Drugs for Human Use; Unapproved and Misbranded Oral Drugs Labeled for Prescription Use and Offered for Relief of Symptoms of Cold, Cough, or Allergy; Enforcement Action Dates, 11794-11798 [2011-4703]

Download as PDF 11794 Federal Register / Vol. 76, No. 42 / Thursday, March 3, 2011 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2011–N–0100] Drugs for Human Use; Unapproved and Misbranded Oral Drugs Labeled for Prescription Use and Offered for Relief of Symptoms of Cold, Cough, or Allergy; Enforcement Action Dates AGENCY: Food and Drug Administration, HHS. ACTION: Notice. The Food and Drug Administration (FDA) is announcing its intention to take enforcement action against unapproved and misbranded oral drug products that are labeled for prescription use and offered for relief of symptoms of cold, cough, or allergy and persons who manufacture or cause the manufacture of such products. These drug products are marketed without approved applications, and many are inappropriately labeled for use in infants and young children. These drug products must obtain FDA approval of a new drug application (NDA) or an abbreviated new drug application (ANDA), or comply with an FDA overthe-counter (OTC) drug final monograph, before marketing. DATES: This notice is effective March 3, 2011. For information about enforcement dates, see SUPPLEMENTARY INFORMATION, section IV. ADDRESSES: All communications in response to this notice should be identified with Docket No. FDA–2011– N–0100 and directed to Sakineh Walther, Division of New Drugs and Labeling Compliance, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 5242, Silver Spring, MD 20993–0002. FOR FURTHER INFORMATION CONTACT: Sakineh Walther, Division of New Drugs and Labeling Compliance, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 5242, Silver Spring, MD 20993–0002, 301– 796–3349, e-mail: sakineh.walther@fda.hhs.gov. SUMMARY: srobinson on DSKHWCL6B1PROD with NOTICES SUPPLEMENTARY INFORMATION: I. Background A. Cold, Cough, and Allergy Products Covered by This Notice This Federal Register notice covers certain unapproved and misbranded drug products that are available in oral form and labeled for prescription use. VerDate Mar<15>2010 16:47 Mar 02, 2011 Jkt 223001 B. Regulatory History of Products Covered by This Notice Many of the drug products covered by this notice contain active ingredients that were introduced into the marketplace without prior review for effectiveness. When initially enacted in 1938, the Federal Food, Drug, and Cosmetic Act (the FD&C Act) required that FDA review and approve ‘‘new drugs’’ for safety, but not effectiveness, before they could legally be sold in interstate commerce.2 The FD&C Act made it the sponsor’s burden to show FDA that its drug was safe through the submission of an NDA. Between 1938 and 1962, if a drug obtained approval, FDA considered drugs that were identical, related, or similar (IRS) 3 to the approved drug to be ‘‘covered’’ by that approval, and allowed those IRS drugs to be marketed without independent approval. In 1962, Congress amended the FD&C Act to require that new drugs be proven effective for their labeled indications, as well as safe. This amendment also required FDA to conduct a retrospective evaluation of effectiveness for all drugs approved as safe between 1938 and 1962. FDA contracted with the National Academy of Sciences/National Research Council (NAS/NRC) to make an initial evaluation of the effectiveness of over 3,400 products that had been approved only for safety between 1938 and 1962. The NAS/NRC reports for these drug products were submitted to FDA in the late 1960s and early 1970s. The Agency reviewed and reevaluated the reports and published its findings in Federal Register notices. FDA’s administrative implementation of the NAS/NRC reports was called the Drug Efficacy Study 1 The term ‘‘extended-release’’ is used in this document to include all timed-release products, including products labeled as ‘‘sustained-release,’’ ‘‘controlled-release,’’ ‘‘delayed-release,’’ or ‘‘longacting.’’ (See 21 CFR 310.502(a)(14).) 2 A ‘‘new drug’’ is defined by the FD&C Act as a drug that is not generally recognized, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling (section 201 of the FD&C Act (21 U.S.C. 321(p)). 3 FDA’s regulations at (21 CFR 310.6(b)(1)) provide: ‘‘An identical, related, or similar drug includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety as well as of any drug moiety related in chemical structure or known pharmacological properties.’’ Implementation (DESI). DESI covered the approximately 3,400 products specifically reviewed by the NAS/NRC, as well as the even larger number of IRS products that entered the market without FDA approval.4 Many of the drug products covered by this notice contain the same active ingredients as drug products that were reviewed for effectiveness through the DESI process. All drugs covered by the DESI review are ‘‘new drugs’’ under the FD&C Act. If FDA’s final DESI determination classifies a drug product as ineffective for one or more indications, that drug product and those IRS to it can no longer be marketed for such indications and are subject to enforcement action as unapproved new drugs. If FDA’s final DESI determination classifies a drug product as effective for one or more of its labeled indications, the drug, and those IRS to it, can be marketed for such indications, provided each product is the subject of an application approved for safety and effectiveness. Those drug products with NDAs approved before 1962 for safety therefore require approved supplements to their original applications if found effective under DESI; IRS drug products require an approved NDA or ANDA, as appropriate. Furthermore, labeling for these drug products may contain only those indications for which the DESI review found the product effective unless the firm marketing the product has received approval for additional indication(s). In the early 1970s, FDA granted temporary exemptions from the time limits established for completing certain phases of the DESI program for certain oral prescription drugs offered for relief of cold, cough, allergy, and related symptoms (38 FR 34481, December 14, 1973). The exemptions were granted because of the close relationship between these prescription drugs and OTC drugs, which were subject to the ongoing OTC drug review. (See 21 CFR part 330.) Postponement of final evaluations of these DESI prescription products enabled the Agency to consider the recommendations of the OTC review panel in addition to any evidence submitted by NDA holders and other parties in response to various DESI notices covering relevant products. II. Safety Concerns With Unapproved New Drugs These products are offered for relief of symptoms relating to cold, cough, or allergy, and include antitussives, expectorants, antihistamines, and nasal decongestants. This notice covers extended-release,1 tannate, and immediate-release drug products. PO 00000 Frm 00044 Fmt 4703 Sfmt 4703 Because marketed unapproved new drug products have not been through 4 Section 310.6(b)(2)) provides that when qualified experts determine that the findings in a DESI notice are applicable to an IRS drug, that IRS drug is affected by the DESI notice. E:\FR\FM\03MRN1.SGM 03MRN1 srobinson on DSKHWCL6B1PROD with NOTICES Federal Register / Vol. 76, No. 42 / Thursday, March 3, 2011 / Notices FDA’s approval process, there may be safety risks associated with them. Some unapproved product labeling omits or modifies safety warnings or other information that is important to ensure safe use, such as drug interactions or potential adverse experiences. FDA is particularly concerned about pediatric labeling for these unapproved products. Some of the unapproved products covered by this notice are labeled and marketed for use in children as young as 1 month of age. Without reviewing applications for these products, FDA has no way to assess the scientific support, if any, for the use of these products in pediatric populations. FDA also has concerns regarding the manufacturing processes for unapproved new drugs and changes in the formulations of these products. When new drugs are marketed without FDA approval, FDA does not have an opportunity, prior to product marketing, to determine whether the manufacturing process for the drugs is adequate to ensure that they are of suitable quality. Additionally, there is no opportunity prior to marketing for FDA to review and approve proprietary names to minimize potential safety issues caused by product name confusion. In fact, FDA has received reports of name confusion associated with unapproved prescription products covered by this notice. Look-alike and sound-alike similarities between product names may contribute to medication errors and adverse events. Similarly, the new drug approval requirement allows the Agency to evaluate proposed changes to approved product formulations to ensure that such modifications meet FDA standards for safety and effectiveness and to ensure that formulation changes are accompanied, as necessary, by appropriate changes in product proprietary names or labeling, or