the 503A(b)(1)(C) in the future. The Agency believes that form. There are, however, two categories list by publishing it in the Federal the timely sharing of information about of exceptions. In the first category, a Register and does not need to go safety concerns relating to compounding particular formulation, indication, through notice and comment drugs for human use without undue dosage form, or route of administration rulemaking. Section 503A(c)(1) of the delay is essential to the protection of of a drug is explicitly excluded from an FD&C Act, however, states that the public health. FDA is concerned that entry on the list because an approved Secretary shall issue regulations to consulting with the advisory committee drug containing the same active implement section 503A, and that and completing the rulemaking process ingredient(s) has not been withdrawn or before issuing regulations to implement are likely to contribute to substantial removed from the market. For such section 503A(b)(1)(C) pertaining to the delay in updating the list to reflect drugs, the formulation, indication, withdrawn or removed rule, among current safety information. FDA dosage form, or route of administration other sections, the Secretary shall therefore is seeking an alternative expressly excluded from the list may be convene and consult an advisory procedure to update the withdrawn or eligible for the exemptions provided in committee on compounding unless the removed list in the future. Although sections 503A and 503B of the FD&C Secretary determines that the issuance FDA is publishing a proposed rule today Act. In the second category, some drugs of such regulations before consultation to add 25 drugs to the list, FDA is also are listed only with regard to certain

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formulations, concentrations, skin. Some cases of agranulocytosis ANDA for CHLOROMYCETIN indications, routes of administration, or were fatal. In 1964, FDA declared drug (chloramphenicol) Capsules, 50 mg, 100 dosage forms because they have been products containing aminopyrine to be mg, and 250 mg. In the Federal Register found to be unsafe or not effective in new drugs and invited NDAs for these of February 11, 2009 (74 FR 6896), FDA those particular formulations, drug products, but only for use as an announced that it was withdrawing concentrations, indications, routes of antipyretic in serious situations where approval of the ANDA, effective March administration, or dosage forms. For other, safer drugs could not be used. 13, 2009. Armenpharm, Ltd., submitted drugs that are listed with these types of FDA received no NDAs for drug a citizen petition dated February 7, 2011 limitations, any compounding of the products containing aminopyrine, and (Docket No. FDA–2011–P–0081), under drug will be closely scrutinized to those unapproved drug products were § 10.30 (21 CFR 10.30), requesting that ensure that the compounding of the removed from the market (see the the Agency determine whether drug does not create a product that is Federal Register of October 4, 1977 (42 CHLOROMYCETIN (chloramphenicol) unsafe or not effective. If it appears to FR 53954), and January 4, 2000 (65 FR Capsules, 250 mg, were withdrawn from do so, FDA may determine that the drug 256)). Aminopyrine was presented to sale for reasons of safety or is not entitled to the exemptions the Advisory Committee at the July 2000 effectiveness. After considering the provided in sections 503A and 503B of meeting, and the Advisory Committee citizen petition, FDA determined that the FD&C Act. Those compounding voted to include aminopyrine on the the drug product was withdrawn for these particular drugs should take note withdrawn or removed list (see the reasons of safety or effectiveness. With of the reasons FDA has cited for Federal Register of June 29, 2000 (65 FR the approval of additional therapies including a drug on this list, and 40104)). with less severe adverse drug effects, carefully consider these reasons when Astemizole: All drug products FDA determined that the risks considering whether or not to containing astemizole. Astemizole, associated with CHLOROMYCETIN compound a drug that is so listed. formerly marketed as HISMANAL 10- (chloramphenicol) Capsules, 250 mg, as The following drug products are mg tablets, was associated with life- then labeled, outweighed the benefits. arranged alphabetically by the threatening heart arrhythmias. Patients Furthermore, CHLOROMYCETIN established names of the active with liver dysfunction or who were (chloramphenicol) Capsules, 250 mg, ingredients contained in the drug taking other drugs that interfered with may cause a number of adverse products and are proposed for inclusion the metabolism of astemizole were also reactions, the most serious being bone in § 216.24. For many of the drugs, the found to be at risk of serious cardiac marrow depression (anemia, proprietary or trade name of some or all adverse events while taking astemizole. thrombocytopenia, and of the drug products that contained the On June 18, 1999, the NDA holder granulocytopenia temporally associated active ingredient are also given in the withdrew HISMANAL (astemizole) 10- with treatment). Additionally, prior to preamble paragraphs describing the mg tablets from the market. In the the removal of the capsule drug product withdrawn or removed drug products. Federal Register of August 23, 1999 (64 from the market, a boxed warning in the In several cases, the withdrawn or FR 45973), FDA announced its prescribing information for both removed drug products are identified determination that HISMANAL chloramphenicol sodium succinate according to the established name of the (astemizole) 10-mg tablets were injection and chloramphenicol capsules active ingredient, listed as a particular removed from the market for safety stated that serious hypoplastic anemia, salt or ester of the active moiety. The reasons. (See also the Federal Register thrombocytopenia, and following list includes a brief summary of January 4, 2000 (65 FR 256).) granulocytopenia are known to occur of the reasons why each drug product is Astemizole was presented to the after administration of chloramphenicol. being proposed for inclusion. Advisory Committee at the July 2000 The boxed warning also described fatal Alatrofloxacin mesylate: All drug meeting, and the Advisory Committee aplastic anemia associated with products containing alatrofloxacin voted