other measures that may be warranted to minimize confusion and risks to patients. Modifications of product formulations that are not made under FDA’s drug approval process thus pose an increased risk of confusing healthcare practitioners and causing harm to consumers, such as underdose or overdose, particularly in pediatric patients. Finally, FDA has specific safety concerns about the products covered by this notice that are marketed as extended-release products. Many of these products contain amounts of active ingredients that could pose safety risks if the same amount of active ingredient were contained in an immediate-release dosage form. Without prior review of applications for these VerDate Mar<15>2010 16:47 Mar 02, 2011 Jkt 223001 products, there is no assurance that the firms that market these products have established appropriate specifications for release of the active ingredients or that the products are properly formulated and manufactured to release their active ingredients to an extent and at a rate that is both safe and effective. III. Legal Status of Products Identified in This Notice A. Extended-Release Products Some of the products covered by this notice are sold as extended-release products. Since 1959, FDA has concluded that all products in extended-release dosage forms are new drugs requiring approved NDAs or ANDAs before being marketed (24 FR 3756, May 9, 1959). Agency review of individual applications for extendedrelease products is needed to ensure that the finished product releases its active ingredient to an extent and at a rate that is both safe, with a predictable and controlled release of the dose, and effective, sustaining the intended effect over the entire dosing interval. Firms submitting applications are required to establish appropriate release specifications supported by clinical evidence, along with data showing that the finished product as manufactured by the firm releases its active ingredient according to those specifications. The Agency’s determination that all products in timed-release dosage form are new drugs requiring approved applications is codified at 21 CFR 310.502(a)(14). Approval of an NDA under section 505(b) of the FD&C Act (21 U.S.C. 355(b)) or an ANDA under section 505(j) of the FD&C Act is required as a condition for marketing all such products. The unapproved extended-release drug products subject to this notice are all labeled for prescription use. Prescription drugs are defined under section 503(b)(1)(A) of the FD&C Act (21 U.S.C. 353(b)(1)(A)) as drugs that, because of toxicity or other potentially harmful effect, are not safe to use except under the supervision of a practitioner licensed by law to administer such drugs.5 A drug that is labeled as a prescription drug but does not meet the definition of ‘‘prescription drug’’ under section 503(b)(1)(A) of the FD&C Act is misbranded under section 503(b)(4)(B) of the FD&C Act (21 U.S.C. 353(b)(4)(B)). Thus, if an extended-release drug 5 The definition of ‘‘prescription drug’’ also includes a drug that is limited by an approved application to use under the professional supervision of a licensed practitioner (21 U.S.C. 353(b)(1)(B)). This prong of the definition obviously does not apply to the unapproved extended-release drug products covered by this notice. PO 00000 Frm 00045 Fmt 4703 Sfmt 4703 11795 covered by this notice is labeled as a prescription product, but does not meet the definition in section 503(b)(1)(A) of the FD&C Act, it is misbranded under section 503(b)(4)(B) of the FD&C Act. If an extended-release drug subject to this notice actually meets the definition of ‘‘prescription drug’’ under 503(b)(1)(A), it is misbranded under section 502(f)(1) of the FD&C Act (21 U.S.C. 352(f)(1)), in that it fails to bear adequate directions for use. An approved prescription drug can satisfy the ‘‘adequate directions for use’’ requirement if it bears the NDAapproved labeling (§§ 201.100(c)(2) and 201.115 (21 CFR 201.100(c)(2) and 201.115)). Because the unapproved prescription extended-release drug products covered by this notice do not have approved applications with approved labeling, they fail to bear ‘‘adequate directions for use,’’ and are misbranded under section 502(f)(1) of the FD&C Act. B. Tannates Some of the products covered by this notice contain active ingredients that are in tannate salt form (tannate drugs). FDA has reviewed the publicly available scientific literature on these ingredients, and has determined that unapproved oral drugs labeled for prescription use and offered for relief of symptoms of cold, cough, or allergy that contain the following ingredients are not generally recognized as safe and effective (GRASE): Brompheniramine tannate; carbetapentane tannate; carbinoxamine tannate; chlorpheniramine tannate; dexbrompheniramine tannate; dexchlorpheniramine tannate; dextromethorphan tannate; diphenhydramine tannate; ephedrine tannate; phenylephrine tannate; pseudoephedrine tannate; pyrilamine tannate; and triprolidine tannate. Therefore, products containing these ingredients are new drugs within the meaning of section 201(p) of the FD&C Act, and require approved NDAs or ANDAs before marketing. The unapproved tannate drug products subject to this notice are all labeled for prescription use. Prescription drugs are defined under section 503(b)(1)(A) of the FD&C Act as drugs that, because of toxicity or other potentially harmful effect, are not safe to use except under the supervision of a practitioner licensed by law to administer such drugs.6 A drug that is 6 The definition of ‘‘prescription drug’’ also includes a drug that is limited by an approved application to use under the professional supervision of a licensed practitioner (21 U.S.C. 353(b)(1)(B)). This prong of the definition obviously E:\FR\FM\03MRN1.SGM Continued 03MRN1 11796 Federal Register / Vol. 76, No. 42 / Thursday, March 3, 2011 / Notices labeled as a prescription drug but does not meet the definition of ‘‘prescription drug’’ under section 503(b)(1)(A) of the FD&C Act is misbranded under section 503(b)(4)(B) of the FD&C Act. Thus, if a tannate drug covered by this notice is labeled as a prescription product, but does not meet the definition in section 503(b)(1)(A) of the FD&C Act, it is misbranded under section 503(b)(4)(B) of the FD&C Act. If a tannate drug covered by this notice actually meets the definition of ‘‘prescription drug,’’ it is misbranded under section 502(f)(1) of the FD&C Act, in that it fails to bear adequate directions for use. An approved prescription drug can satisfy the ‘‘adequate directions for use’’ requirement if it bears the NDAapproved labeling (21 CFR 201.100(c)(2) and 201.115). Because the unapproved prescription tannate drug products covered by this notice do not have approved applications with approved labeling, they fail to bear ‘‘adequate directions for use,’’ and are misbranded under section 502(f)(1) of the FD&C Act. C. Immediate-Release Products The remaining unapproved oral products covered by this notice are immediate-release products labeled for prescription use and offered for relief of symptoms associated with cold, cough, or allergy. The immediate-release products fall into the following three categories: srobinson on DSKHWCL6B1PROD with NOTICES 1. Drugs Inappropriately Labeled for Prescription Use A small number of the immediaterelease products covered by this notice conform to the requirements of the final OTC monograph at 21 CFR part 341, ‘‘Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use’’ (the final OTC Cold Cough monograph), except that they are labeled for prescription use only. Section 503(b)(1) of the FD&C Act establishes the definition of a ‘‘prescription drug.’’ Drug products that do not meet the definition of a prescription drug but are labeled for prescription use are misbranded under section 503(b)(4)(B) of the FD&C Act. If these drugs conform to the requirements of the final OTC Cold Cough monograph, they are not new drugs and they do not require an approved NDA or ANDA in order to be legally marketed OTC.7 does not apply to the unapproved tannate drug products covered by this notice. 