to include astemizole on the administration of the drug and aplastic mesylate. Alatrofloxacin mesylate, withdrawn or removed list (see the anemia attributed to chloramphenicol formerly marketed as TROVAN Federal Register of June 29, 2000 (65 FR that later terminated in leukemia. There Injection, was associated with serious 40104)). liver injury. On June 9, 1999, FDA Cerivastatin sodium: All drug is published literature that suggests that announced in a Public Health Advisory products containing cerivastatin the risk of fatal aplastic anemia that the NDA holder agreed to a limited sodium. Cerivastatin sodium, formerly associated with the oral formulation of distribution of TROVAN (alatrofloxacin marketed as BAYCOL tablets, was chloramphenicol may be higher than the mesylate) Injection and TROVAN associated with increased risk of risk associated with the intravenous (trovafloxacin mesylate) tablets, 100 rhabdomyolysis. Fatal rhabdomyolysis formulation (see the Federal Register of milligrams (mg) and 200 mg, to in- was reported most frequently when July 13, 2012 (77 FR 41412)). FDA is not patient healthcare facilities (Ref. 1). used at higher doses, when used in aware of any oral drug products Subsequently, in the Federal Register of elderly patients, and particularly, with containing chloramphenicol currently June 16, 2006 (71 FR 34940), FDA concomitant use of gemfibrozil (LOPID). being marketed. announced that it was withdrawing the In an August 8, 2001, ‘‘Dear Healthcare Cisapride: All drug products approval of the NDA for TROVAN Professional Letter,’’ the NDA holder containing cisapride. Cisapride, Injection after the NDA holder notified stated that it discontinued the marketing formerly marketed as PROPULSID the Agency that the drug product was and distribution of all dosage strengths tablets and suspension, was associated no longer marketed and requested that of BAYCOL (Ref. 2). with serious cardiac arrhythmias and the approval of the NDA be withdrawn. Chloramphenicol: All oral drug death. In an April 12, 2000 ‘‘Dear Aminopyrine: All drug products products containing chloramphenicol. Healthcare Professional Letter,’’ the containing aminopyrine. Aminopyrine Chloramphenicol was formerly NDA holder stated that it would was associated with agranulocytosis, a marketed as CHLOROMYCETIN discontinue marketing the drug as of condition characterized by a decrease in (chloramphenicol) Capsules. In a letter July 14, 2000, and make the product the number of certain blood cells and dated October 9, 2007, the application available only through an lesions on the mucous membrane and holder requested withdrawal of the investigational limited access program

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(Ref. 3). Cisapride was presented to the approved supplements for TEQUIN dated January 12, 2007, FDA informed Advisory Committee at the July 2000 (gatifloxacin). This revised labeling the NDA holder that the RAXAR NDA meeting, and the Advisory Committee deleted references to TEQUIN injection, should be withdrawn because of the voted to include cisapride on the 10 mg/mL (200 mg), indicating that this cardiovascular risks stated previously. withdrawn or removed list (see the product was no longer being marketed; The NDA holder sent a letter to FDA on Federal Register of June 29, 2000 (65 FR therefore, the product was moved from March 20, 2007, agreeing with FDA’s 40104)). the prescription drug product list to the determination to initiate the withdrawal Esmolol hydrochloride: All parenteral ‘‘Discontinued Drug Product List’’ of the RAXAR NDA, and FDA drug products containing esmolol HCl section of the ‘‘Approved Drug Products subsequently announced that approval that supply 250 mg/milliliter (mL) of With Therapeutic Equivalence of the NDA was withdrawn (see the concentrated esmolol per 10-mL Evaluations’’ (the Orange Book). In Federal Register of June 14, 2007 (72 FR ampule. Esmolol hydrochloride (HCl), response to a citizen petition from 32852), and July 9, 2007 (72 FR 37244)). 250 mg/mL per 10-mL ampule, formerly Apotex Corp. (Docket No. FDA–2005–P– Grepafloxacin was presented to the marketed as BREVIBLOC Injection 250 0369),1 FDA determined, as set forth in Advisory Committee at the July 2000 mg/mL per 10-mL ampule, was the Federal Register of February 3, 2006 meeting, and the Advisory Committee associated with increased risk of (71 FR 5858), that TEQUIN injection, 10 voted to include grepafloxacin on the medication errors resulting in serious mg/mL (200 mg), was not withdrawn for withdrawn or removed list (see the adverse events, including deaths. The reasons of safety and effectiveness. On Federal Register of June 29, 2000 (65 FR NDA holder sent a letter to FDA on June May 1, 2006, Public Citizen Research 40104)). 28, 2007, notifying the Agency that the Group submitted a citizen petition Methoxyflurane: All drug products company had decided to cease the (Docket No. FDA–2006–P–0081),2 under containing methoxyflurane. manufacture and distribution of § 10.30, requesting that FDA Methoxyflurane, formerly marketed as BREVIBLOC (esmolol HCl) Injection, immediately ban TEQUIN because of PENTHRANE Inhalation Liquid, 99.9 250 mg/mL, 10-mL ampule. In a citizen the increased risk of dysglycemia percent, was associated with serious, petition dated March 27, 2008 (Docket (hypoglycemia, low blood sugar, and irreversible, and even fatal No. FDA–2008–P–0284), submitted hyperglycemia, high blood sugar) in nephrotoxicity and hepatotoxicity in under § 10.30 and in accordance with 21 humans. In June 2006, the NDA holder humans. In the Federal Register of CFR 314.122 and 314.161, Bedford announced that it would no longer August 16, 2001 (66 FR 43017), FDA Laboratories (Bedford) requested that market TEQUIN. In the Federal Register announced that it was withdrawing the the Agency determine whether of September 9, 2008 (73 FR 52357), approval of the NDA after the NDA BREVIBLOC (esmolol HCl) Injection, FDA announced its determination that holder notified the Agency that 250 mg/mL, 10-mL ampule, was all dosage forms and strengths of PENTHRANE (methoxyflurane) withdrawn from sale for reasons of TEQUIN (gatifloxacin) were withdrawn Inhalation Liquid was no longer being safety or effectiveness. In the Federal from the market for safety reasons. marketed under the NDA and requested Register of May 5, 2010 (75 FR 24710), There are currently approved withdrawal of the application. In a FDA announced its determination that citizen petition dated August 25, 2004 gatifloxacin ophthalmic solutions on the 3 BREVIBLOC (esmolol HCl) Injection 250 market. Thus, FDA is proposing to (Docket No. FDA–2004–P–0337), mg/mL, 10-mL ampule, was withdrawn include all drug products containing submitted under § 10.30, and in from the market for safety reasons. gatifloxacin, except ophthalmic accordance with § 314.161, AAC Etretinate: All drug products Consulting Group requested that the solutions, on the withdrawn or removed containing etretinate. Etretinate was Agency determine whether list. formerly marketed as TEGISON PENTHRANE (methoxyflurane) Grepafloxacin: All drug products Capsules. In a letter dated September Inhalation Liquid, 99.9 percent, was containing grepafloxacin. 