7 In addition to any other applicable requirements, firms that manufacture OTC drugs must comply with the labeling requirements at 21 CFR 201.66. VerDate Mar<15>2010 16:47 Mar 02, 2011 Jkt 223001 2. Drugs Containing Ingredients Included in the Final OTC Cold Cough Monograph But Labeled With Nonconforming Indications or Dosing Regimens The majority of the immediate-release products covered by this notice are labeled for prescription use and contain ingredients that are included in the final OTC Cold Cough monograph, but have indications, dosing regimens, or both, that are inconsistent with that monograph. FDA has reviewed the indications and dosing regimens (dosing intervals and dosage amounts) in the labeling of over 300 such products, and has reviewed the publicly available scientific literature for studies of these products.8 In no case did FDA find literature sufficient to support a determination that one of these products was GRASE for relief of symptoms of cold, cough, or allergy. Therefore, these products are all ‘‘new drugs’’ within the meaning of section 201(p) of the FD&C Act, that require approved NDAs or ANDAs before marketing. The unapproved immediate-release drug products subject to this notice that contain ingredients that are included in the final OTC Cold Cough monograph, but with indications, dosing regimens, or both, that are inconsistent with that monograph, are all labeled for prescription use. Prescription drugs are defined under section 503(b)(1)(A) of the FD&C Act as drugs that, because of toxicity or other potentially harmful effect, are not safe to use except under the supervision of a practitioner licensed by law to administer such drugs.9 A drug that is labeled as a prescription drug but does not meet the definition of ‘‘prescription drug’’ under section 503(b)(1)(A) of the FD&C Act is misbranded under section 503(b)(4)(B) of the FD&C Act. Thus, if an immediaterelease drug covered by this notice is labeled as a prescription product, but does not meet the definition in section 503(b)(1)(A), it is misbranded under section 503(b)(4)(B). If an immediaterelease drug covered by this notice does meet the definition of ‘‘prescription drug’’ in 503(b)(1)(A), it is misbranded under section 502(f)(1) of the FD&C Act, 8 The over 300 products reviewed by FDA represent all products in this category that FDA was able to identify. 9 The definition of ‘‘prescription drug’’ also includes a drug that is limited by an approved application to use under the professional supervision of a licensed practitioner (21 U.S.C. 353(b)(1)(B)). This prong of the definition obviously does not apply to the unapproved immediaterelease drug products subject to this notice and containing ingredients that are included in the final OTC Cold Cough monograph, but with indications, dosing regimens, or both, that are inconsistent with that monograph. PO 00000 Frm 00046 Fmt 4703 Sfmt 4703 in that it fails to bear adequate directions for use. An approved prescription drug can satisfy the ‘‘adequate directions for use’’ requirement if it bears the NDAapproved labeling (§§ 201.100(c)(2) and 201.115). Because the unapproved prescription immediate-release drug products subject to this notice that contain ingredients that are included in the final OTC Cold Cough monograph, but with indications, dosing regimens, or both, that are inconsistent with that monograph, do not have approved applications with approved labeling, they fail to bear ‘‘adequate directions for use,’’ and are misbranded under section 502(f)(1). 3. Drugs Containing Ingredients Not Included in the Final OTC Cold Cough Monograph The remaining immediate-release products covered by this notice are labeled for prescription use and contain active ingredients that are not included in the final OTC Cold Cough monograph. FDA has reviewed the publicly available scientific literature on these ingredients, and has determined that the products covered by this notice and offered for relief of symptoms of cold, cough, or allergy that contain the following ingredients are not GRASE: Atropine; carbetapentane; cyproheptadine; dyphylline; hyoscyamine; methscopolamine nitrate; phenyltoloxamine; potassium guaiacosulfonate; promethazine; and scopolamine. Therefore, products covered by this notice containing these ingredients and marketed for relief of symptoms of cold, cough, or allergy are new drugs within the meaning of section 201(p) of the FD&C Act, and require approved NDAs or ANDAs prior to marketing. The unapproved immediate-release drug products that are subject to this notice and that contain active ingredients not included in the final OTC Cold Cough monograph are all labeled for prescription use. Prescription drugs are defined under section 503(b)(1)(A) of the FD&C Act as drugs that, because of toxicity or other potentially harmful effect, are not safe to use except under the supervision of a practitioner licensed by law to administer such drugs.10 A drug that is 10 The definition of ‘‘prescription drug’’ also includes a drug that is limited by an approved application to use under the professional supervision of a licensed practitioner (21 U.S.C. 353(b)(1)(B)). This prong of the definition obviously does not apply to the unapproved immediaterelease drug products covered by this notice that contain active ingredients not included in the final OTC Cold Cough monograph. E:\FR\FM\03MRN1.SGM 03MRN1 Federal Register / Vol. 76, No. 42 / Thursday, March 3, 2011 / Notices srobinson on DSKHWCL6B1PROD with NOTICES labeled as a prescription drug but does not meet the definition of ‘‘prescription drug’’ under section 503(b)(1)(A) is misbranded under section 503(b)(4)(B) of the FD&C Act. Thus, if an immediaterelease drug covered by this notice is labeled as a prescription product, but does not meet the definition in section 503(b)(1)(A), it is misbranded under section 503(b)(4)(B). If a drug covered by this notice meets the definition of ‘‘prescription drug’’ in 503(b)(1)(A), it is misbranded under section 502(f)(1) of the FD&C Act, in that it fails to bear adequate directions for use. An approved prescription drug can satisfy the ‘‘adequate directions for use’’ requirement if it bears the NDAapproved labeling (§§ 201.100(c)(2) and 201.115). Because the unapproved prescription immediate-release drug products covered by this notice that contain active ingredients not included in the final OTC Cold Cough monograph do not have approved applications with approved labeling, they fail to bear ‘‘adequate directions for use,’’ and are misbranded under section 502(f)(1) of the FD&C Act. IV. Notice of Enforcement Action Although not required to do so by the Administrative Procedure Act, the FD&C Act, or any rules issued under its authority, or for any other legal reason, FDA is providing this notice to persons 11 who are marketing unapproved and misbranded oral drug products labeled for prescription use and offered for relief of symptoms relating to cold, cough, or allergy that the Agency intends to take enforcement action against such products and those who manufacture them or cause them to be manufactured or shipped in interstate commerce. Manufacturing or shipping the drug products covered by this notice can result in enforcement action, including seizure, injunction, or other judicial or administrative proceeding. Consistent with policies described in the Agency’s guidance entitled ‘‘Marketed Unapproved Drugs—Compliance Policy Guide’’ (the Marketed Unapproved Drugs CPG) (https://www.fda.gov/ downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ UCM070290.pdf), the Agency does not expect to issue a warning letter or any other further warning to firms marketing drug products covered by this notice prior to taking enforcement action. The Agency also reminds firms that, as stated in the Marketed Unapproved Drugs CPG, any unapproved drug 11 A ‘‘person’’ includes individuals, partnerships, corporations, and associations (21 U.S.C. 321(e)). VerDate Mar<15>2010 16:47 Mar 02, 2011 Jkt 223001 marketed without a required approved application is subject to Agency enforcement action at any time. The issuance of this notice does not in any way obligate the Agency to issue similar notices or any notice in the future regarding marketed unapproved drugs.12 As described in the Marketed Unapproved Drugs CPG, the Agency may, at its discretion, identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug solely on the ground that it lacks an approved application under section 505 of the FD&C Act. With respect to drug products covered by this notice, the Agency intends to exercise its enforcement discretion for only a limited period of time because there are safety issues with respect to the products covered by this notice and numerous marketed products that have approved applications or comply with the applicable OTC drug final monograph are offered to treat symptoms relating to cold, cough, and allergy. Therefore, the Agency intends to implement this notice as follows. For the effective date of this notice, see the DATES section of this document. FDA intends to take enforcement action against any drug product covered by this notice that is not listed with the Agency in full compliance with section 510 of the FD&C Act (21 U.S.C. 360) before March 2, 2011, and is manufactured, shipped, or otherwise introduced or delivered for introduction into interstate commerce by any person on or after March 3, 2011. FDA also intends to take enforcement action against any drug product covered by this notice that is listed with FDA in full compliance with section 510 of the FD&C Act but is not being commercially used or sold 13 in the United States on March 2, 2011 and that is manufactured, shipped, or otherwise introduced or delivered for introduction into interstate commerce by any person on or after March 3, 2011. However, for drug products covered by this notice that are commercially used or sold in the United States, have a National Drug Code (NDC) number listed with FDA, and are in full 12 The Agency’s general approach for dealing with these products in an orderly manner is spelled out in the Marketed Unapproved Drugs CPG. That CPG, however, provides