23, 1999, the NDA holder requested that withdrawn from sale for reasons of Grepafloxacin, formerly marketed as FDA withdraw the approval of the NDA safety or effectiveness. In the Federal RAXAR tablets, was associated with for TEGISON (etretinate) Capsules Register of September 6, 2005 (70 FR cardiac repolarization, manifested as because it had discontinued marketing 53019), FDA announced its QTc interval prolongation on the the product. The letter also stated that determination that PENTHRANE electrocardiogram, which could put the drug was not withdrawn for safety Inhalation Liquid, 99.9 percent, was reasons. However, in an patients at risk of Torsade de Pointes. withdrawn from the market for safety acknowledgement letter dated December The NDA holder sent a letter to FDA on reasons. 30, 2002, FDA informed the NDA holder March 5, 2003, requesting that FDA Novobiocin sodium: All drug products that TEGISON (etretinate) Capsules was withdraw the approval of the NDA for containing novobiocin sodium. removed from the market because it RAXAR tablets, stating that the product Novobiocin sodium, formerly marketed posed a greater risk of birth defects than was no longer being marketed. In an as ALBAMYCIN capsule, 250 mg, was SORIATANE (acitretin), the product acknowledgment letter dated June 20, associated with adverse reactions that that replaced TEGISON (etretinate) 2003, FDA stated that RAXAR included relatively common skin Capsules (see the Federal Register of (grepafloxacin) tablets had been reactions, jaundice, hepatic failure, and September 10, 2003 (68 FR 53384)). removed from the market because of blood dyscrasias (neutropenia, anemia, Subsequently, in the Federal Register of safety concerns. In a followup letter and thrombocytopenia). Literature also September 10, 2003, FDA announced it revealed concerns about the 1 was withdrawing approval of the NDA. This citizen petition was originally assigned development of novobiocin-resistant docket number 2005P–0023/CP1. The number was Gatifloxacin: All drug products changed to FDA–2005–P–0369 as a result of FDA’s Staphylococci during treatment and a containing gatifloxacin (except transition to its new docketing system (http:// potential for drug interactions. On June ophthalmic solutions). Gatifloxacin was www.regulations.gov) in January 2008. formerly marketed as TEQUIN tablets, 2 This citizen petition was originally assigned 3 This citizen petition was originally assigned injection, and oral suspension. In docket number 2006P–0178. The number was docket number 2004P–0379. The number was changed to FDA–2006–P–0081 as a result of FDA’s changed to FDA–2004–P–0337 as a result of FDA’s January 2003, FDA received revised transition to its new docketing system (http:// transition to its new docketing system (http:// product labeling relating to several www.regulations.gov) in January 2008. www.regulations.gov) in January 2008.

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9, 1999, the NDA holder sent an annual March 19, 2013, the NDA holder to exclude PPA. In a notice published in report to FDA that indicated that requested withdrawal of approval of the Federal Register on August 14, 2001 ALBAMYCIN (novobiocin sodium) NDA 20–553 for original OXYCONTIN. (66 FR 42665), FDA offered an capsule, 250 mg, was no longer being In the Federal Register of April 18, 2013 opportunity for a hearing on a proposal manufactured, and on June 27, 2007, the (78 FR 23273), FDA published notice of to issue an order, under section 505(e) NDA holder sent a letter to FDA its determination that original of the FD&C Act, withdrawing approval notifying the Agency that ALBAMYCIN OXYCONTIN, NDA 20–553, was of 13 NDAs and 8 ANDAs for products (novobiocin sodium) capsule, 250 mg, withdrawn from sale for reasons of containing phenylpropanolamine. had been discontinued. In the Federal safety or effectiveness. The notice (Although the August 14, 2001, notice Register of February 11, 2009 (74 FR concluded that ‘‘[o]riginal OXYCONTIN stated that FDA proposed to withdraw 6896), FDA announced that it was . . . poses an increased potential for approval of 16 NDAs and 8 ANDAs, the withdrawing approval of the NDA in abuse by certain routes of notice listed only 13 NDAs and 8 response to the NDA holder’s administration, when compared to ANDAs.) FDA withdrew approval of withdrawal request. Crixmore LLC reformulated OXYCONTIN. Based on ANDA 71–099 for BROMATAPP submitted a citizen petition dated July the totality of the data and information Extended-Release Tablets in a notice 9, 2008 (Docket No. FDA–2008–P– available to the Agency at this time, published in the Federal Register of 0431), under § 10.30, requesting that the FDA concludes that the benefits of February 20, 2002 (67 FR 7702) after the Agency determine whether original OXYCONTIN no longer application holder informed FDA that ALBAMYCIN (novobiocin sodium) outweigh its risks.’’ In the Federal the product was no longer being capsule, 250 mg, was withdrawn from Register of August 7, 2013 (78 FR marketed and requested withdrawal. In sale for reasons of safety or 48177), FDA announced that it was the Federal Register of February 20, effectiveness. In the Federal Register of withdrawing the approval of NDA 20– 2014 (79 FR 9744), FDA announced that January 19, 2011 (76 FR 3143), FDA 553. In addition, because the drug the NDA and ANDA products announced its determination that approval process is the most appropriate containing PPA were no longer shown ALBAMYCIN (novobiocin sodium) way for FDA to evaluate the effect and to be safe for use under the conditions capsule, 250 mg, was withdrawn from labeling of products with potentially that formed the basis upon which the the market for reasons of safety or abuse-deterrent properties, applications were approved, and thus effectiveness. compounding of opioid products with the Agency was withdrawing approval Oxycodone hydrochloride: All potentially abuse-deterrent properties of 20 products containing PPA. extended-release drug products will be closely scrutinized. Polyethylene glycol (PEG) 3350, containing oxycodone hydrochloride Pemoline: All drug products sodium chloride, sodium bicarbonate, that have not been determined by FDA containing pemoline. Pemoline, potassium chloride, and bisacodyl: All to have abuse-deterrent properties. formerly marketed as CYLERT tablets drug products containing PEG 3350, OXYCONTIN (oxycodone and chewable tablets, was associated sodium chloride, sodium bicarbonate, hydrochloride) extended-release tablets with liver failure. FDA determined that and potassium chloride for oral were approved in multiple strengths the overall risk of liver toxicity from solution, and 10 mg or more of under NDA 20–553 in 1995. The CYLERT and generic pemoline bisacodyl delayed-release tablets. PEG formulation was often abused by outweighed the benefits of the drug. On 3350, sodium chloride, sodium manipulating the product to defeat its October 24, 2005, FDA announced in an bicarbonate, and potassium chloride for extended-release mechanism, causing FDA Alert that the NDA and ANDA oral solution, and four bisacodyl the oxycodone to be released more holders chose to stop sales and delayed-release tablets, 5 mg (20-mg rapidly. This product was voluntarily marketing of CYLERT and generic bisacodyl), formerly marketed as withdrawn from sale following pemoline in May 2005 (Ref. 4). HALFLYTELY AND BISACODYL Pergolide mesylate: All drug products introduction of a reformulated version, TABLETS BOWEL PREP KIT (20-mg containing pergolide mesylate. also marketed as OXYCONTIN bisacodyl), was associated with Pergolide mesylate, formerly marketed (oxycodone hydrochloride) extended- ischemic colitis. The NDA holder as PERMAX tablets, was associated with release tablets, which was developed informed FDA that it ceased to increased risk of heart valve damage. On with physicochemical properties manufacture and market HALFLYTELY March 29, 2007, FDA announced in a intended to make the tablets more AND BISACODYL TABLETS BOWEL Public Health Advisory that the NDA difficult to manipulate for purposes of PREP KIT (20-mg bisacodyl) as of and ANDA holders agreed to withdraw abuse or misuse and was approved in September 25, 2007. On July 15, 2008, PERMAX and generic pergolide multiple strengths under NDA 22–272 FDA received a citizen petition (Docket mesylate from the market (Ref. 5). in 2010. Several parties submitted No. FDA–2008–P–0412), submitted Phenylpropanolamine (PPA): All drug citizen petitions under § 10.30, under § 10.30, from Foley & Lardner products containing PPA. A study requesting that the Agency determine LLP. The petition requested that the demonstrated that PPA was associated whether original OXYCONTIN Agency determine whether with increased risk of hemorrhagic (oxycodone HCl) extended-release HALFLYTELY AND BISACODYL stroke. On November 6, 2000, FDA tablets were voluntarily withdrawn from TABLETS BOWEL PREP KIT (PEG– announced in a Public Health Advisory sale for reasons other than safety or 3350, sodium chloride, sodium 4 that it was taking steps to remove PPA effectiveness. In a letter to FDA dated bicarbonate, and potassium chloride for from all drug products and requested oral solution and four bisacodyl delayed 4 that all drug companies discontinue Varam, Inc., Docket No. FDA–2011–P–0473 release tablets, 5 mg) (HALFLYTELY (June 9, 2011) (10, 15, 20, 30, 40, 50, 80, and 160 marketing products containing PPA AND BISACODYL TABLETS BOWEL mg); Sheppard, Mullin, Richter & Hampton LLP, (Ref. 6). In response to FDA’s request, Docket No. FDA–2010–P–0540 (October 8, 2010) PREP KIT (20-mg bisacodyl)), companies reformulated their products (10, 15, 20, 30, 40, 60, and 80 mg); Lachman manufactured by Braintree Laboratories, Consultant Services, Inc., Docket No. FDA–2010–P– Inc. (Braintree), was withdrawn from 0526 (September 30, 2010) (10, 15, 20, 30, 40, 60, withdrawal of the 160 mg strength, Docket No. 80, and 160 mg). Lachman also submitted a petition FDA–2001–P–0473 (formerly Docket No. 2001P– sale for reasons of safety or in 2001 concerning just Purdue Pharma LP’s 2001 0426) (September 18, 2001). effectiveness. In the Federal Register of

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March 19, 2010 (75 FR 13292), FDA results of the study showed that when higher chance of heart attack, stroke, announced its determination that propoxyphene was taken at therapeutic and worsening heart chest pain that can HALFLYTELY AND BISACODYL doses, there were significant changes to become a heart attack, compared to a TABLETS BOWEL PREP KIT (20-mg the electrical activity of the heart which placebo. On March 30, 2007, FDA bisacodyl) was withdrawn from the can increase the risk for serious announced in a Public Health Advisory market for reasons of safety or abnormal heart rhythms (Ref. 7). In the that the NDA holder agreed to stop effectiveness. Similarly, PEG 3350, Federal Register of March 10, 2014 (79 selling ZELNORM (Ref. 10). On July 27, sodium chloride, sodium bicarbonate, FR 13308), FDA announced that due to 2007, FDA announced that it was and potassium chloride for oral this safety risk, the Agency was permitting the restricted use of solution, and two bisacodyl delayed- withdrawing approval of 54 ZELNORM (tegaserod maleate) under a release tablets, 5 mg (10-mg bisacodyl), propoxyphene products with agreement treatment investigational new drug formerly marketed as HALFLYTELY from holders of the affected (IND) protocol to treat irritable bowel AND BISACODYL TABLETS BOWEL applications. On that date, FDA also syndrome with constipation (IBS–C) PREP KIT (10-mg bisacodyl), was published a notice of opportunity for a and chronic idiopathic constipation associated with ischemic colitis. The hearing on its proposal to withdraw (CIC) in women younger than 55 who NDA holder informed FDA that it approval of three additional meet specific guidelines (Ref. 11). On ceased to manufacture and market propoxyphene products for which FDA April 2, 2008, FDA announced that the HALFLYTELY AND BISACODYL had not received correspondence from sponsor of ZELNORM notified FDA that TABLETS BOWEL PREP KIT (10-mg the application holders requesting that it would no longer provide ZELNORM bisacodyl) as of July 17, 2010. On FDA withdraw approval (see the (tegaserod maleate) under a treatment September 23, 2010, FDA received a Federal Register of March 10, 2014 (79 IND protocol to treat IBS–C and CIC in citizen petition (Docket No. FDA–2010– FR 13310)). women younger than 55; however, the P–0507), submitted under § 10.30, from Rapacuronium bromide: All drug sponsor agreed to continue to supply Perrigo Company (Perrigo) requesting products containing rapacuronium ZELNORM for use in emergency that the Agency determine whether bromide. Rapacuronium bromide, situations (Ref. 12). HALFLYTELY AND BISACODYL formerly marketed as RAPLON for Troglitazone: All drug products TABLETS BOWEL PREP KIT (PEG– Injection, was associated with the containing troglitazone. Troglitazone, 3350, sodium chloride, sodium occurrence of bronchospasm. In a letter formerly marketed as REZULIN and bicarbonate, and potassium chloride for dated March 27, 2001, the NDA holder PRELAY Tablets, a treatment for type 2 oral solution and two bisacodyl delayed announced that it voluntarily withdrew diabetes, was shown to be more toxic to release tablets, 5 mg) (HALFLYTELY all batches of RAPLON for Injection the liver than two other more recently AND BISACODYL TABLETS BOWEL from the market (Ref. 8). FDA approved drugs that offered a similar PREP KIT (10-mg bisacodyl)), subsequently announced in the Federal benefit. In a letter dated May 1, 2002, manufactured by Braintree, was Register of March 19, 2012 (77 FR the holder of the NDA for REZULIN withdrawn from sale for reasons of 16039) that it was withdrawing the (troglitazone) Tablets requested that safety or effectiveness. In the Federal approval of the NDA. FDA withdraw the NDA for REZULIN Rofecoxib: All drug products Register of August 17, 2011 (76 FR (troglitazone) Tablets because it had containing rofecoxib. Rofecoxib, 51037), FDA announced its discontinued marketing the product in formerly marketed as VIOXX, was March 2000. FDA subsequently determination that HALFLYTELY AND associated with increased risk of serious announced in the Federal Register of BISACODYL TABLETS BOWEL PREP cardiovascular events, including heart January 10, 2003 (68 FR 1469) that it KIT (10-mg bisacodyl) was withdrawn attack and stroke. On September 30, was withdrawing the approval of the from the market for reasons of safety or 2004, FDA announced in a Public NDA for REZULIN. In a letter dated effectiveness. Health Advisory that the NDA holder December 31, 2002, the holder of the Propoxyphene: All drug products voluntarily withdrew VIOXX from the NDA for PRELAY (troglitazone) Tablets containing propoxyphene. market (Ref. 9). requested that FDA withdraw the Propoxyphene, formerly marketed Sibutramine hydrochloride: All drug approval of the NDA for PRELAY under various names such as DARVON products containing sibutramine (troglitazone) Tablets because it never and DARVOCET, was associated with hydrochloride. Sibutramine marketed the drug and had no plans to serious toxicity to the heart. In a drug hydrochloride (HCl), formerly marketed market the drug in the future. In the safety communication dated November as MERIDIA oral capsules, was Federal Register of August 11, 2003 (68 19, 2010, FDA announced it had associated with increased risk of heart FR 47581), FDA concluded that requested that companies voluntarily attack and stroke. In a letter dated PRELAY was voluntarily withdrawn withdraw propoxyphene from the U.S. October 12, 2010, the NDA holder after review of safety data showed that market and that FDA was requested that FDA withdraw the REZULIN was more toxic to the liver recommending against the continued approval of the NDA for MERIDIA. In an than two other more recently approved use and prescribing of the pain reliever acknowledgment letter dated November drugs that offered a similar benefit, and propoxyphene because new data 1, 2010, FDA stated that the benefits of FDA announced that it was showed that the drug can cause serious MERIDIA (sibutramine HCl) oral withdrawing approval of the NDA for toxicity to the heart, even when used at capsules no longer outweighed the risks PRELAY. Troglitazone was presented to therapeutic doses. FDA concluded that in any identifiable population. FDA the Advisory Committee at the July 2000 the safety risks of propoxyphene subsequently announced in the Federal meeting, and the Advisory Committee outweighed its limited benefits for pain Register of December 21, 2010 (75 FR voted to include troglitazone on the relief at recommended doses. The 80061) that it was withdrawing approval withdrawn or removed list (see the Agency’s recommendation was based on of the NDA. Federal Register of June 29, 2000 (65 FR all available data including data from a Tegaserod maleate: All drug products 40104)). then-new study that evaluated the containing tegaserod maleate. Trovafloxacin mesylate: All drug effects that increasing doses of Tegaserod maleate, formerly marketed products containing trovafloxacin propoxyphene have on the heart. The as ZELNORM, was associated with a mesylate. Trovafloxacin mesylate,

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formerly marketed as TROVAN tablets, March 8, 1999, FDA included all drug economic impact on a substantial 100 mg and 200 mg, was associated with products containing bromfenac sodium number of small entities. serious liver injury. On June 9, 1999, in the list codified at § 216.24 when Section 202(a) of the Unfunded FDA announced in a Public Health FDA published the 1999 final rule (64 Mandates Reform Act of 1995 requires Advisory that the NDA holder agreed to FR 10944). Since then, FDA has that Agencies prepare a written a limited distribution of TROVAN approved bromfenac ophthalmic statement, which includes an (alatrofloxacin mesylate) Injection and solutions, and although one of these, assessment of anticipated costs and TROVAN (trovafloxacin mesylate) XIBROM (bromfenac ophthalmic benefits, before proposing ‘‘any rule that tablets, 100 mg and 200 mg, to in- solution) 0.09%, was discontinued by includes any Federal mandate that may patient healthcare facilities (Ref. 1). The the NDA holder in 2011, FDA result in the expenditure by State, local, holders of the NDAs for TROVAN announced its determination in the and tribal governments, in the aggregate, (trovafloxacin mesylate) tablets, 100 mg Federal Register of May 13, 2011 (76 FR or by the private sector, of $100,000,000 and 200 mg, and TROVAN/ 28045) that it was not withdrawn for or more (adjusted annually for inflation) ZITHROMAX COMPLIANCE PAK reasons of safety or effectiveness. (See in any one year.’’ The current threshold (trovafloxacin mesylate/azithromycin also Docket No. FDA–2011–P–0128.) after adjustment for inflation is $141 for oral suspension) notified the Agency Approved bromfenac ophthalmic million, using the most current (2013) that the drug products were no longer solutions are currently on the market. Implicit Price Deflator for the Gross marketed and requested that the Thus, FDA is proposing to include all Domestic Product. We do not expect approval of the NDAs be withdrawn (see drug products containing bromfenac this proposed rule to result in any 1- the Federal Register of September 22, sodium on the list with an exception for year expenditure that would meet or 1999 (64 FR 51325), and June 16, 2006 ophthalmic solutions. exceed this amount. (71 FR 34940)). FDA announced it was For the convenience of the reader, the This rule proposes to amend § 216.24 withdrawing approval of the NDAs in regulatory text of § 216.24 provided concerning pharmacy compounding. the Federal Register of September 22, with this proposed rule includes the Specifically, the proposed rule would 1999 (64 FR 51325), and June 16, 2006 drug products proposed for addition add to or modify the list of drug (71 FR 34940). and modification discussed in this products that may not be compounded Valdecoxib: All drug products document and the drug products under the exemptions provided by containing valdecoxib. Valdecoxib, codified by the 1999 final rule. sections 503A and 503B of the FD&C formerly marketed as BEXTRA, was Act because the drug products were associated with increased risk of serious IV. Environmental Impact withdrawn or removed from the market cardiovascular events and an increased FDA has determined under 21 CFR because such drug products or risk of serious skin reactions (e.g., toxic 25.30(h) that this action is of a type that components of such drug products were epidermal necrolysis, Stevens-Johnson does not individually or cumulatively found to be unsafe or not effective (see syndrome, erythema multiforme) have a significant effect on the human section III). The Agency is proposing to compared to other nonsteroidal anti- environment. Therefore, neither an add 25 drug products to the list and to inflammatory drugs. On April 7, 2005, environmental assessment nor an FDA announced in an FDA Alert that it modify the description of 1 drug environmental impact statement is had concluded that the overall risk product on the list to add an exception. required. versus benefit profile of BEXTRA The Agency is not aware of any routine use of these drug products in pharmacy (valdecoxib) was unfavorable and that V. Analysis of Impacts the NDA holder had voluntarily compounding and, therefore, does not removed BEXTRA from the market (Ref. FDA has examined the impacts of the estimate any compliance costs or loss of 13). In letters dated May 27, 2011, proposed rule under Executive Order sales as a result of the prohibition August 8, 2011, and October 31, 2011, 12866, Executive Order 13563, the against compounding these drugs for the holder of the NDA for BEXTRA Regulatory Flexibility Act (5 U.S.C. human use. However, the Agency (valdexoxib) Tablets requested that FDA 601–612) and the Unfunded Mandates invites the submission of comments and withdraw the NDA for BEXTRA Reform Act of 1995 (Pub. L. 104–4). solicits current compounding usage data (valdexoxib) Tablets. FDA subsequently Executive Orders 12866 and 13563 for these drug products, if they are announced in the Federal Register of direct Agencies to assess all costs and compounded for human use. August 2, 2013 (78 FR 46984) that it was benefits of available regulatory Unless an Agency certifies that a rule withdrawing approval of the NDA. alternatives and, when regulation is will not have a significant economic necessary, to select regulatory impact on a substantial number of small C. Amendment To Modify the approaches that maximize net benefits entities, the Regulatory Flexibility Act Description of a Drug Product on the (including potential economic, requires Agencies to analyze regulatory List environmental, public health and safety, options to minimize any significant FDA is proposing to amend § 216.24 and other advantages; distributive economic impact of a regulation on to modify the description of bromfenac impacts; and equity). The Agency small entities. Most pharmacies meet sodium on the list. believes that this proposed rule is not a the Small Business Administration Bromfenac sodium: All drug products significant regulatory action as defined definition of a small entity, which is containing bromfenac sodium (except by Executive Order 12866. defined as having annual sales less than ophthalmic solutions). The use of The Regulatory Flexibility Act $25.5 million for this industry. The bromfenac sodium, formerly marketed requires Agencies to analyze regulatory Agency is not aware of any routine as DURACT (bromfenac sodium) options that would minimize any compounding of these drug products Capsules, was associated with fatal significant impact of a rule on small and does not estimate any compliance hepatic failure. The manufacturer of entities. Because small businesses are costs or loss of sales to small businesses DURACT Capsules voluntarily not expected to incur any compliance as a result of the prohibition against withdrew the drug from the market on costs or loss of sales due to this compounding these drugs. Therefore, June 22, 1998 (see the Federal Register regulation, we propose to certify that the Agency proposes to certify that this of October 8, 1998 (63 FR 54082)). On this rule will not have a significant proposed rule will not have a significant