notice that any product that is being marketed illegally, and the persons responsible for causing the illegal marketing of the product, are subject to FDA enforcement action at any time. 13 For purposes of this notice, the term ‘‘commercially used or sold’’ means that the product has been used in a business or activity involving retail or wholesale marketing and/or sale. PO 00000 Frm 00047 Fmt 4703 Sfmt 4703 11797 compliance with section 510 of the FD&C Act before March 2, 2011 (‘‘currently marketed and listed’’), the Agency intends to exercise its enforcement discretion as follows. FDA intends to initiate enforcement action against any currently marketed and listed product covered by this notice that is manufactured on or after June 1, 2011 or that is shipped on or after August 30, 2011.14 Further, FDA intends to take enforcement action against any person who manufactures or ships such products after these dates. Any person who has submitted or submits an application for a drug product covered by this notice but has not received approval must comply with this notice. The Agency, however, does not intend to exercise its enforcement discretion as outlined previously if the following apply: (1) A manufacturer or distributor of drug products covered by this notice is violating other provisions of the FD&C Act, including, but not limited to, violations related to FDA’s current good manufacturing practices, adverse drug event reporting, labeling or misbranding requirements other than those identified in this notice or (2) it appears that a firm, in response to this notice, increases its manufacture or interstate shipment of drug products covered by this notice above its usual volume during these periods. Nothing in this notice, including FDA’s intent to exercise its enforcement discretion, alters any person’s liability or obligations in any other enforcement action, or precludes the Agency from initiating or proceeding with enforcement action in connection with any other alleged violation of the FD&C Act, whether or not related to a drug product covered by this notice. Similarly, a person who is or becomes enjoined from marketing unapproved or misbranded drugs may not resume marketing of such products based on FDA’s exercise of enforcement discretion that is set forth in this notice. Drug manufacturers and distributors should be aware that the Agency is exercising its enforcement discretion as described previously only in regard to 14 If FDA finds it necessary to take enforcement action against a product covered by this notice, the agency may take action relating to all of the defendant’s other violations of the FD&C Act at the same time. For example, if a firm continues to manufacture or market a product covered by this notice after the applicable enforcement date has passed, to preserve limited agency resources, FDA may take enforcement action relating to all of the firm’s unapproved drugs that require applications at the same time. (See, e.g., United States v. Sage Pharmaceuticals, 210 F.3d 475, 479–480 (5th Cir. 2000) (permitting the Agency to combine all violations of the act in one proceeding, rather than taking action against multiple violations of the act in ‘‘piecemeal fashion’’).) E:\FR\FM\03MRN1.SGM 03MRN1 11798 Federal Register / Vol. 76, No. 42 / Thursday, March 3, 2011 / Notices drug products covered by this notice that are marketed under an NDC number listed with the Agency in full compliance with section 510 of the FD&C Act before March 2, 2011. As previously stated, drug products covered by this notice that are currently marketed but not listed with the Agency on the date of this notice must, as of the effective date of this notice, have approved applications prior to their shipment in interstate commerce. Moreover, any person or firm that has submitted or submits an application but has yet to receive approval for such products is still responsible for full compliance with this notice. V. Discontinued Products Some firms may have previously discontinued the manufacturing or distribution of products covered by this notice without removing them from the listing of their products under section 510(j) of the FD&C Act. Other firms may discontinue manufacturing or marketing listed products in response to this notice. Firms that wish to notify the Agency of product discontinuation should send a letter, signed by the firm’s chief executive officer, fully identifying the discontinued product(s), including NDC number(s), and stating that the product(s) has (have) been discontinued. The letter should be sent to Sakineh Walther (see ADDRESSES). Firms should also update the listing of their products under section 510(j) of the FD&C Act to reflect discontinuation of products covered by this notice. FDA plans to rely on its existing records, including its drug listing records, or other available information when it targets violations for enforcement action. This notice is issued under the Federal Food, Drug, and Cosmetic Act (sections 502 and 505 (21 U.S.C. 352 and 355)) and under authority delegated to the Assistant Commissioner for Policy under section 1410.21 of the FDA Staff Manual Guide. Dated: February 22, 2011. Leslie Kux, Acting Assistant Commissioner for Policy. srobinson on DSKHWCL6B1PROD with NOTICES [FR Doc. 2011–4703 Filed 3–2–11; 8:45 am] DEPARTMENT OF HEALTH AND HUMAN SERVICES DEPARTMENT OF HEALTH AND HUMAN SERVICES Health Resources and Services Administration National Institutes of Health Advisory Committee on Organ Transplantation; Notice of Meeting Health Resources and Services Administration, HHS. AGENCY: ACTION: Notice; correction. The Health Resources and Services Administration published a notice in the Federal Register of February 9, 2011 (76 FR 7223–7224) announcing an Advisory Committee on Organ Transplantation meeting on March 8, 2011. The type of meeting, time and place have been changed. SUMMARY: Correction In the Federal Register of February 9, 2011, in FR Doc. 2011–2839, on page 7223, 2nd column, under the heading Department of Health and Human Services, Health Resources and Services Administration, Advisory Committee on Organ Transplantation; Notice of Meeting, change the Times and Place to read: The meeting will be an Audio Conference Call on March 8, 2011, from 12 noon to 4 p.m. EST. To access the conference call, call the USA Toll Free Number 888–469–1090 and enter the Passcode 2741198. The conference call leader is Patricia A. Stroup. Participants should call no later than 11:45 a.m. EST in order for logistics to be set up. Participants are asked to register for the conference call by contacting Brittany Carey, HRM/Professional and Scientific Associates (PSA), the logistical support contractor for the meeting, at (703) 889– 9033 or b_carey@team-psa.com. The registration deadline is March 7, 2011. The Department will try to accommodate those wishing to participate in the call. The next face-to-face ACOT meeting is planned for August 2011. Details regarding an August meeting will be published in a subsequent Federal Register notice. Reva Harris, Acting Director, Division of Policy and Information Coordination. BILLING CODE 4160–01–P [FR Doc. 2011–4755 Filed 3–2–11; 8:45 am] BILLING CODE 4165–15–P VerDate Mar<15>2010 16:47 Mar 02, 2011 Jkt 223001 PO 00000 Frm 00048 Fmt 4703 Sfmt 4703 National Institute on Aging; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of the following meeting. The meeting will be closed to the public in accordance with the provisions set forth in sections 552b(c)(4) and 552b(c)(6), Title 5 U.S.C., as amended. The grant applications and the discussions could disclose confidential trade secrets or commercial property such as patentable material, and personal information concerning individuals associated with the grant applications, the disclosure of which would constitute a clearly unwarranted invasion of personal privacy. Name of Committee: National Institute on Aging Special Emphasis Panel; Member Conflict. Date: March 15, 2011. Time: 9 a.m. to 10 a.m. Agenda: To review and evaluate grant applications. Place: National Institute on Aging, Gateway Building, 7201 Wisconsin Avenue, Suite 2C212, Bethesda, MD 20892 (Telephone Conference Call). Contact Person: Ramesh Vemuri, PhD, Chief, Scientific Review Branch, National Institute on Aging, National Institutes of Health, 7201 Wisconsin Avenue, Suite 2C– 212, Bethesda, MD 20892, 301–402–7700, rv23r@nih.gov. This notice is being published less than 15 days prior to the meeting due to the timing limitations imposed by the review and funding cycle. (Catalogue of Federal Domestic Assistance Program Nos. 93.866, Aging Research, National Institutes of Health, HHS) Dated: February 25, 2011. Jennifer S. Spaeth, Director, Office of Federal Advisory Committee Policy. [FR Doc. 2011–4826 Filed 3–2–11; 8:45 am] BILLING CODE 4140–01–P DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Center for Research Resources; Notice of Closed Meetings Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of the following meetings. The meetings will be closed to the public in accordance with the provisions set forth in sections E:\FR\FM\03MRN1.SGM 03MRN1