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economic impact on a substantial Professionals/PublicHealthAdvisories/ www.fda.gov/Drugs/DrugSafety/ number of small entities. ucm053103.htm. PostmarketDrugSafetyInformationfor 2. Letter from E. Paul Mac Carthy, Vice PatientsandProviders/ucm103223.htm. VI. Paperwork Reduction Act of 1995 President, Head U.S. Medical Science, 13. FDA Alert—Information for Healthcare Bayer Corporation, to Healthcare Professionals: Valdecoxib (marketed as The submission of comments on this Professional, Re: Market withdrawal of Bextra) (April 7, 2005), http:// proposed rule and the submission of Baycol (cerivastatin) (August 8, 2001), www.fda.gov/Drugs/DrugSafety/ additional nominations for the list that http://www.fda.gov/downloads/Safety/ PostmarketDrugSafetyInformationfor is the subject of this rulemaking would MedWatch/SafetyInformation/Safety PatientsandProviders/ucm124649.htm. be submissions in response to a Federal AlertsforHumanMedicalProducts/ List of Subjects in 21 CFR Part 216 Register notice, in the form of UCM173692.pdf. comments, which are excluded from the 3. Letter from Jan Gheuens, Vice President, Drugs, Prescription drugs. definition of ‘‘information’’ under 5 CFR Medical Affairs, Janssen Pharmaceutica, Therefore, under the Federal Food, to Healthcare Professional (April 12, Drug, and Cosmetic Act and under 1320.3(h)(4) of OMB regulations on the 2000), PROPULSID (cisapride) Dear Paperwork Reduction Act (i.e., facts or Healthcare Professional Letter (April authority delegated to the Commissioner opinions submitted in response to 2000), http://www.fda.gov/Safety/ of Food and Drugs, the proposed rule general solicitations of comments from MedWatch/SafetyInformation/Safety that published on January 4, 2000 (65 the public, published in the Federal AlertsforHumanMedicalProducts/ FR 256), is withdrawn and it is Register or other publications, ucm175000.htm. proposed that 21 CFR part 216 be regardless of the form or format thereof, 4. FDA Alert—Information for Healthcare amended as follows: provided that no person is required to Professionals: Pemoline Tablets and Chewable Tablets (marketed as CYLERT) supply specific information pertaining PART 216—HUMAN DRUG (October 2005), http://www.fda.gov/ COMPOUNDING to the commenter, other than that Drugs/DrugSafety/PostmarketDrugSafety necessary for self-identification, as a InformationforPatientsandProviders/ ■ 1. The authority citation for 21 CFR condition of the Agency’s full ucm126461.htm. part 216 is revised to read as follows: consideration of the comment). The 5. FDA Public Health Advisory—Pergolide proposed rule contains no other (marketed as PERMAX) (March 29, Authority: 21 U.S.C. 351, 352, 353a, 353b, collection of information. 2007), http://www.fda.gov/Drugs/Drug 355, and 371. Safety/PostmarketDrugSafetyInformation ■ 2. The heading for part 216 is revised VII. Request for Comments forPatientsandProviders/DrugSafety to read as set forth above. ■ Interested persons may submit either InformationforHeathcareProfessionals/ 3. Section 216.24 is revised to read as PublicHealthAdvisories/ucm051285.htm. follows: electronic comments regarding this 6. FDA Public Health Advisory—Safety of document to http://www.regulations.gov Phenylpropanolamine (November 6, § 216.24 Drug products withdrawn or or written comments to the Division of 2000), http://www.fda.gov/Drugs/Drug removed from the market for reasons of Dockets Management (see ADDRESSES). It Safety/PostmarketDrugSafetyInformation safety or effectiveness. is only necessary to send one set of forPatientsandProviders/DrugSafety The following drug products were comments. Identify comments with the InformationforHeathcareProfessionals/ withdrawn or removed from the market docket number found in the brackets in PublicHealthAdvisories/ucm052236.htm. because such drug products or 7. FDA Drug Safety Communication—FDA the heading of this document. Received components of such drug products were comments may be seen in the Division Recommends Against the Continued Use of Propoxyphene (November 19, 2010), found to be unsafe or not effective. The of Dockets Management between 9 a.m. http://www.fda.gov/Drugs/DrugSafety/ following drug products may not be and 4 p.m., Monday through Friday, and ucm234338.htm. compounded under the exemptions will be posted to the docket at http:// 8. Letter from Deborah Shapse, Medical provided by section 503A(a) or section www.regulations.gov. Director, Organon, Inc., Re: Voluntary 503B(a) of the Federal Food, Drug, and Market Withdrawal of RAPLON VIII. References Cosmetic Act: (rapacuronium bromide) for Injection, Adenosine phosphate: All drug The following references have been All Batches (March 27, 2001), http:// products containing adenosine placed on display in the Division of www.fda.gov/downloads/Safety/ phosphate. MedWatch/SafetyInformation/Safety Dockets Management (see ADDRESSES) Adrenal cortex: All drug products AlertsforHumanMedicalProducts/ and may be seen by interested persons UCM173891.pdf. containing adrenal cortex. between 9 a.m. and 4 p.m., Monday 9. FDA Public Health Advisory—Safety of Alatrofloxacin mesylate: All drug through Friday, and are available VIOXX (September 30, 2004), http:// products containing alatrofloxacin electronically at http:// www.fda.gov/Drugs/DrugSafety/ mesylate. www.regulations.gov. (FDA has verified PostmarketDrugSafetyInformationfor Aminopyrine: All drug products the Web site addresses in this reference PatientsandProviders/ucm106274.htm. containing aminopyrine. section, but FDA is not responsible for 10. FDA Public Health Advisory—Tegaserod Astemizole: All drug products any subsequent changes to the Web sites maleate (marketed as ZELNORM) (March containing astemizole. after this document publishes in the 30, 2007), http://www.fda.gov/Drugs/ Azaribine: All drug products DrugSafety/PostmarketDrugSafety Federal Register.) containing azaribine. InformationforPatientsandProviders/ Benoxaprofen: All drug products 1. FDA Public Health Advisory Letter from DrugSafetyInformationforHeathcare containing benoxaprofen. Murray M. Lumpkin, Deputy Center Professionals/PublicHealthAdvisories/ Bithionol: All drug products Director (Review Management), Center ucm051284.htm. containing bithionol. for Drug Evaluation and Research, FDA, 11. FDA News Release, ‘‘FDA Permits Bromfenac sodium: All drug products Re: Food and Drug Administration Restricted Use of Zelnorm for Qualifying TROVAN (Trovafloxacin/Alatrofloxacin Patients’’ (July 27, 2007), http:// containing bromfenac sodium (except Mesylate) Interim Recommendations www.fda.gov/NewsEvents/Newsroom/ ophthalmic solutions). (June 9, 1999), http://www.fda.gov/ PressAnnouncements/2007/ Butamben: All parenteral drug Drugs/DrugSafety/PostmarketDrugSafety ucm108956.htm. products containing butamben. InformationforPatientsandProviders/ 12. FDA—ZELNORM (tegaserod maleate) Camphorated oil: All drug products DrugSafetyInformationforHeathcare Information (April 2, 2008), http:// containing camphorated oil.