Agencies

[Federal Register Volume 76, Number 42 (Thursday, March 3, 2011)]
[Notices]
[Pages 11794-11798]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-4703]



[[Page 11794]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-N-0100]


Drugs for Human Use; Unapproved and Misbranded Oral Drugs Labeled 
for Prescription Use and Offered for Relief of Symptoms of Cold, Cough, 
or Allergy; Enforcement Action Dates

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA) is announcing its 
intention to take enforcement action against unapproved and misbranded 
oral drug products that are labeled for prescription use and offered 
for relief of symptoms of cold, cough, or allergy and persons who 
manufacture or cause the manufacture of such products. These drug 
products are marketed without approved applications, and many are 
inappropriately labeled for use in infants and young children. These 
drug products must obtain FDA approval of a new drug application (NDA) 
or an abbreviated new drug application (ANDA), or comply with an FDA 
over-the-counter (OTC) drug final monograph, before marketing.

DATES: This notice is effective March 3, 2011. For information about 
enforcement dates, see SUPPLEMENTARY INFORMATION, section IV.

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. FDA-2011-N-0100 and directed to Sakineh 
Walther, Division of New Drugs and Labeling Compliance, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 5242, Silver Spring, MD 20993-0002.

FOR FURTHER INFORMATION CONTACT: Sakineh Walther, Division of New Drugs 
and Labeling Compliance, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 5242, 
Silver Spring, MD 20993-0002, 301-796-3349, e-mail: 
sakineh.walther@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

A. Cold, Cough, and Allergy Products Covered by This Notice

    This Federal Register notice covers certain unapproved and 
misbranded drug products that are available in oral form and labeled 
for prescription use. These products are offered for relief of symptoms 
relating to cold, cough, or allergy, and include antitussives, 
expectorants, antihistamines, and nasal decongestants. This notice 
covers extended-release,\1\ tannate, and immediate-release drug 
products.
---------------------------------------------------------------------------

    \1\ The term ``extended-release'' is used in this document to 
include all timed-release products, including products labeled as 
``sustained-release,'' ``controlled-release,'' ``delayed-release,'' 
or ``long-acting.'' (See 21 CFR 310.502(a)(14).)
---------------------------------------------------------------------------

B. Regulatory History of Products Covered by This Notice

    Many of the drug products covered by this notice contain active 
ingredients that were introduced into the marketplace without prior 
review for effectiveness. When initially enacted in 1938, the Federal 
Food, Drug, and Cosmetic Act (the FD&C Act) required that FDA review 
and approve ``new drugs'' for safety, but not effectiveness, before 
they could legally be sold in interstate commerce.\2\ The FD&C Act made 
it the sponsor's burden to show FDA that its drug was safe through the 
submission of an NDA. Between 1938 and 1962, if a drug obtained 
approval, FDA considered drugs that were identical, related, or similar 
(IRS) \3\ to the approved drug to be ``covered'' by that approval, and 
allowed those IRS drugs to be marketed without independent approval.
---------------------------------------------------------------------------

    \2\ A ``new drug'' is defined by the FD&C Act as a drug that is 
not generally recognized, by experts qualified by scientific 
training and experience to evaluate the safety and effectiveness of 
drugs, as safe and effective for use under the conditions 
prescribed, recommended, or suggested in its labeling (section 201 
of the FD&C Act (21 U.S.C. 321(p)).
    \3\ FDA's regulations at (21 CFR 310.6(b)(1)) provide: ``An 
identical, related, or similar drug includes other brands, 
potencies, dosage forms, salts, and esters of the same drug moiety 
as well as of any drug moiety related in chemical structure or known 
pharmacological properties.''
---------------------------------------------------------------------------

    In 1962, Congress amended the FD&C Act to require that new drugs be 
proven effective for their labeled indications, as well as safe. This 
amendment also required FDA to conduct a retrospective evaluation of 
effectiveness for all drugs approved as safe between 1938 and 1962. FDA 
contracted with the National Academy of Sciences/National Research 
Council (NAS/NRC) to make an initial evaluation of the effectiveness of 
over 3,400 products that had been approved only for safety between 1938 
and 1962. The NAS/NRC reports for these drug products were submitted to 
FDA in the late 1960s and early 1970s. The Agency reviewed and 
reevaluated the reports and published its findings in Federal Register 
notices. FDA's administrative implementation of the NAS/NRC reports was 
called the Drug Efficacy Study Implementation (DESI). DESI covered the 
approximately 3,400 products specifically reviewed by the NAS/NRC, as 
well as the even larger number of IRS products that entered the market 
without FDA approval.\4\ Many of the drug products covered by this 
notice contain the same active ingredients as drug products that were 
reviewed for effectiveness through the DESI process.
---------------------------------------------------------------------------

    \4\ Section 310.6(b)(2)) provides that when qualified experts 
determine that the findings in a DESI notice are applicable to an 
IRS drug, that IRS drug is affected by the DESI notice.
---------------------------------------------------------------------------

    All drugs covered by the DESI review are ``new drugs'' under the 
FD&C Act. If FDA's final DESI determination classifies a drug product 
as ineffective for one or more indications, that drug product and those 
IRS to it can no longer be marketed for such indications and are 
subject to enforcement action as unapproved new drugs. If FDA's final 
DESI determination classifies a drug product as effective for one or 
more of its labeled indications, the drug, and those IRS to it, can be 
marketed for such indications, provided each product is the subject of 
an application approved for safety and effectiveness. Those drug 
products with NDAs approved before 1962 for safety therefore require 
approved supplements to their original applications if found effective 
under DESI; IRS drug products require an approved NDA or ANDA, as 
appropriate. Furthermore, labeling for these drug products may contain 
only those indications for which the DESI review found the product 
effective unless the firm marketing the product has received approval 
for additional indication(s).
    In the early 1970s, FDA granted temporary exemptions from the time 
limits established for completing certain phases of the DESI program 
for certain oral prescription drugs offered for relief of cold, cough, 
allergy, and related symptoms (38 FR 34481, December 14, 1973). The 
exemptions were granted because of the close relationship between these 
prescription drugs and OTC drugs, which were subject to the ongoing OTC 
drug review. (See 21 CFR part 330.) Postponement of final evaluations 
of these DESI prescription products enabled the Agency to consider the 
recommendations of the OTC review panel in addition to any evidence 
submitted by NDA holders and other parties in response to various DESI 
notices covering relevant products.

II. Safety Concerns With Unapproved New Drugs

    Because marketed unapproved new drug products have not been through

[[Page 11795]]

FDA's approval process, there may be safety risks associated with them. 
Some unapproved product labeling omits or modifies safety warnings or 
other information that is important to ensure safe use, such as drug 
interactions or potential adverse experiences. FDA is particularly 
concerned about pediatric labeling for these unapproved products. Some 
of the unapproved products covered by this notice are labeled and 
marketed for use in children as young as 1 month of age. Without 
reviewing applications for these products, FDA has no way to assess the 
scientific support, if any, for the use of these products in pediatric 
populations.
    FDA also has concerns regarding the manufacturing processes for 
unapproved new drugs and changes in the formulations of these products. 
When new drugs are marketed without FDA approval, FDA does not have an 
opportunity, prior to product marketing, to determine whether the 
manufacturing process for the drugs is adequate to ensure that they are 
of suitable quality. Additionally, there is no opportunity prior to 
marketing for FDA to review and approve proprietary names to minimize 
potential safety issues caused by product name confusion. In fact, FDA 
has received reports of name confusion associated with unapproved 
prescription products covered by this notice. Look-alike and sound-
alike similarities between product names may contribute to medication 
errors and adverse events.
    Similarly, the new drug approval requirement allows the Agency to 
evaluate proposed changes to approved product formulations to ensure 
that such modifications meet FDA standards for safety and effectiveness 
and to ensure that formulation changes are accompanied, as necessary, 
by appropriate changes in product proprietary names or labeling, or 
other measures that may be warranted to minimize confusion and risks to 
patients. Modifications of product formulations that are not made under 
FDA's drug approval process thus pose an increased risk of confusing 
healthcare practitioners and causing harm to consumers, such as 
underdose or overdose, particularly in pediatric patients.
    Finally, FDA has specific safety concerns about the products 
covered by this notice that are marketed as extended-release products. 
Many of these products contain amounts of active ingredients that could 
pose safety risks if the same amount of active ingredient were 
contained in an immediate-release dosage form. Without prior review of 
applications for these products, there is no assurance that the firms 
that market these products have established appropriate specifications 
for release of the active ingredients or that the products are properly 
formulated and manufactured to release their active ingredients to an 
extent and at a rate that is both safe and effective.

III. Legal Status of Products Identified in This Notice

A. Extended-Release Products

    Some of the products covered by this notice are sold as extended-
release products. Since 1959, FDA has concluded that all products in 
extended-release dosage forms are new drugs requiring approved NDAs or 
ANDAs before being marketed (24 FR 3756, May 9, 1959). Agency review of 
individual applications for extended-release products is needed to 
ensure that the finished product releases its active ingredient to an 
extent and at a rate that is both safe, with a predictable and 
controlled release of the dose, and effective, sustaining the intended 
effect over the entire dosing interval. Firms submitting applications 
are required to establish appropriate release specifications supported 
by clinical evidence, along with data showing that the finished product 
as manufactured by the firm releases its active ingredient according to 
those specifications.
    The Agency's determination that all products in timed-release 
dosage form are new drugs requiring approved applications is codified 
at 21 CFR 310.502(a)(14). Approval of an NDA under section 505(b) of 
the FD&C Act (21 U.S.C. 355(b)) or an ANDA under section 505(j) of the 
FD&C Act is required as a condition for marketing all such products.
    The unapproved extended-release drug products subject to this 
notice are all labeled for prescription use. Prescription drugs are 
defined under section 503(b)(1)(A) of the FD&C Act (21 U.S.C. 
353(b)(1)(A)) as drugs that, because of toxicity or other potentially 
harmful effect, are not safe to use except under the supervision of a 
practitioner licensed by law to administer such drugs.\5\ A drug that 
is labeled as a prescription drug but does not meet the definition of 
``prescription drug'' under section 503(b)(1)(A) of the FD&C Act is 
misbranded under section 503(b)(4)(B) of the FD&C Act (21 U.S.C. 
353(b)(4)(B)). Thus, if an extended-release drug covered by this notice 
is labeled as a prescription product, but does not meet the definition 
in section 503(b)(1)(A) of the FD&C Act, it is misbranded under section 
503(b)(4)(B) of the FD&C Act. If an extended-release drug subject to 
this notice actually meets the definition of ``prescription drug'' 
under 503(b)(1)(A), it is misbranded under section 502(f)(1) of the 
FD&C Act (21 U.S.C. 352(f)(1)), in that it fails to bear adequate 
directions for use. An approved prescription drug can satisfy the 
``adequate directions for use'' requirement if it bears the NDA-
approved labeling (Sec. Sec.  201.100(c)(2) and 201.115 (21 CFR 
201.100(c)(2) and 201.115)). Because the unapproved prescription 
extended-release drug products covered by this notice do not have 
approved applications with approved labeling, they fail to bear 
``adequate directions for use,'' and are misbranded under section 
502(f)(1) of the FD&C Act.
---------------------------------------------------------------------------

    \5\ The definition of ``prescription drug'' also includes a drug 
that is limited by an approved application to use under the 
professional supervision of a licensed practitioner (21 U.S.C. 
353(b)(1)(B)). This prong of the definition obviously does not apply 
to the unapproved extended-release drug products covered by this 
notice.
---------------------------------------------------------------------------

B. Tannates

    Some of the products covered by this notice contain active 
ingredients that are in tannate salt form (tannate drugs). FDA has 
reviewed the publicly available scientific literature on these 
ingredients, and has determined that unapproved oral drugs labeled for 
prescription use and offered for relief of symptoms of cold, cough, or 
allergy that contain the following ingredients are not generally 
recognized as safe and effective (GRASE): Brompheniramine tannate; 
carbetapentane tannate; carbinoxamine tannate; chlorpheniramine 
tannate; dexbrompheniramine tannate; dexchlorpheniramine tannate; 
dextromethorphan tannate; diphenhydramine tannate; ephedrine tannate; 
phenylephrine tannate; pseudoephedrine tannate; pyrilamine tannate; and 
triprolidine tannate. Therefore, products containing these ingredients 
are new drugs within the meaning of section 201(p) of the FD&C Act, and 
require approved NDAs or ANDAs before marketing.
    The unapproved tannate drug products subject to this notice are all 
labeled for prescription use. Prescription drugs are defined under 
section 503(b)(1)(A) of the FD&C Act as drugs that, because of toxicity 
or other potentially harmful effect, are not safe to use except under 
the supervision of a practitioner licensed by law to administer such 
drugs.\6\ A drug that is

[[Page 11796]]

labeled as a prescription drug but does not meet the definition of 
``prescription drug'' under section 503(b)(1)(A) of the FD&C Act is 
misbranded under section 503(b)(4)(B) of the FD&C Act. Thus, if a 
tannate drug covered by this notice is labeled as a prescription 
product, but does not meet the definition in section 503(b)(1)(A) of 
the FD&C Act, it is misbranded under section 503(b)(4)(B) of the FD&C 
Act. If a tannate drug covered by this notice actually meets the 
definition of ``prescription drug,'' it is misbranded under section 
502(f)(1) of the FD&C Act, in that it fails to bear adequate directions 
for use. An approved prescription drug can satisfy the ``adequate 
directions for use'' requirement if it bears the NDA-approved labeling 
(21 CFR 201.100(c)(2) and 201.115). Because the unapproved prescription 
tannate drug products covered by this notice do not have approved 
applications with approved labeling, they fail to bear ``adequate 
directions for use,'' and are misbranded under section 502(f)(1) of the 
FD&C Act.
---------------------------------------------------------------------------