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Carbetapentane citrate: All oral gel Mepazine: All drug products Propoxyphene: All drug products drug products containing containing mepazine hydrochloride or containing propoxyphene. carbetapentane citrate. mepazine acetate. Rapacuronium bromide: All drug Casein, iodinated: All drug products Metabromsalan: All drug products products containing rapacuronium containing iodinated casein. containing metabromsalan. bromide. Cerivastatin sodium: All drug Methamphetamine hydrochloride: All Reserpine: All oral dosage form drug products containing cerivastatin parenteral drug products containing products containing more than 1 sodium. methamphetamine hydrochloride. milligram of reserpine. Chloramphenicol: All oral drug Methapyrilene: All drug products Rofecoxib: All drug products products containing chloramphenicol. containing methapyrilene. containing rofecoxib. Chlorhexidine gluconate: All tinctures Methopholine: All drug products Sibutramine hydrochloride: All drug of chlorhexidine gluconate formulated containing methopholine. products containing sibutramine Methoxyflurane: All drug products for use as a patient preoperative skin hydrochloride. preparation. containing methoxyflurane. Mibefradil dihydrochloride: All drug Sparteine sulfate: All drug products Chlormadinone acetate: All drug containing sparteine sulfate. products containing chlormadinone products containing mibefradil dihydrochloride. Sulfadimethoxine: All drug products acetate. containing sulfadimethoxine. Chloroform: All drug products Nitrofurazone: All drug products containing nitrofurazone (except topical Sulfathiazole: All drug products containing chloroform. containing sulfathiazole (except for Cisapride: All drug products drug products formulated for dermatalogic application). those formulated for vaginal use). containing cisapride. Suprofen: All drug products Cobalt: All drug products containing Nomifensine maleate: All drug containing suprofen (except ophthalmic cobalt salts (except radioactive forms of products containing nomifensine solutions). cobalt and its salts and cobalamin and maleate. Sweet spirits of nitre: All drug its derivatives). Novobiocin sodium: All drug products products containing sweet spirits of Dexfenfluramine hydrochloride: All containing novobiocin sodium. Oxycodone hydrochloride: All nitre. drug products containing extended-release drug products dexfenfluramine hydrochloride. Tegaserod maleate: All drug products containing oxycodone hydrochloride Diamthazole dihydrochloride: All containing tegaserod maleate. that have not been determined by FDA drug products containing diamthazole Temafloxacin hydrochloride: All drug to have abuse-deterrent properties. dihydrochloride. products containing temafloxacin. Oxyphenisatin: All drug products Dibromsalan: All drug products Terfenadine: All drug products containing oxyphenisatin. containing terfenadine. containing dibromsalan. Oxyphenisatin acetate: All drug ′ ′ Diethylstilbestrol: All oral and 3,3 ,4 ,5-tetrachlorosalicylanilide: All products containing oxyphenisatin ′ ′ parenteral drug products containing 25 drug products containing 3,3 ,4 ,5- acetate. tetrachlorosalicylanilide. milligrams or more of diethylstilbestrol Pemoline: All drug products per unit dose. Tetracycline: All liquid oral drug containing pemoline. products formulated for pediatric use Dihydrostreptomycin sulfate: All drug Pergolide mesylate: All drug products products containing containing tetracycline in a containing pergolide mesylate. concentration greater than 25 dihydrostreptomycin sulfate. Phenacetin: All drug products milligrams/milliliter. Dipyrone: All drug products containing phenacetin. containing dipyrone. Phenformin hydrochloride: All drug Ticrynafen: All drug products Encainide hydrochloride: All drug products containing phenformin containing ticrynafen. products containing encainide hydrochloride. Tribromsalan: All drug products hydrochloride. Phenylpropanolamine: All drug containing tribromsalan. Esmolol hydrochloride: All parenteral products containing Trichloroethane: All aerosol drug dosage form drug products containing phenylpropanolamine. products intended for inhalation esmolol hydrochloride that supply 250 Pipamazine: All drug products containing trichloroethane. milligrams/milliliter of concentrated containing pipamazine. Troglitazone: All drug products esmolol per 10-milliliter ampule. Polyethylene glycol 3350, sodium containing troglitazone. Etretinate: All drug products chloride, sodium bicarbonate, Trovafloxacin mesylate: All drug containing entretinate. potassium chloride, and bisacodyl: All products containing trovafloxacin Fenfluramine hydrochloride: All drug drug products containing polyethylene mesylate. products containing fenfluramine glycol 3350, sodium chloride, sodium Urethane: All drug products hydrochloride. bicarbonate, and potassium chloride for containing urethane. Flosequinan: All drug products oral solution, and 10 milligrams or more Valdecoxib: All drug products containing flosequinan. of bisacodyl delayed-release tablets. containing valdecoxib. Gatifloxacin: All drug products Potassium arsenite: All drug products Vinyl chloride: All aerosol drug containing gatifloxacin (except containing potassium arsenite. products containing vinyl chloride. ophthalmic solutions). Potassium chloride: All solid oral Zirconium: All aerosol drug products Gelatin: All intravenous drug dosage form drug products containing containing zirconium. products containing gelatin. potassium chloride that supply 100 Zomepirac sodium: All drug products Glycerol, iodinated: All drug products milligrams or more of potassium per containing zomepirac sodium. containing iodinated glycerol. dosage unit (except for controlled- Gonadotropin, chorionic: All drug release dosage forms and those products Dated: June 25, 2014. products containing chorionic formulated for preparation of solution Leslie Kux, gonadotropins of animal origin. prior to ingestion). Assistant Commissioner for Policy. Grepafloxacin: All drug products Povidone: All intravenous drug [FR Doc. 2014–15371 Filed 7–1–14; 8:45 am] containing grepafloxacin. products containing povidone. BILLING CODE 4164–01–P

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