    \6\ The definition of ``prescription drug'' also includes a drug 
that is limited by an approved application to use under the 
professional supervision of a licensed practitioner (21 U.S.C. 
353(b)(1)(B)). This prong of the definition obviously does not apply 
to the unapproved tannate drug products covered by this notice.
---------------------------------------------------------------------------

C. Immediate-Release Products

    The remaining unapproved oral products covered by this notice are 
immediate-release products labeled for prescription use and offered for 
relief of symptoms associated with cold, cough, or allergy. The 
immediate-release products fall into the following three categories:
1. Drugs Inappropriately Labeled for Prescription Use
    A small number of the immediate-release products covered by this 
notice conform to the requirements of the final OTC monograph at 21 CFR 
part 341, ``Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic 
Drug Products for Over-the-Counter Human Use'' (the final OTC Cold 
Cough monograph), except that they are labeled for prescription use 
only. Section 503(b)(1) of the FD&C Act establishes the definition of a 
``prescription drug.'' Drug products that do not meet the definition of 
a prescription drug but are labeled for prescription use are misbranded 
under section 503(b)(4)(B) of the FD&C Act. If these drugs conform to 
the requirements of the final OTC Cold Cough monograph, they are not 
new drugs and they do not require an approved NDA or ANDA in order to 
be legally marketed OTC.\7\
---------------------------------------------------------------------------

    \7\ In addition to any other applicable requirements, firms that 
manufacture OTC drugs must comply with the labeling requirements at 
21 CFR 201.66.
---------------------------------------------------------------------------

2. Drugs Containing Ingredients Included in the Final OTC Cold Cough 
Monograph But Labeled With Nonconforming Indications or Dosing Regimens
    The majority of the immediate-release products covered by this 
notice are labeled for prescription use and contain ingredients that 
are included in the final OTC Cold Cough monograph, but have 
indications, dosing regimens, or both, that are inconsistent with that 
monograph. FDA has reviewed the indications and dosing regimens (dosing 
intervals and dosage amounts) in the labeling of over 300 such 
products, and has reviewed the publicly available scientific literature 
for studies of these products.\8\ In no case did FDA find literature 
sufficient to support a determination that one of these products was 
GRASE for relief of symptoms of cold, cough, or allergy. Therefore, 
these products are all ``new drugs'' within the meaning of section 
201(p) of the FD&C Act, that require approved NDAs or ANDAs before 
marketing.
---------------------------------------------------------------------------

    \8\ The over 300 products reviewed by FDA represent all products 
in this category that FDA was able to identify.
---------------------------------------------------------------------------

    The unapproved immediate-release drug products subject to this 
notice that contain ingredients that are included in the final OTC Cold 
Cough monograph, but with indications, dosing regimens, or both, that 
are inconsistent with that monograph, are all labeled for prescription 
use. Prescription drugs are defined under section 503(b)(1)(A) of the 
FD&C Act as drugs that, because of toxicity or other potentially 
harmful effect, are not safe to use except under the supervision of a 
practitioner licensed by law to administer such drugs.\9\ A drug that 
is labeled as a prescription drug but does not meet the definition of 
``prescription drug'' under section 503(b)(1)(A) of the FD&C Act is 
misbranded under section 503(b)(4)(B) of the FD&C Act. Thus, if an 
immediate-release drug covered by this notice is labeled as a 
prescription product, but does not meet the definition in section 
503(b)(1)(A), it is misbranded under section 503(b)(4)(B). If an 
immediate-release drug covered by this notice does meet the definition 
of ``prescription drug'' in 503(b)(1)(A), it is misbranded under 
section 502(f)(1) of the FD&C Act, in that it fails to bear adequate 
directions for use. An approved prescription drug can satisfy the 
``adequate directions for use'' requirement if it bears the NDA-
approved labeling (Sec. Sec.  201.100(c)(2) and 201.115). Because the 
unapproved prescription immediate-release drug products subject to this 
notice that contain ingredients that are included in the final OTC Cold 
Cough monograph, but with indications, dosing regimens, or both, that 
are inconsistent with that monograph, do not have approved applications 
with approved labeling, they fail to bear ``adequate directions for 
use,'' and are misbranded under section 502(f)(1).
---------------------------------------------------------------------------

    \9\ The definition of ``prescription drug'' also includes a drug 
that is limited by an approved application to use under the 
professional supervision of a licensed practitioner (21 U.S.C. 
353(b)(1)(B)). This prong of the definition obviously does not apply 
to the unapproved immediate-release drug products subject to this 
notice and containing ingredients that are included in the final OTC 
Cold Cough monograph, but with indications, dosing regimens, or 
both, that are inconsistent with that monograph.
---------------------------------------------------------------------------

3. Drugs Containing Ingredients Not Included in the Final OTC Cold 
Cough Monograph
    The remaining immediate-release products covered by this notice are 
labeled for prescription use and contain active ingredients that are 
not included in the final OTC Cold Cough monograph. FDA has reviewed 
the publicly available scientific literature on these ingredients, and 
has determined that the products covered by this notice and offered for 
relief of symptoms of cold, cough, or allergy that contain the 
following ingredients are not GRASE: Atropine; carbetapentane; 
cyproheptadine; dyphylline; hyoscyamine; methscopolamine nitrate; 
phenyltoloxamine; potassium guaiacosulfonate; promethazine; and 
scopolamine. Therefore, products covered by this notice containing 
these ingredients and marketed for relief of symptoms of cold, cough, 
or allergy are new drugs within the meaning of section 201(p) of the 
FD&C Act, and require approved NDAs or ANDAs prior to marketing.
    The unapproved immediate-release drug products that are subject to 
this notice and that contain active ingredients not included in the 
final OTC Cold Cough monograph are all labeled for prescription use. 
Prescription drugs are defined under section 503(b)(1)(A) of the FD&C 
Act as drugs that, because of toxicity or other potentially harmful 
effect, are not safe to use except under the supervision of a 
practitioner licensed by law to administer such drugs.\10\ A drug that 
is

[[Page 11797]]

labeled as a prescription drug but does not meet the definition of 
``prescription drug'' under section 503(b)(1)(A) is misbranded under 
section 503(b)(4)(B) of the FD&C Act. Thus, if an immediate-release 
drug covered by this notice is labeled as a prescription product, but 
does not meet the definition in section 503(b)(1)(A), it is misbranded 
under section 503(b)(4)(B). If a drug covered by this notice meets the 
definition of ``prescription drug'' in 503(b)(1)(A), it is misbranded 
under section 502(f)(1) of the FD&C Act, in that it fails to bear 
adequate directions for use. An approved prescription drug can satisfy 
the ``adequate directions for use'' requirement if it bears the NDA-
approved labeling (Sec. Sec.  201.100(c)(2) and 201.115). Because the 
unapproved prescription immediate-release drug products covered by this 
notice that contain active ingredients not included in the final OTC 
Cold Cough monograph do not have approved applications with approved 
labeling, they fail to bear ``adequate directions for use,'' and are 
misbranded under section 502(f)(1) of the FD&C Act.
---------------------------------------------------------------------------

    \10\ The definition of ``prescription drug'' also includes a 
drug that is limited by an approved application to use under the 
professional supervision of a licensed practitioner (21 U.S.C. 
353(b)(1)(B)). This prong of the definition obviously does not apply 
to the unapproved immediate-release drug products covered by this 
notice that contain active ingredients not included in the final OTC 
Cold Cough monograph.
---------------------------------------------------------------------------

IV. Notice of Enforcement Action

    Although not required to do so by the Administrative Procedure Act, 
the FD&C Act, or any rules issued under its authority, or for any other 
legal reason, FDA is providing this notice to persons \11\ who are 
marketing unapproved and misbranded oral drug products labeled for 
prescription use and offered for relief of symptoms relating to cold, 
cough, or allergy that the Agency intends to take enforcement action 
against such products and those who manufacture them or cause them to 
be manufactured or shipped in interstate commerce.
---------------------------------------------------------------------------

    \11\ A ``person'' includes individuals, partnerships, 
corporations, and associations (21 U.S.C. 321(e)).
---------------------------------------------------------------------------

    Manufacturing or shipping the drug products covered by this notice 
can result in enforcement action, including seizure, injunction, or 
other judicial or administrative proceeding. Consistent with policies 
described in the Agency's guidance entitled ``Marketed Unapproved 
Drugs--Compliance Policy Guide'' (the Marketed Unapproved Drugs CPG) 
(https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf), the 
Agency does not expect to issue a warning letter or any other further 
warning to firms marketing drug products covered by this notice prior 
to taking enforcement action. The Agency also reminds firms that, as 
stated in the Marketed Unapproved Drugs CPG, any unapproved drug 
marketed without a required approved application is subject to Agency 
enforcement action at any time. The issuance of this notice does not in 
any way obligate the Agency to issue similar notices or any notice in 
the future regarding marketed unapproved drugs.\12\
---------------------------------------------------------------------------

    \12\ The Agency's general approach for dealing with these 
products in an orderly manner is spelled out in the Marketed 
Unapproved Drugs CPG. That CPG, however, provides notice that any 
product that is being marketed illegally, and the persons 
responsible for causing the illegal marketing of the product, are 
subject to FDA enforcement action at any time.
---------------------------------------------------------------------------

    As described in the Marketed Unapproved Drugs CPG, the Agency may, 
at its discretion, identify a period of time during which the Agency 
does not intend to initiate an enforcement action against a currently 
marketed unapproved drug solely on the ground that it lacks an approved 
application under section 505 of the FD&C Act. With respect to drug 
products covered by this notice, the Agency intends to exercise its 
enforcement discretion for only a limited period of time because there 
are safety issues with respect to the products covered by this notice 
and numerous marketed products that have approved applications or 
comply with the applicable OTC drug final monograph are offered to 
treat symptoms relating to cold, cough, and allergy. Therefore, the 
Agency intends to implement this notice as follows.
    For the effective date of this notice, see the DATES section of 
this document. FDA intends to take enforcement action against any drug 
product covered by this notice that is not listed with the Agency in 
full compliance with section 510 of the FD&C Act (21 U.S.C. 360) before 
March 2, 2011, and is manufactured, shipped, or otherwise introduced or 
delivered for introduction into interstate commerce by any person on or 
after March 3, 2011. FDA also intends to take enforcement action 
against any drug product covered by this notice that is listed with FDA 
in full compliance with section 510 of the FD&C Act but is not being 
commercially used or sold \13\ in the United States on March 2, 2011 
and that is manufactured, shipped, or otherwise introduced or delivered 
for introduction into interstate commerce by any person on or after 
March 3, 2011.
---------------------------------------------------------------------------

    \13\ For purposes of this notice, the term ``commercially used 
or sold'' means that the product has been used in a business or 
activity involving retail or wholesale marketing and/or sale.
---------------------------------------------------------------------------

    However, for drug products covered by this notice that are 
commercially used or sold in the United States, have a National Drug 
Code (NDC) number listed with FDA, and are in full compliance with 
section 510 of the FD&C Act before March 2, 2011 (``currently marketed 
and listed''), the Agency intends to exercise its enforcement 
discretion as follows. FDA intends to initiate enforcement action 
against any currently marketed and listed product covered by this 
notice that is manufactured on or after June 1, 2011 or that is shipped 
on or after August 30, 2011.\14\ Further, FDA intends to take 
enforcement action against any person who manufactures or ships such 
products after these dates. Any person who has submitted or submits an 
application for a drug product covered by this notice but has not 
received approval must comply with this notice.
---------------------------------------------------------------------------

    \14\ If FDA finds it necessary to take enforcement action 
against a product covered by this notice, the agency may take action 
relating to all of the defendant's other violations of the FD&C Act 
at the same time. For example, if a firm continues to manufacture or 
market a product covered by this notice after the applicable 
enforcement date has passed, to preserve limited agency resources, 
FDA may take enforcement action relating to all of the firm's 
unapproved drugs that require applications at the same time. (See, 
e.g., United States v. Sage Pharmaceuticals, 210 F.3d 475, 479-480 
(5th Cir. 2000) (permitting the Agency to combine all violations of 
the act in one proceeding, rather than taking action against 
multiple violations of the act in ``piecemeal fashion'').)
---------------------------------------------------------------------------

    The Agency, however, does not intend to exercise its enforcement 
discretion as outlined previously if the following apply: (1) A 
manufacturer or distributor of drug products covered by this notice is 
violating other provisions of the FD&C Act, including, but not limited 
to, violations related to FDA's current good manufacturing practices, 
adverse drug event reporting, labeling or misbranding requirements 
other than those identified in this notice or (2) it appears that a 
firm, in response to this notice, increases its manufacture or 
interstate shipment of drug products covered by this notice above its 
usual volume during these periods.
    Nothing in this notice, including FDA's intent to exercise its 
enforcement discretion, alters any person's liability or obligations in 
any other enforcement action, or precludes the Agency from initiating 
or proceeding with enforcement action in connection with any other 
alleged violation of the FD&C Act, whether or not related to a drug 
product covered by this notice. Similarly, a person who is or becomes 
enjoined from marketing unapproved or misbranded drugs may not resume 
marketing of such products based on FDA's exercise of enforcement 
discretion that is set forth in this notice.
    Drug manufacturers and distributors should be aware that the Agency 
is exercising its enforcement discretion as described previously only 
in regard to

[[Page 11798]]

drug products covered by this notice that are marketed under an NDC 
number listed with the Agency in full compliance with section 510 of 
the FD&C Act before March 2, 2011. As previously stated, drug products 
covered by this notice that are currently marketed but not listed with 
the Agency on the date of this notice must, as of the effective date of 
this notice, have approved applications prior to their shipment in 
interstate commerce. Moreover, any person or firm that has submitted or 
submits an application but has yet to receive approval for such 
products is still responsible for full compliance with this notice.

V. Discontinued Products

    Some firms may have previously discontinued the manufacturing or 
distribution of products covered by this notice without removing them 
from the listing of their products under section 510(j) of the FD&C 
Act. Other firms may discontinue manufacturing or marketing listed 
products in response to this notice. Firms that wish to notify the 
Agency of product discontinuation should send a letter, signed by the 
firm's chief executive officer, fully identifying the discontinued 
product(s), including NDC number(s), and stating that the product(s) 
has (have) been discontinued. The letter should be sent to Sakineh 
Walther (see ADDRESSES). Firms should also update the listing of their 
products under section 510(j) of the FD&C Act to reflect 
discontinuation of products covered by this notice. FDA plans to rely 
on its existing records, including its drug listing records, or other 
available information when it targets violations for enforcement 
action.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (sections 502 and 505 (21 U.S.C. 352 and 355)) and under authority 
delegated to the Assistant Commissioner for Policy under section 
1410.21 of the FDA Staff Manual Guide.

    Dated: February 22, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-4703 Filed 3-2-11; 8:45 am]
BILLING CODE 4160-01-P

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